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niT•. COIINCII. g''OR ToBAcco RI:sEnRcH -iT.S.A., IxC. 8lugufst 31, 1976 MEMORANDUM TO: Drs. Hockett, Jacobson, Sommers. Stone ar:d Wyatt FItAM: W. td. Gardner StIHJECT: Site Visit. Application 1105. Irving P. Crawford, M.D., Microbiology Department, Scripps Clinic and Research Foundation, La Jolla, California. °heukocyte Elastase-Complement Interactions in the Etiology of Emphysema." Drs. Crawford and Hugli (Department of Mi.crobiology and Department of Molecular Biology respectively) are •really co-investigators. David Stane had talked earlier with Dr. Crawford about his work on the purification of AAT, and later Stone ahd Lisanti had seen him. Crawford is really a medical geneticist and spends approximately half time on human genetics and half on microbiological genetics. He was interested in the genetics of AAT and hence his initial studies. When be heard about Hugli's work on C3a and C5 he became concerned with the possible effects of proteases on these and hence the application. Crawford's first work on AAT was with two sibs - 38-year deceased women and severe emphysema, men 50-years alive and not too greatly handicapped, both smokers. Dr. Kidokoro from Dr. Moser's lab contacted him and Crawford and, a fellow, now a t Mayo's, collaborated in a study of AAT deficient male patients and ..ompared pulmonary deficiency with levels of ATT. Variables other than age and smoking seemed important. This work is in pressi and preprint available. Dr. Hugli has trained and is now associated in Dr. Miller Eberherd's department. The latter has been associated with C3 and C5 complement for years, some work being done with Dr. Cochrane. These complement components can produce anophylotoxins (shock inducing substances). Dr. Hugli has developed a unique method of getting an evaluation of PMN chemotoxis. P lastic valium caps are taped to s carified (epidermis removed by electric razor with no bleeding) filled with media to which inhibitors or stimulators, CS or its derivatives, are added and the PMN's counted for 1, 2 & 3 or more hours. Ta*o hours usually gives reliable numbers. Hug1i had at least ten rounded marks on his arm. As many as 18 tests can be run simultaneously on the same rabbit and two on a mouse. Crawford has been studying human leukocyti c elastase (HLE) and a method of evoking and quantitating PMN chemotoxis was available and a protease - C5 derivative was a powerful chemotactic agent.

2 , .4 !t ~? `.', Q.) +3 .[ () % 9 The objectives,are listed on pages 2b and 2c and were reiterated. The possibility exists of (1) determining persons who may be at risk and,possibly preventing progress of emphysema. The approach is primarily basic PMN elastolytic activity. The pulmonary section at Scripps has increased from 1/2 tu 2 1/2 persons recently. They have adequate human material with blood bank resources combined. Dr. Moser's facility will not be needed. This was a most impressive visit. We met the technician (Coryill) at the amino acid sequencer. The plasma for C5 and PM'N elastase are quite expensive. W. U. Gardner WUG:ek