Molecular Mechanisms Of Multiple Organ Dtsfybctuib Syndrome In The Earty Phase Of Sepsis And Experimental Therapy By HSP-70 Gene Transfection

PurposeSepsis, a common surgical complication, is terminal clinical manifestation of systemic inflammation response syndrome. Multiple organ dysfunction syndrome(MODS) is a common clinical challenge if the systemic inflammatory response syndrome could not be properly cured. Although the the development of antibiotics has brought about the effective control for sepsis, in patients with out shock, the mortality of sepsis is about 30-40% while the mortality reachs 70-90% in patients with shock. Therefore, Sepsis and the MODS are still the major interests of clinical research in surgery. The purpose of this study was aimed of elucidate the clinical characteristics and the pathogensis of MODS in the early phase of sepsis and to explore the possible approach for prevention and treatment of sepsis and MODS.Methods(l).Rat model of sepsis was established by cecal ligation andpuncture(CLP). The pathological changes of heart, lung, liver, kindey was determined by light microscope and electronic microscope. (2).Blood biochemical parameters was measured to evaluate the functional changes of heart, lung and kindey. (3). Western blotting was employed of determine the expression and the phosphorylation of Mitogen-activated protein kinases(MAPKs). (4).Adenovirus-mediated HSP-70 gene transfection was performed in rats with sepsis, which was aimed to test possibility of antagonizing the sepsis and MODS by gene transfer. The therapeutic effects of HSP-70 gene transfection were evaluated by determine the functional and morphogical changes of hearts, lung, liver and the activation of MAPKs in these organs.Results and conclusions(l).Rat model of CLP could simulate the clinical profile of sepsis. MODS in the early phase of sepsis was characterized by the elevation of serum pro-inflammatory cytokines and the morphological damage of multiple organs; (2).Increases in serum pro-inflammatory cytokines in the early phase of sepsis indicated the overexpression of pro-inflammatory cytokines in the body. In CLP rats, serum TNF- α increased at 3 hour and peaked at 6 hour. Serum IL-1 β began to elevate at 6 hour and reached the peak at 24 hour, then restored to the control. Serum IL-6 was significantly higher than control at 3 hour, and peaked at 12 hour, thereafter, at 72 hour post CLP, IL-6 returned to the control level. IL-10 , an anti-inflammatorycytokine, began to increase in serum at 24 hour, reached its peak at 48 hour, and returned to control at 72 hour. (3). Differential activation of MAPKs was observed in the heart, lung, liver of the rats with sepsis. ERK in heart was activated at 3 hour and 12 hour while JNK activation was determined at 6 hour and last for 24 hour. p38MAPK in heart was activated at 3 hour and lasted for 24 hour. JNK activation in lung occurred earlier than in heart while JNK activation in liver was only determined at 3 hour and 12 hour post CLP. Considering the function of MAPK is an important event participating the mechanism of sepsis and MODS. These data was the first evidence documenting the activation of MAPKs in sepsis.(4). HSP-70 gene transfection conld effectivly antagonize the sepsis and MODS in rats with CLP. The protective and therapeutic effects of HSP-70 gene transfect was demonstrated by down-regulating blood proinflammatory cytokine level, inhibiting the activation of MAPKs in heart, lung and liver at their control level and so on. These results suggested that tranfer of HSP-70 gene and up-regulation of its expression in the body provide the protective effects against sepsis and MODS. Hsp-70 gene tranfect might be of clinical relevance in the prevention and treatment of sepsis and MODS.