Chronic lipopolysaccharide exposure on airway function, cell infiltration,and nitric oxide generation in conscious guinea pigs: Effect of rolipram and dexamethasone

This study investigated whether a correlation between airway hyperreactivit y (AHR), leukocyte influx, and nitric oxide (NO) existed in guinea pigs chr onically exposed to lipopolysaccharide (LPS). The effect of the corticoster oid, dexamethasone, or phosphodiesterase-4 (PDE4) inhibitor, rolipram, on t hese features was studied. Airway function was measured in conscious guinea pigs (specific airways conductance) before and after single, double, or ch ronic (nine) LPS (30 mug.ml(-1), 1h) exposures. Airway reactivity to inhale d histamine (1 mM, 20 s) was assessed before and at various times after LPS challenges. Leukocytes and NO metabolites were measured in bronchoalveolar lavage fluid (BALF). AHR occurred at 1 h after a single LPS challenge and was resolved by 4 h. This coincided with reduction and recovery, respective ly, of BALF NO levels. The AHR and NO deficiency were extended to 4 h, afte r a double LPS exposure. Chronic LPS exposures, 48 h apart, initially cause d persistent bronchodilations, whereas later exposures produced progressive ly persistent bronchoconstrictions. There was AHR 24 h after the eighth cha llenge. Twenty-four hours after the ninth LPS exposure, macrophages, neutro phils, eosinophils, and NO metabolites were elevated in BALF. Dexamethasone (20 mg.kg(-1) i.p.) or rolipram (1 mg.kg(-1) i.p.) prevented single and ch ronic LPS-induced AHR, the respective deficiency and elevation in NO metabo lites, and the chronic LPS-induced leukocyte influx. Dexamethasone exacerba ted, whereas rolipram reversed, the chronic LPS-induced bronchoconstriction s. This study demonstrates for the first time that chronic LPS causes persi stent bronchoconstriction, neutrophilic inflammation, AHR, and NO overprodu ction in guinea pig airways. These rolipram-sensitive features suggest the potential of PDE4 inhibitors in airway disease.