Plasma gelsolin is a marker and therapeutic agent in animal sepsis*

Abstract

We propose that circulation of particulate actin is a marker for sepsis-induced cell injury, that plasma gelsolin has a crucial protective role in sepsis, and that gelsolin replacement represents a potential therapy for this common lethal condition.

Global Shapes of F-actin Depolymerization-competent Minimal Gelsolins

“…The therapeutic potential of G1-G3 and minimal gelsolin (residues 28 -161) was also evident by the fact that these F-actin depolymerization-competent fragments of gelsolin were capable of protecting septic mice from mortality as compared with the nondepolymerizing fragment G4-G6. Moreover, the LPS-binding fragment, G2-G6, was also incapable of protecting mice from mortality, suggesting that the depolymerizing activity of gelsolin is required for this protection instead of the LPS sequestration as has also been suggested earlier (23). These results demonstrate for the first time that depolymerization-competent truncated gelsolins can be used at lower doses (4-fold lesser amount in this study) for the gelsolin replacement therapy in critical illnesses.…”

“…Furthermore, the treatment of LPS-challenged mice with GSN and F-actin depolymerization-competent truncated gelsolins, G1-G3 and 28 -161, resulted in a significant decrease in IL-6 and IFN-␥ levels and a significant increase in IL-10 and TNF-␣ levels compared with the saline-treated mice shifting the immune response from the pro-inflammatory mode to antiinflammatory mode as reported earlier (23). IL-6 and IFN-␥ are among major proinflammatory cytokines, whereas IL-10 is an immune modulator cytokine that reduces the expression of other pro-inflammatory cytokines by the heme oxygenase-1-mediated pathway (49).…”

“…The effective dose of exogenous recombinant human gelsolin leading to the improvement in the animal survival in the LPS-induced sepsis mouse model was 8 mg, whereas it was 10 mg in the rat model of cecal ligation and double puncture-induced sepsis (23,25). Because a mouse with an average weight of 20 g and a rat with an average weight of 300 g would theoretically have about 0.32 and 4.8 mg of endogenous plasma gelsolin, respectively, earlier studies have used ϳ25ϫ and 2ϫ amounts of exogenous gelsolin per dose in the mouse and rat models, respectively.…”

“…In Vivo Activity of Minimal Gelsolin in Septic Mice-The current literature concludes that intraperitoneal administration of LPS induces sepsis in mice, and repletion with exogenous recombinant full-length gelsolin improves the survivability in the experimental animal models (23)(24)(25). The effective dose of exogenous recombinant human gelsolin leading to the improvement in the animal survival in the LPS-induced sepsis mouse model was 8 mg, whereas it was 10 mg in the rat model of cecal ligation and double puncture-induced sepsis (23,25).…”

“…At the time of admission of patients to an intensive care unit, the pGSN levels below the critical threshold have been associated with the adverse outcomes, although an improvement in the pGSN levels has been documented in the patients recovering from the illnesses. In addition, a repletion with the exogenous recombinant pGSN increases the survivability and counters the adverse outcomes in various rodent models (23)(24)(25) advocating a need for the "gelsolin replacement therapy." However, the optimum dosage of exogenous gelsolin found to be effective in mice (ϳ8 mg of protein per animal) is high, and the translation of this dosage to human body weight projects the need of a very large amount (ϳ28 g for 70 kg or 150 pounds of body mass) of recombinant protein per administration.…”