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C tt. . s P , November 4, 1977 MEMoRANDUM TO: W. T. Hoyt FROM: Leonard S. Zahn SUBJECT: American College of Chest Physicians Las Vegas, Oct. 30-Nov. 3, 1977 CC: AY WUG RCH WK The major items of relevance at this meeting were the two papers reported from the industry-supported Harvard project under the direction of Gary Huber. Of these, the greatest interest was focused (prior to the meeting) on the paper dealing with lung tissue changes in rats after they were exposed to cigarette smoke. Because all con- cerned have received the full texts of the two papers (which were presented without change), there is no need to describe their contents. However, it might be of in- terest to describe certain events related to these papers and for that I'll go back to last year's ACCP meeting in Atlanta. At the October 1976 meeting, Huber gave a paper on the "super macrophage" aspect of the project. He was in- terviewed by several press people, among them a lay re- porter for the local Un.ited Press International bureau who subsequently wrote a story that moved on the syndi- cate's newswires. This story appeared in the Boston Globe and, I was told, Huber later called the ACCP's public relations spokeswoman to complain that he had been mis- quoted in a certain part referring to the Surgeon Gen- eral's 1964 report. (Actually, as I recall the press conference, the UPI reporter wrote down what Huber had told her, he read it and approved it.) He said he would never again agree to talk with the press (presumably he meant the lay press) at future ACCP meetings. Subse- quently, I learned, AACP's top people, apparently want- ing to avoid any kind of publicity, decided that lay writers would i2ot be notified of, or invited to attend, ACCP meetings. Such was the case for the Las Vegas ses- sion. Apparently advance notices and information were sent only to a few medical and paramedical journals. I received an invitation to attend. Medical Tribune and International Medical News Service (which publishes six medical specialty newspapers were represented in the press room as were a few drug company "house organs." (The Huber paper was discussed with the medical writers.) A local newspaper reporter, who had somehow heard of eonard v ] __ PUBLIC RELATIONS.COUNSEL uanl ~d~"A~ssociales,lnc. (P. 0. BOX 223) 13 LINCOLN ROAD • GREAT NECK, N.Y. 11021 •(212)~895-7445

2. the meeting,, appeared in the press room but was told the material was highly technical and not of any general news interest. On Sunday (Oct. 30) I saw Huber at the meeting hotel and he asked if I had received copies of the papers he"d sent the day before to the project's sponsors. I said they must have arrived after I'd left New York and asked if he had extra copies. He said he did not but that members of his group would be arriving later that day in Las Vegas with some copies. On Monday morning Huber told me that on Saturday (Oct. 29) the Harvard news office had mailed copies of the two papers, with a brief covering,note, to about 40 major newss outlets (e.g., Washington Post,, New York Times, etc.). He also told me he'd given the press room single copies of both papers to be reproduced. - Just before this, the ACCP's public relations woman told me Huber had informed her he would not discuss the papers with any press people. Huber delivered his paper late Tuesday afternoon (the program had listed another member of his group as lead author;, the text given to the press room had Huber as sole author). The other Harvard paper was delivered after a few other papers were presented. About 90-100 persons were in the meeting room.' After the session, in the corridor outside, Huber asked me my assessment of reaction to his paper. It roused no apparent interest, I said, and he agreed. (There were a few questions: was there evidence of any inflammatory reaction (increased number of neutrophils) and was there measurement of elastic recoil? Huber replied: "These changes" were seen in both~controls and exposed animals but they have not yet been quantified in terms of putting numerical values on them. As.for recoil, it was important first to describe a morphological response and t'we are now in the process of evaluating that.") Huber then told me that on Monday the Harvard news office had issued what he called a "newsletter" on his paper, apparently to the same press list to which copies of the texts of the two papers had been sent on Saturday. The text of the "newsletter" had been read to him on the phone, he said, and he had approved it. He did not know whether it was an actual press release, whether it had been messengered to local (Boston) media or sent by

regular mail. The text of it seemed to be a little longer than his original paper, he said, and included comments that had been discussed several weeks earlier for a pos- sible release by Harvard. He told me the medical editor of the Boston Globe had prepared an article on the paper for the Sunday edition but would run it earlier, if any news medium carried something,. (I've not heard of, or seen, any press coverage as of today.) -0- Other items of interest: 1. At a symposium on parenchymal lung disease,, Charles Kuhn III of St. Louis (Washington U+niversity) spoke on emphy- sema, reviewing evidence for the hypothesis that the dis- ease results from~proteolytic enzyme destruction of lung tissue. The chief cause of emphysema is tobacco smoking, he said. Some.of his comments bear mentioning: Several lines of evidence make alveolar macrophages "appealing" candidates for a source of elastase that causes emphysema. Autopsy studies of young cigarette smokers who died accidentally have found lesions consistently seen in smokers and not in nonsmokers -- respiratory bronchiolitis. This condition really consists of the accumulation of macrophages in the respiratory bronchioles. Lungs of cig- arette smokers contain up to 10 times as many macrophages as do lungs from nonsmokers and these macrophages appear to be activated. These are large cells filled with lysosomal granules that contain a yellow pigment (he used slides to illustrate his talk) which appears to be derived from the waxy material in the tobacco leaf. These lysosomes also seem to contain needle-like crystals that appear to be particles of clay which get on the tobacco leaf during curing and also can be found in the tobacco smoke. Their importance is that they may serve to activate the macrophages. Macrophages from smokers, compared with those from nonsmokers, have increased acid hydrolase content, increased protease ac- tivity, increased glucose utilization,, andwill aggluti- nate (cause adhesion and clumping) with a plant lectin, Con A, to indicate there is some alteration in the prop- erties of the membrane. They have diminished pinocytosis (cellular process of engulfing liquids from~tissue) but they appear to be competent at killing bacteria.

4. C Very little is known about human alveolar macrophages a~nd the elastase they synthesize and secrete but do not store. A recent important finding is that macrophages from cigarette smokers' lungs have more elastolytic activity than do those from nonsmokers. This is based on studies with cells lavaged from the lungs of four smokers a_ad~four nonsmokers. Because smokers' lungs contain more macro- phages than do lungs from nonsmokers, it's evident that several-fold more elastase must be released into the lungs of smokers than into the lungs of nonsmokers. It's not known what is actually happening in the lungs of man. A way is needed to determine whether elastin de- gradation is occurring, e.g., in patients with alpha -anti- trypsin (AAT) deficiency or in heavy cigarette smoke~s. There are preliminary data from one laboratory which is working with animals. Elastin has cross-links called desmo- sines (?); these are not found in any other body protein and, therefore, urinary excretion of desomine can be used to measure elastin degradation (at least in experimental animals). "With luck, then," urinary desmosine will dis- close whether elastin breakdown occurrs at a measurable rate in high risk populations such as heavy smokers or in- dividuals with AAT deficiency. Shouldit be established that elastolysis is important in the pathogenesis of emphysema in man, what does this mean for therapy? Prevention of smoking is the logical way to minimize emphysema as a public health problem. For high risk populations who have an 80% chance of developing ob- structive lung disease, it might be worthwhile to try pro- phylactic intervention: prevent elastase release from in- flammatory cells or inhibit elastase extracellularly (i.e., replace the absent inhibitors). Once the pathogenic enzymes can be isolated and puri- fied, synthetic inhibitors can be made. Such inhibitors have been made for leukocyte elastase but they are too toxic for use in man. No such inhibitors are available for elastase from alvelolar macrophages. AAT can be puri£iedefficiently and in large amounts. It's unlikely AAT is immunogenic. Its half-life is suf- ficiently long so that consideration might be given to injecting it periodically in AAT-deficient subjects. How- ever, no trials have been undertaken. Another approach is to limit elastase release from macrophages. Tetracyline has been found to be an elastase inhibitor.

2. "Effect of carbon monoxide on exercise performance in chronic obstructive lung disease" -- Wilbert S. Aronow, Irving,, Cal. Studies have shown that increased carboxy- hemoglobin (COHb) levels cause a significant reduction in exercise performance in patients with angina pectoris, in patients with intermittent claudication and in normal per- sons. A study was undertaken on the effect of increased COHb levels -- of the magnitude that could occur after cig- arette smoking or heavy carbon monoxide (CO) pollution -- on exercise performance in patients with chronic obstruct- ive lung disease (COPD). Subjects were 10 men (mean age 59.2 years) with COPD, ex-smokers, no history of cardio- vascular disease. During the double-blind, randomized, cross-over study, the subjects breathed 100 ppm of CO vs. compressed, purified air for one hour during exercise periods. There was decreased exercise performance after breathing CO. The conclusion: IncreasedCOHb levels of the magnitude seen after smoking or heavy atmospheric CO pollution im- pair exercise performance in COPD patients. "This signif- icant reduction...is probably a cardiovascular limitation rather than a respiratory limitati;on." 3. "Pulmonary function abnormalities in garnetting workers exposed to synthetic fibers" -- William Rom, Salt Lake City (Irving Selikoff listedas a co-author . Garnet- ting consists of recycling and shredding to fiber form various synthetic and natural fabrics. The purpose of the study was to see what effects synthetic fiber dust had on the lung. Subjects included 53 male garnetters and 133 unexposed male controls who lived in the same area of Hudson, N.Y. Forty-four of the garnetters were smokers, five had never smoked, four were ex-smokers. Thirty-one of the workers had lung,obstruction as measured by various functional criteria; 26 of the men were smokers. The prev- alence of obstruction was the same with or without the presence of smoking history. However, the number of non- smokers was small. The garnetters had a significantly greater prevalence of abnormaliy when compared to the controls. Differences in certain lung functions for the two groups were significant only for those with a history of smoking. Q C.7 4. "Diagnosis of asbestosis in a longitudinal survey **J of pipe coverers" -- Raymond L.H. Murphy, Boston. A study ~ was begun in late 1965-early 1966 of 101 shipyard pipe ~ coverers and 95 other yard workers not exposed to asbestos ~ X-rays, lung sounds and lung function tests were used to formulate diagnostic criteria for "asbestosis" over a period

6. of time (there were no biopsies). Abnormalities were more common in the pipe coverers than in the controls in 1965 and were found to have increased when the groups were re- examined in 1972. In Q and A, Marvin Sackner of Miami suggested that perhaps the pipe coverers smoked more than did the controls and that there was a synergism between asbestos and smok- ing. Murphy said cigarette smoking rates between the sub- jects and controls were similar -- 56% in pipe coverers in 1966 and 54/ in the controls. A similar breakdown ex- isted for ex-smokers and nonsmokers. Therefore, he said, the abnormalities seen were not attributed to smoking. -0- Joseph C. Ross, a pulmonary internist from Charleston, S.C., was installed as the new president of ACCP. He is professor and chairman, department of inedicine, Medical University of South Carolina.