Expression And Gene Modulation Of Tumor Necrosis Factor Receptor In Multiple Organ Failure

Multiple organ failure(MOF) is the most dangerous complication after trauma and infection. The incidence of MOF in population of high risk is about 6% to 7%. MOF develops rapidly and has a high mortality from 30% to 100%, in average about 70%. The mechanism of MOF is very complicated. There are two different types of MOF, rapid single-phase and delayed two-phase. The latter is met more often in clinic.To better understand the pathogenesis, the pathological process and the mechanism of MOF, experimentation to replicate an ideal animal model is mandatory. So rat model of MOF was first replicated in our study. 36 healthy male SD rats weighed from 250g to 300g were randomly divided into three groups which were subjected to hemorrhagic shock(group H, n=10), endotoxiemia (group E, n 10) and hemorrhagic shock plus endotoxiemia (group M, n=l6) respectively. Blood specimens were collected at pre-hemorrhage and the terminal for serum SGPT, SGOT, Cr, BUN and gas analysis, which were used to judge if MOF happened by comparing with itself. The pathomorphology of major organs were observed. The incidence and mortality of MOF in group M were respectively 100% and 50%, both much higher than the others. Two-hits were used in this experimentation, which simulated clinical features of delayed two-phase MOF. It was successful to reproduce the animal model of MOF by this simple and easy method.It has been proved that tumor necrosis factor (TNF) plays a veryimPortant role in the process of MOF. It is dependent on its transmembranereceptor wrR to elicit its function. To further investigate the change ofMRl exPressed in MOF and its significance, RT-PCR andimmunohistochemistry methods were aPplied to detect the exPression ofMRl at the levels of InRNA and protein. TNFRl was increasinglyexPressed in MODS indicated that the function of TN'F could be modulated atthe level of receptor' TN'F is presumed to possess beneficial effects for thehost by stimulation of inflammatory cells and viral replication and may beinvolved in the regulation of normal tissue homeostasis. On the other hand,when the production of this cytokine and its recePor is inaPpropriatelycontrolled harmful manifestations occur. TN'F could protect the cells in theearlier stage of MODS by activating NF- K B, but when there were obstaclesin the process of protein synthesis, the function of TN'F was mainly to inducecellular aPoptosis.AttemPts to control the adverse effects of TNF would be of clinicalimportance. Soluble tumor necrosis factor receptor (swrR) has beenidentified in MOF which interferes with the binding of Wi to itstransmembrane receptor. To stUdy the change of sTN'FRl in MOF, ELISAwas aPplied to assay serum swrRl concentration of group M atpre-hemorrhage and the terminal. Our results demonStrate that the produCtionof sMRl is increased in the process of MODS. This is mainly because ofthe increasing expression and shed of transmembrane wrRl. swrRl isformed and released at the cell surface by cleavage. The shed oftransmembrane T'N'FRl is a self regulating mechanism. The sTNFRl cancomPete for TNF with the cell surface receptor and thus block its activity Itwas therefore suggested that it functions as physiological allenuator of theactivity of TN'F. Thus wr-induced SIRS can be patly reduced. sTNFRlmay be an important agent that blocks hannful effects of TNF, and, therefore, useful in clinical application.