Tobacco Documents Online

4 ~ . _ . .. . . . ~...._ . ~ --.-~.: i-~ . . . . .- . .. _ . _ _ . _ . ..._ ~ L . ~. . ..... ._.u.... .~..~.~.._._.._~._~....~._~___......~_ ..~. THT•. COUNCIL FOR TOBACCO RESEARCH-U.$.~l.. INC. Merorandun Rb. Dr. S.C. Scampss and Staff F'ran : D.H. Ford and R.C. Hockett Re: Site visit with Dr. J. Repine and• staff at the Webb-Waring Institute in Denver Colorado, August 15, 1983 Grant No. 1322 M R2, entitled "Basic Nlechanisms of Iung Injury frrm abCygPS! Radi.cals. ° Personnel :'lhere have been f~oane changes since our last visit. SMe of the residents active in the pr+cmgram have :rnved on to permaneant positions and been replaced by an equa]l number of enthusiastic young people interestsd in p:a].n:onaLy medicine. All are supported by other than CM funds. overviea: Dr. Repine reviewed the orgin and developmeixt of the program and its accartplishments to date, which are impressive. In the last 6 nmonths, 12 presentations have been made at various meetings, and 8 papers were published, while 17 papers have been accepted for publication. (See progress report for titlee) During the past few months they have been . working on an assay for DMSO to be applied to alveolar macropt:ages and PM~ts. Mi1e this will serve to measure the levels of DMSO in cells (indicating the levels of free radicals) , it may also be used to measure rate of change (irxcrease or decrease) of the level of free radicals. Such an assay will presumably be useful in measuring the degree of effectiveness of free radical scavengers. Dr. Repine also described the perfused lung preparation they have been using (deronstrat~ed in actual functioning state in the laboratoacy) . He will be subnitting an addendum to his report to deionstate what measurps they have undertaken to verify the viability of this preparation. Presentations by Staff: Dr. Ruth Harada: dhserved that hyperoxia causes PAM to release factors which recriut PMtvs fran blood, activating them to release free radicals and elastase. 7his is similar to her o;mments of last year. Naa, hawever, she has noted that PAMs not only release a chemtauin to attract PrIINs, but another chanical factor which prevents the acctamil.ation of Ms. 7his latter factor is enitted if the PAFLs are not stimulated. Thus, PAMs attracted by hyperoxia or injury beooane activated and release a chewtaxin to attract MAs, while unactivated PAMs would release the seaond cherotaxin, which appears to prevent PMN accuirnilation. , Wfiile Dr. Harada had indicated last year that she would try to characterize the cheaotaxfn, she made little progress other than to note that now there are two bf then with MWs of 5000 and 1000, and that they seen to be proteins. Fturther, she may also have a lipogenase present in the supernatants she has been analyzing so far and which MV earVlicate her separations. Will be proceeding to further evaluate these cherotaxins this year. Dr. C. Michael Hvwman: Dr. Boaenan will be leaving Webb-Waring, but will continue to wo in oon3unc-,ion with Dr. Repine. He has observed that hyperoxia da¢nagce endothelial ee].].s in culture, prestianab.ly by causing them

2 to release oxygen rad.tcals. The damage can be prevented by superoxide dismutase (SOD). Que.stion: Does hyperoxenia induced damage of endothelial cells contribute to the development of atherosclerosis? The MLSO assay under dev+Plopnent will presumably be helpful in this study to determine the levels of free radicals released in endothelial cells subjected to elevated levels. Dr. Janice Jackson: Dr. Jackson has just joined the pxogram and is a pulL-nnary ellow. Sy using a perfused, aereated lung preparation she has shown that free radicals induce vasocontriction by causing a release of the arachadonic acid metabolite, thranboxane e. This was prevented by pretreatmer-t with S(~. Dimethyl thiourea, a cRenfcal free radical scavenger prevented the increase in Pt+Ais and subsequent edeea which follows hyperoxia, but did not prevent the vasooonstsiction and release of' thrcnboxane. She concludes that the increase in blood pressure followin hyperoxia in the perfused lung systen does not cause the lung damage, which increasingly appears to be due to the presence of the MNs attracted by the ch~.erotaxin released by the PAMs. Dr. Carl Mite: Dr. idv.te's study is coneerned with mechanisas vde e ung may be protected against free radicals in ARUS and brnnchopu]manary dysplasia. Cbserved that pre-exposure of rats to hyperoxia increased pulMonary levels of SCD, catalase (CAT) and glutathione. F.lzcapsulation of SM and CAT in lysosanes was undertaken and the enzymes injected IV. 7he CAT provedeffective in preventing lung damage from free oxygen radicals. SM was ineffective in this particular mod.el. Dr. Dennis Clifford: Dr. Clifford has observed that RBCs, which oontasns a lot o£ SOb and CAT, when perfused into the isolated lung preparation, decrease the eaaoa and leakage of albumin into lung tissue caused by hyperoxia apparently preventing lung iniutiy. He used RBCs from htmian.s in this study and the question which arose is as to what effect gmking by the human doner would have on the effectiveness of the RBCs in preventing hyperoxia lung injury. Vbuld binding of nicotine to RBC menibrane receptors influence the outoomEa? Ooamient: It seem from Dr. Repine's progress report and fraan the pr~s~senent~onst~ at the Webb-Waring Institute that the group has pretty well established that oxygen free radicals oontribute in a significant way to lung injury, potentially relating to either emphysema ox ' . atherosc '_erosist,Ale a considerable amotimt of chenistiy still needs to be done with the chemotaxins, others lines of investigation wrnuld seans to be emerging:ie., the nature of the signals which turn on or off the release of Cherotaxins or released SOD and CAT or to what degree does the release of these signals differentiate whicli person develops emphysenki or not. This still appears to be an interesting productive pmgrffin with a great deal of reler,rance to the interests of CPR and as such continues to merit our support. D.H. Fbrd and R.C. Hodtett