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v- TiII: COUNCIL Folt ToBAcc•o RraLaiaczl-U.S9.A., Bc. MEMORANDUM i J February 4, 1980 TO: Drs. Ford, Hockett, Meier, Sommers and Stone n . ;: ~. ~ S FROM: IV. U. Gardner SUBJECT: Application 1322. John E. Repine, M.D., Webb-Waring Lung Institute. Denver, Colorado. "Protection from Cigarette Smoke Induced Lung Injury Using Dimethyl- sulfoxide (DMSO) - A Scavenger of Hydroxyl Radical (-OH).° Applicant. Aged 34 years, M.D. University of Minnesota 1971; intern and resident University of Minnesota Hospitals 1971-75; Instructor, Assistant Professor, Associate Professor of Internal Medicine University of Minnesota 1975-79; AssociaEe Professor of Internal Medicine, University of Colorado 1979-; Assistant Director Webb-Waring Lung Institute, Denver 1979-. His first reported research was on the effects of phorbol myristate acetate on PMNs, the activation of PMNs, their bacterial activity and, more recently, of PAMs. One preprint on increased superoxide anion production by PAMs from young asymptomatic cigarette smokers was enclosed. It was found that -OH radical was higher in PAMs of cigarette smokers. •OH caused the PAMs to release proteolytic enzymes. Dr. Ruth Harada, Instructor in Medicine, will be full-time on the project, M.D. University of Colorado 1974, aged 32 years. Proposal. Four questions are asked and their answers will be sought. AMs of rats exposed to smoke in vitro and in vivo -- also human cigarette smokers -- will be assayed for 'OH release. Thiourea, a potent scavenger for •OH, will be used to detect the extra cellular '0H. Experiments will be done on the mechanism by which CS stimulates the AMs release •0H. It is assumed that the Fenton reaction (Fe++ + H2O2 -J* Fe+++ +•0H +-oH) may form the •0H. Fe++ and Mn** and NADPH oxidase in AMs of smokers and nonsmokers will be examined. The possible direct damage to the lung of •0H, or impairment of alpha-l-antiprotease, or the abnormal release of elastase and attraction of additibn AMs. Will DMSO protect the lungs against injury by CS! It is a scavenger of •OH and an antiinflamatory substance, unusually effective because of its penetrative capacity. The protocols are brief but the investigators have already used most of the procedures required. Budget. A major item is the salaries of a research fellow (R. Harada) and a research technician: approximately $a0,000. The requests for consumable supplies and the maintenance of animals and equipment seems reasonable. He has 2 grants, one from the Americar. Heart Association and one from NIH-HL, which have titles similar to the present application. Three other applications are pending. This laboratory has had a site visit by staff. Comment. This is a proposal for the support of basic research as well as possible applied aspects. It supplements the work by Murad and Janoff. Although the applicant seems somewhnt biased about the involvement of cigarette smoke in the etiology of emphysema, he does state an interest in why far from all cigarette smokers db.wt acquire measurable lung damage. High rating for merit and relevance. W. U. Gardner WUG:ek