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/6(~ / 7`t" sI :r j- REPORT OF SITE VISIT H lt9 17 :ti31 17 SUBJECT: Application 901: George Weinbaum, Ph.D., and Philip Kimbel, M.D., Albert Einstein Medical Center, Philadelphia. "The Effect of Air-Bourne Pollutants on Lung Proteinase: Anti- proteinase Levels. A site visit was conducted at the Korman Building of the Albert Einstein Medical Center on December 10, 1973, from 9:30-11:45 am. Present were Drs. Weinbaum, Kimbelv David Meranze, Bruce Sloan, Ph.D. (Research Associate), and Takemoto (Visiting Fellow). Dr. Weinbaum presented what was in effect an illustrated progress report, including new directions of this work, together with plans for its continuation. Recently the work has been concentrated on dog and human polymorphonuclear leucocyte proteinases - although there have also been some comparative studies with lung macrophages and b lood monocyte extracts. Also, while earlier many of the studies of proteolytic enzymes were conducted with the lungs of living dogs as target tissue, it has proved feasible (as well as much more economical) to use excised lobes. In fact even further econom,y may be effected by injection of subsegments of single lobes, using balloon-tipped catheters and a marker dye mixed with the injectate. Material will be instilled within a buffered solution rather than introduced as an aerosol. Varying substrates have beer, used for testing proteolytic activity, including not only hemoglobin and histone,• and lung tissue as suc:i, but the residuum of lung after treatment with collagenase or, alternatively, the residuum after treatment with elastase. An asset in these studies is that the group appears to be in friendly communi- cation with Dr. Janoff and his group at Stony Brook. The most noteworthy recent findings are: 1. That proteinases capablE of producing emphysema do not necessarily have comparable digestive effects on hemoglobin and other proteins. 2. That bicarbonate b uffers "stimulate" proteolytic activity of leucocyte homogenates, or possibly exert an effect on the system by inactivation or disassociation of an inhibitor. 3. Th at the active material in leucocyte extracts is not the same as collagenase and elastase. This is indicated by the varying re]ative concentrations of the materials active against various substrates in extracts prepared in different solutions from the leucocyte homogenate. 4. That an inhibitor of leucocyte proteinase active in producing emphysema can be obtained in p ulmonary lavage fluid free d of cells by centrifu- gation. This substance also is an elastase inhibitor. Fractionation of this material on DEAE cellulose is being carried out and certain specific active fractions are being isolated.

-2- During the visit a number of histological prepdrations were examined both from in vivo and in vitxo "emphysema" proparations. These clearly differed from controls with good evidence of loss of interalveclar septa. Latoratory facilities were also inspected and these appeared to be adequate for the studies p roposed. The major question to which this group now wishes to address itself is the characterization of the surface extracted limg antiproteinase, its comparison with other inhibitors of the active proteolytic enzymes such as al-antitrypsin, and the assessment of its significance in the pathogenesis of emphysema. This work appears to be in competent hands and is worth pursuing in the manner just outlined. As such it will involve a very large effort on the part of this small group of investigators. Studies on additional effects of oxides. of nitrogen in cigarette smoke, presented in broad outline in the original appli- cation, would add additional complicat:ing factors in the total analysis, and may be somewhat remote in time. The investigators stated that when the time came t o expose animals to pollutants they would seek advice on specifics, especially with respect to exposure to cigarette smoke. This group has just been notified that a grant supporting a major part of th is work has been renewed by the NIH, and will be available in April. Especially since the direction of this work is nc longer the same as that originally presented to the CTR, it was suggested, and the investigatots agreed, to submit a revised protocol that will outline more specifically the particular phases of the plan for which they are requesting additional support from CTR. bt c~7(re) ~rf, ,~, ~vy?~- or ~,~~~~'e~~491r. 12/13/73 AAL/jp