Biomedical subjects

Martin G Schwacha

Publications and source records attributed to Martin G Schwacha.

17 recordsLinked to original sources

PubMed2003

Upregulation of hepatic prolactin receptor gene expression by 17beta-estradiol following trauma-hemorrhage.

Although studies show protective effects of 17beta-estradiol (E2) or prolactin (PRL) treatment in male rats after trauma-hemorrhage (TH), the mechanism of the salutary effects of these agents remains unknown. Because E2 modulates PRL receptor (PRL-R) expression in the liver, we examined whether E2 treatment after T-H has any effects on hepatic PLR-R gene expression. Male Sprague-Dawley rats were subjected to trauma (i.e., 5-cm midline laparotomy) and hemorrhage (35-40 mmHg for 90 min) followed by fluid resuscitation (Ringer lactate) or sham operation and then treated with E2 (50 microg/kg body wt sc) or vehicle immediately before resuscitation. Liver samples were collected at 3 h thereafter, and PRL-R mRNA expression was determined by PCR. Liver expression of PRL-R short-form gene was unaffected by T-H, whereas that of the long-form gene was suppressed. Treatment of T-H rats with E2 significantly increased PRL-R short-form gene expression and normalized PRL-R long-form gene expression to sham levels. In the isolated hepatocytes, PRL-R short-form gene expression was predominant compared with the long-form gene. In contrast, only the short form was detected in Kupffer cells. In vitro treatment by E2 demonstrated an increase in the PRL-R long-form gene in hepatocytes, but E2 had no effect on PRL-R short-form gene expression in either the Kupffer cells or hepatocytes. Thus E2 treatment after T-H in males appears to directly upregulate PRL-R long-form gene expression in hepatocytes. However, the upregulation of the PRL-R short form might involve the interaction of multiple cell types in the liver.

Animals↗

PubMed2003

Androgen-mediated modulation of macrophage function after trauma-hemorrhage: central role of 5alpha-dihydrotestosterone.

Androgens have been implicated as the causative factor for the postinjury immune dysfunction in males; however, it remains unknown whether androgens directly affect macrophages. To study this, male mice were sham operated or subjected to trauma (i.e., midline laparotomy) and hemorrhagic shock (mean arterial pressure, 30 +/- 5 mmHg for 90 min and then resuscitated). The mice received the 5alpha-reductase inhibitor 4-hydroxyandrostenedione (4-OHA) before resuscitation. Plasma TNF-alpha, IL-6, and IL-10 levels were elevated after trauma-hemorrhage and normalized by 4-OHA. TNF-alpha and IL-6 production by splenic macrophages was decreased after injury, whereas Kupffer cell production of these mediators was enhanced. 4-OHA normalized cytokine production. Androgens suppressed cytokine production by splenic macrophages from hemorrhaged mice, whereas it enhanced TNF-alpha and IL-6 production by Kupffer cells. The addition of 4-OHA in vitro normalized cytokine production by cells treated with testosterone, but it had no effect on dihydrotestosterone-treated cells. These results indicate that androgens directly affect macrophage function in males after trauma and hemorrhagic shock and that the intracellular conversion of testosterone to dihydrotestosterone is of particular importance in mediating the androgen-induced effects.

Androgens↗

PubMed2003

Mechanism of the salutary effects of 17beta-estradiol following trauma-hemorrhage: direct downregulation of Kupffer cell proinflammatory cytokine production.

Kupffer cells have been reported as a major source of proinflammatory cytokines (i.e. IL-6, TNF-alpha), which have been implicated in the pathogenesis of trauma-hemorrhage. Previous studies have shown a protective effect of 17beta-estradiol on immune function and physiological responses following trauma-hemorrhage. In this study, we investigated whether 17beta-estradiol has a direct effect on Kupffer cell cytokine production following trauma-hemorrhage. Male Sprague-Dawley rats were subjected to trauma (midline laparotomy) and hemorrhage (35-40 mmHg for 90 min followed by fluid resuscitation) or sham operation. Two hours later, Kupffer cells were isolated and cultured with 17beta-estradiol in the presence and absence of lipopolysaccharide stimulation. Kupffer cell IL-6 and TNF-alpha production increased following trauma-hemorrhage. Incubation with 17beta-estradiol attenuated the production of IL-6 by cells from both sham and trauma-hemorrhage animals in a dose-dependent manner. The suppression of IL-6 production by 17beta-estradiol was paralleled by a decrease in mRNA levels. In contrast to IL-6, the effects of 17beta-estradiol on TNF-alpha production were minimal. In conclusion, these results indicate the direct downregulation of Kupffer cell IL-6 production by 17beta-estradiol at a molecular level, which might explain in part the previously observed salutary effects of estradiol treatment following trauma-hemorrhage.

Animals↗

PubMed2003

Immunoprotection in proestrus females following trauma-hemorrhage: the pivotal role of estrogen receptors.

Immune responses in proestrus females are not altered after trauma-hemorrhage, whereas they are markedly depressed in males. Elevated levels of female sex steroids appear to be responsible for maintaining immune responses but it remains unknown, whether estrogen per se is responsible. To study this, proestrus female C3H/HeN mice were subjected to laparotomy (i.e., soft tissue trauma) and hemorrhagic shock (35+/-5 mmHg for 90 min, then resuscitated) or sham operation and received the estrogen receptor antagonist EM-800 or vehicle during resuscitation. Two hours following trauma-hemorrhage, splenocyte proliferation, IL-2, IL-3, IFN-gamma release, and splenic macrophage IL-6 release was maintained in vehicle-treated females. In EM-800-treated females, however, these immune parameters were significantly depressed. Following trauma-hemorrhage, Kupffer cell TNF-alpha release and circulating TNF-alpha were increased only in EM-800-treated females. These findings indicate that the ability of proestrus females to maintain immune function following trauma-hemorrhage is estrogen-dependent and mediated via estrogen receptors.

Animals↗

PubMed2003

Macrophages and post-burn immune dysfunction.

The activation of a pro-inflammatory cascade after burn injury appears to be important in the development of subsequent immune dysfunction, susceptibility to sepsis and multiple organ failure. Macrophages are major producers of pro-inflammatory mediators and their productive capacity for these mediators is markedly enhanced following thermal injury. Thus, macrophage hyperactivity (as defined by increased productive capacity for pro-inflammatory mediators) appears to be of critical importance in the development of post-burn immune dysfunction. This review will focus on the current state of knowledge with regards to the role of macrophages in the development of post-burn immune dysfunction. Particular areas of discussion include: nitric oxide synthase (NOS) and cyclooxygenase (COX) enzyme systems, macrophages and the T-helper (Th)-1/Th-2 cytokine responses, alterations in macrophages signal transduction and a potential role for gamma/delta T-cells in the development of macrophage hyperactivity following thermal injury. A more comprehensive understanding of the relationship between macrophage activity and post-burn immune dysfunction will hopefully provide the basis for improved therapeutic regimes in the treatment of burn patients.

Burns↗

PubMed2003

Effect of estradiol administration on splanchnic perfusion after trauma-hemorrhage and sepsis.

PURPOSE OF REVIEW: This review focuses on the latest mechanistic understanding of the effects of estradiol on the splanchnic circulation and the possibility of estradiol treatment as an adjunct for the treatment of trauma-hemorrhage and sepsis. RECENT FINDINGS: Systemic hypotension induced by shock accompanies marked alterations in blood flow to various organs. Decreased splanchnic perfusion is frequently observed after insults, such as severe hemorrhage or sepsis, which leads to the destruction of the intestinal mucosal barrier and hepatic dysfunction. Studies suggest that estradiol acts as a facilitator of the intestinal blood flow via the increased production of nitric oxide, decreased production of vasoconstrictors, attenuated neutrophil adhesion, and decreased formation of oxygen free radicals. SUMMARY: Trauma-hemorrhage results in decreased circulating blood volume. In contrast, sepsis is an inflammatory state mainly mediated by bacterial products. However, these divergent insults show similar pathophysiologic alterations in terms of the splanchnic circulation. Because estradiol effectively protects the organs from circulatory failure after various adverse circulatory conditions, many studies are being performed to clarify the molecular mechanism of estradiol action with regard to tissue circulation. Estradiol improves the macro- and microcirculation of the splanchnic organs by multiple mechanisms. Nonetheless, it remains unclear which mechanism plays the most important role in the treatment of trauma-hemorrhage and sepsis. Additional studies are required to elucidate the precise mechanism of estradiol action and to determine the usefulness of estradiol treatment for severe hemorrhage and sepsis in patients.

Animals↗

PubMed2003

Endocrine targets in experimental shock.

Modified resuscitation regimens and cytokine blockade/receptor antagonism after trauma have not been successful in decreasing the mortality rates from sepsis in trauma patients; therefore, an alternative approach using endocrine targets as modulators or inhibitors may be useful. Information regarding the influence of gender and hormones on immune and cardiovascular responses after nonthermal trauma-hemorrhagic shock is, on the one hand, considerable but, on the other hand, disappointingly incomplete. Trauma-hemorrhagic shock produces gender dimorphic immune and cardiovascular responses; men exhibit cardiovascular depression and are immunosuppressed, whereas proestrus women do not show cardiovascular or immunologic depression under those conditions. Furthermore, experimental studies have demonstrated the use of hormones, hormone antagonists, sex steroids, and receptor antagonists as salutary adjuncts, without any adverse effects on gastrointestinal, hepatic, and renal functions, for restoring the depressed immune and cardiovascular responses after trauma-hemorrhage. Thus, flutamide, dehydroepiandrosterone, metoclopramide, and 17beta-estradiol, which are readily availably clinically and do not produce any adverse hemodynamic effects, appear to be safe and novel agents/hormones for the treatment of immune and cardiovascular depression after severe blood loss in male and female trauma victims.

Endocrine System↗

PubMed2003

Gender dimorphism in neutrophil priming and activation following trauma-hemorrhagic shock.

Although gender influences T-cell, macrophage and organ functions following trauma-hemorrhage and resuscitation (T-H), it remains unknown whether it also influences polymorphonuclear cell (PMN) activity under such conditions. To study this, proestrus female and male Sprague-Dawley rats underwent trauma-hemorrhage followed by fluid resuscitation. Circulating PMNs were assessed for superoxide (O2-) and elastase production and tissues were analyzed for myeloperoxidase (MPO) activity and TBARS (thiobarbituric acid reactive substances) as a marker of oxidative injury, at 2 and 24 h after resuscitation. PMA stimulated O2- production was not influenced by T-H or gender. In contrast, fMLP-stimulated O2- and LPS-stimulated elastase release by PMNs from male T-H rats was greater than that of females. A significant MPO activity and TBARS in tissues of both male and female rats was induced; however, MPO activity and TBARS levels were higher in males following T-H. Levels of the chemokine CINC-1 were elevated in the lungs of male, but not of proestrus females after T-H. Thus, decreased PMN priming and activation in proestrus females, compared to males, occurs following T-H resulting in decreased cellular injury and organ damage that is likely to contribute to improved outcome under those conditions.

Animals↗

PubMed2002

Trauma-haemorrhage-induced alterations in thymic prolactin receptor expression: implications in immune dysfunction.

Male gender and age appear to be causative factors in development of immunodepression and septic complications following trauma-haemorrhage. Studies have demonstrated that administration of the sex hormone prolactin following trauma-haemorrhage in male mice prevents immunodepression. Since the thymus is the primary location of the T-cell-lymphopoiesis, we investigated the effect of trauma-haemorrhage to thymic prolactin-receptor (PRLr)-expression in male and proestrus female mice in three different age groups (young, adult, aged) by flow cytometry and PCR. C3H/HeN mice were subjected to laparotomy (i.e., soft-tissue trauma) and hemorrhagic shock (35+/-5mmHg for 90min, then resuscitated) or sham operation. Twenty-four hours later thymocytes were isolated. Trauma-haemorrhage upregulated PRLr expression in young and mature mice of both genders, however, the increase was attenuated in females. In contrast, in aged mice PRLr expression was elevated in both genders, independent of trauma-haemorrhage and was not further increased under such conditions. These findings suggest that the gender dimorphism in the immune response to trauma-haemorrhage may in part be related to differences in thymic PRLr expression under such conditions.

Aging↗

PubMed2002

Differential expression and tissue compartmentalization of the inflammatory response following thermal injury.

Studies have shown that both animal tissue-fixed immune cells and human peripheral blood mononuclear cell (PBMC) functions are altered after burn injury. Additional studies suggest that the burn injury-induced alterations in these divergent cell populations from different species are similar. It remains unknown, however, whether the observed changes in animal tissue-fixed immune cell function following thermal injury also occurs to a similar extent in the PBMC population. The aim of our study was to compare PBMC and tissue-fixed immune cell functions from the same animal using a murine burn model. At 7 days post-burn, mice were more susceptible to sepsis and delayed type hypersensitivity responses were suppressed. Splenocytes isolated from injured mice displayed suppressed proliferation and increased IL-10 production. In contrast, PBMC from injured mice displayed suppressed proliferation, IL-2 and IFN-gamma production. Splenic macrophage nitric oxide, PGE(2), TNF-alpha, IL-6 and IL-10 production was enhanced post-burn and IL-12 production was suppressed. PBMC from such animals displayed enhanced PGE(2) production and suppressed IL-6 and IL-12 production. These results indicate that while an immunosuppressive Th(2) phenotype (increased IL-10 and/or suppressed IL-2, IFN-gamma) was induced in both the splenic and PBMC compartments post-injury, differential expression and dimorphism in the response also exists. Thus, the assessment of only PBMC function in burn patients may not accurately reflect the patient's actual immune status at the tissue level.

Animals↗

PubMed2002

Relationships between burn size, immunosuppression, and macrophage hyperactivity in a murine model of thermal injury.

Burn injury induces immune dysfunction and alters numerous physiological parameters. While clinical studies indicate that burn injury size profoundly impacts patient immune status, only limited experimental studies have systematically addressed its impact on immune functional parameters. In the present study, mice were subjected to burn injuries of varying sizes and splenic immune cells (splenocytes and macrophages) were isolated 7 days thereafter. Burn injury suppressed splenic T-cell proliferation in an injury size-dependent manner that correlated with the release of the immunosuppressive mediators PGE(2) and nitric oxide. In addition, a shift towards an immunosuppressive Th-2 cytokine profile and a hyperactive macrophage phenotype (increased release of inflammatory mediators) was observed post-injury, however, this effect was in part independent of burn size. Thus, unlike patient survival data, burn injury-induced changes in immune function do not necessarily correlate with the size of the injury.

Animals↗

PubMed2002

Female sex hormones regulate macrophage function after trauma-hemorrhage and prevent increased death rate from subsequent sepsis.

OBJECTIVE: To determine whether reduction of circulating female sex hormones by ovariectomy causes suppression of macrophage (Mphi) function after trauma-hemorrhage and increases susceptibility to subsequent sepsis. SUMMARY BACKGROUND DATA: Studies indicate that immune functions are markedly depressed in males but not in proestrus females after trauma-hemorrhage. Although male sex steroids are immunosuppressive, it remains unknown whether female sex hormones are immunoprotective after trauma-hemorrhage. METHODS: Circulating female sex hormones were reduced by ovariectomy of 8-week-old female CBA/J mice. Two weeks afterward, ovariectomy and proestrus sham-ovariectomy mice were subjected to laparotomy (i.e., soft tissue trauma) and hemorrhagic shock (35 +/- 5 mm Hg for 90 minutes, then resuscitated) or sham operation. Two hours afterward, splenic and peritoneal Mphi and Kupffer cells were isolated and cytokine production was assessed. In a second series of experiments, animals were subjected to sepsis by cecal ligation and puncture at 24 hours after trauma-hemorrhage or sham operation, and survival was assessed. RESULTS: Release of interleukin-1 and interleukin-6 by splenic and peritoneal Mphi from proestrus mice was maintained after trauma-hemorrhage, whereas release of interleukin-1 and interleukin-6 by Mphi from ovariectomized mice was depressed by approximately 50%. In contrast, trauma-hemorrhage resulted in a fourfold increase of Kupffer cell release of tumor necrosis factor-alpha in ovariectomized females and a fivefold increase in plasma concentrations of tumor necrosis factor-alpha. Release of tumor necrosis factor-alpha and plasma concentrations were unchanged in proestrus mice under such conditions. When proestrus and ovariectomized animals were subjected to sepsis by cecal ligation and puncture at 24 hours after trauma-hemorrhage or sham operation, ovariectomized mice had a significantly higher death rate than proestrus mice. CONCLUSIONS: These findings suggest that female sex hormones play a critical role in maintaining immune responses after trauma-hemorrhage by suppressing the elaboration of tumor necrosis factor-alpha and prevent the increased lethality from subsequent sepsis. Thus, female sex hormones may be a useful adjunct in preventing trauma-induced immunodepression and increased susceptibility to subsequent sepsis.

Analysis of Variance↗

PubMed2002

Preservation of splenic immune functions by female sex hormones after trauma-hemorrhage.

OBJECTIVES: Immune functions are markedly depressed in males but not in proestrus females after trauma-hemorrhage. Nonetheless, it is unclear what role sex steroids play in the maintenance of immune function in females after trauma-hemorrhage. DESIGN: Prospective, controlled animal study. SETTING: University research laboratory. SUBJECTS: Eight-week-old female CBA/J mice. INTERVENTIONS: Mice underwent sham-ovariectomy or ovariectomy. Two weeks thereafter, ovariectomized and proestrus sham-ovariectomized mice were subjected to laparotomy (i.e., soft tissue trauma) and hemorrhagic shock (35 +/- 5 mm Hg for 90 mins, resuscitated) or sham operation. Splenocyte proliferation and interleukin-2, interleukin-3, and interferon-gamma release were determined at 2 hrs after trauma-hemorrhage. MEASUREMENTS AND MAIN RESULTS: These immune functional capacities were maintained in proestrus sham-ovariectomized mice after trauma-hemorrhage, whereas they were suppressed in ovariectomized mice subjected to trauma-hemorrhage. 17beta-Estradiol in vitro had no effect on splenocyte functions in proestrus sham-ovariectomized females; however, addition of 17beta-estradiol to splenocytes from ovariectomized females subjected to trauma-hemorrhage normalized immune functional capacities. CONCLUSIONS: These findings suggest that elevated circulating 17beta-estradiol in proestrus females plays a direct role in the maintenance of immunocompetence after trauma-hemorrhage.

Animals↗

PubMed2002

Cyclooxygenase 2-mediated suppression of macrophage interleukin-12 production after thermal injury.

Macrophage (Mphi) prostaglandin (PG)E(2) production has been implicated in immunosuppression and increased susceptibility to sepsis after thermal injury. Deficient interleukin (IL)-12 production has also been implicated in these postburn complications. The present study examined the relationship between Mphi cyclooxygenase (COX)-2 activity and IL-12 production after thermal injury. C57BL/6 female mice were subjected to a 25% total body surface area full-thickness burn. Mphi were isolated 7 days later, or the mice were subjected to sepsis by cecal ligation and puncture (CLP). IL-12 production by Mphi from injured mice was suppressed by >50%, whereas COX-2 expression and PGE(2) production were increased twofold. The COX-2 inhibitor NS-398 suppressed PGE(2) production and normalized IL-12 production in the injury group, whereas it had no effect on IL-10 production. Injured mice subjected to CLP had lower IL-12 plasma levels compared with sham-treated mice subjected to CLP. NS-398 treatment prevented the suppression in plasma IL-12 levels in the injury group. Thus elevated Mphi COX-2 activity, independent of IL-10, suppresses Mphi IL-12 production after thermal injury and may play an important role in the observed immunosuppression under such conditions.

Animals↗

PubMed2002

Estrogen pretreatment protects males against hypoxia-induced immune depression.

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(2), 40 microg/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(2)-5% O(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(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(2)-pretreated mice. In summary, these findings indicate that administration of E(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.

Animals↗

PubMed2002

Gender dimorphism in immune responses following trauma and hemorrhage.

Previous studies have shown marked immunosuppression in males after trauma and hemorrhage. By contrast, immunosuppression was not evident in proestrous female animals. Further support for these findings came from studies demonstrating the immunosuppressive effects of male sex hormones and immunoenhancing effects of female sex hormones. In this regard, administration of 17beta-estradiol or prolactin to male animals after trauma and hemorrhage significantly improved immune function. Furthermore, castration or androgen receptor blockade with flutamide after trauma and hemorrhage in male mice showed similar beneficial effects. Thus, regulation of sex hormone synthesis or their receptor activity appears to be a useful therapeutic approach for patients to cope with the deleterious sequelae of severe trauma and hemorrhage.

Androgens↗

PubMed2002

The cellular basis of post-burn immunosuppression: macrophages and mediators.

Major thermal injury induces the activation of an inflammatory cascade that contributes to the development of subsequent immunosuppression, increased susceptibility to sepsis and multiple organ failure. The productive capacity of macrophages for inflammatory mediators, (i.e., nitric oxide, prostaglandins, TNF-alpha, IL-6 etc.), is profoundly increased post-burn, thereby implicating macrophages in the development of the post-burn immunosuppression. This review will focus on recent findings with regards to the role of macrophages in the development of post-burn immunosuppression with particular emphasis on the role of nitric oxide and prostaglandins.

Animals↗