The female intestine is more resistant than the male intestine to gut injury and inflammation when subjected to conditions associated with shock states

Abstract

. The female intestine is more resistant than the male intestine to gut injury and inflammation when subjected to conditions associated with shock states. Am J Physiol Gastrointest Liver Physiol 288: G466 -G472, 2005. First published October 21, 2004; doi:10.1152/ajpgi.00036.2004.-Having documented that proestrus female rats are more resistant to shock-induced acute gut and hence lung injury than male rats, we tested the hypothesis that the female gut is more resistant to injury and produces less of an inflammatory response than the male gut when exposed to conditions associated with shock states (hypoxia and acidosis) utilizing the ex vivo Ussing chamber system. Ileal mucosal membranes harvested from normal male and female rats mounted in Ussing chamber systems were exposed to normoxia or 40 min of hypoxia at a normal pH (pH 7.3) or acidosis (pH 6.8). Cytokine and nitric oxide levels in the serosal compartment of the Ussing chamber were measured at the end of the 3-h experimental period to assess the immunoinflammatory response, whereas FITC-dextran (mol wt 4,300) was employed to assess barrier function. Histomorphological changes were used to quantitate gut mucosal injury. Hypoxia, acidosis, or hypoxia plus acidosis was associated with a significant increase in proinflammatory cytokine production [interleukin (IL)-6, tumor necrosis factor, and macrophage inflammatory protein (MIP)-2] by the male compared with the female intestinal segments. In contrast, the female gut manifested a higher anti-inflammatory response (nitric oxide and IL-10) and improved intestinal barrier function as well as less evidence of mucosal injury than the male intestinal segments. Administration of estradiol or the testosterone receptor antagonist, flutamide, to male rats abrogated the increase in gut injury and the increased IL-6 and MIP-2 response observed after hypoxia plus acidosis. These results suggest that gender differences in the ex vivo intestinal response to stresses, such as hypoxia and acidosis, exist and that the administration of estradiol or blockade of the testosterone receptor to male rats mitigates these gender differences.Ussing chamber; gender; ileal membrane; hypoxia/low pH; nitric oxide ALTHOUGH MULTIPLE ORGAN DYSFUNCTION syndrome (MODS) is the leading cause of death in intensive care units today (14), effective therapies have been slow to be developed, at least in part, because of an incomplete understanding of its basic biology (14). Consequently, studies directed at elucidating the pathophysiology of MODS have assumed major clinical importance. Over the years, we and others have focused on the role of gut ischemia/injury as a factor in the subsequent development of MODS (7, 13). Most recently, these studies have documented that, after trauma-hemorrhagic shock (T/ HS), the gut becomes a cytokine-generating organ (17) and that factors exiting the gut via the mesenteric lymphatics contribute to lung injury, endothelial cell dysfunction, and neutrophil activation (2, 14 -16, 19, 41). Although these studies illust...

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