Interleukin1 (IL-1) and tumor necrosis factor (TNF) are hormone-like regulatory proteins which participate in many phsyioogical and pathophysiological processes. INflammatory mediator functions have been attributed to these cytokines but their importance in local acute inflammatory responses has not been clarified. We hypothesize that coordinated intrapulmonary production of IL-1 and TNF is an important regulatory process in the evolution of acute immune complex induced lung injury and that these cytokines substantially influence the intensity and character of the inflammatory response. IgG immune complex lung injury in the rat is complement and neutrophil-dependent while IgA immune complex lung injury is complement-dependent but apparently macrophage or monocyte mediated. A parallel series of in vivo and in vitro studies using these complementary models should provide insights into the functions of IL-1 and TNF in the context of two distinct pathogenetic sequences. Using specific neutralizing ant-cytokine antibodies and recombinant or highly purified IL- 1 and TNF, in vivo studies will be employed to directly examine the intrapulmonary requirements for these substances in the development of immune complex lung injury. Influxes of specific populations of inflammatory cells (monocytes, neutrophils and interstitial lung macrophages) will be analyzed using in vivo radioisotopic cell labeling studies. Using neutrophil an complement-depletion procedures, the regulatory influences of complement and neutrophil influx on intrapulmonary IL-1 and TNF elaboration will be assessed by measuring the biological activities of these cytokines in lung lavage fluids and inflammatory cells at different time points during the evolution of lung injury. Parallel in vitro studies using cytokine bioassays, biochemical analyses, and mRNA hybridization techniques (dot and Northern) will focus on mechanisms through which immune complexes and complement regulate IL-1 and TNF production. Recent studies suggest that Il-1, and TNF and supernatant fluids from zymosan activated alveolar macrophages potentiate oxidant production by rat alveolar macrophages activated with immune complexes. Biochemical and functional analyses of effector cell oxidant production and enzyme secretion will be carried out to investigate the mechanism(s) operative in this potential amplification process. the proposed studies focus on mediator function of IL-1 and TNF in the context of two distinct lung injury models and will therefore help clarify their role i pulmonary inflammation as well as provide a rational basis for future investigations of mechanisms that underlie broader groups of inflammatory diseases.
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