Bacterial pneumonia substantially contributes to the morbidity and mortality among individuals abusing alcohol. The goal of this project is to elucidate the in vivo events that lead to impaired lung host defense against infection in acute and chronic alcohol-treated rats. We proposed that alcohol disrupts the normal evolution of proinflammatory cytokines elaborated by the alveolar macrophage (AM) during the course of an infectious challenge which leads to an acquired immunodeficient state. Our previous work has shown that alcohol suppresses AM expression of tumor necrosis factor-alpha (TNF), which is known to be a potent stimulus for the AM to produce granulocyte colony-stimulating factor (G- CSF). G-CSF is a cytokine that increases both the number and function of neutrophils (PMN). It is our hypothesis that alcohol-induced inhibition of AM-derived TNF directly contributes to the adverse effects of ethanol on PMN function and host defense by suppressing the normal autocrine amplification pathway responsible for macrophage G-CSF production. This proposal will test this hypothesis in a rat model and has 4 Specific Aims; 1) to characterize the effect of alcohol on cytokine responses to in vivo and ex vivo LPS challenge; 2) to delineate the mechanism(s) of alcohol-induced suppression of TNF and G-CSF; 3) to determine the role of endogenous G-CSF on the antibacterial defenses of the lung and PMN kinetic during an intrapulmonary infectious challenge; 4) to examine whether exogenously administered cytokines can reverse or attenuated the host defense deficits induced by alcohol. To accomplish these aims we will: a) examine the effect of alcohol dose on LPS-induced suppression of TNF and G-CSF both in vivo and ex vivo in isolated AM, the duration of this suppression, and whether depletion of TNF alters the in vivo and ex vivo LPS-induced G-CSF responses; b) determine if alcohol- induced increases in corticosterone contribute to the immunosuppressive effects of alcohol on lung host defense; c) examine the effects of an anti-G CSF antibody on pulmonary antibacterial defense and neutrophil function during an infectious challenge; d) determine if the administration of gamma-interferon and/or G-CSF attenuates the suppressive effects of alcohol on lung host defense. The identification of the basic mechanisms underlying alcohol-induced suppression of lung antibacterial defenses will increase our understanding of the host- cytokine network and may provide the foundation for innovative approaches in the treatment of these infections in susceptible patients.
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