The female intestine is more resistant than the male intestine to gut injury and inflammation when subjected to conditions associated with shock states
Hiroshi Homma,
Erik Hoy,
Da-Zhong Xu,
Qi Lu,
Rena Feinman, and
Edwin A. Deitch
Department of Surgery, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey
Submitted 22 January 2004
; accepted in final form 15 October 2004
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ABSTRACT
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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, 1416, 19, 41). Although these studies illustrate the concept that the gut plays a role in the pathogenesis of T/HS-induced lung injury, they were conducted with male rats exclusively. Based on recent studies documenting that proestrus rats are relatively resistant to T/HS-induced immune depression (4), we tested whether female rats were more resistant to T/HS-induced acute lung injury than male rats. In this study (1), T/HS caused gut and lung injury in the male but not the female rats, and the mesenteric lymph from the male but not the female rats subjected to T/HS caused endothelial cell injury. From these results, we concluded that the resistance of female rats to hemorrhagic shock-induced lung injury appears to be secondary to their resistance to shock-induced gut injury. Although the reasons why the female gut is more resistant to T/HS-induced intestinal injury than the male remains to be fully determined, there are several possible explanations. One possibility is that intestinal microcirculatory blood flow is better preserved in females than males during low-flow states, such as hemorrhagic shock. Another possibility is that the female gut is more resistant to intestinal injury than the male gut when exposed to similar levels of intestinal ischemia. Last, the inflammatory response of the intestine to low-flow states and/or ischemia may be less in female than male rats, thereby potentially limiting the extent of gut injury. Consequently, the aim of this study was to test the hypothesis that the intestine of proestrus female rats 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). The rationale for testing the intestinal segments at an acidotic and a normal pH is based on clinical studies indicating that, during periods of shock or decreased splanchnic perfusion, the pH of the gut is acidic (22) and animal models showing that loss of intestinal barrier function is greater when the extracellular intestinal pH is acidic (36).
Because of the inherent complexities of performing these types of studies in vivo, we have utilized the ex vivo Ussing chamber model system. In this system, intestinal segments harvested from male or female rats can be exposed to shock-like conditions (hypoxia and reoxygenation with or without acidosis) without the confounding variables associated with in vivo studies (18). Thus, using this model system, we compared the effects of hypoxia/reoxoygenation and acidosis on intestinal injury and barrier function and the intestinal production of tumor necrosis factor (TNF)-
, interleukin (IL)-6, IL-10, macrophage inflammatory protein (MIP)-2, and nitric oxide (NO) using intestinal segments harvested from male or proestrus female rats. We measured IL-6, TNF-
, and MIP-2, since proinflammatory cytokines and chemokines are elevated in trauma patients and in animal models of shock, injury, and inflammation and have been implicated in the pathogenesis of MODS (14, 20, 26). Likewise, because there is substantial evidence indicating that bioactive NO production plays a complex but important role in gut injury with modest increases in NO being protective and larger increases being deleterious (37), we also measured NO production and the anti-inflammatory cytokine IL-10.
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MATERIALS AND METHODS
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Animals.
Specific pathogen-free Sprague-Dawley rats (weight: male, 315385 g, female: 275350 g) were used. Animals were housed for at least 1 wk before use and were maintained according to the recommendations of the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The rats were fed standard laboratory chow (Diet 5001; Ralston Purina, St. Louis, MO) and water ad libitum. The experiments were approved by the New Jersey Medical School Animal Care and Use Committee.
Experimental design and Ussing chamber system.
Ileal mucosal membranes were harvested from normal male and proestrus female rats (estrus stage verified by vaginal smears) and were mounted in Ussing chambers as previously described (18). Briefly, once the rats were anesthetized with pentobarbital sodium (50 mg/kg) given intraperitoneally, the viscera was exposed, and 2-cm Peyers patch-free segments of the distal ileum were harvested. The ileal segments were opened along the mesenteric border and washed in cold medium to remove the luminal contents, after which the serosa and the external longitudinal muscle layers were removed by blunt dissection. The ileal mucosal membranes then were mounted between the two halves of the Ussing chamber (1.12 cm2 opening). Two calomel voltage-sensitive electrodes and two Ag-AgCl current-passing electrodes (World Precision Instrument, Sarasota, FL) were connected to the Ussing chamber via agar bridges. Both the mucosal and serosal sides of the chamber were connected to circulating reservoirs containing DMEM, supplemented with 20 mM L-glutamine (Sigma). Ports were present in each of the reservoirs for sample collection and the addition of reagents. The temperature of the reservoirs was maintained at 37°C by a jacketed circulating water bath. The fluid within the reservoirs was oxygenated and driven by a gas lift column of 95% O2-5% CO2. The time required to harvest the ileal segments and prepare and mount them in the Ussing chambers averaged 34 min and never exceeded 5 min. Thus the "ischemic" insult associated with the procedure was limited and was similar between the male and female rats.
The membranes were allowed to stabilize for 15 min. After this 15-min stabilization period, the transepithelial electrical potential difference (PD) and the transmembrane resistance (R) were measured. PD in millivolts across the mucosal membrane was measured directly. R in Ohms per square centimeter was determined using Ohms law by passing a 50-µA current through the membrane and measuring the change in PD. The PD is indicative of tissue viability, whereas R is considered to reflect membrane integrity.
After baseline PD and R were measured, fluorescein isothiocyanate (FITC)-dextran with a molecular weight of 4,300 (Sigma) was added as a permeability probe to the medium on the mucosal side of the Ussing chamber to achieve a final concentration of 0.01 mM.
The membranes were then randomly assigned to one of four groups. In group 1, the membranes were maintained at normoxic condition (95% O2-5% CO2) with a normal pH (pH 7.3). These conditions were chosen to mimic normoxia. Because the only oxygen available to the intestinal segment is dissolved in the medium, a higher concentration (95%) of oxygen than normal is needed to maintain adequate tissue oxygenation. Group 2 consisted of ileal membranes exposed to normoxia with a low pH (pH 6.8). The intestinal segments in group 3 were exposed to hypoxia (40 min at 95% N2-5% CO2) at a normal pH and then reoxygenated, whereas group 4 was subjected to the same hypoxia-reoxygenation insult plus acidosis (pH 6.8). The pH of the media was checked several times during the 180-min experiment, and hydrochloric acid was added as needed to maintain a pH of 6.8 in the acidosis group.
Measurements of PD and R were taken at the following times: 0, 40, 120, and 180 min. Samples were collected from the serosal compartment at the end of the 180-min experiment. TNF-
, IL-6, MIP-2, and FITC-dextran concentrations and NO levels were measured in these samples. In addition, the mucosal membranes were harvested for morphological analysis at the end of the 180-min experimental period.
In a second set of experiments, the ability of estradiol or testosterone receptor blockade to abrogate the response to hypoxia plus acidosis was tested in male rats. In this experiment, male rats received either estradiol (1 mg/kg iv over 5 min; see Ref. 31), the testosterone receptor blocker flutamide (25 mg/kg sc; see Ref. 34), or vehicle (saline). Later (1 h), the rats were killed, and their ileal mucosal membranes were harvested and mounted in the Ussing chamber.
Assays.
FITC-dextran (mol wt 4,300) was used to evaluate the permeability of the intestinal segments as follows. Samples of the medium from the serosal compartments were collected at the end of the 180-min experimental period and placed in a 96-well plate. FITC-dextran concentrations were determined by fluorescein detection (FL-500 Microplate Fluorescence Reader; BIO-TEK, Winooski, VT) at an excitation wavelength of 485 nm and an emission wavelength of 530 nm.
IL-6, IL-10, TNF-
, and MIP-2 levels in medium from the serosal chambers were measured using ELISA kits specific for rat IL-6, IL-10, TNF-
, and MIP-2 (Biosource, Camarillo, CA).
NO production was assessed by measuring total nitrite and nitrate levels in 100-µl samples collected from the serosal compartment using the nitrate reductase and Greiss reagent, as previously described (30). The samples were read at 543 nm with a spectrophotometer. Sodium nitrite (Sigma) was used as the standard.
Ileal mucosal membrane histology.
At the end of the 180-min experimental period, the ileal mucosal membranes mounted in the Ussing chamber were harvested and fixed in 10% buffered formalin. The tissue was then dehydrated and embedded in paraffin, as previously described (42). Briefly, in a blinded fashion, the incidence of villous damage was assessed in five random fields (magnification x200). Villi were considered injured if there was evidence of villus edema, lifting of the epithelium of the basement membrane, or ulceration. The degree of villous damage was then expressed as the incidence of villus injury (i.e., no. of injured villi divided by the total number of villi counted).
Statistical analysis.
All results are expressed as means ± SD. Continuous data (cytokines, NO, FITC-dextran concentration, PD, and R) were analyzed by two-way ANOVA with Tukey-Kramer multiple-comparisons test. The Students t-test was used to compare males and females in the same conditions. Statistical significance was considered to be reached at P
0.05.
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RESULTS
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In both the proestrus female and the male rats, the resistance values (Table 1) of the ileal membranes of all the groups decreased in a similar fashion over time, a response that is consistent with the literature (18). The resistance values of the membranes exposed to hypoxia were significantly lower at the end of the 40-min hypoxic period than the normoxic membranes at this time point. This response was true for both genders, although the resistance was decreased to a greater degree in the male than the female ileal membranes of the normoxia-acidosis group at the end of the 40-min hypoxic period (Table 1). The PD of male and female ileal membranes, even under normoxic conditions, had decreased after 40 min in the Ussing chamber (Fig. 1A). However, the PD of the female ileal membranes remained stable, whereas the PD of the male ilea continued to significantly (P < 0.05) decrease over the 180-min experimental period. Thus, at 40, 120, and 180 min, the PD of the female ileal membranes incubated under normoxic conditions was significantly higher than the male membranes (Fig. 1A). Similar trends were observed in the ileal membranes exposed to normoxia plus acidosis (Fig. 1B). Thus the PD was better preserved in the female than the male groups.

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Fig. 1. The potential difference (PD) of each group of male and female ileal membranes decreased over time (P < 0.01, baseline vs. 40, 120, and 180 min). At the end of the hypoxic period, the PD was decreased in ileal membranes incubated at normal (A) or acidic (B) pH and did not return to levels observed in the normoxic groups (P < 0.01 at 40, 120, and 180 min vs. same time point and gender). The PD was better preserved in the male normoxia (A) and male normoxia pH 6.8 (B) than in the comparable female groups (*P < 0.01). The PD of the male ileal membranes exposed to hypoxia pH 6.8 (B) had recovered to a greater extent than the female membranes at 120 and 180 min (ÜP < 0.01). Data are expressed as means ± SD, with n = 6 rats/group.
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Compared with the normoxic groups, ileal membranes exposed to a 40-min hypoxic insult manifested a lower PD that persisted throughout the 180-min experimental period (Fig. 1, A and B). In both the male and female hypoxia pH 7.3, as well as in the female hypoxia plus acidosis groups, the PD of the ileal membranes partially recovered after the 40-min hypoxia period but never reached the levels observed in the normoxia groups. However, at the end of the 40-min hypoxic period and at 120 and 180 min, the PD of the female ileal membranes subjected to hypoxia plus acidosis was higher than the comparable male membranes.
Hypoxia combined with acidosis increased the mucosal permeability of both the male and female intestinal segments, with the male intestinal segments being increased to a greater extent than the female ileal membranes (Fig. 2). Additionally, the permeability of the intestinal membranes to the dextran permeability probe appeared to be greater in the male than the female rats under nonstressed conditions (normoxia) and during normoxia or hypoxia plus acidosis (Fig. 2). However, after a pure hypoxic insult, this gender difference was lost (Fig. 2). Morphologically, the male, but not the proestrus female, intestinal segments subjected to hypoxia or acidosis or the two combined developed evidence of mucosal injury (Fig. 3). Although the incidence of villus injury was higher in the male rats, the magnitude of villus injury, when it occurred, was similar between the male and female rats (Fig. 4).

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Fig. 2. Ileal mucosal permeability to fluorescein isothiocyanate (FITC)-dextran. Data are expressed as means ± SD, with n = 6 rats/group.*P < 0.05 vs. comparable female group. **P < 0.05 vs. all other male and female groups. #P < 0.05 vs. normoxia and pH 7.3 female group.
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Fig. 3. Percentage of ileal villi with evidence of mucosal injury. Data are expressed as means ± SD, with n = 4 rats/group. *P < 0.05 vs. comparable female group and P < 0.01 vs. normoxic pH 7.3 male or female groups.
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Fig. 4. Representative micrographs of proestrus female (A) and male (B) intestinal segments after 180 min of normoxia at pH 7.3 showing normal morphology. After exposure to hypoxia plus acidosis, the female intestinal segment (C) appears relatively unchanged, whereas the male intestinal segment (D) shows evidence of villous edema and epithelial denudation (arrows). Magnification is x200.
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Gender differences in the proinflammatory cytokine response to hypoxia and/or acidosis were observed with an increase in IL-6 production by the ileal membranes from the males but not the females (Fig. 5). A similar trend was observed for TNF-
and MIP-2, where the levels in the serosal chambers of the male intestinal segments were higher than the females, although these differences only reached statistical significance in the hypoxia plus acidosis groups (Figs. 6 and 7). In contrast to proinflammatory cytokine and chemokine production, IL-10 levels were higher in the serosal chambers of the female than the male rats under all conditions (Fig. 8). NO production was also higher in female intestinal segments under normoxic conditions and under conditions of normoxia plus acidosis or hypoxia plus acidosis, but not hypoxia alone (Fig. 9).

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Fig. 5. Interleukin (IL)-6 concentrations in serosal fluid samples at 180 min after exposure to normoxia or hypoxia with or without acidosis. Data are expressed as means ± SD, with n = 6 rats/group. *P < 0.05 vs. comparable female group. #P < 0.05 vs. normoxia pH 7.3 male or female groups.
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Fig. 6. Tumor necrosis factor (TNF)- concentrations in serosal fluid samples at 180 min after exposure to normoxia or hypoxia with or without acidosis. Data are expressed as means ± SD, with n = 6 rats/group. *P < 0.05 vs. male or female normoxia pH 7.3 groups.
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Fig. 7. Macrophage inflammatory protein (MIP)-2 concentrations in serosal fluid samples at 180 min after exposure to normoxia or hypoxia with or without acidosis. Data are expressed as means ± SD, with n = 6 rats/group. *P < 0.05 vs. male and female normoxia pH 7.3 groups.
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Fig. 8. IL-10 concentrations in serosal fluid samples at 180 min after exposure to normoxia or hypoxia with or without acidosis. Data are expressed as means ± SD, with n = 6 rats/group. *P < 0.01 vs. comparable female groups. #P < 0.01 vs. all other groups.
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Fig. 9. Nitric oxide concentrations in serosal fluid samples at 180 min after exposure to normoxia or hypoxia with or without acidosis. Data are expressed as means ± SD, with n = 6 rats/group. *P < 0.05 vs. comparable male group.
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Next, to further evaluate the hypothesis that the differences between the male and female intestinal response to hypoxia plus acidosis was related to sex hormones, we tested whether the administration of estradiol and/or the blockade of testosterone, utilizing the testosterone receptor antagonist flutamide, would limit gut injury and reduce the proinflammatory response in male rats. Consistent with the earlier results, intestinal permeability and gut injury were increased in the male rat intestinal segments exposed to hypoxic and acidotic conditions (Table 2). However, the administration of estradiol or flutamide largely abrogated these changes. Likewise, the increased proinflammatory response (IL-6 and MIP-2) observed when the male rat intestinal segments were subjected to hypoxia and acidosis was prevented by estradiol and flutamide pretreatment (Table 3). Last, estradiol and flutamide pretreatment increased the IL-10 response of the male intestinal segments exposed to hypoxia and acidosis (Table 3).
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Table 3. Estradiol and flutamide modulate cytokine and chemokine production after exposure of ileal segments to hypoxia plus acidosis
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DISCUSSION
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Based on our recent work in male rats, it appears that, after an episode of splanchnic ischemia, gut-derived factors are critical for the development of shock-induced distant organ and cellular dysfunction (2, 6, 16, 27, 41, 43). However, some human (8, 23, 32, 37) and animal (4, 5) studies suggest that females may tolerate sepsis and shock better than males, and recent animal work suggests that the reduction in shock-induced acute lung injury is the result of the relative resistance of the female rat to T/HS-induced gut injury (1, 9). Although there is some evidence that female rats have an improved hemodynamic response after trauma (3) and that the administration of estradiol during the resuscitative phase of hemorrhagic shock improves intestinal perfusion (24), the mechanisms by which the female gut is more resistant to T/HS-induced injury than the male gut remain to be elucidated.
One possible explanation for why the female gut is more resistant to T/HS-induced injury is that the female gut tolerates an ischemic episode better than the male gut. Thus the goal of the current study was to test the hypothesis that female rats have less shock-induced acute injury than male rats because their guts are more resistant to injury and their proinflammatory response is blunted. Because of the potential confounding effects of differences in vasomotor tone and the immunoinflammatory responses observed in vivo when male and proestrus female rats are subjected to T/HS (35, 24), we used the ex vivo Ussing chamber model system to test this hypothesis. In the Ussing chamber system, these confounding variables are avoided, and it is possible to ensure that the hypoxic insult to which the male and female guts are exposed is identical. Because in vivo (35) and in vitro (40) studies indicate that at an acidotic pH the response of the gut to an insult is magnified and clinical studies document that intestinal acidosis is common during periods of hemorrhage or hypotension (22), to more accurately model the in vivo effects of gut ischemia in the Ussing system, we added experimental arms where the intestinal mucosal segments were tested under acidic conditions.
The results of this study indicate that there are functional and physiological differences between the proestrus female and the male intestine that may contribute to the resistance of the proestrus female to hemorrhagic shock-induced gut injury. Specifically, the PD, morphology, and barrier function (as reflected in permeability to dextran) of the female gut was better preserved than the male gut during ex vivo nonstress conditions (i.e., 3-h normoxic period) and when the intestinal segments were exposed to acidosis under normoxic or hypoxic conditions. Likewise, there were gender differences in the intestinal inflammatory response, as reflected by an augmented IL-6 response in the male but not the female intestinal segments under conditions of acidosis, hypoxia, or hypoxia plus acidosis. A similar trend was observed for TNF-
and MIP-2, where their levels of production were higher in the male than the female intestinal segments exposed to hypoxia plus acidosis. In contrast to the proinflamatory cytokine response, production of the anti-inflammatory cytokine IL-10 increased to a greater extent in the female than the male intestinal segments. Additionally, NO production by the female intestinal segments during normoxia and during acidosis and hypoxia plus acidosis was greater than that observed in the male intestinal segments. It appears that these differences in gut function, morphology, and inflammatory response between the proestrus female and the male intestinal segments subjected to hypoxia plus acidosis were related to the effects of both estradiol and testosterone, since the pretreatment of male rats with estradiol or the testosterone receptor antagonist flutamide limited gut injury and dysfunction and the intestinal proinflammatory response. These results are consistent with studies showing that estradiol inhibits cytokine production via a nuclear factor-
B-mediated mechanism (25) and that estradiol potentiates modest increases in NO production by stimulating constitutive NO synthase (cNOS), while at the same time limiting excessive NO production by inhibiting inducible NOS induction (29). Last, Mizushima et al. (31) recently documented that the administration of estradiol to male rats after an episode of T/HS reduces IL-6 plasma levels and improves cardiovascular and hepatic function.
Although in vivo extrapolation of these in vitro studies should be done with caution, the observation that cytokine and chemokine production by the male, in contrast to the female, gut is increased by hypoxia and acidosis, while the levels of NO production by the female gut are higher than the male gut, may have relevance to the relative resistance of the proestrus female vs. the male gut to T/HS-induced injury. For example, increased IL-6 production is associated with increased neutrophil sequestration in the gut after an episode of hemorrhagic shock (21), and IL-6 has been shown to potentiate pulmonary neutrophil sequestration (38). Thus decreased production of IL-6, TNF, and MIP-2 by the gut during hypoxic insults is likely to be beneficial. On the other hand, increased basal production of NO may exert a number of beneficial effects on the splanchnic circulation during low-flow states in addition to its ability to limit shock-induced increased vasomotor tone and thereby improve tissue perfusion (29). These beneficial effects of NO include inhibition of platelet aggregation, neutrophil adherence, and inflammation (12, 44). Additionally, estradiol has been shown to decrease endothelial cell superoxide production via a cNOS-mediated NO-dependent mechanism (28). Last, substantial evidence indicates that endothelial dysfunction manifested as decreased bioactive NO levels is one of the earliest changes occurring after ischemia-reperfusion and that this early pathophysiological change significantly contributes to subsequent functional and cellular injury in a variety of pathophysiological pathways (23, 39). This decrease in bioactive NO appears to be the result of a decrease in the production of NO by the endothelial cell cNOS. In this light, several reports have shown that endothelial NOS-mediated NO production is better maintained in females and is increased after the administration of estradiol (10, 11, 29).
In summary, the results of the current study suggest that the female gut is more resistant than the male gut to hypoxia- and reoxygenation-mediated and acidosis-induced decreases in barrier function and tissue injury. Additionally, the male gut appears to manifest more of an inflammatory response than the female gut, as reflected in increased IL-6, TNF, and MIP-2 levels and decreased IL-10 and NO production. The mechanisms by which sex hormones modulate the intestinal inflammatory response to hypoxia and/or acidosis will require further study, although it appears that both male and female sex hormones are involved.
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GRANTS
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This study was supported by National Institute of General Medical Sciences Grant GM-59841 (E. A. Deitch).
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FOOTNOTES
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Address for reprint requests and other correspondence: E. A. Deitch, Dept. of Surgery, MSB G506, UMDNJ, New Jersey Medical School, 185 South Orange Ave., Newark, NJ 07103-2714 (E-mail: edeitch{at}umdnj.edu)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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