Plasma gelsolin

{{short description|Protein in the immune system}} {{Infobox protein family | Symbol = Plasma Gelsolin | Name = Plasma Gelsolin | image = 3FFN background removed.png | width = 300 | caption = Crystal structure of the cytoplasmic form of human Gelsolin ({{PDB2|3FFN}}) | Pfam = PF00626 | Pfam_clan = CL0092 | InterPro = IPR007123 | SMART = | PROSITE = | MEROPS = | SCOP = 1vil | TCDB = | OPM family = | OPM protein = | CAZy = | CDD = | PDB = {{PDB2|2FGH}}, {{PDB2|1H1V}}, {{PDB2|3CIP}}, {{PDB2|6QW3}}, {{PDB2|1D0N}}, {{PDB2|1KCQ}}, {{PDB2|1P8X}}, {{PDB2|3C15}}, {{PDB2|3FFN}}, {{PDB2|5DD2}}, {{PDB2|5UBO}}, {{PDB2|5ZZ0}}, {{PDB2|6LJK}}, {{PDB2|1C0F}}, {{PDB2|1EQY}}, {{PDB2|1ESV}}, {{PDB2|1RGI}}, {{PDB2|1YAG}}, {{PDB2|2FH1}}, {{PDB2|2FH2}}, {{PDB2|2FH3}}, {{PDB2|2FH4}}, {{PDB2|2LLF}}, {{PDB2|3FFK}}, {{PDB2|3TU5}}, {{PDB2|5FAE}}, {{PDB2|5FAF}}, {{PDB2|5H3M}}, {{PDB2|5H3N}}, {{PDB2|5O2Z}}, {{PDB2|6JCO}}, {{PDB2|6JEG}}, {{PDB2|6JEH}}, {{PDB2|6LJE}}, {{PDB2|6Q9R}}, {{PDB2|6Q9Z}}, {{PDB2|6QBF}}, {{PDB2|1SVY}}, {{PDB2|4CBX}}, {{PDB2|1D4X}}, {{PDB2|1MDU}}, {{PDB2|1NLV}}, {{PDB2|1NM1}}, {{PDB2|1NMD}}, {{PDB2|1NPH}}, {{PDB2|1P8Z}}, {{PDB2|1SOL}}, {{PDB2|1YVN}}, {{PDB2|2FF3}}, {{PDB2|2FF6}}, {{PDB2|3A5L}}, {{PDB2|3A5M}}, {{PDB2|3A5N}}, {{PDB2|3A5O}}, {{PDB2|3CJB}}, {{PDB2|3CJC}}, {{PDB2|5MVV}}, {{PDB2|1C0G}} }}

'''Plasma gelsolin''' ('''pGSN''') is an 83 kDa abundant protein constituent of normal plasma and an important component of the innate immune system. The identification of pGSN in ''Drosophila melanogaster''<ref>{{Cite journal|last=Shi|first=Yigong|date=2004-08-01|title=Caspase activation, inhibition, and reactivation: A mechanistic view|journal=Protein Science|volume=13|issue=8|pages=1979–1987|doi=10.1110/ps.04789804|pmid=15273300|pmc=2279816|issn=0961-8368}}</ref> and ''C. elegans''<ref>{{Cite journal|last1=Klaavuniemi|first1=Tuula|last2=Yamashiro|first2=Sawako|last3=Ono|first3=Shoichiro|date=2008-09-19|title=''Caenorhabditis elegans'' Gelsolin-like Protein 1 Is a Novel Actin Filament-severing Protein with Four Gelsolin-like Repeats|journal=Journal of Biological Chemistry|volume=283|issue=38|pages=26071–26080|doi=10.1074/jbc.M803618200|pmid=18640981|pmc=2533794|issn=0021-9258|doi-access=free}}</ref> points to an ancient origin early in evolution.<ref>{{Cite journal| doi = 10.1002/bies.20200| issn = 1521-1878| volume = 27| issue = 4| pages = 388–396| last1 = Archer| first1 = Stuart K.| last2 = Claudianos| first2 = Charles| last3 = Campbell| first3 = Hugh D.| title = Evolution of the gelsolin family of actin-binding proteins as novel transcriptional coactivators| journal = BioEssays| date = 2005| pmid = 15770676| s2cid = 40585071}}</ref> Its extraordinary structural conservation reflects its critical regulatory role in multiple essential functions.<ref name="Lee1992" /> Its roles include the breakdown of filamentous actin released from dead cells, activation of macrophages, and localization of the inflammatory response. Substantial decreases in plasma levels are observed in acute and chronic infection and injury in both animal models and in humans. Supplementation therapies with recombinant human pGSN have been shown effective in more than 20 animal models.

pGSN has a cytoplasmic isoform (cGSN) known to be an actin-binding protein controlling cytoskeletal dynamics. cGSN is expressed from the same gene, and is identical to pGSN except for its lack of a 24 amino acid N-terminal extension.

==History== The cellular isoform of Gelsolin was discovered in 1979 in the lab of Thomas P. Stossel. Its name comes from observed calcium-dependent reversible ''gel-sol'' transitions of macrophage cytoplasmic extract.<ref name=Original>{{cite journal |last1=Yin |first1=Helen L. |last2=Stossel |first2=Thomas P. |title=Control of cytoplasmic actin gel-sol transformation by gelsolin, a calcium-dependent regulatory protein |journal=Nature |date=18 October 1979 |volume=281 |issue=5732 |pages=583–586 |doi=10.1038/281583a0 |pmid=492320 |bibcode=1979Natur.281..583Y |s2cid=4250013 |url=https://www.nature.com/articles/281583a0 |access-date=13 February 2020|url-access=subscription }}</ref> Around the same time a similarly sized plasma protein was discovered and shown to depolymerize actin; it was named Brevin, due to its ability to shorten actin filaments.<ref name=Chaponnier1979>{{Cite journal| doi = 10.1007/bf01949928| issn = 0014-4754| volume = 35| issue = 8| pages = 1039–1041| last1 = Chaponnier| first1 = C.| last2 = Borgia| first2 = R.| last3 = Rungger-Brändle| first3 = E.| last4 = Weil| first4 = R.| last5 = Gabbiani| first5 = G.| title = An actin-destabilizing factor is present in human plasma| journal = Experientia| date = 1979-08-15| pmid = 477868| s2cid = 21319139| url = https://archive-ouverte.unige.ch/unige:10879}}</ref><ref name=Norberg1979>{{Cite journal| doi = 10.1111/j.1432-1033.1979.tb04204.x| issn = 0014-2956| volume = 100| issue = 2| pages = 575–583| last1 = Norberg| first1 = Renee| last2 = Thorstensson| first2 = Rigmor| last3 = Utter| first3 = Goran| last4 = Fagraeus| first4 = Astrid| title = F-Actin-Depolymerizing Activity of Human Serum| journal = European Journal of Biochemistry| date = 1979-10-15| pmid = 389627| doi-access = }}</ref><ref>{{Cite journal| doi = 10.1016/0014-5793(80)81291-9| issn = 0014-5793| volume = 121| issue = 1| pages = 175–177| last1 = Harris| first1 = H.E.| last2 = Bamburg| first2 = J.R.| last3 = Weeds| first3 = A.G.| title = Actin filament disassembly in blood plasma| journal = FEBS Letters| date = 1980-11-17| pmid = 6893965| s2cid = 30794630| doi-access = free| bibcode = 1980FEBSL.121..175H}}</ref><ref>{{Cite journal| doi = 10.1016/0014-5793(81)80017-8| issn = 0014-5793| volume = 123| issue = 1| pages = 49–53| last1 = Harris| first1 = H.E.| last2 = Gooch| first2 = J.| title = An actin depolymerizing protein from pig plasma| journal = FEBS Letters| date = 1981-01-12| pmid = 6894126| s2cid = 27405593| doi-access = free| bibcode = 1981FEBSL.123...49H}}</ref><ref>{{Cite journal| doi = 10.1073/pnas.78.11.6798| issn = 0027-8424| volume = 78| issue = 11| pages = 6798–6802| last1 = Harris| first1 = D. A.| last2 = Schwartz| first2 = J. H.| title = Characterization of brevin, a serum protein that shortens actin filaments| journal = Proceedings of the National Academy of Sciences| date = 1981-11-01| pmid = 6947253| pmc = 349138| bibcode = 1981PNAS...78.6798H| doi-access = free}}</ref> In 1986 it was demonstrated that Brevin was identical to cellular Gelsolin except for a 24 AA N-terminal extension, and was renamed Plasma Gelsolin.<ref name=Kwiatkowski1986/>

==Structure==

[[File:3FFN solution structure no binding.png|thumb|400px|A solution phase representation of pGSN in the presence of Ca²⁺ adapted from {{PDB2|3FFN}} and low-resolution SAXS information.<ref name=SAXS>{{cite journal |last1=Ashish |title=Global Structure Changes Associated with Ca²⁺ Activation of Full-length Human Plasma Gelsolin |journal=J Biol Chem |date=31 August 2007 |volume=282 |issue=35 |pages=25884–25892 |doi=10.1074/jbc.M702446200 |pmid=17604278 |s2cid=25974945 |url=https://www.jbc.org/content/282/35/25884.full.pdf |access-date=12 February 2020|doi-access=free }}</ref> The 24 AA N-terminal extension unique to the plasma isoform was manually added (left, light blue); no structural information for it is known nor represented. Colors represent the six domains of Gelsolin.<ref name=Burtnick1997>{{cite journal |last1=Burtnick |first1=Leslie D. |last2=Koepf |first2=Edward K. |last3=Grimes |first3=Jonathan |last4=Jones |first4=E. Yvonne |last5=Stuart |first5=David I. |last6=McLaughlin |first6=Paul J. |last7=Robinson |first7=Robert C. |title=The Crystal Structure of Plasma Gelsolin: Implications for Actin Severing, Capping, and Nucleation |journal=Cell |date=22 August 1997 |volume=90 |issue=4 |pages=661–670 |doi=10.1016/s0092-8674(00)80527-9 |pmid=9288746 |s2cid=11112433 |url=https://www.cell.com/action/showPdf?pii=S0092-8674%2800%2980527-9 |access-date=12 February 2020|doi-access=free |url-access=subscription }}</ref><ref>{{cite journal |last1=Nag |first1=Shalini |last2=Ma |first2=Qing |last3=Wang |first3=Hui |last4=Chumnarnsilpa |first4=Sakesit |last5=Lee |first5=Wei Lin |last6=Larsson |first6=Mårten |last7=Kannan |first7=Balakrishnan |last8=Hernandez-Valladares |first8=Maria |last9=Burtnick |first9=Leslie D. |last10=Robinson |first10=Robert C. |title=Ca²⁺ binding by domain 2 plays a critical role in the activation and stabilization of gelsolin |journal=PNAS |date=7 July 2009 |volume=106 |issue=33 |pages=13713–13718 |doi=10.1073/pnas.0812374106 |pmid=19666512 |pmc=2720848 |bibcode=2009PNAS..10613713N |url=https://www.pnas.org/content/pnas/106/33/13713.full.pdf |access-date=12 February 2020|doi-access=free }}</ref>]]

Plasma Gelsolin is a 755 AA, 83 kDa plasma protein made up of six "gelsolin domains," each composed of a 5-6 strand β-sheet between one long and one short α-helix.<ref name="Nag2013Gymnast">{{Cite journal| doi = 10.1002/cm.21117| issn = 1949-3584| volume = 70| issue = 7| pages = 360–384| last1 = Nag| first1 = Shalini| last2 = Larsson| first2 = Mårten| last3 = Robinson| first3 = Robert C.| last4 = Burtnick| first4 = Leslie D.| title = Gelsolin: The tail of a molecular gymnast: Gelsolin Superfamily Proteins| journal = Cytoskeleton| date = 2013-06-10| pmid = 23749648| doi-access = free}}</ref> It exhibits a weak homology between domains S1 and S4, S2 and S5, and S3 and S6, and is identical to the cytoplasmic form of the protein except for the addition of a 24 AA N-terminal extension. Additionally a 27 AA N-terminal signal peptide is cleaved prior to pGSN's secretion from the cell. Both forms of the protein are encoded by highly conserved genes on chromosome 9 in humans, but are under the control of different promoters.<ref name=Kwiatkowski1986>{{Cite journal| doi = 10.1038/323455a0| issn = 0028-0836| volume = 323| issue = 6087| pages = 455–458| last1 = Kwiatkowski| first1 = D. J.| last2 = Stossel| first2 = T. P.| last3 = Orkin| first3 = S. H.| last4 = Mole| first4 = J. E.| last5 = Colten| first5 = H. R.| last6 = Yin| first6 = H. L.| title = Plasma and cytoplasmic gelsolins are encoded by a single gene and contain a duplicated actin-binding domain| journal = Nature| date = 1986-10-02| pmid = 3020431| bibcode = 1986Natur.323..455K| s2cid = 4356162}}</ref> There is a single disulfide bond formed on the second domain of the plasma protein,<ref name=Nag2013Gymnast/> there are no documented natural post-translational modifications, and the pI ≈ 6.<ref>{{Cite journal| issn = 0021-9258| volume = 259| issue = 8| pages = 5271–5276| last1 = Yin| first1 = H. L.| last2 = Kwiatkowski| first2 = D. J.| last3 = Mole| first3 = J. E.| last4 = Cole| first4 = F. S.| title = Structure and biosynthesis of cytoplasmic and secreted variants of gelsolin.| journal = Journal of Biological Chemistry| date = 1984-04-25| doi = 10.1016/S0021-9258(17)42985-1| pmid = 6325429| doi-access = free}}</ref><ref>{{Citation| last1 = Moon| first1 = Myeong Hee| last2 = Kang| first2 = Duk Jin| title = Apparatus for protein separation using capillary isoelectric focusing—hollow fiber flow field flow fractionation and method thereof| access-date = 2020-03-02| date = 2013-11-19| url = https://patents.google.com/patent/US8585884/en}}</ref>

===Isoforms and mutations=== Aside from the cellular form, the only other known isoform is Gelsolin-3, an identical non-secreted protein containing an 11 AA, rather than 24 AA, N-terminal extension. It has been found in brain, testes, and lung oligodendrocytes, and is reportedly involved in myelin remodeling during spiralization around the axon.<ref>{{Cite journal| doi = 10.1046/j.1471-4159.1997.69030995.x| issn = 0022-3042| volume = 69| issue = 3| pages = 995–1005| last1 = Vouyiouklis| first1 = Demetrius A.| last2 = Brophy| first2 = Peter J.| title = A Novel Gelsolin Isoform Expressed by Oligodendrocytes in the Central Nervous System| journal = Journal of Neurochemistry| date = 2002-11-18| pmid = 9282921| s2cid = 44552710}}</ref>

Plasma Gelsolin is highly conserved,<ref name="Lee1992">{{Cite journal|last1=Lee|first1=William M.|last2=Galbraith|first2=Robert M.|date=1992-05-14|title=The Extracellular Actin-Scavenger System and Actin Toxicity|journal=New England Journal of Medicine|volume=326|issue=20|pages=1335–1341|doi=10.1056/NEJM199205143262006|issn=0028-4793|pmid=1314333}}</ref> and its only known mutations are single point mutations. One of several such mutations leads to Finnish Familial Amyloidosis, a disorder in which pGSN becomes more conformationally flexible and susceptible to enzymatic cleavage resulting in accumulation of peptide fragments into amyloid fibrils. D187N/Y is the most common mutation with additional reports of G167R, N184K, P432R, A551P, and Ala7fs in the medical literature.<ref>{{Cite journal| doi = 10.1073/pnas.1902189116| issn = 0027-8424| volume = 116| issue = 28| pages = 13958–13963| last1 = Zorgati| first1 = Habiba| last2 = Larsson| first2 = Mårten| last3 = Ren| first3 = Weitong| last4 = Sim| first4 = Adelene Y. L.| last5 = Gettemans| first5 = Jan| last6 = Grimes| first6 = Jonathan M.| last7 = Li| first7 = Wenfei| last8 = Robinson| first8 = Robert C.| title = The role of gelsolin domain 3 in familial amyloidosis (Finnish type)| journal = Proceedings of the National Academy of Sciences| date = 2019-07-09| pmid = 31243148| pmc = 6628662| bibcode = 2019PNAS..11613958Z| doi-access = free}}</ref> In addition to this several mutations as well as down-regulation of the protein are associated with breast cancer.<ref>{{Cite journal| doi = 10.1155/2013/795410| issn = 0278-0240| volume = 34| issue = 2| pages = 71–80| last1 = Baig| first1 = Ruqia Mehmood| last2 = Mahjabeen| first2 = Ishrat| last3 = Sabir| first3 = Maimoona| last4 = Masood| first4 = Nosheen| last5 = Ali| first5 = Kashif| last6 = Malik| first6 = Faraz Arshad| last7 = Kayani| first7 = Mahmood Akhtar| title = Mutational Spectrum of Gelsolin and Its Down Regulation Is Associated with Breast Cancer| journal = Disease Markers| date = 2013| pmid = 23324580| pmc = 3809971| doi-access = free}}</ref>

===Ca²⁺=== At moderate pH in the absence of Ca²⁺ pGSN is compact and globular. Low pH or the presence of >nM Ca²⁺ is associated with an elongated structure with greater backbone flexibility.<ref name=SAXS/> This flexibility exposes the actin binding sites.<ref name=Burtnick1997/> Since physiological levels of Ca²⁺ are ~2 mM, pGSN is natively elongated and able to bind to leaked actin from cellular damage.

==Functions== {{See also|#Therapeutic potential}}

===Binding=== Plasma Gelsolin is a sticky protein known to bind to a number of peptides and proteins: Actin (see: Relationships with actin),<ref name="Original" /><ref>{{Cite journal| doi = 10.1007/BF01766670| issn = 0142-4319| volume = 11| issue = 4| pages = 323–330| last = Edgar| first = Alasdair John| title = Gel electrophoresis of native gelsolin and gelsolin-actin complexes| journal = Journal of Muscle Research and Cell Motility| date = 1990-08-01| pmid = 2174905| s2cid = 11355042}}</ref><ref>{{Cite journal| doi = 10.1038/sj.emboj.7600280| issn = 0261-4189| volume = 23| issue = 14| pages = 2713–2722| last1 = Burtnick| first1 = Leslie D| last2 = Urosev| first2 = Dunja| last3 = Irobi| first3 = Edward| last4 = Narayan| first4 = Kartik| last5 = Robinson| first5 = Robert C| title = Structure of the N-terminal half of gelsolin bound to actin: roles in severing, apoptosis and FAF| journal = The EMBO Journal| date = 2004-07-21| pmid = 15215896| pmc = 514944}}</ref> Apo-H,<ref name="Bohgaki">{{Cite journal| doi = 10.1111/j.1582-4934.2009.00940.x| issn = 1582-1838| volume = 15| issue = 1| pages = 141–151| last1 = Bohgaki| first1 = Miyuki| last2 = Matsumoto| first2 = Masaki| last3 = Atsumi| first3 = Tatsuya| last4 = Kondo| first4 = Takeshi| last5 = Yasuda| first5 = Shinsuke| last6 = Horita| first6 = Tetsuya| last7 = Nakayama| first7 = Keiichi I.| last8 = Okumura| first8 = Fumihiko| last9 = Hatakeyama| first9 = Shigetsugu| last10 = Koike| first10 = Takao| title = Plasma gelsolin facilitates interaction between β2 glycoprotein I and α5β1 integrin| journal = Journal of Cellular and Molecular Medicine| date = 2011-01-24| pmid = 19840195| pmc = 3822501}}</ref> Aβ,<ref name="Ray2000"/><ref name="Chauhan1999"/> α-Synuclein,<ref>{{Cite journal| doi = 10.1016/j.bbrc.2011.07.027| issn = 0006-291X| volume = 412| issue = 1| pages = 32–38| last1 = Welander| first1 = Hedvig| last2 = Bontha| first2 = Sai Vineela| last3 = Näsström| first3 = Thomas| last4 = Karlsson| first4 = Mikael| last5 = Nikolajeff| first5 = Fredrik| last6 = Danzer| first6 = Karin| last7 = Kostka| first7 = Marcus| last8 = Kalimo| first8 = Hannu| last9 = Lannfelt| first9 = Lars| last10 = Ingelsson| first10 = Martin| last11 = Bergström| first11 = Joakim| title = Gelsolin co-occurs with Lewy bodies in vivo and accelerates α-synuclein aggregation in vitro| journal = Biochemical and Biophysical Research Communications| date = 2011-08-19| pmid = 21798243| bibcode = 2011BBRC..412...32W}}</ref> Integrin,<ref name="Bohgaki" /> Tcp-1,<ref>{{Cite journal| doi = 10.1007/s12192-015-0637-5| issn = 1355-8145| volume = 21| issue = 1| pages = 55–62| last1 = Svanström| first1 = Andreas| last2 = Grantham| first2 = Julie| title = The molecular chaperone CCT modulates the activity of the actin filament severing and capping protein gelsolin in vitro| journal = Cell Stress and Chaperones| date = 2015-09-12| pmid = 26364302| pmc = 4679748}}</ref> Fibronectin,<ref>{{Cite journal| issn = 0021-9258| volume = 259| issue = 21| pages = 13262–13266| last1 = Lind| first1 = S. E.| last2 = Janmey| first2 = P. A.| title = Human plasma gelsolin binds to fibronectin| journal = The Journal of Biological Chemistry| date = 1984-11-10| doi = 10.1016/S0021-9258(18)90687-3| pmid = 6092370| doi-access = free}}</ref> Syntaxin-4,<ref>{{Cite journal| doi = 10.1210/me.2011-1112| issn = 0888-8809| volume = 26| issue = 1| pages = 128–141| last1 = Kalwat| first1 = Michael A.| last2 = Wiseman| first2 = Dean A.| last3 = Luo| first3 = Wei| last4 = Wang| first4 = Zhanxiang| last5 = Thurmond| first5 = Debbie C.| title = Gelsolin Associates with the N Terminus of Syntaxin 4 to Regulate Insulin Granule Exocytosis| journal = Molecular Endocrinology| date = 2012-01-01| pmid = 22108804| pmc = 3248323}}</ref> Tropomyosin,<ref>{{Cite journal| doi = 10.1111/febs.12431| issn = 1742-4658| volume = 280| issue = 18| pages = 4600–4611| last1 = Khaitlina| first1 = Sofia| last2 = Fitz| first2 = Helene| last3 = Hinssen| first3 = Horst| title = The interaction of gelsolin with tropomyosin modulates actin dynamics| journal = The FEBS Journal| date = 2013-07-11| pmid = 23844991| doi-access = free}}</ref> fatty acids and phospholipids (see: Binding and inactivation of diverse inflammatory mediators): LPA,<ref name="Meerschaert1998" /><ref name="Goetzl2000" /><ref name="Mintzer2005" /> LPS (endotoxin),<ref name="Mintzer2005" /><ref name="Bucki2005" /><ref name="Bucki2008" /> LTA,<ref name="Bucki2008" /> PAF,<ref name="Osborn2007" /> S1P,<ref name="Bucki2010" /> polyphosphoinositides including PIP₂;<ref name="Janmey1987b">{{Cite journal| doi = 10.1038/325362a0| issn = 0028-0836| volume = 325| issue = 6102| pages = 362–364| last1 = Janmey| first1 = P. A.| last2 = Stossel| first2 = T. P.| title = Modulation of gelsolin function by phosphatidylinositol 4,5-bisphosphate| journal = Nature| date = 1987-01-22| pmid = 3027569| bibcode = 1987Natur.325..362J| s2cid = 4324043}}</ref><ref name=Lin1997>{{Cite journal| doi = 10.1074/jbc.272.33.20443| issn = 0021-9258| volume = 272| issue = 33| pages = 20443–20450| last1 = Lin| first1 = Keng-Mean| last2 = Wenegieme| first2 = Elizabeth| last3 = Lu| first3 = Pei-Jung| last4 = Chen| first4 = Ching-Shih| last5 = Yin| first5 = Helen L.| title = Gelsolin Binding to Phosphatidylinositol 4,5-Bisphosphate Is Modulated by Calcium and pH| journal = Journal of Biological Chemistry| date = 1997-08-15| pmid = 9252353| doi-access = free}}</ref><ref name=Lin1997a>{{Cite journal| doi = 10.1083/jcb.138.4.811| issn = 0021-9525| volume = 138| issue = 4| pages = 811–820| last1 = Sun| first1 = Hui-qiao| last2 = Lin| first2 = Keng-mean| last3 = Yin| first3 = Helen L.| title = Gelsolin Modulates Phospholipase C Activity In Vivo through Phospholipid Binding| journal = The Journal of Cell Biology| date = 1997-08-25| pmid = 9265648| pmc = 2138049}}</ref> and nucleic acids: Ap3A,<ref name="Vartanian2003" /> ATP,<ref name="Yamamoto1990" /><ref name="Urosev2006" /> ADP.<ref name="Laham1995" /> PIP₂, a phospholipid component of cell membranes, competes with ATP and actin for pGSN binding,<ref>{{Cite journal| doi = 10.1371/journal.pone.0201826| issn = 1932-6203| volume = 13| issue = 8| pages = –0201826| last1 = Szatmári| first1 = Dávid| last2 = Xue| first2 = Bo| last3 = Kannan| first3 = Balakrishnan| last4 = Burtnick| first4 = Leslie D.| last5 = Bugyi| first5 = Beáta| last6 = Nyitrai| first6 = Miklós| last7 = Robinson| first7 = Robert C.| others = Eugene A. Permyakov (ed.)| title = ATP competes with PIP2 for binding to gelsolin| journal = PLOS ONE| date = 2018-08-07| pmid = 30086165| pmc = 6080781| bibcode = 2018PLoSO..1301826S| doi-access = free}}</ref> and will dissociate F-Actin-capped pGSN.<ref name="Janmey1987"/><ref name="Janmey1987a">{{Cite journal| issn = 0021-9258| volume = 262| issue = 25| pages = 12228–12236| last1 = Janmey| first1 = P. A.| last2 = Iida| first2 = K.| last3 = Yin| first3 = H. L.| last4 = Stossel| first4 = T. P.| title = Polyphosphoinositide micelles and polyphosphoinositide-containing vesicles dissociate endogenous gelsolin-actin complexes and promote actin assembly from the fast-growing end of actin filaments blocked by gelsolin| journal = The Journal of Biological Chemistry| date = 1987-09-05| doi = 10.1016/S0021-9258(18)45341-0| pmid = 3040735| doi-access = free}}</ref>

===Relationships with actin=== ====Actin toxicity and removal==== {{See also|#Debridement}}

Actin is the most abundant cellular protein, and its release into extracellular fluid and circulation following cellular injury from disease<ref name="Lee1992" /><ref>{{Cite journal| doi = 10.1164/ajrccm.162.1.9806088| issn = 1073-449X| volume = 162| issue = 1| pages = 288–294| last1 = Erukhimov| first1 = Jeffrey A.| last2 = Tang| first2 = Zi-Lue| last3 = Johnson| first3 = Bruce A.| last4 = Donahoe| first4 = Michael P.| last5 = Razzack| first5 = Jamal A.| last6 = Gibson| first6 = Kevin F.| last7 = Lee| first7 = William M.| last8 = Wasserloos| first8 = Karla J.| last9 = Watkins| first9 = Simon A.| last10 = Pitt| first10 = Bruce R.| title = Actin-Containing Sera From Patients With Adult Respiratory Distress Syndrome Are Toxic to Sheep Pulmonary Endothelial Cells| journal = American Journal of Respiratory and Critical Care Medicine| date = July 2000| pmid = 10903256| s2cid = 23974368}}</ref> or injury<ref>{{Cite journal| doi = 10.1136/bjsm.2004.017566| issn = 0306-3674| volume = 39| issue = 11| pages = 830–834| last = Martinez-Amat| first = A| title = Release of α-actin into serum after skeletal muscle damage| journal = British Journal of Sports Medicine| date = 2005-11-01| pmid = 16244192| pmc = 1725075}}</ref> leads to increased blood viscosity,<ref name="Lee1992" /> hindered microcirculation,<ref name="Haddad1990">{{Cite journal|last1=Haddad|first1=J G|last2=Harper|first2=K D|last3=Guoth|first3=M|last4=Pietra|first4=G G|last5=Sanger|first5=J W|date=February 1990|title=Angiopathic consequences of saturating the plasma scavenger system for actin.|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=87|issue=4|pages=1381–1385|doi=10.1073/pnas.87.4.1381|issn=0027-8424|pmc=53479|pmid=2154744|bibcode=1990PNAS...87.1381H|doi-access=free}}</ref> and activation of platelets.<ref>{{Cite journal| doi = 10.1016/0006-291X(81)91967-7| issn = 0006-291X| volume = 100| issue = 3| pages = 1314–1319| last1 = Scarborough| first1 = Victoria D.| last2 = Bradford| first2 = Harvey R.| last3 = Ganguly| first3 = Pankaj| title = Aggregation of platelets by muscle actin. A multivalent interaction model of platelet aggregation by ADP| journal = Biochemical and Biophysical Research Communications| date = 1981-06-16| pmid = 6895029| bibcode = 1981BBRC..100.1314S}}</ref><ref name="Vasconcellos">{{Cite journal| doi = 10.1182/blood.V82.12.3648.bloodjournal82123648| issn = 0006-4971| volume = 82| issue = 12| pages = 3648–3657| last1 = Vasconcellos| first1 = Ca| last2 = Lind| first2 = Se| title = Coordinated inhibition of actin-induced platelet aggregation by plasma gelsolin and vitamin D-binding protein| journal = Blood| access-date = 2020-02-13| date = 1993-12-15| pmid = 8260702| url = https://ashpublications.org/blood/article/82/12/3648/48248/Coordinated-inhibition-of-actininduced-platelet| doi-access = free| url-access = subscription}}</ref> Hemodialysis patients with low levels of pGSN and high levels of actin in blood had markedly higher mortality.<ref name=Lee2009>{{Cite journal|last1=Lee|first1=Po-Shun|last2=Sampath|first2=Kartik|last3=Karumanchi|first3=S. Ananth|last4=Tamez|first4=Hector|last5=Bhan|first5=Ishir|last6=Isakova|first6=Tamara|last7=Gutierrez|first7=Orlando M.|last8=Wolf|first8=Myles|last9=Chang|first9=Yuchiao|last10=Stossel|first10=Thomas P.|last11=Thadhani|first11=Ravi|date=2009-04-23|title=Plasma Gelsolin and Circulating Actin Correlate with Hemodialysis Mortality|journal=Journal of the American Society of Nephrology|volume=20|issue=5|pages=1140–1148|doi=10.1681/ASN.2008091008|pmid=19389844|pmc=2678046|issn=1046-6673}}</ref> Actin is a major component of biofilms that accumulate at local sites of injury and infection, impeding access of host immune components and therapeutics such as antibiotics. Biofilms are particularly pathogenic in the setting of foreign bodies like indwelling catheters and tissue implants.<ref name="Walker2005"/>

Actin exchanges between monomeric (G) and filamentous (F) forms according to the concentrations of it, ATP, and cations.<ref>{{Cite journal| doi = 10.1002/bip.22155| issn = 0006-3525| volume = 99| issue = 4| pages = 245–256| last1 = Kudryashov| first1 = Dmitri S.| last2 = Reisler| first2 = Emil| title = ATP and ADP Actin States| journal = Biopolymers| date = April 2013| pmid = 23348672| pmc = 3670783}}</ref> pGSN along with Vitamin D-binding protein (DBP) bind and clear monomeric actin.<ref name="Janmey1987"/> DBP binds with greater affinity to G-actin, leaving pGSN available to sever F-actin.<ref name=Lind1986>{{Cite journal| doi = 10.1172/JCI112634| issn = 0021-9738| volume = 78| issue = 3| pages = 736–742| last1 = Lind| first1 = S E| last2 = Smith| first2 = D B| last3 = Janmey| first3 = P A| last4 = Stossel| first4 = T P| title = Role of plasma gelsolin and the vitamin D-binding protein in clearing actin from the circulation.| journal = Journal of Clinical Investigation| date = 1986-09-01| pmid = 3018044| pmc = 423663}}</ref> Furthermore, DBP is capable of removing one actin from a 2:1 actin-pGSN complex, restoring its ability to sever F-actin.<ref>{{Cite journal| doi = 10.1016/0006-291X(86)90878-8| issn = 0006-291X| volume = 136| issue = 1| pages = 72–79| last1 = Janmey| first1 = Paul A.| last2 = Stossel| first2 = Thomas P.| last3 = Lind| first3 = Stuart E.| title = Sequential binding of actin monomers to plasma gelsolin and its inhibition by vitamin D-binding protein| journal = Biochemical and Biophysical Research Communications| date = 1986-04-14| pmid = 3010978| bibcode = 1986BBRC..136...72J}}</ref> F-actin, severed and capped by pGSN, is removed by sinusoidal endothelial cells of the liver.<ref>{{Cite journal|last1=Herrmannsdoerfer|first1=A. J.|last2=Heeb|first2=G. T.|last3=Feustel|first3=P. J.|last4=Estes|first4=J. E.|last5=Keenan|first5=C. J.|last6=Minnear|first6=F. L.|last7=Selden|first7=L.|last8=Giunta|first8=C.|last9=Flor|first9=J. R.|last10=Blumenstock|first10=F. A.|date = December 1993|title=Vascular clearance and organ uptake of G- and F-actin in the rat|journal=The American Journal of Physiology|volume=265|issue=6 Pt 1|pages=–1071–1081|doi=10.1152/ajpgi.1993.265.6.G1071|issn=0002-9513|pmid=8279558}}</ref> pGSN removes 60% of actin trapped in fibrin clots ''in vitro'' leading to an increased rate of clot lysis.<ref name=Janmey1992/>

====Severing, capping, nucleation, and polymerization==== Although pGSN is capable of initiating the polymerization of actin through nucleation, its primary relationship with it in blood is depolymerization through filament severing.<ref name="Lee1992" /> Actin severing occurs rapidly in the presence of pGSN and Ca²⁺.<ref name="Janmey1987">{{Cite journal| issn = 0006-4971| volume = 70| issue = 2| pages = 524–530| last1 = Janmey| first1 = P. A.| last2 = Lind| first2 = S. E.| title = Capacity of human serum to depolymerize actin filaments| journal = Blood| date = August 1987| doi = 10.1182/blood.V70.2.524.524| pmid = 3038216| doi-access = free}}</ref> pGSN wraps around filaments, non-enzymatically cleaving them.<ref name="Nag2013Gymnast" /> It remains attached, "capping" the barbed/plus end of the severed filament and inducing a torsional twist that is cooperative through its length.<ref>{{Cite journal| doi = 10.1006/jmbi.1994.0049| issn = 0022-2836| volume = 245| issue = 5| pages = 598–607| last1 = Orlova| first1 = A.| last2 = Prochniewicz| first2 = E.| last3 = Egelman| first3 = E. H.| title = Structural dynamics of F-actin: II. Cooperativity in structural transitions| journal = Journal of Molecular Biology| date = 1995-02-03| pmid = 7844829}}</ref><ref>{{Cite journal| doi = 10.1006/jmbi.1996.0435| issn = 0022-2836| volume = 260| issue = 5| pages = 756–766| last1 = Prochniewicz| first1 = Ewa| last2 = Zhang| first2 = Qingnan| last3 = Janmey| first3 = Paul A.| last4 = Thomas| first4 = David D.| title = Cooperativity in F-Actin: Binding of Gelsolin at the Barbed End Affects Structure and Dynamics of the Whole Filament| journal = Journal of Molecular Biology| date = August 1996| pmid = 8709153}}</ref> Capping has a reported binding affinity <250 pM in the presence of Ca²⁺ that is substantially weakened in its absence. Capping also blocks further polymerization at the fast growing, barbed end.<ref name="Janmey1985">{{Cite journal| doi = 10.1021/bi00335a046| issn = 0006-2960| volume = 24| issue = 14| pages = 3714–3723| last1 = Janmey| first1 = Paul A.| last2 = Chaponnier| first2 = Christine| last3 = Lind| first3 = Stuart E.| last4 = Zaner| first4 = Ken S.| last5 = Stossel| first5 = Thomas P.| last6 = Yin| first6 = Helen L.| title = Interactions of gelsolin and gelsolin-actin complexes with actin. Effects of calcium on actin nucleation, filament severing, and end blocking| journal = Biochemistry| date = July 1985| pmid = 2994715}}</ref>

While no evidence exists for nucleating/polymerizing of G-actin by pGSN ''in vivo'', the ability of it to do so ''in vitro'' is well documented.<ref>{{Cite journal| issn = 0021-9258| volume = 259| issue = 19| pages = 11868–11875| last1 = Doi| first1 = Y.| last2 = Frieden| first2 = C.| title = Actin polymerization. The effect of brevin on filament size and rate of polymerization.| journal = Journal of Biological Chemistry| date = 1984-10-10| doi = 10.1016/S0021-9258(20)71292-5| pmid = 6480587| doi-access = free}}</ref><ref>{{Cite journal| doi = 10.1529/biophysj.107.123125| issn = 0006-3495| volume = 95| issue = 3| pages = 1050–1062| last1 = Brooks| first1 = F.J.| last2 = Carlsson| first2 = A.E.| title = Actin Polymerization Overshoots and ATP Hydrolysis as Assayed by Pyrene Fluorescence| journal = Biophysical Journal| date = August 2008| pmid = 18390612| pmc = 2479571| bibcode = 2008BpJ....95.1050B}}</ref> Actin polymerization is initiated by the production of an actin trimer nucleus.<ref>{{Cite journal| doi = 10.1016/S0006-3495(01)75731-1| issn = 0006-3495| volume = 81| issue = 2| pages = 667–674| last1 = Sept| first1 = David| last2 = McCammon| first2 = J. Andrew| title = Thermodynamics and Kinetics of Actin Filament Nucleation| journal = Biophysical Journal| date = 2001-08-01| pmid = 11463615| pmc = 1301543| bibcode = 2001BpJ....81..667S}}</ref> Formation of nuclei is energetically disfavored, but dimers and/or trimers can be catalyzed/stabilized by a number of cellular proteins.<ref>{{Cite journal| doi = 10.1111/febs.13381| issn = 1742-464X| volume = 282| issue = 19| pages = 3824–3840| last1 = Qu| first1 = Zheng| last2 = Silvan| first2 = Unai| last3 = Jockusch| first3 = Brigitte M.| last4 = Aebi| first4 = Ueli| last5 = Schoenenberger| first5 = Cora-Ann| last6 = Mannherz| first6 = Hans Georg| title = Distinct actin oligomers modulate differently the activity of actin nucleators| journal = FEBS Journal| date = October 2015| pmid = 26194975| doi-access = free}}</ref> In excess of a 2:1 actin:gelsolin stoichiometry and in the presence of Ca²⁺, gelsolin will bind three actin monomers.<ref>{{Cite journal| doi = 10.1007/BF01766670| issn = 0142-4319| volume = 11| issue = 4| pages = 323–330| last = Edgar| first = Alasdair John| title = Gel electrophoresis of native gelsolin and gelsolin-actin complexes| journal = Journal of Muscle Research and Cell Motility| date = August 1990| pmid = 2174905| s2cid = 11355042}}</ref> A monomer adds to the trimer creating a tetramer that undergoes an internal conversion to an active tetramer witnessed by a concentration-independent lag phase. Subsequent fibrilization proceeds by monomer addition.<ref>{{Cite journal| issn = 0021-9258| volume = 259| issue = 14| pages = 8794–8800| last1 = Lal| first1 = A. A.| last2 = Korn| first2 = E. D.| last3 = Brenner| first3 = S. L.| title = Rate constants for actin polymerization in ATP determined using cross-linked actin trimers as nuclei| journal = The Journal of Biological Chemistry| date = 1984-07-25| doi = 10.1016/S0021-9258(17)47223-1| pmid = 6746624| doi-access = free}}</ref> Gelsolin remains attached to the fast-growing (barbed/plus) end of actin, producing short, slow-growing fibrils.<ref>{{Cite journal| doi = 10.1007/BF01753587| issn = 1573-2657| volume = 7| issue = 5| pages = 446–454| last1 = Janmey| first1 = Paul A.| last2 = Stossel| first2 = Thomas P.| title = Kinetics of actin monomer exchange at the slow growing ends of actin filaments and their relation to the elongation of filaments shortened by gelsolin| journal = Journal of Muscle Research & Cell Motility| date = 1986-10-01| pmid = 3025252| s2cid = 2644111}}</ref>

These actions are similar to those of cytoplasmic form of pGSN, cGSN, which contributes to structural changes of cells through both nucleating/polymerizing and severing/capping.<ref name="Nag2013Gymnast"/>

===Amyloid prevention and clearance=== pGSN may play an important role in the prevention and management of amyloidosis in several diseases. It is found in complex with Aβ in plasma<ref name="Chauhan1999" /> and reported to both inhibit amyloid formation and defibrillize preformed fibrils ''in vitro''.<ref name="Ray2000" /> Mice with an Alzheimer's disease model given pGSN showed a 5-fold decrease in progression of Cerebral Amyloid Angiopathy.<ref>{{Cite journal| volume = 71| issue = 11| pages = 1009–17| last1 = Gregory| first1 = Julia L| last2 = Prada| first2 = Claudia M| last3 = Fine| first3 = Sara J| last4 = Garcia-Alloza| first4 = Monica| last5 = Betensky| first5 = Rebecca A| last6 = Arbel-Ornath| first6 = Michal| last7 = Greenberg| first7 = Steven M| last8 = Bacskai| first8 = Brian J| last9 = Frosch| first9 = Matthew P| title = Reducing Available Soluble A-Amyloid Prevents Progression of Cerebral Amyloid Angiopathy in Transgenic Mice| journal = J Neuropathol Exp Neurol| date = 2012| doi = 10.1097/NEN.0b013e3182729845| pmid = 23095848| pmc = 3491571}}</ref> pGSN has also been found in Lewy Bodies, amyloid containing protein aggregates associated with Parkinson's disease and Dementia with Lewy bodies.<ref>{{Cite journal| doi = 10.1111/j.1750-3639.2007.00048.x| issn = 1015-6305| volume = 17| issue = 2| pages = 139–145| last1 = Leverenz| first1 = James B.| last2 = Umar| first2 = Imran| last3 = Wang| first3 = Qing| last4 = Montine| first4 = Thomas J.| last5 = McMillan| first5 = Pamela J.| last6 = Tsuang| first6 = Debby W.| last7 = Jin| first7 = Jinghua| last8 = Pan| first8 = Catherine| last9 = Shin| first9 = Jenny| last10 = Zhu| first10 = David| last11 = Zhang| first11 = Jing| title = Proteomic identification of novel proteins in cortical lewy bodies| journal = Brain Pathology (Zurich, Switzerland)| date = 2007-04-01| pmid = 17388944| s2cid = 24457175| pmc = 8095629}}</ref><ref>{{Cite journal| doi = 10.1016/j.bbrc.2011.07.027| issn = 0006-291X| volume = 412| issue = 1| pages = 32–38| last1 = Welander| first1 = Hedvig| last2 = Bontha| first2 = Sai Vineela| last3 = Näsström| first3 = Thomas| last4 = Karlsson| first4 = Mikael| last5 = Nikolajeff| first5 = Fredrik| last6 = Danzer| first6 = Karin| last7 = Kostka| first7 = Marcus| last8 = Kalimo| first8 = Hannu| last9 = Lannfelt| first9 = Lars| last10 = Ingelsson| first10 = Martin| last11 = Bergström| first11 = Joakim| title = Gelsolin co-occurs with Lewy bodies in vivo and accelerates α-synuclein aggregation in vitro| journal = Biochemical and Biophysical Research Communications| date = 2011-07-21| pmid = 21798243| bibcode = 2011BBRC..412...32W}}</ref>

==Role in inflammation==

===Macrophage stimulation=== ====MARCO receptor==== Macrophage receptor MARCO is responsible for pathogen recognition and phagocytosis. Macrophages incubated with actin at concentrations consistent with lung injury showed decreased uptake of bacteria. Uptake was restored when actin was administered in the presence of pGSN.<ref name=MARCO>{{Cite journal| doi = 10.1152/ajplung.00067.2017| issn = 1040-0605| volume = 312| issue = 6| pages = –1018–L1028| last1 = Ordija| first1 = Christine M.| last2 = Chiou| first2 = Terry Ting-Yu| last3 = Yang| first3 = Zhiping| last4 = Deloid| first4 = Glen M.| last5 = de Oliveira Valdo| first5 = Melina| last6 = Wang| first6 = Zhi| last7 = Bedugnis| first7 = Alice| last8 = Noah| first8 = Terry L.| last9 = Jones| first9 = Samuel| last10 = Koziel| first10 = Henry| last11 = Kobzik| first11 = Lester| title = Free actin impairs macrophage bacterial defenses via scavenger receptor MARCO interaction with reversal by plasma gelsolin| journal = American Journal of Physiology. Lung Cellular and Molecular Physiology| date = 2017-06-01| pmid = 28385809| pmc = 5495953}}</ref>

====NOS3==== NOS3 is an enzyme that is protective against systemic inflammation and myocardial dysfunction.<ref>{{Cite journal| doi = 10.1097/SHK.0b013e3181cdc327| issn = 1073-2322| volume = 34| issue = 3| pages = 281–290| last1 = Bougaki| first1 = Masahiko| last2 = Searles| first2 = Robert J.| last3 = Kida| first3 = Kotaro| last4 = De Yu| first4 = Jia| last5 = Buys| first5 = Emmanuel S.| last6 = Ichinose| first6 = Fumito| title = NOS3 protects against systemic inflammation and myocardial dysfunction in murine polymicrobial sepsis| journal = Shock (Augusta, Ga.)| date = 2010-09-01| pmid = 19997049| pmc = 3774000}}</ref><ref>{{Cite journal| doi = 10.1186/1471-2350-13-58| issn = 1471-2350| volume = 13| issue = 1| page = 58| last1 = Jimenez-Sousa| first1 = Ma Angeles| last2 = López| first2 = Elisabeth| last3 = Fernandez-Rodríguez| first3 = Amanda| last4 = Tamayo| first4 = Eduardo| last5 = Fernández-Navarro| first5 = Pablo| last6 = Segura-Roda| first6 = Laura| last7 = Heredia| first7 = María| last8 = Gómez-Herreras| first8 = José I.| last9 = Bustamante| first9 = Jesús| last10 = García-Gómez| first10 = Juan Miguel| last11 = Bermejo-Martin| first11 = Jesús F.| last12 = Resino| first12 = Salvador| title = Genetic polymorphisms located in genes related to immune and inflammatory processes are associated with end-stage renal disease: a preliminary study| journal = BMC Medical Genetics| date = 2012-07-20| pmid = 22817530| pmc = 3412707| doi-access = free}}</ref> pGSN activates phosphorylation of Ser¹¹⁷⁷ in NOS3 and Ser⁴⁷³ in Akt.<ref name=NOS3>{{Cite journal| doi = 10.1152/ajplung.00094.2015| issn = 1040-0605| volume = 309| issue = 1| pages = –11–L16| last1 = Yang| first1 = Zhiping| last2 = Chiou| first2 = Terry Ting-Yu| last3 = Stossel| first3 = Thomas P.| last4 = Kobzik| first4 = Lester| title = Plasma gelsolin improves lung host defense against pneumonia by enhancing macrophage NOS3 function| journal = American Journal of Physiology. Lung Cellular and Molecular Physiology| date = 2015-07-01| pmid = 25957291| pmc = 4491512}}</ref> NOS3 is known to be activated by phosphorylation of Akt.<ref>{{Cite journal| doi = 10.1210/er.2001-0045| issn = 0163-769X| volume = 23| issue = 5| pages = 665–686| last1 = Chambliss| first1 = Ken L.| last2 = Shaul| first2 = Philip W.| title = Estrogen Modulation of Endothelial Nitric Oxide Synthase| journal = Endocrine Reviews| date = October 2002| pmid = 12372846| doi-access = free}}</ref> Mouse macrophage uptake and killing of bacteria ''in vitro'' was enhanced by pGSN, and no significant enhancement was found for NOS3^-/- macrophages. ''In vivo'', mice showed 15-fold improvement in bacterial clearance when given pGSN, and no significant enhancement was found for NOS3^-/- mice.<ref name=NOS3/>

===Inflammatory mediators=== pGSN has been shown to bind to the fatty acid inflammatory mediators LPA,<ref name="Meerschaert1998"/><ref name="Goetzl2000"/><ref name=Mintzer2005>{{Cite journal| doi = 10.1016/j.bbamem.2005.12.009| issn = 0005-2736| volume = 1758| issue = 1| pages = 85–89| last1 = Mintzer| first1 = Evan| last2 = Sargsyan| first2 = Hasmik| last3 = Bittman| first3 = Robert| title = Lysophosphatidic acid and lipopolysaccharide bind to the PIP2-binding domain of gelsolin| journal = Biochimica et Biophysica Acta (BBA) - Biomembranes| date = 2006-01-18| pmid = 16460666| doi-access = free}}</ref> LPS (endotoxin),<ref name=Mintzer2005/><ref name="Bucki2005"/><ref name=Bucki2008>{{Cite journal| doi = 10.4049/jimmunol.181.7.4936| issn = 0022-1767| volume = 181| issue = 7| pages = 4936–4944| last1 = Bucki| first1 = Robert| last2 = Byfield| first2 = Fitzroy J.| last3 = Kulakowska| first3 = Alina| last4 = McCormick| first4 = Margaret E.| last5 = Drozdowski| first5 = Wieslaw| last6 = Namiot| first6 = Zbigniew| last7 = Hartung| first7 = Thomas| last8 = Janmey| first8 = Paul A.| title = Extracellular Gelsolin Binds Lipoteichoic Acid and Modulates Cellular Response to Proinflammatory Bacterial Wall Components| journal = The Journal of Immunology| date = 2008-10-01| pmid = 18802097| doi-access = free}}</ref> LTA,<ref name=Bucki2008/> PAF,<ref name="Osborn2007"/> S1P,<ref name="Bucki2010"/> and polyphosphoinositides including PIP₂.<ref name="Janmey1987"/><ref name=Lin1997/><ref name=Lin1997a/> Mediators of inflammation, the body's innate healing mechanism, accumulate at the site of the injury to begin the processes of defense and repair,<ref name=":0" /><ref name=":1" /><ref name=":2" /> and the depletion of local pGSN allows them to do their work.<ref name=":3" />

See Binding and inactivation of diverse inflammatory mediators

==Therapeutic potential== The broad therapeutic potential of pGSN supplementation resides in the fact that the molecule embodies a multifunctional system contributing importantly to innate immunity rather than a pharmacologic intervention with selective and specific activities.

Plasma gelsolin's primary function is to keep inflammation local and enhance the function of the innate immune system. It functions through a pleiotropic mechanism of action; severing toxic filamentous actin (F-actin), binding inflammatory mediators, and enhancing pathogen clearance. These mechanisms are quite distinct from other anti-inflammatory agents that function as antagonists of individual mediators or inhibitors of specific enzymes, and work to ablate inflammation. Most systemic anti-inflammatory agents also suppress the immune system<ref>{{Cite journal| doi = 10.1016/j.cellimm.2009.03.007| issn = 0008-8749| volume = 258| issue = 1| pages = 18–28| last1 = Bancos| first1 = Simona| last2 = Bernard| first2 = Matthew P.| last3 = Topham| first3 = David J.| last4 = Phipps| first4 = Richard P.| title = Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells| journal = Cellular Immunology| date = 2009| pmid = 19345936| pmc = 2693360}}</ref><ref>{{Cite journal| doi = 10.1016/j.mce.2010.04.005| issn = 0303-7207| volume = 335| issue = 1| pages = 2–13| last1 = Coutinho| first1 = Agnes E.| last2 = Chapman| first2 = Karen E.| title = The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights| journal = Molecular and Cellular Endocrinology| date = 2011-03-15| pmid = 20398732| pmc = 3047790}}</ref> and often require caution in administration because they increase the risk of infection.<ref>{{Cite journal| issn = 1076-2191| volume = 11| issue = 6| pages = 277–285| last = Gm| first = Anstead| title = Steroids, retinoids, and wound healing.| journal = Advances in Wound Care: The Journal for Prevention and Healing| date = 1998-10-01| pmid = 10326344}}</ref> Plasma gelsolin is unique in that it has also been demonstrated to enhance the antimicrobial action of macrophages,<ref name=MARCO/> which engulf and digest cellular debris and pathogens, boosting immunity against both gram positive and gram negative bacterial infections.<ref name=NOS3/>

===Mechanisms of action=== Plasma gelsolin plays a central role in the body's innate immune system and is responsible for localizing inflammation—a mechanism so central to species survival that it has been highly conserved by evolution.<ref name="Lee1992" /> Experimental and epidemiology data suggest that pGSN performs the role of a buffer or shield that modulates the inflammatory response to injury or infection.<ref name=Bucki2012/> The system accomplishes this goal in three key ways described below:

====Debridement==== Plasma gelsolin binds and severs filamentous actin exposed from cells damaged by injury,<ref name=Chaponnier1979/><ref name=Norberg1979/><ref>{{Cite journal| issn = 0006-4971| volume = 70| issue = 2| pages = 524–530| last1 = Janmey| first1 = P. A.| last2 = Lind| first2 = S. E.| title = Capacity of human serum to depolymerize actin filaments| journal = Blood| date = 1987-08-01| doi = 10.1182/blood.V70.2.524.524| pmid = 3038216| doi-access = free}}</ref> including both infectious and sterile injury. Actin has been reported to activate platelets,<ref name=Vasconcellos/> interfere with fibrinolysis,<ref name=Janmey1992>{{Cite journal| issn = 0006-4971| volume = 80| issue = 4| pages = 928–936| last1 = Janmey| first1 = P. A.| last2 = Lamb| first2 = J. A.| last3 = Ezzell| first3 = R. M.| last4 = Hvidt| first4 = S.| last5 = Lind| first5 = S. E.| title = Effects of actin filaments on fibrin clot structure and lysis| journal = Blood| date = 1992-08-15| doi = 10.1182/blood.V80.4.928.928| pmid = 1323346| doi-access = free}}</ref><ref>{{Cite journal| volume = 266| issue = 8| pages = 5273–5278| last1 = Stuart E LindS| last2 = Smith| first2 = Carolyn J| title = Actin Is a Noncompetitive Plasmin Inhibitor| journal = Journal of Biological Chemistry| date = 1991-03-15| doi = 10.1016/S0021-9258(19)67783-5| pmid = 1848244| url = https://www.jbc.org/content/266/8/5273.full.pdf| doi-access = free}}</ref> damage endothelial cells,<ref>{{Cite journal| doi = 10.1164/ajrccm.162.1.9806088| issn = 1073-449X| volume = 162| issue = 1| pages = 288–294| last1 = Erukhimov| first1 = Jeffrey A.| last2 = Tang| first2 = Zi-Lue| last3 = Johnson| first3 = Bruce A.| last4 = Donahoe| first4 = Michael P.| last5 = Razzack| first5 = Jamal A.| last6 = Gibson| first6 = Kevin F.| last7 = Lee| first7 = William M.| last8 = Wasserloos| first8 = Karla J.| last9 = Watkins| first9 = Simon A.| last10 = Pitt| first10 = Bruce R.| title = Actin-Containing Sera From Patients With Adult Respiratory Distress Syndrome Are Toxic to Sheep Pulmonary Endothelial Cells| journal = American Journal of Respiratory and Critical Care Medicine| date = 2000-07-01| pmid = 10903256| s2cid = 23974368}}</ref> and to function as a danger signal (DAMP).<ref>{{Cite journal| doi = 10.15252/emmm.201607227| issn = 1757-4684| volume = 9| issue = 3| pages = 285–288| last = Sousa| first = Caetano Reis e| title = Sensing infection and tissue damage| journal = EMBO Molecular Medicine| date = 2017-03-01| pmid = 28119319| pmc = 5331196}}</ref> Administration of large quantities of filamentous actin to rats resulted in lethal pulmonary hemorrhage and thrombosis.<ref name="Haddad1990"/>

Another key "toxicity" of exposed actin is the fact that it is a major component of biofilms that accumulate at local sites of injury and infection, and that it impedes the access of host immune components and therapeutics such as antibiotics.<ref name=Walker2005/><ref>{{Cite journal| doi = 10.1099/jmm.0.005728-0| issn = 0022-2615| volume = 58| issue = Pt 4| pages = 492–502| last1 = Parks| first1 = Quinn M.| last2 = Young| first2 = Robert L.| last3 = Poch| first3 = Katie R.| last4 = Malcolm| first4 = Kenneth C.| last5 = Vasil| first5 = Michael L.| last6 = Nick| first6 = Jerry A.| title = Neutrophil enhancement of Pseudomonas aeruginosa biofilm development: human F-actin and DNA as targets for therapy| journal = Journal of Medical Microbiology| date = 2009-04-01| pmid = 19273646| pmc = 2677169}}</ref> Biofilms are particularly pathogenic in the setting of foreign bodies like indwelling catheters and tissue implants.<ref name=Walker2005>{{Cite journal| doi = 10.1128/IAI.73.6.3693-3701.2005| issn = 0019-9567| volume = 73| issue = 6| pages = 3693–3701| last1 = Walker| first1 = T. S.| last2 = Tomlin| first2 = K. L.| last3 = Worthen| first3 = G. S.| last4 = Poch| first4 = K. R.| last5 = Lieber| first5 = J. G.| last6 = Saavedra| first6 = M. T.| last7 = Fessler| first7 = M. B.| last8 = Malcolm| first8 = K. C.| last9 = Vasil| first9 = M. L.| last10 = Nick| first10 = J. A.| title = Enhanced Pseudomonas aeruginosa Biofilm Development Mediated by Human Neutrophils| journal = Infection and Immunity| date = 2005-06-01| pmid = 15908399| pmc = 1111839}}</ref> As a result of actin exposure at the local site of injury, the local level of plasma gelsolin around the site of the injury initially becomes depleted as it "debrides" the local involved site.<ref name="Osborn2007" /> Mediators of inflammation, the body's innate healing mechanism, accumulate at the site of the injury to begin the processes of defense and repair, and the depletion of local plasma gelsolin allows them to do their work.<ref name="Osborn2007" /> While local pGSN levels are depressed, the presence of this abundant protein in the circulation ensures that the inflammatory process stays local, and that stores of plasma gelsolin are available to address further injury so that the overall immune response remains intact.

====Augmentation of macrophage antimicrobial activity==== pGSN has antimicrobial activity ''in vitro'' and ''in vivo''. Administration of pGSN subcutaneously or by inhalation to mice challenged with lethal inocula of ''S. pneumoniae'' or even more lethal combinations of influenza virus and bacteria markedly diminished the number of viable bacteria in the animals' airways and significantly reduced mortality. The number of inflammation-inducing neutrophils was also considerably reduced, presumably as a result of enhanced bacterial clearance. This is true for contemporaneous or delayed administration of recombinant pGSN.<ref name=NOS3/><ref name="ReferenceA">{{Cite journal| doi = 10.1093/ofid/ofx163.1215| issn = 2328-8957| volume = 4| issue = Suppl 1| pages = –474–S475| last1 = Yang| first1 = Zhiping| last2 = Levinson| first2 = Susan| last3 = Stossel| first3 = Thomas| last4 = DiNubile| first4 = Mark| last5 = Kobzik| first5 = Lester| title = Delayed Therapy with Plasma Gelsolin Improves Survival in Murine Pneumococcal Pneumonia| journal = Open Forum Infectious Diseases| date = 2017-10-04| pmc = 5630930}}</ref>

A basis of pGSN's antimicrobial action is that it enhances the ability of cultivated lung macrophages to ingest gram positive and gram negative bacteria. This has been demonstrated ''in vitro''.<ref name=NOS3/> Improved phagocytosis is the product of pGSN debriding actin bound to macrophage scavenger receptors preventing their function.<ref name=MARCO/> pGSN also increases the ability of macrophages to kill ingested microorganisms by inducing macrophage nitric oxide synthase activity.<ref name=NOS3/>

====Binding and inactivation of diverse inflammatory mediators==== pGSN binds to a number of inflammatory mediators and signaling agents. Binding to LPA occurs at the same site on the molecule that ligates actin and interacts with polyphosphoinositides.<ref name=Meerschaert1998/> Subsequent studies showed that gelsolin alters the effector function of LPA's receptor binding.<ref name=Goetzl2000/><ref name=Osborn2007/> Binding to inflammatory mediators, and in some cases inhibition of their effector function, has been shown for platelet-activating factor,<ref name=Osborn2007/> lipopolysaccharide endotoxin,<ref name=Bucki2005/> sphingosine-1-phosphate,<ref name=Bucki2008/> and lipoteichoic acid<ref name=Bucki2010/> and small molecule purinergic agonists including ATP and ADP.<ref name=Vartanian2003>{{Cite journal| issn = 0021-2938| volume = 52| issue = 1| pages = 9–16| last = Vartanian| first = Amalia A| title = Gelsolin and plasminogen activator inhibitor-1 are Ap3A-binding proteins| journal = The Italian Journal of Biochemistry| date = March 2003| pmid = 12833632}}</ref><ref name=Urosev2006>{{Cite journal| doi = 10.1016/j.jmb.2006.01.027| issn = 0022-2836| volume = 357| issue = 3| pages = 765–772| last1 = Urosev| first1 = Dunja| last2 = Ma| first2 = Qing| last3 = Tan| first3 = Agnes L.C.| last4 = Robinson| first4 = Robert C.| last5 = Burtnick| first5 = Leslie D.| title = The Structure of Gelsolin Bound to ATP| journal = Journal of Molecular Biology| date = 2006-03-31| pmid = 16469333}}</ref><ref name=Laham1995>{{Cite journal| doi = 10.1111/j.1432-1033.1995.001_c.x| issn = 0014-2956| volume = 234| issue = 1| pages = 1–7| last1 = Laham| first1 = Lorraine E.| last2 = Way| first2 = Michael| last3 = Yin| first3 = Helen L.| last4 = Janmey| first4 = Paul A.| title = Identification of Two Sites in Gelsolin with Different Sensitivities to Adenine Nucleotides| journal = European Journal of Biochemistry| date = 1995-11-15| pmid = 8529627| doi-access = free}}</ref><ref name=Yamamoto1990>{{Cite journal| doi = 10.1093/oxfordjournals.jbchem.a123229| issn = 0021-924X| volume = 108| issue = 4| pages = 505–506| last1 = Yamamoto| first1 = Hideo| last2 = Ito| first2 = Hiroaki| last3 = Nakamura| first3 = Hideji| last4 = Hayashi| first4 = Eijiro| last5 = Kishimoto| first5 = Susumu| last6 = Hashimoto| first6 = Tadao| last7 = Tagawa| first7 = Kunio| title = Human Plasma Gelsolin Binds Adenosine Triphosphate| journal = The Journal of Biochemistry| access-date = 2020-02-28| date = 1990-10-01| pmid = 1963427| url = https://academic.oup.com/jb/article/108/4/505/800225| url-access = subscription| doi-access = free}}</ref> The binding of pGSN to Aβ Alzheimer peptide has also been well documented.<ref name=Ray2000/><ref name=Chauhan1999/><ref name=Ji2015>{{Cite journal| doi = 10.3233/JAD-141548| issn = 1875-8908| volume = 44| issue = 1| pages = 13–25| last1 = Ji| first1 = Lina| last2 = Zhao| first2 = Xi| last3 = Hua| first3 = Zichun| title = Potential Therapeutic Implications of Gelsolin in Alzheimer's Disease| journal = Journal of Alzheimer's Disease| date = 2015-01-06| pmid = 25208622}}</ref>

{| class="wikitable" |+ style="text-align: left;" | Role of mediators which bind to plasma gelsolin |- ! Mediator !! Role |- | LPA<ref name=Meerschaert1998>{{Cite journal| doi = 10.1093/emboj/17.20.5923| issn = 1460-2075| volume = 17| issue = 20| pages = 5923–5932| last = Meerschaert| first = K.| title = Gelsolin and functionally similar actin-binding proteins are regulated by lysophosphatidic acid| journal = The EMBO Journal| date = 1998-10-15| pmid = 9774337| pmc = 1170920}}</ref><ref name=Goetzl2000>{{Cite journal| doi = 10.1074/jbc.275.19.14573| issn = 0021-9258| volume = 275| issue = 19| pages = 14573–14578| last1 = Goetzl| first1 = Edward J.| last2 = Lee| first2 = Hsinyu| last3 = Azuma| first3 = Toshifumi| last4 = Stossel| first4 = Thomas P.| last5 = Turck| first5 = Christoph W.| last6 = Karliner| first6 = Joel S.| title = Gelsolin Binding and Cellular Presentation of Lysophosphatidic Acid| journal = Journal of Biological Chemistry| date = 2000-05-12| pmid = 10799543| doi-access = free}}</ref><ref name=Mintzer2005/> || A phospholipid derivative that can act as a signaling molecule and activates G protein coupled receptors. It has been associated with cell proliferation. |- | LPS/endotoxin<ref name=Mintzer2005/><ref name=Bucki2005>{{Cite journal| doi = 10.1021/bi0503504| issn = 0006-2960| volume = 44| issue = 28| pages = 9590–9597| last1 = Bucki| first1 = Robert| last2 = Georges| first2 = Penelope C.| last3 = Espinassous| first3 = Quentin| last4 = Funaki| first4 = Makoto| last5 = Pastore| first5 = Jennifer J.| last6 = Chaby| first6 = Richard| last7 = Janmey| first7 = Paul A.| title = Inactivation of Endotoxin by Human Plasma Gelsolin ^†| journal = Biochemistry| date = 2005-07-19| pmid = 16008344}}</ref><ref name=Bucki2008/> || Found in the outer membrane of Gram-negative bacteria, it elicits a strong immune response in animals. |- | PAF<ref name=Osborn2007>{{Cite journal| doi = 10.1152/ajpcell.00510.2006| issn = 0363-6143| volume = 292| issue = 4| pages = –1323–C1330| last1 = Osborn| first1 = Teresia M.| last2 = Dahlgren| first2 = Claes| last3 = Hartwig| first3 = John H.| last4 = Stossel| first4 = Thomas P.| title = Modifications of cellular responses to lysophosphatidic acid and platelet-activating factor by plasma gelsolin| journal = American Journal of Physiology. Cell Physiology| date = 2007-04-01| pmid = 17135294}}</ref> || A potent phospholipid activator and mediator of many leukocyte functions, including platelet aggregation, inflammation, and anaphylaxis. It is produced in response to specific stimuli by a variety of cell types, including neutrophils, basophils, platelets, and endothelial cells. |- | Aβ<ref name=Ray2000>{{Cite journal| doi = 10.1016/S0006-8993(99)02315-X| issn = 0006-8993| volume = 853| issue = 2| pages = 344–351| last1 = Ray| first1 = Indrani| last2 = Chauhan| first2 = Abha| last3 = Wegiel| first3 = Jerzy| last4 = Chauhan| first4 = Ved P.S.| title = Gelsolin inhibits the fibrillization of amyloid beta-protein, and also defibrillizes its preformed fibrils| journal = Brain Research| date = 2000-01-24| pmid = 10640633| s2cid = 41363612}}</ref><ref name=Chauhan1999>{{Cite journal| volume = 258| issue = 2| pages = 241–6| last1 = Chauhan| first1 = Ved P S| last2 = Ray| first2 = Indrani| last3 = Chauhan| first3 = Abha| last4 = Wisniewski| first4 = Henryk M| title = Binding of Gelsolin, a Secretory Protein, to Amyloid β-Protein| journal = Biochemical and Biophysical Research Communications| date = 1999| doi = 10.1006/bbrc.1999.0623| pmid = 10329371| bibcode = 1999BBRC..258..241C}}</ref> || A peptide of 36–43 amino acids that is the main constituent of amyloid plaques in the brains of Alzheimer's disease patients. |- | LTA<ref name=Bucki2008/> || A major constituent of the cell wall of Gram-positive bacteria able to stimulate a specific immune response in animals. |- | S1P<ref name=Bucki2010>{{Cite journal| doi = 10.1152/ajpcell.00051.2010| issn = 0363-6143| volume = 299| issue = 6| pages = –1516–C1523| last1 = Bucki| first1 = Robert| last2 = Kułakowska| first2 = Alina| last3 = Byfield| first3 = Fitzroy J.| last4 = Żendzian-Piotrowska| first4 = Małgorzata| last5 = Baranowski| first5 = Marcin| last6 = Marzec| first6 = Michał| last7 = Winer| first7 = Jessamine P.| last8 = Ciccarelli| first8 = Nicholas J.| last9 = Górski| first9 = Jan| last10 = Drozdowski| first10 = Wiesław| last11 = Bittman| first11 = Robert| last12 = Janmey| first12 = Paul A.| title = Plasma gelsolin modulates cellular response to sphingosine 1-phosphate| journal = American Journal of Physiology. Cell Physiology| date = 2010-12-01| pmid = 20810916| pmc = 3006327}}</ref> || A blood borne lipid mediator and major regulator of vascular and immune systems. In the vascular system, S1P regulates angiogenesis, vascular stability, and permeability. In the immune system it is recognized as a major regulator of trafficking of T-cells and B-cells. Inhibition of S1P receptors has been shown to be critical for immunomodulation. |}

===Anti-microbial resistance=== Antimicrobial resistance is a global threat that leads to an estimated 700,000 deaths annually with projections of 10M deaths per year and lost economic potential of $100T by 2050.<ref>{{cite journal | vauthors = Hoffman SJ, Outterson K, Røttingen JA, Cars O, Clift C, Rizvi Z, Rotberg F, Tomson G, Zorzet A | title = An international legal framework to address antimicrobial resistance | journal = Bulletin of the World Health Organization | volume = 93 | issue = 2 | page = 66 | date = February 2015 | pmid = 25883395 | pmc = 4339972 | doi = 10.2471/BLT.15.152710 }}</ref><ref>{{cite web |last1=O'Neill |first1=Jim |title=Tackling drug-resistant infections globally: final report and recommendations |url=https://amr-review.org/sites/default/files/160525_Final%20paper_with%20cover.pdf |website=amr-review.org |publisher=Review on Antimicrobial Resistance |access-date=5 March 2020}}</ref> The United States has released a national action plan to combat antibiotic resistant bacteria.<ref>{{cite web |title=FACT SHEET: Obama Administration Releases National Action Plan to Combat Antibiotic-Resistant Bacteria |url=https://obamawhitehouse.archives.gov/the-press-office/2015/03/27/fact-sheet-obama-administration-releases-national-action-plan-combat-ant |website=obamawhitehouse.archives.gov |date=27 March 2015 |access-date=5 March 2020}}</ref>

Recombinant pGSN (rhu-pGSN) supplementation alone shows improved survival and decreased bacteria counts in several mouse models.<ref name="ReferenceA"/><ref name=Yang2019>{{Cite journal| doi = 10.1093/infdis/jiz353| issn = 0022-1899| volume = 220| issue = 9| pages = 1498–1502| last1 = Yang| first1 = Zhiping| last2 = Bedugnis| first2 = Alice| last3 = Levinson| first3 = Susan| last4 = Dinubile| first4 = Mark| last5 = Stossel| first5 = Thomas| last6 = Lu| first6 = Quan| last7 = Kobzik| first7 = Lester| title = Delayed Administration of Recombinant Plasma Gelsolin Improves Survival in a Murine Model of Penicillin-Susceptible and Penicillin-Resistant Pneumococcal Pneumonia| journal = The Journal of Infectious Diseases| date = 2019-09-26| pmid = 31287867| pmc = 6761947}}</ref> The bactericidal activity of the antimicrobial peptide LL-37 was shown to be inhibited by F-actin. It formed bundles with F-actin ''in vitro'' that were dissolved by pGSN, restoring bactericidal activity. Bacteria growth was reduced when pGSN was added cystic fibrosis sputum, which is known to contain F-actin.<ref>{{Cite journal| doi = 10.1165/rcmb.2002-0191OC| issn = 1044-1549| volume = 28| issue = 6| pages = 738–745| last1 = Weiner| first1 = Daniel J.| last2 = Bucki| first2 = Robert| last3 = Janmey| first3 = Paul A.| title = The Antimicrobial Activity of the Cathelicidin LL37 Is Inhibited by F-actin Bundles and Restored by Gelsolin| journal = American Journal of Respiratory Cell and Molecular Biology| date = June 2003| pmid = 12600826}}</ref>

When mice were given a penicillin-resistant strain of pneumococcal pneumonia, penicillin had no effect on mortality or morbidity. rhu-pGSN improved both mortality and morbidity on its own, and the combination of rhu-pGSN and penicillin gave further improvement of both suggesting possible synergism.<ref name=Yang2019/>

===Levels of the Protein=== Plasma gelsolin is produced and secreted by virtually every cell type with muscle contributing the largest amount.<ref name=Muscle>{{Cite journal| issn = 0021-9258| volume = 263| issue = 17| pages = 8239–8243| last1 = Kwiatkowski| first1 = D. J.| last2 = Mehl| first2 = R.| last3 = Izumo| first3 = S.| last4 = Nadal-Ginard| first4 = B.| last5 = Yin| first5 = H. L.| title = Muscle is the major source of plasma gelsolin| journal = The Journal of Biological Chemistry| date = 1988-06-15| doi = 10.1016/S0021-9258(18)68469-8| pmid = 2836420| doi-access = free}}</ref> At normal levels of >200&nbsp;mg/L, it is a highly abundant protein in the circulation.<ref name=Smith1987/>

Decreased levels are often associated with ill health and disease.<ref name=Bucki2012>{{Cite journal| doi = 10.2174/138920308786733912| issn = 1389-2037| volume = 9| issue = 6| pages = 541–551| last1 = Bucki| first1 = Robert| last2 = Levental| first2 = Ilya| last3 = Kulakowska| first3 = Alina| last4 = Janmey| first4 = Paul A.| title = Plasma gelsolin: function, prognostic value, and potential therapeutic use| journal = Current Protein & Peptide Science| date = 2008-12-01| pmid = 19075745}}</ref><ref name=Peddada2012>{{Cite journal| doi = 10.1016/j.mehy.2011.10.024| issn = 0306-9877| volume = 78| issue = 2| pages = 203–210| last1 = Peddada| first1 = Nagesh| last2 = Sagar| first2 = Amin| last3 = Ashish| last4 = Garg| first4 = Renu| title = Plasma gelsolin: A general prognostic marker of health| journal = Medical Hypotheses| date = February 2012| pmid = 22082609}}</ref> A growing list of insults showing loss of pGSN includes COVID-19,<ref name="Overmyer2021">{{cite journal |last1=Overmyer |first1=Katherine A. |last2=Shishkova |first2=Evgenia |last3=Miller |first3=Ian J. |last4=Balnis |first4=Joseph |last5=Bernstein |first5=Matthew N. |last6=Peters-Clarke |first6=Trenton M. |last7=Meyer |first7=Jesse G. |last8=Quan |first8=Quiwen |last9=Muehlbauer |first9=Laura K. |last10=Trujillo |first10=Edna A. |last11=He |first11=Yuchen |last12=Chopra |first12=Amit |last13=Chieng |first13=Hau C. |last14=Tiwari |first14=Anupama |last15=Judson |first15=Marc A. |last16=Paulson |first16=Brett |last17=Brademan |first17=Dain R. |last18=Zhu |first18=Yunun |last19=Serrano |first19=Lia R. |last20=Linke |first20=Vanessa |last21=Drake |first21=Lisa A. |last22=Adam |first22=Alejandro P. |last23=Schwartz |first23=Bradford S. |last24=Singer |first24=Harold A. |last25=Swanson |first25=Scott |last26=Mosher |first26=Deane F. |last27=Sweart |first27=Ron |last28=Coon |first28=Joshua J. |last29=Jaitovich |first29=Ariel |title=Large-Scale Multi-omic Analysis of COVID-19 Severity |journal=Cell Systems |date=Jan 20, 2021 |volume=12 |issue=1 |pages=23–40.E7 |doi=10.1016/j.cels.2020.10.003 |pmid=33096026 |pmc=7543711 }}</ref><ref name="Messner2020">{{Cite journal| doi = 10.1016/j.cels.2020.05.012| issn = 2405-4712| volume = 11| issue = 1| pages = 11–24.e4| last1 = Messner| first1 = Christoph B.| last2 = Demichev| first2 = Vadim| last3 = Wendisch| first3 = Daniel| last4 = Michalick| first4 = Laura| last5 = White| first5 = Matthew| last6 = Freiwald| first6 = Anja| last7 = Textoris-Taube| first7 = Kathrin| last8 = Vernardis| first8 = Spyros I.| last9 = Egger| first9 = Anna-Sophia| last10 = Kreidl| first10 = Marco| last11 = Ludwig| first11 = Daniela| last12 = Kilian| first12 = Christiane| last13 = Agostini| first13 = Federica| last14 = Zelezniak| first14 = Aleksej| last15 = Thibeault| first15 = Charlotte| last16 = Pfeiffer| first16 = Moritz| last17 = Hippenstiel| first17 = Stefan| last18 = Hocke| first18 = Andreas| last19 = Von Kalle| first19 = Christof| last20 = Campbell| first20 = Archie| last21 = Hayward| first21 = Caroline| last22 = Porteous| first22 = David J.| last23 = Marioni| first23 = Riccardo E.| last24 = Langenberg| first24 = Claudia| last25 = Lilley| first25 = Kathryn S.| last26 = Kuebler| first26 = Wolfgang M.| last27 = Mülleder| first27 = Michael| last28 = Drosten| first28 = Christian| last29 = Suttorp| first29 = Norbert| last30 = Witzenrath| first30 = Martin| last31 = Kurth| first31 = Florian| last32 = Sander| first32 = Leif Erik| last33 = Ralser| first33 = Markus| title = Ultra-High-Throughput Clinical Proteomics Reveals Classifiers of COVID-19 Infection| journal = Cell Systems| date = July 2020| pmid = 32619549| pmc = 7264033}}</ref><ref name="Asare-Werehene2022">{{Cite journal| doi = 10.3389/fimmu.2022.1011084| issn = 1664-3224| volume = 13| article-number = 1011084| last1 = Asare-Werehene| first1 = Meshach| last2 = McGuinty| first2 = Michaeline| last3 = Vranjkovic| first3 = Agatha| last4 = Galipeau| first4 = Yannick| last5 = Cowan| first5 = Juthaporn| last6 = Cameron| first6 = Bill| last7 = Cooper| first7 = Curtis L.| last8 = Langlois| first8 = Marc-André| last9 = Crawley| first9 = Angela M.| last10 = Tsang| first10 = Benjamin K.| title = Longitudinal profiles of plasma gelsolin, cytokines and antibody expression predict COVID-19 severity and hospitalization outcomes| journal = Frontiers in Immunology| date = 2022-09-06| doi-access = free| pmid = 36148234| pmc = 9489255}}</ref> pneumonia,<ref name="Self2019">{{Cite journal|last1=Self|first1=Wesley H|last2=Wunderink|first2=Richard G|last3=DiNubile|first3=Mark J|last4=Stossel|first4=Thomas P|last5=Levinson|first5=Susan L|last6=Williams|first6=Derek J|last7=Anderson|first7=Evan J|last8=Bramley|first8=Anna M|last9=Jain|first9=Seema|last10=Edwards|first10=Kathryn M|last11=Grijalva|first11=Carlos G|date=2019-09-13|title=Low Admission Plasma Gelsolin Concentrations Identify Community-acquired Pneumonia Patients at High Risk for Severe Outcomes|journal=Clinical Infectious Diseases|volume=69|issue=7|pages=1218–1225|doi=10.1093/cid/ciy1049|pmid=30561561|pmc=6743831|issn=1058-4838}}</ref> sepsis,<ref>{{Cite journal| doi = 10.1186/cc6988| issn = 1364-8535| volume = 12| issue = 4| pages = –106| last1 = Wang| first1 = HaiHong| last2 = Cheng| first2 = BaoLi| last3 = Chen| first3 = QiXing| last4 = Wu| first4 = ShuiJing| last5 = Lv| first5 = Chen| last6 = Xie| first6 = GuoHao| last7 = Jin| first7 = Yue| last8 = Fang| first8 = XiangMing| title = Time course of plasma gelsolin concentrations during severe sepsis in critically ill surgical patients| journal = Critical Care| date = 2008| pmid = 18706105| pmc = 2575595| doi-access = free}}</ref> SIRS,<ref>{{Cite journal| doi = 10.1016/j.clinbiochem.2016.10.018| issn = 0009-9120| volume = 50| issue = 3| pages = 127–133| last1 = Horváth-Szalai| first1 = Zoltán| last2 = Kustán| first2 = Péter| last3 = Mühl| first3 = Diána| last4 = Ludány| first4 = Andrea| last5 = Bugyi| first5 = Beáta| last6 = Kőszegi| first6 = Tamás| title = Antagonistic sepsis markers: Serum gelsolin and actin/gelsolin ratio| journal = Clinical Biochemistry| date = February 2017| pmid = 27823961}}</ref> traumatic brain injury,<ref>{{Cite journal| doi = 10.1016/j.jcrc.2012.01.002| issn = 0883-9441| volume = 27| issue = 5| pages = 527–1–527.e6| last1 = Jin| first1 = Yong| last2 = Li| first2 = Bo-You| last3 = Qiu| first3 = Ling-Li| last4 = Ling| first4 = Yuan-Ren| last5 = Bai| first5 = Zhi-Qiang| title = Decreased plasma gelsolin is associated with 1-year outcome in patients with traumatic brain injury| journal = Journal of Critical Care| access-date = 2020-03-04| date = 2012-10-01| pmid = 22386223| url = http://www.sciencedirect.com/science/article/pii/S0883944112000068| url-access = subscription}}</ref> autoimmune diseases,<ref>{{Cite journal| doi = 10.1177/0961203313507985| issn = 1477-0962| volume = 22| issue = 14| pages = 1455–1461| last1 = Hu| first1 = Yl| last2 = Li| first2 = H.| last3 = Li| first3 = W. H.| last4 = Meng| first4 = H. X.| last5 = Fan| first5 = Y. Z.| last6 = Li| first6 = W. J.| last7 = Ji| first7 = Y. T.| last8 = Zhao| first8 = H.| last9 = Zhang| first9 = L.| last10 = Jin| first10 = X. M.| last11 = Zhang| first11 = F. M.| title = The value of decreased plasma gelsolin levels in patients with systemic lupus erythematosus and rheumatoid arthritis in diagnosis and disease activity evaluation| journal = Lupus| date = December 2013| pmid = 24122723| s2cid = 22637925}}</ref> chronic kidney disease,<ref name="Lee2009" /><ref name="Lee2006"/> HIV-1 disease,<ref>{{Cite journal| doi = 10.1089/aid.2016.0154| issn = 0889-2229| volume = 33| issue = 3| pages = 254–260| last1 = Sinha| first1 = Kislay Kumar| last2 = Peddada| first2 = Nagesh| last3 = Jha| first3 = Pravin Kumar| last4 = Mishra| first4 = Anshul| last5 = Pandey| first5 = Krishna| last6 = Das| first6 = Vidya Nand Ravi| last7 = Ashish| last8 = Das| first8 = Pradeep| title = Plasma Gelsolin Level in HIV-1-Infected Patients: An Indicator of Disease Severity| journal = AIDS Research and Human Retroviruses| date = March 2017| pmid = 27700141}}</ref> tick-borne encephalitis and Lyme,<ref>{{Cite journal| doi = 10.1159/000324373| issn = 1660-2862| volume = 8| issue = 5| pages = 375–380| last1 = Kułakowska| first1 = Alina| last2 = Zajkowska| first2 = Joanna M.| last3 = Ciccarelli| first3 = Nicholas J.| last4 = Mroczko| first4 = Barbara| last5 = Drozdowski| first5 = Wiesław| last6 = Bucki| first6 = Robert| title = Depletion of Plasma Gelsolin in Patients with Tick-Borne Encephalitis and Lyme Neuroborreliosis| journal = Neurodegenerative Diseases| date = 2011| pmid = 21389683| pmc = 3121545}}</ref> malaria,<ref>{{Cite journal| doi = 10.1093/clinids/24.5.951| issn = 1058-4838| volume = 24| issue = 5| pages = 951–954| last1 = Huang| first1 = S.| last2 = Rhoads| first2 = S. L.| last3 = DiNubile| first3 = M. J.| title = Temporal association between serum gelsolin levels and clinical events in a patient with severe falciparum malaria| journal = Clinical Infectious Diseases| date = May 1997| pmid = 9142799| doi-access = }}</ref><ref>{{Cite journal| doi = 10.1371/journal.pone.0026495| issn = 1932-6203| volume = 6| issue = 10| last1 = Kassa| first1 = Fikregabrail Aberra| last2 = Shio| first2 = Marina Tiemi| last3 = Bellemare| first3 = Marie-Josée| last4 = Faye| first4 = Babacar| last5 = Ndao| first5 = Momar| last6 = Olivier| first6 = Martin| title = New Inflammation-Related Biomarkers during Malaria Infection| journal = PLOS ONE| date = 2011-10-20| article-number = e26495| pmid = 22028888| pmc = 3197653| bibcode = 2011PLoSO...626495K| doi-access = free}}</ref> hepatitis,<ref>{{Cite journal| doi = 10.1016/0016-5085(92)91731-i| issn = 0016-5085| volume = 102| issue = 5| pages = 1686–1692| last1 = Ito| first1 = H.| last2 = Kambe| first2 = H.| last3 = Kimura| first3 = Y.| last4 = Nakamura| first4 = H.| last5 = Hayashi| first5 = E.| last6 = Kishimoto| first6 = T.| last7 = Kishimoto| first7 = S.| last8 = Yamamoto| first8 = H.| title = Depression of plasma gelsolin level during acute liver injury| journal = Gastroenterology| date = May 1992| pmid = 1314752| doi-access = free}}</ref> burns,<ref name=Huang2011>{{Cite journal| doi = 10.1371/journal.pone.0025748| issn = 1932-6203| volume = 6| issue = 11| pages = –25748| last1 = Huang| first1 = Li-feng| last2 = Yao| first2 = Yong-ming| last3 = Li| first3 = Jin-feng| last4 = Dong| first4 = Ning| last5 = Liu| first5 = Chen| last6 = Yu| first6 = Yan| last7 = He| first7 = Li-xin| last8 = Sheng| first8 = Zhi-yong| title = Reduction of Plasma Gelsolin Levels Correlates with Development of Multiple Organ Dysfunction Syndrome and Fatal Outcome in Burn Patients| journal = PLOS ONE| date = 2011-11-01| pmid = 22069445| pmc = 3206022| bibcode = 2011PLoSO...625748H| doi-access = free}}</ref><ref>{{Cite journal| doi = 10.1016/j.burns.2014.02.020| issn = 1879-1409| volume = 40| issue = 8| pages = 1552–1555| last1 = Xianhui| first1 = Li| last2 = Pinglian| first2 = Li| last3 = Xiaojuan| first3 = Wang| last4 = Wei| first4 = Chen| last5 = Yong| first5 = Yang| last6 = Feng| first6 = Ran| last7 = Peng| first7 = Sun| last8 = Gang| first8 = Xue| title = The association between plasma gelsolin level and prognosis of burn patients| journal = Burns: Journal of the International Society for Burn Injuries| date = December 2014| pmid = 24690274}}</ref> multiple organ dysfunction syndrome,<ref name=Huang2011/> trauma associated with injury<ref>{{Cite journal| doi = 10.1164/ajrccm.160.5.9807137| issn = 1535-4970| volume = 160| issue = 5| pages = 1673–1681| last1 = Mounzer| first1 = Karam C.| last2 = Moncure| first2 = Michael| last3 = Smith| first3 = Yolanda R.| last4 = DiNUBILE| first4 = Mark J.| title = Relationship of Admission Plasma Gelsolin Levels to Clinical Outcomes in Patients after Major Trauma| journal = American Journal of Respiratory and Critical Care Medicine| date = November 1999| pmid = 10556139}}</ref> or surgery,<ref name="Lee2006">{{Cite journal| doi = 10.1097/01.sla.0000201798.77133.55| issn = 0003-4932| volume = 243| issue = 3| pages = 399–403| last1 = Lee| first1 = Po-Shun| last2 = Drager| first2 = Leslie R.| last3 = Stossel| first3 = Thomas P.| last4 = Moore| first4 = Francis D.| last5 = Rogers| first5 = Selwyn O.| title = Relationship of plasma gelsolin levels to outcomes in critically ill surgical patients| journal = Annals of Surgery| date = March 2006| pmid = 16495706| pmc = 1448930}}</ref> bone marrow transplantation,<ref>{{Cite journal| doi = 10.1182/blood-2002-06-1672| issn = 1528-0020| volume = 100| issue = 13| pages = 4367–4371| last1 = DiNubile| first1 = Mark J.| last2 = Stossel| first2 = Thomas P.| last3 = Ljunghusen| first3 = Olof C.| last4 = Ferrara| first4 = James L. M.| last5 = Antin| first5 = Joseph H.| title = Prognostic implications of declining plasma gelsolin levels after allogeneic stem cell transplantation| journal = Blood| access-date = 2020-02-12| date = 2002-12-15| pmid = 12393536| url = https://ashpublications.org/blood/article/100/13/4367/106047/Prognostic-implications-of-declining-plasma| doi-access = free}}</ref> and multiple sclerosis.<ref>{{Cite journal| doi = 10.1186/1471-2377-10-107| issn = 1471-2377| volume = 10| issue = 1| page = 107| last1 = Kułakowska| first1 = Alina| last2 = Ciccarelli| first2 = Nicholas J| last3 = Wen| first3 = Qi| last4 = Mroczko| first4 = Barbara| last5 = Drozdowski| first5 = Wiesław| last6 = Szmitkowski| first6 = Maciej| last7 = Janmey| first7 = Paul A| last8 = Bucki| first8 = Robert| title = Hypogelsolinemia, a disorder of the extracellular actin scavenger system, in patients with multiple sclerosis| journal = BMC Neurology| date = December 2010| pmid = 21040581| pmc = 2989318| doi-access = free}}</ref> Severely depleted levels (<150&nbsp;mg/L) strongly correlate with the onset of systemic inflammatory dysregulation and predict increased morbidity and mortality across a broad spectrum of clinical presentations in the critical care setting. The magnitude of decline in pGSN correlates with the likelihood of mortality in seriously ill patients.<ref name="Lee2009" /><ref name="Lee2006" /><ref name="Lee2008">{{Cite journal| doi = 10.1371/journal.pone.0003712| issn = 1932-6203| volume = 3| issue = 11| pages = –3712| last1 = Lee| first1 = Po-Shun| last2 = Patel| first2 = Sanjay R.| last3 = Christiani| first3 = David C.| last4 = Bajwa| first4 = Ednan| last5 = Stossel| first5 = Thomas P.| last6 = Waxman| first6 = Aaron B.| title = Plasma Gelsolin Depletion and Circulating Actin in Sepsis—A Pilot Study| journal = PLOS ONE| date = 2008-11-12| pmid = 19002257| pmc = 2577888| bibcode = 2008PLoSO...3.3712L| doi-access = free}}</ref>

Mediators of inflammation, the body's innate healing mechanism, accumulate at the site of the injury to begin the processes of defense and repair,<ref name=":0">{{Cite journal| doi = 10.1016/j.bbalip.2012.06.014| issn = 0006-3002| volume = 1831| issue = 1| pages = 86–92| last1 = Zhao| first1 = Yutong| last2 = Natarajan| first2 = Viswanathan| title = Lysophosphatidic acid (LPA) and its Receptors: Role in Airway Inflammation and Remodeling| journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids| date = January 2013| pmid = 22809994| pmc = 3491109}}</ref><ref name=":1">{{Cite journal| issn = 1550-6606| volume = 127| issue = 3| pages = 1250–1255| last1 = Shaw| first1 = J. O.| last2 = Pinckard| first2 = R. N.| last3 = Ferrigni| first3 = K. S.| last4 = McManus| first4 = L. M.| last5 = Hanahan| first5 = D. J.| title = Activation of human neutrophils with 1-O-hexadecyl/octadecyl-2-acetyl-sn-glycerol-3-phosphorylcholine (platelet activating factor).| journal = The Journal of Immunology| access-date = 2020-03-05| date = 1981-09-01| doi = 10.4049/jimmunol.127.3.1250| url = https://www.jimmunol.org/content/127/3/1250| pmid = 6267133| s2cid = 23647018| url-access = subscription}}</ref><ref name=":2">{{Cite journal| doi = 10.1007/s00281-011-0287-3| issn = 1863-2300| volume = 34| issue = 1| pages = 73–91| last1 = Obinata| first1 = Hideru| last2 = Hla| first2 = Timothy| title = Sphingosine 1-phosphate in coagulation and inflammation| journal = Seminars in Immunopathology| date = 2012-01-01| pmid = 21805322| pmc = 3237867}}</ref> and the depletion of local plasma gelsolin allows them to do their work.<ref name=":3">{{Cite journal| doi = 10.3390/ijms19092516| issn = 1422-0067| volume = 19| issue = 9| last1 = Piktel| first1 = Ewelina| last2 = Levental| first2 = Ilya| last3 = Durnaś| first3 = Bonita| last4 = Janmey| first4 = Paul A.| last5 = Bucki| first5 = Robert| title = Plasma Gelsolin: Indicator of Inflammation and Its Potential as a Diagnostic Tool and Therapeutic Target| journal = International Journal of Molecular Sciences| date = 2018-08-25| page = 2516| pmid = 30149613| pmc = 6164782| doi-access = free}}</ref> As a result of actin exposure at the local site of injury, the local level of plasma gelsolin around the site of the injury initially becomes depleted as it "debrides" the local involved site (see: Debridement). While local pGSN levels are depressed, the presence of this abundant protein in the circulation ensures that the inflammatory process stays local,<ref name=Peddada2012/> and that stores of plasma gelsolin are available to address further injury so that the overall immune response remains intact (see: Binding and inactivation of diverse inflammatory mediators).

Measured levels are higher in serum than plasma due to pGSN's affinity for fibrin.<ref name=Smith1987>{{Cite journal| issn = 0022-2143| volume = 110| issue = 2| pages = 189–195| last1 = Smith| first1 = D. B.| last2 = Janmey| first2 = P. A.| last3 = Herbert| first3 = T. J.| last4 = Lind| first4 = S. E.| title = Quantitative measurement of plasma gelsolin and its incorporation into fibrin clots| journal = The Journal of Laboratory and Clinical Medicine| date = August 1987| pmid = 3036979}}</ref>

===Animal studies===

Human plasma gelsolin has been produced in recombinant form in ''E. coli'' (rhu-pGSN), and its efficacy as a therapeutic has been studied ''in vivo'' in a number of animal models of inflammatory disease. In models of injury that cause actin release and inflammatory organ damage, pGSN levels consistently drop. In models where gelsolin levels are replenished, adverse outcomes can be prevented. To date, rhu-pGSN has been studied in many independent laboratories providing evidence of efficacy in >20 animal models. Following are descriptions of selected animal studies. All stated results are relative to those of placebo treatments.

{| class="wikitable" summary ="Table of summarized results from twelve animal models of disease. This table contains three columns: The first column lists the investigated disease (e.g. influenza); the second, the animal model used (e.g. mouse); and the third, the major results of the trial." |+ style="text-align: left;" | Summary of clinical results from selected animal studies |- ! Disease !! Model !! Results |- | influenza || mouse || Mice given a highly lethal form of influenza show increased survival at 12 day end of study point as well as decreased morbidity and decreased expression of pro-inflammatory genes when rhu-pGSN is administered 3 to 6 days after infection.<ref>{{Cite journal| doi = 10.12688/f1000research.21082.2| issn = 2046-1402| volume = 8| page = 1860| last1 = Yang| first1 = Zhiping| last2 = Bedugnis| first2 = Alice| last3 = Levinson| first3 = Susan| last4 = DiNubile| first4 = Mark| last5 = Stossel| first5 = Thomas| last6 = Lu| first6 = Quan| last7 = Kobzik| first7 = Lester| title = Delayed administration of recombinant plasma gelsolin improves survival in a murine model of severe influenza| journal = F1000Research| date = 2020-02-21| pmid = 31824672| pmc = 6894358| doi-access = free}}</ref> |- | pneumococcal pneumonia || mouse || Mice were given pneumococcal challenge 7 days after being given influenza. Supplementation of endogenous pGSN with rhu-pGSN improved bacterial clearance 15-fold, reduced neutrophilic inflammation, improved recovery of initial weight loss, and showed a dose-dependent improvement on survival. No antibiotics were given, demonstrating pGSN's ability to stimulate the innate immune response.<ref name="NOS3"/> |- | burn || rat || Rats receiving 40% body surface area burn showed 90% loss of endogenous pGSN within 12 hours and slowly recovered to almost 50% after 6 days. Intravenous administration of rhu-pGSN partially or totally prevented the burn-associated increase in pulmonary microvascular permeability in a dose-dependent manner.<ref>{{Cite journal| doi = 10.1152/japplphysiol.01074.2002| issn = 8750-7587| volume = 96| issue = 1| pages = 25–31| last1 = Rothenbach| first1 = Patricia A.| last2 = Dahl| first2 = Benny| last3 = Schwartz| first3 = Jason J.| last4 = O'Keefe| first4 = Grant E.| last5 = Yamamoto| first5 = Masaya| last6 = Lee| first6 = William M.| last7 = Horton| first7 = Jureta W.| last8 = Yin| first8 = Helen L.| last9 = Turnage| first9 = Richard H.| title = Recombinant plasma gelsolin infusion attenuates burn-induced pulmonary microvascular dysfunction| journal = Journal of Applied Physiology| date = January 2004| pmid = 12730154}}</ref> See also<ref>{{Cite journal| doi = 10.1186/1742-2094-8-118| issn = 1742-2094| volume = 8| issue = 1| page = 118| last1 = Zhang| first1 = Qing-Hong| last2 = Chen| first2 = Qi| last3 = Kang| first3 = Jia-Rui| last4 = Liu| first4 = Chen| last5 = Dong| first5 = Ning| last6 = Zhu| first6 = Xiao-Mei| last7 = Sheng| first7 = Zhi-Yong| last8 = Yao| first8 = Yong-Ming| title = Treatment with gelsolin reduces brain inflammation and apoptotic signaling in mice following thermal injury| journal = Journal of Neuroinflammation| date = 2011-09-21| pmid = 21936896| pmc = 3191361| doi-access = free}}</ref> |- | sepsis || mouse || Mice were intraperitoneally injected with endotoxin (LPS) or subjected to cecal ligation and puncture (CLP) (a small amount of intestinal contents were extracted into the cavity and the wound was sutured). Endogenous pGSN levels dropped to 50% post-challenge. Survival substantially improved with rhu-pGSN treatment in both groups: LPS study, 90% vs 0%; CLP study: 30% vs 0%.<ref name=MouseSepsis>{{Cite journal| doi = 10.1097/01.CCM.0000253815.26311.24| issn = 0090-3493| volume = 35| issue = 3| pages = 849–855| last1 = Lee| first1 = Po-Shun| last2 = Waxman| first2 = Aaron B.| last3 = Cotich| first3 = Kara L.| last4 = Chung| first4 = Su Wol| last5 = Perrella| first5 = Mark A.| last6 = Stossel| first6 = Thomas P.| title = Plasma gelsolin is a marker and therapeutic agent in animal sepsis*| journal = Critical Care Medicine| access-date = 2020-02-12| date = March 2007| pmid = 17205019| s2cid = 21641666| url = https://insights.ovid.com/crossref?an=00003246-200703000-00024| url-access = subscription}}</ref> |- | sepsis || rat || Relative to a previous mouse study<ref name=MouseSepsis/> a smaller dosage of rhu-pGSN decreased morbidity in a double CLP sepsis model relative to sham treatments. The dosage was effective in intraveneous and subcutaneous injections, but less so with intraperitoneal injection (qualitative but not statistically significant) despite the latter being the site of injury. This evidenced the need for systemic availability of pGSN for recovery.<ref>{{Cite journal| doi = 10.1016/j.cyto.2011.02.006| issn = 1043-4666| volume = 54| issue = 3| pages = 235–238| last1 = Cohen| first1 = Taylor S.| last2 = Bucki| first2 = Robert| last3 = Byfield| first3 = Fitzroy J.| last4 = Ciccarelli| first4 = Nicholas J.| last5 = Rosenberg| first5 = Brenna| last6 = DiNubile| first6 = Mark J.| last7 = Janmey| first7 = Paul A.| last8 = Margulies| first8 = Susan S.| title = Therapeutic potential of plasma gelsolin administration in a rat model of sepsis| journal = Cytokine| date = June 2011| pmid = 21420877| pmc = 3083472}}</ref> |- | Acute respiratory distress syndrome || mouse || Mice were subjected to 95% O₂ for 72 hr and treated with rhu-pGSN after 24 and 48 hr. Hyperoxia produced severe diffuse congestion and edema with hemorrhage visible in lung histopathology, 70% reduction in endogenous pGSN, and an influx of neutrophils. Treatment with rhu-pGSN led to a 23% decrease in the authors' histopathological score, 65% decrease in BAL fluid neutrophil count, and a 29% reduction in an overall acute lung injury score.<ref>{{Cite journal| doi = 10.2310/6650.2002.33518| issn = 1081-5589| volume = 50| issue = 1| pages = 54–60| last1 = Christofidou-Solomidou| first1 = Melpo| last2 = Scherpereel| first2 = Arnaud| last3 = Solomides| first3 = Charalambos C.| last4 = Christie| first4 = Jason D.| last5 = Stossel| first5 = Thomas P.| last6 = Goelz| first6 = Susan| last7 = DiNubile| first7 = Mark J.| title = Recombinant Plasma Gelsolin Diminishes the Acute Inflammatory Response to Hyperoxia in Mice| journal = Journal of Investigative Medicine| access-date = 2020-02-24| date = 2002-01-01| url = https://jim.bmj.com/content/50/1/54| pmid = 11813829| s2cid = 1981768| url-access = subscription}}</ref> |- | stroke || rat || Researchers induced middle cerebral artery occlusion with a direct injection of Endothelin 1, a vasoconstrictor. Animals treated with pGSN at the site of injury exhibited 50% infarction area, >2x use of both forepaws during exploration, and a decrease in whisker-stimulated reaction time (9 s, pGSN treated; 19 s untreated; 1 s healthy rat).<ref>{{Cite journal| doi = 10.1186/2040-7378-3-13| issn = 2040-7378| volume = 3| issue = 1| page = 13| last1 = Le| first1 = Huong T| last2 = Hirko| first2 = Aaron C| last3 = Thinschmidt| first3 = Jeffrey S| last4 = Grant| first4 = Maria| last5 = Li| first5 = Zhimin| last6 = Peris| first6 = Joanna| last7 = King| first7 = Michael A| last8 = Hughes| first8 = Jeffrey A| last9 = Song| first9 = Sihong| title = The protective effects of plasma gelsolin on stroke outcome in rats| journal = Experimental & Translational Stroke Medicine| date = 2011| pmid = 22047744| pmc = 3224589| doi-access = free}}</ref> |- | multiple sclerosis || mouse || Mice with experimental autoimmune encephalomyelitis show decreased levels of pGSN in blood and increased levels in the brain. All rhu-pGSN-treated mice survived whereas 60% of control died within 30 days. Rhu-pGSN mice scored significantly better on clinical scores, smaller brain lesions imaged by MRI, less extra-cellular actin, and decreased myeloperoxidase activity.<ref>{{Cite journal| doi = 10.1016/j.jneuroim.2015.08.006| issn = 0165-5728| volume = 287| pages = 36–42| last1 = Kevin Li-Chun| first1 = Hsieh| last2 = Schob| first2 = Stefan| last3 = Zeller| first3 = Matthias W.G.| last4 = Pulli| first4 = Benjamin| last5 = Ali| first5 = Muhammad| last6 = Wang| first6 = Cuihua| last7 = Chiou| first7 = Terry Ting-Yu| last8 = Tsang| first8 = Yuk-Ming| last9 = Lee| first9 = Po-Shun| last10 = Stossel| first10 = Thomas P.| last11 = Chen| first11 = John W.| title = Gelsolin decreases actin toxicity and inflammation in murine multiple sclerosis| journal = Journal of Neuroimmunology| date = October 2015| pmid = 26439960| pmc = 4595933}}</ref> |- | Alzheimer's || mouse || Two models of Alzheimer's were tested. Treatment mice that were tail-injected with a plasmid encoding human pGSN showed reduction in Aβ₄₂ in brain tissue, decreased amyloid, and increased concentration of microglia.<ref>{{Cite journal| doi = 10.1038/sj.mt.6300253| issn = 1525-0016| volume = 15| issue = 9| pages = 1623–1629| last1 = Hirko| first1 = Aaron C| last2 = Meyer| first2 = Edwin M| last3 = King| first3 = Michael A| last4 = Hughes| first4 = Jeffery A| title = Peripheral Transgene Expression of Plasma Gelsolin Reduces Amyloid in Transgenic Mouse Models of Alzheimer's Disease| journal = Molecular Therapy| date = September 2007| pmid = 17609655| doi-access = free}}</ref> See also<ref>{{Cite journal| issn = 1529-2401| volume = 23| issue = 1| pages = 29–33| last1 = Matsuoka| first1 = Yasuji| last2 = Saito| first2 = Mitsuo| last3 = LaFrancois| first3 = John| last4 = Saito| first4 = Mariko| last5 = Gaynor| first5 = Kate| last6 = Olm| first6 = Vicki| last7 = Wang| first7 = Lili| last8 = Casey| first8 = Evelyn| last9 = Lu| first9 = Yifan| last10 = Shiratori| first10 = Chiharu| last11 = Lemere| first11 = Cynthia| last12 = Duff| first12 = Karen| title = Novel therapeutic approach for the treatment of Alzheimer's disease by peripheral administration of agents with an affinity to beta-amyloid| journal = The Journal of Neuroscience| date = 2003-01-01| doi = 10.1523/JNEUROSCI.23-01-00029.2003| pmid = 12514198| pmc = 6742136}}</ref> |- | radiation || mouse || Mice irradiated with ¹³⁷Cs γ-rays show a 50-75% decrease in endogenous levels of pGSN. Bleeding is a common consequence of heavy radiation exposure. Administration of rhu-pGSN improved clotting indices in later, but not middle, phases of recovery. Rhu-pGSN improved GSH and MDA oxidative stress indices.<ref>{{Cite journal| doi = 10.1007/s12013-014-0210-3| issn = 1559-0283| volume = 71| issue = 1| pages = 389–396| last1 = Li| first1 = Mingjuan| last2 = Cui| first2 = Fengmei| last3 = Cheng| first3 = Ying| last4 = Han| first4 = Ling| last5 = Wang| first5 = Jia| last6 = Sun| first6 = Ding| last7 = Liu| first7 = Yu-long| last8 = Zhou| first8 = Ping-kun| last9 = Min| first9 = Rui| title = Gelsolin: role of a functional protein in mitigating radiation injury| journal = Cell Biochemistry and Biophysics| date = 2014-08-28| pmid = 25164111| s2cid = 942471| url=https://www.researchgate.net/publication/265135256| access-date = 2020-02-25}}</ref> |- | pain and inflammation || mouse || Intraperitoneal injection of acetic acid causes a pain response quantified by writhing.<ref>{{Cite journal| doi = 10.4103/0976-500X.103699| issn = 0976-500X| volume = 3| issue = 4| page = 348| last = Gawade| first = Shivaji P.| title = Acetic acid induced painful endogenous infliction in writhing test on mice| journal = Journal of Pharmacology & Pharmacotherapeutics| date = 2012| doi-broken-date = 12 July 2025| pmid = 23326113| pmc = 3543562| doi-access = free}}</ref> Both rhu-pGSN and diclofenac sodium (DS), a standard analgesic drug, caused ~55% reduction in writhing. Similarly, tails placed in hot water caused mice to retract them in an average time of 2.3 s. DS increased time to withdrawal from 5.1 to 7.6 s depending on time of drug administration; rhu-pGSN increased time from 2.9 to 5.5 s. Both DS and rhu-pGSN showed significant reductions in swelling associated with paw injection of an inflammatory agent, γ-carrageenan, as well as decreases in measured cytokines TNF-α and IL-6.<ref>{{Cite journal| doi = 10.1371/journal.pone.0135558| issn = 1932-6203| volume = 10| issue = 8| pages = –0135558| last1 = Gupta| first1 = Ashok Kumar| last2 = Parasar| first2 = Devraj| last3 = Sagar| first3 = Amin| last4 = Choudhary| first4 = Vikas| last5 = Chopra| first5 = Bhupinder Singh| last6 = Garg| first6 = Renu| last7 = Ashish| last8 = Khatri| first8 = Neeraj| others = Prasun K Datta (ed.)| title = Analgesic and Anti-Inflammatory Properties of Gelsolin in Acetic Acid Induced Writhing, Tail Immersion and Carrageenan Induced Paw Edema in Mice| journal = PLOS ONE| date = 2015-08-14| pmid = 26426535| pmc = 4537109| bibcode = 2015PLoSO..1035558G| doi-access = free}}</ref> |- | diabetes || mouse || Endogenous levels of pGSN decrease by ~50% with type 2 diabetes(T2D) in both humans and mice. In an oral glucose tolerance test, rhu-pGSN brought blood sugar levels down to levels comparable to sitagliptin, a T2D drug. Daily dose of rhu-pGSN kept blood sugar levels close to normal for the 7 days of treatment. Daily dose of sitagliptin increased levels of endogenous pGSN.<ref>{{Cite journal| doi = 10.1155/2014/152075| issn = 2314-6745| volume = 2014| article-number = 152075| last1 = Khatri| first1 = Neeraj| last2 = Sagar| first2 = Amin| last3 = Peddada| first3 = Nagesh| last4 = Choudhary| first4 = Vikas| last5 = Chopra| first5 = Bhupinder Singh| last6 = Garg| first6 = Veena| last7 = Garg| first7 = Renu| last8 = Ashish| title = Plasma Gelsolin Levels Decrease in Diabetic State and Increase upon Treatment with F-Actin Depolymerizing Versions of Gelsolin| journal = Journal of Diabetes Research| date = 2014| pmid = 25478578| pmc = 4247973| doi-access = free}}</ref> |}

===Human Studies=== In 2019 [https://bioaegistherapeutics.com/ BioAegis Therapeutics] conducted a Phase Ib/IIa safety study administering recombinant human pGSN to sick patients with community acquired pneumonia; no safety issues were found.<ref>{{cite journal |last1=BioAegis Therapeutics |title=A Phase 1b/2a Study of the Safety and Pharmacokinetics of Rhu-plasma Gelsolin in Hospitalized Subjects With CAP |url=https://clinicaltrials.gov/ct2/show/results/NCT03466073 |website=ClinicalTrials.gov |date=14 January 2020 |publisher=U.S. National Library of Medicine |access-date=24 February 2020}}</ref> A 2020 Phase IIb placebo-controlled efficacy study has been approved for acute severe pneumonia due to COVID-19. The primary outcome was the proportion of patients surviving on Day 14 without mechanical ventilation, vasopressors, or dialysis. Evaluation of efficacy of rhu-pGSN was confounded by high survival rates of both treatment and placebo cohorts resulting from improvements made to the standard of care for COVID pneumonia.<ref>{{cite web |last1=BioAegis Therapeutics |title=Rhu-pGSN for Severe Covid-19 Pneumonia |url=https://clinicaltrials.gov/ct2/show/NCT04358406 |website=ClinicalTrials.gov |publisher=U.S. National Library of Medicine |access-date=16 July 2020}}</ref> A 600 patient 2024 Phase II placebo-controlled ARDS efficacy study is underway.<ref>{{cite web |last1=BioAegis Therapeutics |title=Rhu-pGSN for Acute Respiratory Distress Syndrome (ARDS) |url=https://clinicaltrials.gov/study/NCT05947955|website=ClinicalTrials.gov |publisher=U.S. National Library of Medicine |access-date=20 May 2026}}</ref> The study is a collaboration between BioAegis Therapeutics and BARDA.

==See also== Cytoplasmic gelsolin

Actin

Vitamin D-binding protein

==References== {{Reflist}}

Category:Proteins