[4] 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.

[15] 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.

[11] There is a single disulfide bond formed on the second domain of the plasma protein,[15] there are no documented natural post-translational modifications, and the pI ≈ 6.

It has been found in brain, testes, and lung oligodendrocytes, and is reportedly involved in myelin remodeling during spiralization around the axon.

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.

Plasma Gelsolin is a sticky protein known to bind to a number of peptides and proteins: Actin (see: Relationships with actin),[5][21][22] Apo-H,[23] Aβ,[24][25] α-Synuclein,[26] Integrin,[23] Tcp-1,[27] Fibronectin,[28] Syntaxin-4,[29] Tropomyosin,[30] fatty acids and phospholipids (see: Binding and inactivation of diverse inflammatory mediators): LPA,[31][32][33] LPS (endotoxin),[33][34][35]

[59] Although pGSN is capable of initiating the polymerization of actin through nucleation, its primary relationship with it in blood is depolymerization through filament severing.

It is found in complex with Aβ in plasma[25] and reported to both inhibit amyloid formation and defibrillize preformed fibrils in vitro.

[46][39][40] Mediators of inflammation, the body's innate healing mechanism, accumulate at the site of the injury to begin the processes of defense and repair,[78][79][80] and the depletion of local pGSN allows them to do their work.

[81] See Binding and inactivation of diverse inflammatory mediators 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.

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.

[4] Experimental and epidemiology data suggest that pGSN performs the role of a buffer or shield that modulates the inflammatory response to injury or infection.

Actin has been reported to activate platelets,[52] interfere with fibrinolysis,[59][87] damage endothelial cells,[88] and to function as a danger signal (DAMP).

[36] 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.

[76] Improved phagocytosis is the product of pGSN debriding actin bound to macrophage scavenger receptors preventing their function.

[32][36] Binding to inflammatory mediators, and in some cases inhibition of their effector function, has been shown for platelet-activating factor,[36] lipopolysaccharide endotoxin,[34] sphingosine-1-phosphate,[35] and lipoteichoic acid[37] and small molecule purinergic agonists including ATP and ADP.

[95] Recombinant pGSN (rhu-pGSN) supplementation alone shows improved survival and decreased bacteria counts in several mouse models.

[96] Plasma gelsolin is produced and secreted by virtually every cell type with muscle contributing the largest amount.

[116] Severely depleted levels (<150 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.

[53][106][117] Mediators of inflammation, the body's innate healing mechanism, accumulate at the site of the injury to begin the processes of defense and repair,[78][79][80] and the depletion of local plasma gelsolin allows them to do their work.

While local pGSN levels are depressed, the presence of this abundant protein in the circulation ensures that the inflammatory process stays local,[100] 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).

[99] 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.

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.