Tissue lesions lung damage

The elucidation of the mechanism has revealed that this specificity is due to a requirement for metabolic activation for which the Clara cell is particularly suited. Thus, early studies using radiolabeled 4-ipomeanol found that the compound was localized particularly in the lungs (when expressed as nmol g-1 wet weight of tissue), and was covalently bound to lung protein (Fig. 7.38). This binding was five times that seen in the liver. Furthermore, autoradiography revealed that the radiolabeled 4-ipomeanol was bound to the Clara cells, 

the Vmax for the covalent binding to protein is higher for the lung microsomal enzyme than for the liver, whereas the apparent Km for the lung enzyme is about one-tenth that for the liver microsomal enzyme preparation. The lung enzyme, therefore, has a greater affinity for the ipomeanol and activates it more rapidly. GSH inhibited the binding to protein in vitro. 

Studies in vivo indicated that the cause of death was probably pulmonary edema, as the time course for lethality and edema genesis were similar (Fig. 7.39). Also, the pulmonary edema and lethality showed a very similar dose response, and the covalent binding to pulmonary protein was similarly dose dependent (Fig. 7.38). 

Inhibitors of the microsomal enzymes decreased the covalent binding and the Clara cell necrosis and increased the LD50, even though the blood and pulmonary levels of ipomeanol 

Diethyl maleate treatment, which depletes GSH, markedly increased covalent binding to protein and decreased the LD50. 

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Lung Damage. Several studies have reported serious lung damage on the part of chronic marihuana smokers. Bronchitis, emphysema, and lesions of lung tissue have been noted in marihuana users, but it is not known if it is the kind of smoke (marihuana) or the amount of smoke (any smoke, e.g., cigarettes) that is responsible for the damage. 

Exposure to hexachloroethane vapors can cause irritation to the respiratory system. Acute exposure to 260 ppm hexachloroethane had no apparent effect on the lungs and air passages in rats, but acute exposure to a concentration where particulate hexachloroethane was present in the atmosphere caused lung irritation (Weeks et al. 1979). On the other hand, intermediate-duration exposure to 260 ppm hexachloroethane appeared to cause some irritation of the respiratory epithelium, which may have increased susceptibility to respiratory infection. When exposure ceased, the animals recovered, so there were no histopathological indications of tissue damage after a 12-week recovery period. Lesions of the nasal passages, trachea, and bronchi increased mycoplasma infections mucus in the nasal cavities and decreased oxygen consumption were indicators of respiratory tract irritation from repeated episodes of hexachloroethane exposure. 

In mice exposure to 9 ppm caused a 50% decrease in respiratory rate. Lesions included ulceration and necrosis of the respiratory epithelium and moderate damage to lung tissue. Rats administered, via oral gavage, 10, 20, 40, or 80mg/kg for 10 consecutive days or 32 mg/kg for 90 consecutive days had inflammation, necrosis, acantholysis, hyperkeratosis, and epithelial hyperplasia of the forestomach. Chloropicrin was genotoxic in bacterial test systems."... 

Exposure of the lungs to xenobiotics may result in a number of disease conditions including bronchitis, emphysema, asthma, hypersensitivity pneumonitis, pneumoconiosis, and cancer. During repair, damaged lung alveolar epithelium may be replaced by fibrous tissue that does not allow for gas exchange, which intensifies the damage caused by the initial lesion. 

Almost all patients with disease located outside the lungs should receive antifungal therapy therapy usually is initiated with 400 mg.day of an oral azole. Amphotericin B is an alternative therapy and may be necessary in patients with worsening lesions or with disease in particularly critical locations such as the vertebral column. Approximately 50% to 75% of patients treated with amphotericin B for nonmeningeal disease achieve a sustained remission, and therapy usually is curative in patients with infections localized strictly to skin and soft tissues without extensive abscess formation or tissue damage. The efficacy of local injection into joints or the peritoneum, as well as intraarticularor intradermal administration, remains poorly studied. Amphotericin B appears to be most efficacious when cell-mediated immunity is intact (as evidenced by a positive coccidioidin or spherulin skin test or low CF antibody titer). Controlled trials that document these clinical impressions are lacking, however. ... 

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