Ozone (O(3)) is a significant component of atmospheric air pollution and produces detrimental effects in the lung. Although the mechanism of O(3)-induced lung inflammation and injury is unclear, the increased release of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) by lung cells following O(3) exposure may shed some light on this subject. To investigate the role of TNF-alpha in the O(3)-induced pulmonary insult, we intraperitoneally injected rats with either rabbit preimmune serum or rabbit antirat TNF-alpha 1 h prior to O(3) exposure. Approximately 12 h after the end of O(3) exposure the animals were sacrificed, the lungs lavaged, and tissue samples collected for expression of cytokine genes relevant to inflammation. The bronchoalveolar lavage fluid (BALF) was analyzed for albumin as a marker of pulmonary epithelial permeability changes and for fibronectin for its role in lung injury and repair. The lavage cells were collected, counted, and identified to quantitate the inflammatory response. Ozone exposure resulted in a significant increase in BALF albumin and fibronectin as compared to air-exposed controls and a significant increase in BALF polymorphonuclear leukocytes (PMNs). Antibody treatment produced a significant decrease in BALF albumin and PMNs as compared to O(3)-exposed rats given preimmune serum. Antibody treatment did not affect the BALF fibronectin concentration or the total cell count in the BAL. Tissue analysis for gene arrays revealed an activation of IL-1alpha, IL-6, and IL-10 in animals exposed to O(3). The gene expression was downregulated in animals treated with anti-TNF-alpha antibody prior to O(3) exposure. The results suggest a central role for TNF-alpha in the mechanistic pathways critical to lung inflammation. The significance of TNF-alpha in the inflammation and epithelial injury produced by ozone exposure reflects its overall contribution through modulation of other cytokines.
Amiodarone is an antiarrhythmic drug with numerous side effects, the most serious being the development of pulmonary toxicity. We have previously reported that a single intratracheal instillation of amiodarone to Fischer 344 rats results in pulmonary fibrosis within 6 wk of treatment. Presently, the mechanism of amiodarone-induced pulmonary toxicity is unknown. Cytokines that stimulate fibroblast proliferation and/or collagen production may play a role in amiodarone-induced pulmonary toxicity. To investigate this possibility, female rats were given a single intratracheal instillation of amiodarone (6.25 mg/kg), its metabolite desethylamiodarone (5 mg/kg), or vehicle (sterile water). At 1, 2, 3, or 6 wk after treatment the lungs were lavaged and the recovered cells were counted and identified. The alveolar macrophages were isolated by attachment to plastic petri dishes, cultured overnight, and the spent media collected for tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) analyses. Desethylamiodarone treatment resulted in a neutrophilic alveolitis, but the levels of TNF-alpha and TGF-beta were not significantly different from control animals. In contrast, amiodarone treatment resulted in a lymphocytic alveolitis and significantly higher amounts of TNF-alpha were observed at 3 and 6 wk after treatment. A trend toward higher levels of TGF-beta was also noted in the amiodarone-treated group at wk 1-3 but the values were not significantly different from those of controls. In conclusion, the release of TNF-alpha may play a role in the development of amiodarone-induced pulmonary toxicity.
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