Tobacco Documents Online

Tur•. COU.CIL FoR ToBAcco REscARCx-C.S.A., Irc. MEMOMNDUFf TO: Dr. S. C. Sommers FROM: D. H. Ford, R. C. Hockett and D. Stone August 3], 1982 11 ~01 16.5054 SUBJECT: Site visit with Dr. J. E. Repine and staff, Webb-Waring Lung Institute, Denver Colorado, August 23, 1982. Grant No. 1322 MR1; "Basic Mechanisms of Lung Injury from Inhaled Oxidants." ~ The general review of this program and the discussion of specific areas of interest by Dr. Repine and his colleagues followed closdly Progress Report No. 2 covering the work period of from January 1, 1981 to December 31, 1981. Briefly stated the following comments in review were made: 1. Dr. R. Harada.... Hyperoxia has a toxic effect on PAMs, causing them to release factors which influence migration of PMNs to the alveolar region and activate them to form and release proteases, etc. Further, the inflammation caused by hyperoxia induces an inflammation which is associated with a release of albumen into the alveolar spaces. This presumably involves injury to alveolar capillaries. 2. Dr. R. Tate and his group have been working on the possibility that free radicals have an effect on prostaglandins, thromboxanes and leuco- trienes. They have been using an isolated rabbit lung model. Their preliminary data suggest that 02 radicals trigger generation of thromboxane that results in pulmonary hypertension. This was based on observations that purine +xanthine oxidase increase the mean perfusion pressure in the isolated lung model, which parallels the increase in thromboxane B2 which occurs with such treatment. Sug- gests following questions to be investigated: Are other vasoconstrictor pro- staglandins involved, 2. What is the source of vasoactive arachidonate metabolites (plstelets, PhVs, PAMs? 3. Are arachidonate metabolites involved in the patho- genesis of 02 radical induced increases in alveolar-capillary membrane perm- eability? Leukotrienes? Dr. White (member of the Tate group)p using an isolated rat lung prep- aration is working on determing the means whereby the endothelial cells protect themselves from free radical injury...looking for enzymes which are free radical scavengers and the cell types involved. Dr. J. Jackson (also in the Tate Group) reported on preliminary work she has undertaken in vivo in the rabbit demonstrating that 0 radicals increase throm- boxane with subsequent induction of pulmonary edema. Dr.2Clifford (Tate group) is looking for new markers showing the action of 02 radicals following the pro- duction of methane gas after treatment with DMSO. Can measure level of 0 radical produced in vivo and could be used with humans to determine base levels oi free radicals produced. Could be used to determine effects of smoke, etc. Further could determine if there are elevated levels in patients with chronic lung disease.

ff K"! 116 05 055 The bMSO could be administered IV. and results correlated with protease action or levels of desmosine or d 1-AP fragments. Dr. R. M. Sandhaus has just started col.laboratirag with the Repine group. Is interested in effects of 0~ radicals on protease-antiprotease inter- actions. Discussed primarily the tecFiniques to be used. Little data as yet accumulated. May cause lung damage by inactivating prot6ase inhibitors. Dr. Af. Bowman's group is investigating the damage to endothelial cells produced by hyperoxia, which causes them to undergo cytoplasmic changes and finally necrosis (see progress report). What happens to them which makes them mote attractive to binding by PMNs. While focus of this study is at capillary level, it is recognized that hyperoxia could also affect endothelial cells else- where, leading to their damage followed by subsequent exposure of the smooth muscle cells and then atherosclerosis. Observation: A well rounded group with both clinical and basic interests, actively considering the problems of the mechanisms whereby free 02 radicals can induce pulmonary and vascular damage. While they are currently using animal models, some of their future studies should lead to human application. A number of inter- esting future models were discussed. One considers the application of cultured endothelial cells grown on one side of a semipermeable membrane with smooth muscles or fibroblast cells grown on the opposite side wherein the combined culture would be more representative of the normal endothelia;-basement membrane-smooth mu.scle/ fibroblast organization of capillaries or small arterioles, and then determine the effect of hyperoxia. Progress appears to be being made in all 4 major areas invest- igated. We all agree that this is a well organized, highly motivated knowledgeable group which merits continued support. D. H. Ford R. C. Hockett D. Stone DHF/ps