PATHOGENIC MECHANISM IN PULMONARY INFLAMMATION

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We will continue exploration of the potential role of cytokines in the development of lung injury, utilizing experimental models and assessment of bronchoalveolar lavage fluid from human beings with ARDS. The relationship of tumor necrosis factor (TNF), IL-1, IL-8 and macrophage inflammatory proteins (MIF's) to leukocytic accumulation and stimulation in the lungs will be assessed in rabbit models. Clear definition of the interaction of IL-8 and its receptors on leukocytes will be essential in order to interrupt this crucial step. Cloned IL-8 and IL-8 mutants, bearing mutations in the N-terminal and C- terminal regions, outside of the cysteine bridges, have been constructed. These will be assessed for binding to cells bearing IL-8 receptors A and B and to induce a signal transduction. In addition, synthetic peptides, derived from the N- and C- terminal regions found by mutational analyses to be critical, will be used to block the interactions. Antibodies, constructed to region of IL-8 found to be crucial for the interaction of IL-8 and related molecules with these receptors, will be used to block in vitro IL-8 and MIP-receptor interactions and modulate IL-8 responses in vivo in two rabbits models of ARDS. Bronchoalveolar lavage fluids from patients with ARDS will be assessed for evidence of cytokine activity. The effect of exogenous surfactant on these cytokines will be examined.