Prevention of Hypovolemic Circulatory Collapse by IL-6 Activated Stat3

Abstract

Half of trauma deaths are attributable to hypovolemic circulatory collapse (HCC). We established a model of HCC in rats involving minor trauma plus severe hemorrhagic shock (HS). HCC in this model was accompanied by a 50% reduction in peak acceleration of aortic blood flow and cardiomyocyte apoptosis. HCC and apoptosis increased with increasing duration of hypotension. Apoptosis required resuscitation, which provided an opportunity to intervene therapeutically. Administration of IL-6 completely reversed HCC, prevented cardiac dysfunction and cardiomyocyte apoptosis, reduced mortality 5-fold and activated intracardiac signal transducer and activator of transcription (STAT) 3. Pre-treatment of rats with a selective inhibitor of Stat3, T40214, reduced the IL-6-mediated increase in cardiac Stat3 activity, blocked successful resuscitation by IL-6 and reversed IL-6-mediated protection from cardiac apoptosis. The hearts of mice deficient in the naturally occurring dominant negative isoform of Stat3, Stat3β, were completely resistant to HS-induced apoptosis. Microarray analysis of hearts focusing on apoptosis related genes revealed that expression of 29% of apoptosis related genes was altered in HS vs. sham rats. IL-6 treatment normalized the expression of these genes, while T40214 pretreatment prevented IL-6-mediated normalization. Thus, cardiac dysfunction, cardiomyocyte apoptosis and induction of apoptosis pathway genes are important components of HCC; IL-6 administration prevented HCC by blocking cardiomyocyte apoptosis and induction of apoptosis pathway genes via Stat3 and warrants further study as a resuscitation adjuvant for prevention of HCC and death in trauma patients.

Toll-like receptor-2 and interleukin-6 mediate cardiomyocyte protection from apoptosis during Trypanosoma cruzi murine infection

“…Strikingly, IL6 exerted potent antiapoptotic effects, affording complete protection of rat neonatal cardiomyocytes from sphingosine-induced death [2]. It has also been demonstrated that in vivo administration of IL6 completely reversed cardiac dysfunction and abrogated cardiomyocyte apoptosis in an experimental model of hypovolemic circulatory collapse [28]. These IL6 survival properties were mediated, at least in part, through activation of STAT3.…”

Delayed Neutralization of Interleukin 6 Reduces Organ Injury, Selectively Suppresses Inflammatory Mediator, and Partially Normalizes Immune Dysfunction Following Trauma and Hemorrhagic Shock

“…Studies have shown beneficial effects of IL-6 deficiency in experimental paradigms of thermal injury, sepsis, and trauma/hemorrhage (13, 14, 15). In contrast, other studies demonstrate that IL-6 administration prevents epithelial cell and cardiomyocyte apoptosis induced by trauma/hemorrhage (16, 17). Systemic infusion of IL-6 following hemorrhagic shock reduces inflammation and injury in the liver and lung (18).…”

Hyperthermia increases interleukin-6 in mouse skeletal muscle

“…We hypothesize that IL-6, which remains the most predominant myokine yet discovered, has a unique role to play. Recent evidence has shown that very low levels of IL-6 protect mammals from life-threatening conditions induced by severe hemorrhagic shock (3,45,47) and the fact that IL-6 knockout animals are more susceptible to heat stroke (41) provides theoretical support for this hypothesis.…”