Estrogen Receptor Hormone Agonists Limit Trauma Hemorrhage Shock-Induced Gut and Lung Injury in Rats

Abstract

BackgroundAcute lung injury (ALI) and the development of the multiple organ dysfunction syndrome (MODS) is a major cause of death in trauma patients. Earlier studies in trauma hemorrhagic shock (T/HS) have documented that splanchnic ischemia leading to gut inflammation and loss of barrier function is an initial triggering event that leads to gut-induced ARDS and MODS. Since sex hormones have been shown to modulate the response to T/HS and proestrous (PE) females are more resistant to T/HS-induced gut and distant organ injury, the goal of our study was to determine the contribution of estrogen receptor (ER)α and ERβ in modulating the protective response of female rats to T/HS-induced gut and lung injury.Methods/Principal FindingsThe incidence of gut and lung injury was assessed in PE and ovariectomized (OVX) female rats subjected to T/HS or trauma sham shock (T/SS) as well as OVX rats that were administered estradiol (E2) or agonists for ERα or ERβ immediately prior to resuscitation. Marked gut and lung injury was observed in OVX rats subjected to T/HS as compared to PE rats or E2-treated OVX rats subjected to T/HS. Both ERα and ERβ agonists were equally effective in limiting T/HS-induced morphologic villous injury and bacterial translocation, whereas the ERβ agonist was more effective than the ERα agonist in limiting T/HS-induced lung injury as determined by histology, Evan's blue lung permeability, bronchoalevolar fluid/plasma protein ratio and myeloperoxidase levels. Similarly, treatment with either E2 or the ERβ agonist attenuated the induction of the intestinal iNOS response in OVX rats subjected to T/HS whereas the ERα agonist was only partially protective.Conclusions/SignificanceOur study demonstrates that estrogen attenuates T/HS-induced gut and lung injury and that its protective effects are mediated by the activation of ERα, ERβ or both receptors.

Estradiol receptors agonists induced effects in rat intestinal microcirculation during sepsis

“…The nitric oxide (NO) system, a central component in the autoregulatory control of microcirculatory patency, is severely disturbed in sepsis by a heterogeneous expression of iNOS, which associated with a concomitant decrease of endothelial nitric oxide synthase (eNOS) activity due to downregulation of eNOS isozymes or by functional inhibition of eNOS isozymes by the high concentrations of NO produced by iNOS in different areas of organ beds, resulting in pathological shunting of flow (Ince, 2005;Scott et al, 2002). The administration of E2 and DPN was shown to reduce the ileal levels of iNOS in rats with trauma-hemorrhage shock (Doucet al, 2010b). We suggest that the estradiol agonists could partially restore eNOS activity through reduction of iNOS activity and this could explain their effects on the observed FCD changes.…”

“…Female rats groups included the sham group, in which female rats received sham ovariectomy (OVX) 3 weeks before sham colon ascendens stent peritonitis (sham CASP) without further treatment (Sham OVX + Sham CASP). The remaining 3 groups were subjected to ovariectomy 3 weeks before CASP and were treated subcutaneous immediately after CASP by either estradiol receptor alpha (ER-α) agonist propylpyrazoletriol (PPT) (Sigma-Aldrich, Steinheim, Germany) 5 μg/kg dissolved in dimethylsulfoxide (DMSO) (SigmaAldrich, Steinheim, Germany) (OVX + CASP + PPT), the estradiol receptor beta (ER-β)agonist diarylpropionitrile (DPN) (Sigma-Aldrich, Steinheim, Germany) 5 μg/kg dissolved in DMSO (OVX + CASP + DPN), or DMSO placebo treatment (OVX + CASP + DMSO) (Doucet et al, 2010b). The male rats groups included the Sham group, in which male rats received sham CASP without further treatment (Sham CASP).…”

Sex-based differences in the genomic response, innate immunity, organ dysfunction, and clinical outcomes after severe blunt traumatic injury and hemorrhagic shock

“…(6-9) Results from varying animal models suggest that estrogen and testosterone influence the physiologic, immunologic and organ system responses to traumatic injury. (10, 11) While often attributed to differences in circulating sex hormone levels, our understanding of the underlying pathophysiology of gender-based differences in outcomes after severe injury remains incomplete. This is most exemplified in recent large, randomized controlled trials of sex hormone-based interventions after severe traumatic brain injury that, despite promising basic science and pre-clinical results, failed to show significant benefit in outcomes.…”

Intestinal Barrier Function and the Brain-Gut Axis

“…In this line, hemorrhagic shock has been associated with increased intestinal permeability and bacterial translocation [254] through mucus damage and the generation of free radical species [255]. Estrogens exert a protective role against hemorrhagic shockinduced gut and lung injury by the activation of estrogen receptor-α, β or both [256] receptors. Similarly, gut inflammation and loss of gut barrier function has been related to splachnic ischemia-reperfusion through HIF-1 activation [257].…”