The inhibition of silica-induced lung inflammation by dexamethasone as measured by bronchoalveolar lavage fluid parameters and peroxynitrite-dependent chemiluminescence
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The inhalation of silica has been shown to produce a dramatic inflammatory and toxic response within the lungs of humans and laboratory animals. Currently, no effective treatment exists for workers who may have been exposed to the inhalation of silica. The objective of this study was to develop an animal model in which we could evaluate the effect that anti-inflammatory steroids have on the acute silica-induced pulmonary inflammatory response. Male Fischer 344 rats were pretreated with either dexamethasone (2 mg/kg) or saline vehicle (i.p.) on days 1, 3, and 5. On day 6, the animals from the two groups were then intratracheally instilled with either silica (20 mg/0.5 ml saline vehicle) or saline vehicle (0.5 ml). Twenty-four hours after the instillations in the non-steroid group, significant increases occurred in total protein, total number of cells, neutrophils, and lymphocytes recovered from the lungs of animals treated with silica compared to saline controls. Silica also caused dramatic increases in the luminol-dependent chemiluminescence (LDCL) of lung tissue and bronchoalveolar lavage (BAL) cells. The LDCL reaction was markedly decreased by either superoxide dismutase (SOD) orN-nitro-l-arginine methyl ester hydrochloride (l-NAME). SOD is involved in the enzymatic breakdown of superoxide anion, whilel-NAME, a nitric oxide (NO) synthase inhibitor, prevents the formation of NO. When the superoxide anion and NO react, they form the highly oxidizing substance peroxynitrite. This study then implicates peroxynitrite as an agent which may be involved in the silica-induced oxidant lung injury. When the animals were pretreated with the steroid dexamethasone, there was a complete protection against the biochemical, cellular, and chemiluminescent indices of damage caused by silica. The mechanism in which the steroid protects the lung from damage may be due to the ability of dexamethasone to block the induction of NO synthase. With further study in animals, the anti-inflammatory steroids may be useful in the treatment of silicainduced lung injury.
Key wordsSilica Lung Inflammation Dexamethasone Peroxynitrite Chemiluminescence
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- M. Cherniak, The Hawk's Nest Incident: America's Worst Industrial Disaster, pp. 1–194, New Haven Press, Yale University 1986.Google Scholar
- M. R. Becklake,Evaluation of respiratory hazards in the working environment through environmental, epidemiologic and medical surveys. InVIII International Pneumoconioses Conference, Part I, pp. 16–21, 1988.Google Scholar
- T. Gordon and D. O. Amdur,Toxic responses of the lung. InCasarett and Doull's Toxicology, 4th Edition. (Eds. M. O. Amdur, J. Doull and C. D. Klaassen) pp. 383–406, Pergamon, New York 1991.Google Scholar
- J. H. Vincent, D. Mark, A. D. Jones and K. Donaldson,A rationale for assessing exposure — Dose-response relationships for occupational dust-related lung disease. InVIIth International Pneumoconioses Conference, Part I, pp. 151–157, 1988.Google Scholar
- B. Hille, Ionic Channels of Excitable Membranes, pp. 83–113, Sinairer Assoc. Inc., Sunderland, MA 1991.Google Scholar
- G. S. Davis,Pathogenesis of silicosis: Current concepts and hypothesis. Lung164, 139–154 (1980).Google Scholar
- W. N. Rom, P. B. Bitterman, S. I. Pennard, A. Cantin and R. G. Crystal,Characterization of the lower respiratory tract inflammation of non-smoking individuals with interstitial lung disease associated with chronic inhalation of inorganic dusts. Am. Rev. Respir. Dis.136, 1429–1434 (1987).PubMedGoogle Scholar
- B. J. Stuebs, H. J. Cho, N. S. Kwon, M. F. Weise and C. F. Nathan,Purification and characterization of the cytokineinduced macrophage nitric oxide synthase: An FAD and FMN containing flavoprotein. Biochemistry88, 7773–7777 (1991).Google Scholar
- J. J. Denny, W. D. Robson and D. A. Irwin,The prevention of silicosis by metallic aluminum. Can. Med. Assoc. J.37, 1–11 (1937).Google Scholar
- R. Henderson,Use of bronchoalveolar lavage to detect lung damage. Environ. Health Perspect.56, 112–129 (1984).Google Scholar
- K. Van Dyke,Introduction to cellular chemiluminescence: Neutrophil, macrophages and monocytes. InCellular Chemiluminescence. (Eds. K. Van Dyke and V. Castranova) Vol. I, pp. 3–24, CRC Press, Boca Raton, FL 1987.Google Scholar