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C DA-00566-05 Page 34 Numerical Density of Secretory Cells: As are shown in Figure 17, exposure to marijuana smoke resulted in a decrease in the number of unstained secretory cellis and, to a lesser degree, total secretory cells in the tracheal epithelium, and an increase in the number of stained secretory cells in both male and female rats, with~a larger change in the female. As presented in Figure 18, the increase in the number of stained secretory cells after exposure to the smoke was associated significantly (r = 0.37; significance level = 0.0186) with the increase in the epithelial thickness. No significant correlation was found in the decrease in the number of total and:unstai~ned secretory cells versus the increase in the epithelial thickness for the number of animals studied. PuZmona.m.4 Parenchyrr.aZ N.'orp~oZogy: Acceptable animal models that demonstrate a clear-cut cause an&effect relationship betweenismoking and the development of emphysema have never previously been reported. In our relate&studies on the adaptation of the lung following chronic exposure to wholle tobaceo smoke, our animals had an approximate 20% loss in their pulmonary parenchyma distal to the terminal airways, with a proportional loss in their alveolar surface, after 180 consecutive days of exposure. If these effects are not reversible (which is still under study),, this represents, by definition, emphysema. The roLe of the structural and metabolic exposure that we have reported for the alveolar macrophage following exposure to tobacco smoke, as potential mediators in the morphological alterations demonstrable in the airways and lung parenchyma, remains to be determined. We have hypothesized, however, a role for the macrophage as a mediator in development of both;emphysema an&chronic bronchitis, as recently reviewed at an invited presentation to the NCI Smoking and Health Program workshop (manuscript enclosed as Appendix B). This hypothesis will be presented in greater detail, with additional supporting data, at the 22nd Aspen Chest Conference in Colorado this coming June (abstracts enclosed, Appendix B). We have reproduced the six-month tobacco smoke inhalation study described in our last annual report. We have also completed inhalation regimens in matched animals exposed to the gas phase alone of tobacco smoke and to whole marijuana smoke as an additional step in our comparative evaluations. The pulmonary parenchymal tissue samples from these animals have now been sectioned and are currently being analyzed. In addition, whole body and organ weight determinations have been completed on animals exposed for 180 consecutive days to whole tobacco smoke, to whole marijuana smoke, and to the gas phase of tobacco smoke alone, with~matched controls. Finally, physiologic evaluations of the lungs from animals exposed to whole tobacco smoke, whole marijuana smoke, and the gas phase of tobacco smoke alone, with~matched controls, have been undertaken by quantifyi~ng the volume-pressure relationships in representative animals from each group. It would appear, at this point in our evaluation, that the tissue elastic recoil of the lung is significantly altered by whole tobacco smoke, providing a physiologic correlate to the structural analyses that demonstrated a reduction in lung parenchyma distal to the terminal airways and a corresponding reduction in the alveolar surface area. It does not appear, at this state of our analyses, that whole marijuana smoke or the gas phase of tobacco smoke 0 alone have comparable effects on the lung. c,i ~ . C.~ . ~

~ ~ DA-00566-05 Page 35 We have been particularly interested in pursuing a better understanding of the role of 1ipoLysosome accumulation and the metabolic events associated with the generation of oxygen radicals by pulmonary alveolar macrophages in the pathogenesis of chronic bronchitis and emphysema, especially in that the macrophage, as the primary line of defense for the lung, is so altered, by tobacco smoke in both our experimental animals and in human smokers. In that these alterations do not appear to be occurring to the same degree, base on our preliminary data to date from animals expose&for limited periods, after exposure to marijuana smoke or to the gas phase of tobacco smoke alone, it is further intriguing to postulate their importance as mediators in the initial lung damage that leads to emphysema and bronchitis. Unfortunately, the tobacco industry, on whose support our overall program continuationAepends, has terminated their future support for reasons unstated, an&we may never have the opportunity to develop these important observations to thei~r full understanding.