Effects of carbenoxolone on alveolar fluid clearance and lung inflammation in the rat

Objectives: 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which requires oxidized nicotinamide adenine dinucleotide as a cofactor, metabolizes endogenous glucocorticoids. Since 11β-HSD2 has been detected in lung epithelial cells, we examined whether carbenoxolone, a potent inhibitor of 11β-HSD, would enhance endogenous glucocorticoid action on lung fluid balance and inflammation. Design: Controlled laboratory study. Setting: University research laboratory. Subjects: Adult Sprague-Dawley rats (n = 66). Interventions: Rats were intraperitoneally injected with carbenoxolone (2 × 10 mg·kg^-1·day^-1 for 3 days) and allowed free access to water and food. Rats were further challenged with endotoxin instillation (1 mg/kg). Measurements and Main Results: We discovered that carbenoxolone significantly increased messenger RNA expression of all three epithelial sodium channel subunits in distal lung tissues (two-fold increase of α-subunit, four-fold increase of β-subunit, and two-fold increase of γ-subunit) as well as in trachea. Carbanoxolone increased the amiloride-sensitive alveolar fluid clearance significantly. When rats were further challenged by endotoxin instillation (1 mg/kg), pretreatment with carbenoxolone significantly inhibited endotoxin-induced increase in lung neutrophils as well as tumor necrosis factor-α and cytokine-induced neutrophil chemoattractant-1 concentrations in serum and bronchoalveolar lavage fluid. Conclusions: These beneficial effects of carbenoxolone on lung fluid balance and inflammation are very similar to those expected when glucocorticoids are introduced exogenously. We conclude that carbenoxolone increased the actions of endogenous bioactive glucocorticoids on lung cells by reducing local steroid breakdown.