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

Thymosin β4 (Tβ4), a highly conserved peptide with immunomodulatory properties, is the major actin-sequestering peptide in mammalian cells. Recent studies have established that Tβ4 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 Tβ4 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 F1α (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 Tβ4 in sepsis. We report that an LD50 dose of LPS (24 mg/kg) in rats resulted in a significant reduction of Tβ4 levels in the blood. Furthermore, administration of 100 μg of Tβ4 immediately following and at 2 and 4 h after an LD50 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 Tβ4. The rapid disappearance of Tβ4 in the blood following LPS administration or during septic shock suggests that Tβ4 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 Tβ4 may have utility in the clinic in the treatment of septic shock and in syndromes associated with actin toxicities.