Thymosin β4 reduces lethality and down-regulates inflammatory mediators in endotoxin-induced septic shock

Abstract Thymosin β 4 (Tβ 4 ), a highly conserved peptide with immunomodulatory properties, is the major actin-sequestering peptide in mammalian cells. Recent studies have established that Tβ 4 can accelerate wound healing in full thickness skin wounds and following burn injuries to the cornea. In the eye studies, the accelerated healing due to Tβ 4 was accompanied by a significant reduction in polymorphonuclear leukocyte (PMN) infiltration and a several-fold decrease in interleukin-1β ( p ≤0.015) and 6-keto-prostaglandin F 1α (6-keto-PGF1α, p ≤0.05). Given the recognized role of proinflammatory cytokines in septic shock and of extracellular F- and G-actin in the pathophysiology of multiple organ dysfunction, we have investigated the role of Tβ 4 in sepsis. We report that an LD 50 dose of LPS (24 mg/kg) in rats resulted in a significant reduction of Tβ 4 levels in the blood. Furthermore, administration of 100 μg of Tβ 4 immediately following and at 2 and 4 h after an LD 50 dose of LPS (60 mg/kg) in mice significantly reduced mortality rates ( p ≤0.024) and lowered blood levels of a number of inflammatory cytokines, eicosanoids, and other molecules that are highly elevated following endotoxin administration. In studies in human subjects given low doses of endotoxin (4 ng/kg LPS) and in patients with septic shock, we have also observed significant decreases in blood levels of Tβ 4 . The rapid disappearance of Tβ 4 in the blood following LPS administration or during septic shock suggests that Tβ 4 may be involved in early events leading to activation of the inflammatory cascade and ultimately the clinical sequelae of sepsis. The results of this study indicate that Tβ 4 may have utility in the clinic in the treatment of septic shock and in syndromes associated with actin toxicities.