Prevention of Trauma/Hemorrhagic Shock‐Induced Lung Apoptosis by IL‐6‐Mediated Activation of Stat3

Abstract

Acute lung injury (ALI) occurs in up to 37% of patients following trauma/hemorrhagic shock (T/HS) and, in other settings, is due to alveolar epithelial cell (AEC) apoptosis. To determine if AEC apoptosis is a key contributor to ALI following T/HS and whether or not signal transducer and activator of translation (Stat)3 activation can prevent it, rats were pretreated with a Stat3 inhibitor or placebo and subjected to T/HS or sham protocol and resuscitated without or with interleukin (IL)-6. T/HS induced apoptosis in up to 15% of lung cells, 82% of which were AEC. Apoptosis increased with increasing duration of shock and required resuscitation. IL-6 treatment stimulated lung Stat3 activation and prevented AEC apoptosis. Pretreatment of rats with a Stat3 inhibitor blocked the antiapoptotic effect of IL-6. Mice deficient in Stat3β, a naturally occurring dominant negative isoform of Stat3, were resistant to T/HS-induced lung apoptosis. T/HS altered the expression of 87% of apoptosis-related genes. IL-6 treatment normalized expression of 75% of the genes altered by T/HS; Stat3 inhibition prevented normalization of 65% of the gene whose expression was normalized by IL-6. Thus, T/HS-induced AEC apoptosis, which depended on the duration of hypotension, required resuscitation and was prevented by IL-6-mediated activation of Stat3, which acted to normalize the apoptosis transcriptome.

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

“…Interleukin-6 activates cell signaling that leads to the phosphorylation of STAT3 (p-STAT) (4, 16). There is also a simultaneous up regulation of suppresser of cytokine signaling 3 (SOCS3) (26).…”

“…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.…”

Effect of Estrogen on Mitochondrial Function and Intracellular Stress Markers in Rat Liver and Kidney following Trauma-Hemorrhagic Shock and Prolonged Hypotension

“…T-H affects various organs (for example, liver, kidney, lung, heart), but most frequently the liver (1)(2)(3)(4). Recently it has been found that deleterious effects of T-H are influenced by sex hormones (5) and that estrogen (E2) improves immune and cardiovascular response parameters (6).…”