The overall objective of the proposed research is to investigate the generation and catabolism of leukotriene B4 (LTB4) by human polymorphonuclear leukocytes (PMN). Whereas only very small numbers of PMN are present in extravascular sites within the normal lung, numerous PMN are found in the lungs of patients with a number of inflammatory diseases, such as emphysema, idiopathic interstitial fibrosis, the adult respiratory distress syndrome, and asthma. The endogenous factors that cause PMN to accumulate and to promote tissue injury in the lung are not known. It is possible that LTB4, a potent chemoattractant for PMN, may be an important mediator of PMN accumulation in the lung. Human PMN have been shown to generate and respond to LTB4. Results of studies performed by this investigator indicate that PMN also are capable of catabolizing this mediator rapidly, specifically, and primarily by cytochrome P-450-mediated Omega-oxidation. In order to elucidate the roles played by LTB4 and its Omega-oxidation products in regulating PMN function and in mediating tissue inflammation, the applicant proposes the following studies. PMN generation and catabolism of LTB4 will be examined in response to a number of """"""""physiologic"""""""" stimuli. It will be determined specific inhibition of the LTB4 Omega-hydroxylase in human PMN (by carbon monoxide and terminal acetylenic fatty acids) alters PMN responses to cell stimulation. The LTB4 Omega-hydroxylase will be further purified by subfractionating the membrane fraction obtained from human PMN, and it will be determined whether human PMN possess mixed-function oxidase activities other than the Omega-oxidation of LTB4. Finally, the variability of LTB4 Omega-hydroxylase activity between different normal donors will be investigated. Since cytochrome P-450 enzymes are frequently inducible, pharmacologic agents that induce synthesis of the LTB4 Omega-hydroxylase in PMN precursors may augment catabolism of LTB4 by mature PMN and, consequently, reduce acute inflammation in the lung and other tissues. Although generation of LTB4 by PMN might promote inflammation, catabolism of LTB4 by PMN may be a mechanism whereby inflammatory reaction are modulated. A better understanding of the processes which control the balance of LTB4 generation and catabolism may contribute to the development, and rational application, of new therapeutic agents for the treatment of inflammatory diseases of the lung and other tissues.
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