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The acute respiratory distress syndrome (ARDS) is a major cause of morbidity after injury. We hypothesized that alveolar macrophage (AM[PHI]) chemokine and cytokine release after hemorrhage and sepsis is regulated by NF-[kappa]B and MAPK. Adult male rats underwent soft tissue trauma and hemorrhagic shock (~90 min) followed by crystalloid resuscitation. Sepsis was induced by cecal ligation and puncture (CLP) 20 h after resuscitation. AM[PHI] were harvested, and TNF-[alpha], IL-6, and macrophage inflammatory protein (MIP)-2 release and serum IL-6 and TNF-[alpha] levels were measured at 5 h after HCLP. Lung tissues were analyzed for activation of NF-[kappa]B, myeloperoxidase activity, and wet/dry weight ratio. In control animals, AM[PHI] were stimulated with LPS with or without inhibitors of NF-[kappa]B and MAPK. Serum TNF-[alpha] and IL-6 levels and spontaneous AM[PHI] TNF-[alpha] and MIP-2 release were elevated (P < 0.05) after HCLP, concomitantly with the development of lung edema and leukocyte activation. Activation of NF-[kappa]B increased in lungs from the hemorrhage and CLP group compared with shams. Inhibition of NF-[kappa]B or the upstream MAPK significantly decreased LPS-stimulated AM[PHI] activation. Because enhanced release of inflammatory mediators by AM[PHI] may contribute to ARDS after severe trauma, inhibition of intracellular signaling pathways represents a target to attenuate organ injury under those conditions. mitogen-activated protein kinase; leukocytes; macrophage inflammatory protein; acute respiratory distress syndrome; extracellular signal-regulated kinase; nuclear factor-[kappa]B

Hypoxemia depresses cell-mediated immune functions in males, whereas proestrous females do not show such a depression. We hypothesized that elevated systemic estradiol levels in proestrous females prevent hypoxemia-induced immune depression. To study this hypothesis, male C3H/HeN mice were pretreated with 17[beta]-estradiol ([E.sub.2], 40 [micro]g/kg body wt sc) or vehicle for 3 days before induction of hypoxemia and again immediately before induction of hypoxia. The mice were subjected to hypoxemia (95% [N.sub.2]-5% [O.sub.2]) or sham hypoxemia (room air) for 60 min, and plasma and spleen cells were collected 2 h later. In vehicle-treated mice, splenocyte proliferation and interleukin-2 and interleukin-3 production were depressed after hypoxemia. [E.sub.2]-pretreated animals, however, displayed no such depression in splenic T cell parameters after hypoxemia. Splenic macrophage cytokine production was also depressed in vehicle-treated mice subjected to hypoxia, whereas it was normal in [E.sub.2]-pretreated mice. In summary, these findings indicate that administration of [E.sub.2] before hypoxemia prevented the depression of cell-mediated immune functions. Thus administration of 17[beta]-estradiol in high-risk patients before major surgery might decrease hypoxemia-induced immune depression under those conditions. inflammation; cytokines; estradiol; gender

Recent studies indicate that immune responses in proestrus females are maintained after trauma-hemorrhage but markedly depressed in ovariectomized females under such conditions. The current study tested the hypothesis that the decreased estrogen levels after ovariectomy are responsible for this immune depression. To study this hypothesis, ovariectomized female CBA/J mice were subjected to laparotomy (i.e., soft tissue trauma) and hemorrhagic shock (35 [+ or -] 5 mmHg for 90 min, then resuscitated) or sham operation. The mice received either 17 [Beta]-estradiol (E2; 100 [micro] g/25 g body wt) or vehicle subcutaneously during resuscitation. Immune cells were isolated 24 h thereafter. Splenocyte proliferation and interferon-[Gamma], interleukin (IL)-2, and IL-3 release were significantly depressed after trauma-hemorrhage in vehicle-treated mice, whereas these functions were maintained in E2-treated mice. Peritoneal macrophage IL-1 [Beta] and IL-6 release and splenic macrophage IL-6 and IL-12 release were also significantly depressed in vehicle-treated mice after trauma-hemorrhage, and release of these cytokines was restored by E2 treatment. In summary our findings indicate that the depressed splenic and peritoneal immune responses after trauma-hemorrhage can be normalized by a single dose of E2. Thus estrogen appears to be the causative factor in the maintenance of immunocompetence in females after trauma-hemorrhage, and its administration to ovariectomized or postmenopausal females should be helpful in preventing immune depression under such conditions. T lymphocyte; macrophage; inflammation; immunosuppression; gender

Knoferl, Markus W., Doraid Jarrar, Martin G. Schwacha, Martin K. Angele, William G. Cioffi, Kirby I. Bland, and Irshad H. Chaudry. Severe hypoxemia in the absence of blood loss causes a gender dimorphic immune response. Am J Physiol Cell Physiol 279: C2004-C2010, 2000.--A gender dimorphic immune response has been observed after trauma and severe hemorrhage, a condition believed to be associated with tissue hypoxia. Although studies have shown that hypoxemia per se in males causes a systemic inflammatory response, it is unclear if the inflammatory response to hypoxemia exhibits gender dimorphic characteristics. To study this, male and female C3H/HeN mice in the proestrus state of the estrous cycle were subjected to hypoxemia (95% [N.sub.2]-5% [O.sup.2]) or sham hypoxemia (room air) for 60 min. Later (2 h), plasma interleukin (IL)-6 and tumor necrosis factor (TNF)-[Alpha] levels were determined along with splenic immune responses. Plasma IL-6 and TNF-[Alpha] concentrations after hypoxemia were significantly increased in males but not in females. Splenocyte proliferation was depressed in males after hypoxemia but not in females. A shift toward an immunosuppressive Th-2 cytokine profile was observed in males after hypoxemia [decreased interferon-[Gamma] (Th-1) and increased IL-10 (Th-2)], whereas no such shift was observed in females. Splenic macrophage IL-6, IL-10, and IL-12 production were suppressed in males after hypoxemia; however, such suppression was not observed in females. These findings therefore indicate that a gender dimorphic immune response also exists after hypoxemia in the absence of blood loss and tissue trauma, similar to trauma-hemorrhage. Furthermore, because no systemic inflammatory response or alterations in T lymphocyte or macrophage functions are observed in proestrus females but such parameters are markedly altered after severe hypoxemia in males, these studies indicate that proestrus females can tolerate hypoxemia better than males. rodent; inflammation; cytokines; sex steroids; proestrus

The female reproductive cycle is an important variable in the response to trauma-hemorrhage. Am J Physiol Heart Circ Physiol 279: H1015-H1021, 2000.--Although immune functions in proestrus females are maintained after hemorrhage as opposed to decreased responses in males, it remains unknown whether such a sexual dimorphism also exists with regard to cardiovascular and hepatocellular functions under those conditions. To study this, male and female (estrus and proestrus) rats underwent a 5-cm midline laparotomy and were bled to and maintained at a mean blood pressure of 40 mmHg until 40% of the maximal bleed-out volume was returned in the form of Ringer lactate (RL). Rats were then resuscitated with four times the shed blood volume with RL. At 24 h thereafter, cardiac index; heart performance; hepatocellular function; and plasma estradiol, testosterone, and prolactin levels were measured. Cardiovascular and hepatocellular functions were depressed in males and estrus females (P [is less than] 0.05) but were not depressed in proestrus females after resuscitation. Plasma estradiol and prolactin levels were highest in proestrus females (P [is less than] 0.05), whereas males had high testosterone and the lowest estradiol levels (P [is less than] 0.05). Thus the female reproductive cycle is an important variable in the response to hemorrhage. Because low testosterone and high estradiol and prolactin levels appear to be beneficial for organ functions after trauma-hemorrhage, antagonism of testosterone receptors and/or increases in estradiol and prolactin levels in males and estrus females, respectively, may be novel approaches for improving organ functions under such conditions. sex steroids; prolactin; cardiac output; liver function; circulating blood volume

Mizushima, Yasuaki, Ping Wang, Doraid Jarrar, William G. Cioffi, Kirby I. Bland, and Irshad H. Chaudry Preinduction of heat shock proteins protects cardiac and hepatic functions following trauma and hemorrhage. Am. J Physiol. Regulatory Integrative Comp. Physiol. 278: R352-R359, 2000.--Although studies have shown that induction of the heat shock proteins (HSPs), such as HSP-70, has various beneficial effects after ischemia-reperfusion, it remains unknown whether prior induction of HSP-70 has any salutary effects on cardiovascular and hepatocellular functions after trauma-hemorrhage and resuscitation. Male rats were exposed to heat stress (41 [degrees] C, 15 min) and then allowed tv recover for 24 h at room temperature (21 [degrees] C). The rats the underwent laparotomy (i.e., trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the maximal shed blood volume was returned in the form of Ringer lactate. Animals were then resuscitated with four times the volume of shed blood with Ringer lactate over 60 min. The maximal rate of the left ventricular pressure increase or decrease was measured up to 4 h after resuscitation. Cardiac output, hepatocellular function, plasma levels of tumor necrosis factor-[Alpha] (TNF-[Alpha]), and interleukin-6 (IL-6) were determined at 4 h after resuscitation. Cardiac and hepatic tissue were examined for HSP-70 by Western blot analysis. Left ventricular performance, cardiac output, and hepatocellular function decreased significantly following trauma-hemorrhage. Plasma levels of TNF-[Alpha] and IL-6 were also significantly increased. However, prior heat stress attenuated cardiovascular and hepatocellular dysfunction, decreased circulating levels of proinflammatory cytokines following trauma-hemorrhage, and was associated with an increased abundance of HSP-70 in the heart and liver. Our data, therefore, suggest that preinduction of HSP-70 protects cardiovascular and hepatocellular functions following traumahemorrhage and resuscitation. heat shock protein-70; cardiac performance; cardiac output; hepatocellular function; hemorrhagic shock; tumor necrosis factor-[Alpha]; interleukin-6

Jarrar, Doraid, Ping Wang, Grace Y. Song, Markus W. Knoferl, William G. Cioffi, Kirby I. Bland, and Irshad H. Chaudry. Metoclopramide: a novel adjunct for improving cardiac and hepatocellular functions after trauma-hemorrhage. Am. J. Physiol. Endocrinol. Metab. 278: E90-E95, 2000.--Although metoclopramide (MCP) administration after trauma-hemorrhage restores the depressed immune functions, it remains unknown whether this agent has any salutary effects on the depressed cardiovascular and hepatocellular functions under those conditions. Adult male Sprague-Dawley rats underwent a midline laparotomy (i.e., induction of soft-tissue trauma) and were then bled to and maintained at a mean arterial pressure (MAP) of 40 mmHg until 40% of the maximal shed blood volume was returned in the form of Ringer lactate (RL). The rats were then resuscitated with four times the shed blood volume in the form of RL over 60 min. MCP (2 mg/kg body wt) or vehicle was administered subcutaneously at the end of resuscitation. At 24 h after resuscitation, cardiac index and hepatocellular function (i.e., the maximum velocity and the overall efficiency of indocyanine green clearance) were determined. Plasma levels of interleukin (IL)-6 and prolactin were also assayed. The results indicate that treatment with MCP after trauma-hemorrhage and resuscitation significantly improved the depressed cardiac output and hepatocellular function. Furthermore, MCP administration significantly increased circulating levels of prolactin and decreased the plasma levels of the proinflammatory cytokine IL-6. Thus, administration of MCP, which increased prolactin secretion, appears to be a useful adjunct for restoring the depressed cardiac and hepatocellu]ar functions and downregulating inflammatory cytokine release after trauma and hemorrhagic shock. interleukin-6; pro]actin; cardiac output; indocyanine green; liver function