Showing papers by "Yukihiro Yokoyama published in 2003"

Role of thromboxane A2 in early BDL-induced portal hypertension

Abstract: Although the mechanisms of cirrhosis-induced portal hypertension have been studied extensively, the role of thromboxane A2 (TXA2) in the development of portal hypertension has never been explicitly...

Sex Differences in Hepatic Heme Oxygenase Expression and Activity Following Trauma and Hemorrhagic Shock

Abstract: Hypothesis Sex differentially influences heme oxygenase (HO) expression following trauma and hemorrhagic shock. Design Prospective controlled animal study. Setting A university laboratory. Interventions Female Sprague-Dawley rats in the proestrus stage of their estrus cycle and male rats underwent a 5-cm midline laparotomy (ie, induction of soft tissue trauma) and were bled to a mean arterial blood pressure of 35 mm Hg for approximately 90 minutes, after which they were resuscitated with Ringer lactate solution (4 × the shed blood volume). In another group of animals, tin protoporphyrin IX was used to block HO activity. Main Outcome Measures Liver samples were collected for analysis of HO expression and activity, plasma samples were collected, and alanine transaminase levels were determined 5 hours after resuscitation. Portal pressure and bile production were measured in vivo 5 hours after resuscitation. Results Trauma and hemorrhage induced a 2-fold increase in hepatic HO1 expression (the inducible form of HO) in proestrus females compared with males. Hepatic expression of HO2 (a constitutive isoform of HO) was unaffected by sex or trauma and hemorrhage. Blockade of HO in vivo with tin protoporphyrin IX abolished the sex differences caused by diverse HO1 expression. Treatment with tin protoporphyrin IX also elevated the portal pressure, decreased bile production, and increased alanine transaminase to similar levels in proestrus females and males following trauma and hemorrhage. Conclusions Sex influences the hepatic expression of HO1 following trauma and hemorrhage. The enhanced induction of HO1 expression and activity in females after trauma and hemorrhage may attenuate hepatocellular dysfunction and injury by maintaining microcirculation via the increased production of carbon monoxide.

Administration of progesterone after trauma and hemorrhagic shock prevents hepatocellular injury.

Abstract: Hypothesis Administration of a single dose of progesterone following trauma and hemorrhage in progesterone-deficient rats would ameliorate the inflammatory response and hepatocellular damage. Setting A university laboratory. Interventions Ovariectomized female Sprague-Dawley rats (250-350 g; Charles River Laboratories, Wilmington, Mass) underwent a 5-cm midline laparotomy (ie, induction of soft tissue trauma), were bled to a mean arterial blood pressure of 35 mm Hg for about 90 minutes, and then were resuscitated using Ringer lactate solution. Progesterone (25 mg/kg of body weight) or vehicle was administered subcutaneously at the end of resuscitation. In additional animals, Kupffer cells were isolated following trauma, hemorrhage, and resuscitation and treated in vitro with progesterone, lipopolysaccharide, or both. Main Outcome Measures Six hours following resuscitation, plasma tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) levels and liver myeloperoxidase activity were determined. Hepatocellular function (maximum velocity of indocyanine green clearance [V max ] and the efficiency of the active transport or Michaelis-Menten constant [ K m ]) and plasma levels of transaminases were measured 20 hours after resuscitation. Kupffer cell IL-6 and TNF-α production were assessed. Results Plasma levels of TNF-α, IL-6, aspartate aminotransferase, and alanine aminotransferase, as well as hepatic myeloperoxidase activity were increased, whereas indocyanine green clearance was depressed in vehicle-treated rats following trauma-hemorrhage. Animals treated with progesterone showed significantly reduced levels of the TNF-α, IL-6, and transaminases as well as reduced myeloperoxidase activity in the liver. Progesterone-treated animals showed increased V max and K max values for indocyanine green. In vitro treatment of Kupffer cells with progesterone decreased TNF-α production but did not affect the production of IL-6. Conclusion Progesterone administration following trauma-hemorrhage ameliorates the proinflammatory response and, subsequently, the hepatocellular injury via direct action on immunocompetent cells.

Role of thromboxane in producing portal hypertension following trauma-hemorrhage

Abstract: Thromboxane A2 (TXA2) and endothelin-1 (ET-1) have been proposed as the important vasoconstrictors that increase portal venous resistance in paracrine or autocrine fashion. We hypothesized that the...

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

Abstract: 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.

UPREGULATION OF HEPATIC PROLACTIN RECEPTOR GENE EXPRESSION BY 17β-ESTRADIOL FOLLOWING TRAUMA-HEMORRHAGE

Abstract: 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.

The Role of Female Sex Hormones in Preventing Mortality in Sepsis

Abstract: Although severely compromised humoral and cell-mediated immune functions have been observed after the induction of sepsis in male animals, these immune changes are not evident in proestrus females, who have high levels of circulating female sex hormones. Furthermore, when trauma hemorrhage was preceded by the induction of sepsis by cecal ligation and puncture, the subsequent mortality rate was significantly lower in proestrus females compared with males. These results suggest an important role for female sex hormones in protecting animals from severe stresses such as trauma hemorrhage and sepsis. In this regard, estradiol, prolactin, and dehydroepiandrosterone have been shown to restore immune functions and increase the survival rate in sepsis models. In contrast to controlled animal models, human sepsis studies show highly variable results. One of the major reasons for this discrepancy might be due to the lack of information concerning sex hormone levels in human sepsis patients. Experimental animal studies suggest that a careful estimation and correlation between sex hormone levels and outcome from sepsis in humans is needed. Such a study is likely to improve therapeutic treatments for such patients.