Estrogen receptor hormone agonists limit trauma hemorrhage shock-induced gut and lung injury in rats.

Danielle Doucet,Iriana Colorado,Chirag Badami,David Palange,Da-Zhong Xu,Rena Feinman,R Paul Bonitz,Kolenkode B Kannan,Qi Lu,Edwin A Deitch,Paul A Bartell

doi:10.1371/journal.pone.0009421

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.

Highlights

Trauma is the leading cause of death in people under the age of 40 and development of the multiple organ dysfunction syndrome (MODS) is a leading cause of death in trauma patients surviving the initial 72 hour injury period as well as in other intensive care unit patient populations [1]
In previous work, utilizing male rats, non-human primates and mini-pigs, we found that trauma hemorrhagic shock (T/HS)-induced acute lung injury, as well as neutrophil activation, RBC dysfunction, bone marrow suppression and endothelial cell injury and dysfunction were related to gut injury and the release of gut-derived factors into the mesenteric lymphatics rather than the portal vein [6,7,8]
While all of the T/HS groups did show some morphologic evidence of gut injury when compared to their trauma sham shock (T/SS) counterparts (Figure 1A), only the OVX T/HS group demonstrated bacterial translocation to the mesenteric lymph node (MLN) complex (2.76103 and 2.56103 bacteria/gram of tissue aerobic and enteric respectively) (Figure 1B)

Summary

Introduction

Trauma is the leading cause of death in people under the age of 40 and development of the multiple organ dysfunction syndrome (MODS) is a leading cause of death in trauma patients surviving the initial 72 hour injury period as well as in other intensive care unit patient populations [1]. Understanding the mechanisms by which trauma-hemorrhagic shock (T/HS) leads to MODS, as well as the role of sex hormones in modulating this response, is of major potential health importance. We found that sex hormone-related gut protection was associated with abrogation of T/HS-induced lung injury [12], neutrophil activation [11], RBC dysfunction [13] and bone marrow suppression [14,15]. 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)a and ERb in modulating the protective response of female rats to T/HS-induced gut and lung injury

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Conclusion