RESUMEN
Oxidant-mediated reperfusion injury of the gut is a major contributor of the systemic inflammatory response in hemorrhagic shock. Recent studies have suggested that heme-oxygenase-1 (HO-1) represents an endogenous protective mechanism against oxidant stress. We assessed whether HO-1 induction modulates the synthesis of tumor necrosis factor-alpha (TNF-alpha) in hemorrhagic shock. In rats submitted to hemorrhagic shock, pretreatment with hemoglobin (Hb) increased HO-1 mRNA expression in macrophages. This increased expression was associated with a decreased expression of TNF-alpha mRNA, as well as decreased plasma concentrations of TNF-alpha. These effects of Hb were reduced by the HO-1 inhibitor tin-protoporphyrin (Sn-PP 20 micromol/kg), while Sn-PP had no effect in the absence of Hb. In parallel, Hb pretreatment reduced pulmonary edema, vascular injury, and increased mesenteric blood flow, and these effects were reduced by Sn-PP. Thus, induction of HO-1 is protective in hemorrhagic shock, possibly through its antioxidant properties. Interventions that induce HO-1 may be beneficial in the treatment of shock states, leading to a reduced systemic inflammatory response.
Asunto(s)
Modelos Animales de Enfermedad , Hemo Oxigenasa (Desciclizante)/fisiología , Hemo Oxigenasa (Desciclizante)/uso terapéutico , Intestinos/irrigación sanguínea , Daño por Reperfusión/complicaciones , Choque Hemorrágico/enzimología , Choque Hemorrágico/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/enzimología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Factor de Necrosis Tumoral alfa/fisiología , Animales , Evaluación Preclínica de Medicamentos , Fluidoterapia/métodos , Regulación de la Expresión Génica/fisiología , Hemodinámica , Inflamación , Macrófagos Peritoneales/enzimología , Masculino , ARN Mensajero/análisis , ARN Mensajero/genética , Ratas , Ratas Wistar , Resucitación/métodos , Choque Hemorrágico/etiología , Choque Hemorrágico/fisiopatología , Choque Hemorrágico/terapia , Circulación Esplácnica/fisiología , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Síndrome de Respuesta Inflamatoria Sistémica/fisiopatología , Síndrome de Respuesta Inflamatoria Sistémica/terapia , Factor de Necrosis Tumoral alfa/análisisRESUMEN
OBJECTIVES: Intestinal ischemia/reperfusion during hemorrhage and resuscitation may be a major trigger for cytokine expression. To assess whether free radicals produced on tissue reperfusion may play a role in the inflammatory response after hemorrhage, we tested the effect of a free radical scavenger on the production of inflammatory cytokines in a rat model of hemorrhagic shock. DESIGN: A prospective, controlled animal study. SETTING: A university research laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: Hemorrhage was induced in anesthetized rats. by bleeding the animal to achieve a mean arterial blood pressure of 40 mm Hg for 60 mins. Resuscitation was then induced by reinjecting shed blood followed by NaCl 0.9% to maintain arterial blood pressure within control values. Treated rats received the free radical scavenger N-2-mercaptopropionyl glycine (MPG; 20mg/kg iv bolus 30 mins before resuscitation followed by 20 mg/kg/hr). MEASUREMENTS AND MAIN RESULTS: MPG reduced the volume of saline necessary to restore blood pressure during resuscitation (untreated 85+/-6; MPG 35+/-5 mL/kg; p < .05). As compared with untreated rats, MPG markedly reduced the systemic and mesenteric plasma concentrations of tumor necrosis factor (TNF)-alpha (as measured by ELISA) and interleukin (IL)-6 (as measured by bioassay), assessed at the end of resuscitation. MPG also reduced TNF-alpha and IL-6 mRNA expression (as measured by reverse transcriptase-polymerase chain reaction) assessed in peritoneal macrophages isolated from shock rats. Finally, in vitro experiments showed that MPG also markedly reduced the mRNA expression and release of TNF-alpha and IL-6 in peritoneal macrophages isolated from normal rats and subjected to hypoxia and reoxygenation. CONCLUSION: Reactive oxygen species contribute to the production of proinflammatory cytokines during posthemorrhage resuscitation. Free radicals scavengers may be a useful treatment in the prevention of the systemic inflammatory response that occurs in shock states.