IL-6-Mediated Activation of Stat3α Prevents Trauma/Hemorrhagic Shock-Induced Liver Inflammation

Abstract

Trauma complicated by hemorrhagic shock (T/HS) is the leading cause of morbidity and mortality in the United States for individuals under the age of 44 years. Initial survivors are susceptible to developing multiple organ failure (MOF), which is thought to be caused, at least in part, by excessive or maladaptive activation of inflammatory pathways. We previously demonstrated in rodents that T/HS results in liver injury that can be prevented by IL-6 administration at the start of resuscitation; however, the contribution of the severity of HS to the extent of liver injury, whether or not resuscitation is required, and the mechanism(s) for the IL-6 protective effect have not been reported. In the experiments described here, we demonstrated that the extent of liver inflammation induced by T/HS depends on the duration of hypotension and requires resuscitation. We established that IL-6 administration at the start of resuscitation is capable of completely reversing liver inflammation and is associated with increased Stat3 activation. Global assessment of the livers showed that the main effect of IL-6 was to normalize the T/HS-induced inflammation transcriptome. Pharmacological inhibition of Stat3 activity within the liver blocked the ability of IL-6 to prevent liver inflammation and to normalize the T/HS-induced liver inflammation transcriptome. Genetic deletion of a Stat3β, a naturally occurring, dominant-negative isoform of the Stat3, attenuated T/HS-induced liver inflammation, confirming a role for Stat3, especially Stat3α, in preventing T/HS-mediated liver inflammation. Thus, T/HS-induced liver inflammation depends on the duration of hypotension and requires resuscitation; IL-6 administration at the start of resuscitation reverses T/HS-induced liver inflammation, through activation of Stat3α, which normalized the T/HS-induced liver inflammation transcriptome.

Modulation of the Unfolded Protein Response During Hepatocyte and Cardiomyocyte Apoptosis In Trauma/Hemorrhagic Shock

“…Rats were subjected to the sham or T/HS protocols, as described3623 with modifications. Blood was withdrawn into a heparinized syringe to achieve and then maintain the target MAP at 35 mmHg until blood pressure compensation failed.…”

“…The amount of shed blood returned (SBR) defined shock severity as reflected in the duration of hypotension, and the animals used in this analysis received 50% SBR (SBR50; duration of hypotension, 273 ± 24.9 minutes). At the end of the hypotensive period, rats were resuscitated as described3623 and humanely sacrificed 60 minutes after the start of resuscitation in order to capture the first wave of transcriptional changes. Where indicated, rats received 10 μg/kg of recombinant human IL-6 in 0.1 ml PBS at the initiation of the resuscitation or PBS alone.…”

Restoration of lung surfactant protein D by IL-6 protects against secondary pneumonia following hemorrhagic shock

“…Within the first category is the use of IL-6 as a resuscitation adjuvant. We have established that IL-6 as a resuscitation adjuvant is of clear benefit in preventing organ apoptosis and inflammation in rat and porcine models of T/HS, 12–15,41 as well as in reducing the severity of illness in pre-clinical models of bloodstream infections. 20 In addition to potentially preventing AECII apoptosis and pneumonia susceptibility in T/HS patients, this intervention also may prevent heart and liver dysfunction in T/HS by preventing apoptosis of cardiomyocytes 12 and hepatocytes.…”

“…12–15 Samples were then centrifuged 15 min at 5000 RPM and the supernatant collected and evaluated by Bradford assay for total protein quantification.…”

“…Using a rat model of T/HS, 12–15 we previously demonstrated that up to 15% of AECII undergo apoptosis in the acute post-resuscitative phase, and that AECII injury/apoptosis can be prevented when IL-6 is used as a resuscitative adjuvant through a Stat3-mediated mechanism. 14 In this report, we investigated the hypothesis that AECII injury/apoptosis contributes to pneumonia susceptibility in T/HS and that this contribution is mediated, in part, through reductions in SP-D levels.…”