Airway neutrophilia and chemokine mRNA expression in sulfur dioxide-induced bronchitis

Airway inflammation in acute and chronic bronchitis includes a prominent neutrophil influx. Using a rat model of sulfur dioxide (SO2)-induced bronchitis, we investigated the role of the polymorphonuclear leukocyte (PMN) chemokines macrophage inflammatory protein-2 (MIP-2) and KC. Adult female rats were exposed to 230 ppm SO2 for 5 h/day for periods of 1 day to 5 wk. Immunohistochemical identification of rat PMNs in trachea cryostat sections allowed quantitation of a marked neutrophil influx into airways of bronchitic rats (PMNs/trachea ring = 55 +/- 26.2 [1 day SO2] versus 3.6 +/- 2.7 [air]; n = 5, P < or = 0.05). Northern analysis of trachea homogenates demonstrated induction of KC and MIP-2 mRNA expression after 1 day of SO2 and persistence of increased expression after longer exposure periods examined. Pretreatment of rats with dexamethasone (0.5 mg/kg) prior to a 1-day acute SO2 exposure prevented induction of chemokine mRNA and abrogated neutrophil influx completely (PMNs/trachea ring = 6.6 +/- 8.8 versus air controls; n = 5, P = 0.96). To determine if chemokine inhibition by dexamethasone could be further studied in vitro, the rat alveolar macrophage cell line NR8383 was treated with dexamethasone (10(-7) M) before stimulation with lipopolysaccharide (10 micrograms/ml). Pretreatment with dexamethasone substantially decreased induction of both MIP-2 and KC mRNA in response to lipopolysaccharide, indicating the potential utility of in vitro systems to identify additional anti-inflammatory agents. These studies support the hypothesis that the chemokines MIP-2 and KC mediate airway neutrophil influx in both acute and chronic SO2-induced bronchitis in the rat.