THE INHIBITION OF SILICA-INDUCED LUNG INFLAMMATION BY DEXAMETHASONE AS MEASURED BY BRONCHOALVEOLAR LAVAGE FLUID PARAMETERS AND PEROXYNITRITE-DEPENDENT CHEMILUMINESCENCE

The inhalation of silica has been shown to produce a dramatic inflamma tory and toxic response within the lungs of humans and laboratory anim als. 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 pulmo nary 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 intratrach eally instilled with either silica (20mg/0.5 mi saline vehicle) or sal ine vehicle (0.5 mi). Twenty-four hours after the instillations in the non-steroid group, significant increases occurred in total protein, t otal number of cells, neutrophils, and lymphocytes recovered from the lungs of animals treated with silica compared to saline controls. Sili ca also caused dramatic increases in the luminol-dependent chemilumine scence (LDCL) of lung tissue and bronchoalveolar lavage (BAL) cells. T he LDCL reaction was markedly decreased by either superoxide dismutase (SOD) or N-nitro-L-arginine methyl ester hydrochloride (L-NAME). SOD is involved in the enzymatic breakdown of superoxide anion, while L-NA ME, a nitric oxide (NO) synthase inhibitor, prevents the formation of NO. When the superoxide anion and NO react, they form the highly oxidi zing 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 dexamethason e, 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 f urther study in animals, the anti-inffammatory steroids may be useful in the treatment of silica-induced lung injury.