LIVER-LUNG INTERACTIONS DURING GRAM-NEGATIVE ENDOTOXEMIA

点击翻译按钮获取中文摘要

Circulatory shock, inflammation, and organ damage during gram-negative sepsis have been shown to be dependent of the endogenous pro-inflammatory mediators, tumor necrosis factor-alpha(TNF) and interleukin-1(IL-1), after induction from host cells by lipopolysaccharide (LPS). It has been suggested that a cytokine cascade initiated by TNF, amplified by IL-1 and modulated by arachidonic acid metabolites, plays a major pathogenetic role in the adult respiratory distress syndrome (ARDS) with multiple systems organ failure (MSOF) during sepsis. However, the pathways by which altered cytokine kinetics and metabolism affect organ interactions in ARDS are poorly understood. The central premise of the proposal is that the liver, by modulating host regulation of the acute inflammatory response to LPS mediated by TNF, IL-1 and products of arachidonic acid metabolism, is a pivotal organ influencing the pathogenesis of sepsis-related acute lung injury. The objective of the proposed research is to test the HYPOTHESIS that changes in hepatic performance influencing the stimulus-response characteristics of endogenous mediator release and metabolism result in a liver-lung axis of inflammation during gram-negative infection. We plan to characterize the temporal pattern of release by the liver of TNF and IL-1 early (<3 hours) after induction by LPS, intact bacteria, and recombinant (r) TNF using an isolated, perfused rat liver (IPRL) preparation. During ex situ, cell-free perfusion, accompanying changes in the biosynthesis of the cyclooxygenase products, prostaglandins E2,I2, and thromboxane A2 and the lipoxygenase metabolite leukotriene (LT) B4, which influence cytokine expression and inflammation, will also be defined. We will then determine the independent effects of on-going ischemic-hypoxic liver injury, pre-existing hepatocytic damage, up-regulation of macrophage effector function by BCG priming, previous exposure to LPS, and prior in vivo cyclooxygenase inhibition on TNF and IL-1 kinetics in the IPRL. We will further establish whether systemic injections of cell-free perfusates from the IPRL studies alter lung microvascular permeability and alveolar inflammation in intact animals with both normal and impaired liver function. In parallel studies, mechanisms of organ interactions will be determined by analyzing pulmonary responses to individual systemic injections of rTNF and IL-1, and lipoxygenase mediation of lung injury during liver failure will be assessed by administering LTB4. Supernatants from isolated Kupffer cells with and without co-cultured hepatocytes will be compared with IPRL perfusates regarding the time course of TNF, IL-1, and arachidonic acid metabolite release and their effects on the function of cultured alveolar macrophages. Results from these studies should yield new information on the regulation of immune and inflammatory responses to endotoxemia, their derangement with altered hepatic function, and their relation to sepsis-induced acute lung injury. This will enable a synthesis integrating the signal transduction of peptide and non-peptide mediators with organ system interactions, and provide further insight into potential therapeutic interventions to ameliorate ARDS with MSOF.