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Inhibition of Epithelial Sodium Channel Activity by Inter‐α‐Trypsin Inhibitor

Entry of sodium (Na+) ions in lung epithelial cells through amiloride sensitive Na+ channels (ENaC) is the first and limiting step in vectorial Na+ transport, a crucial step in lung fluid homeostasis. Previous studies have shown that serine protease inhibitors decrease ENaC activity by inactivating channel‐activating proteases. Inter‐α‐Trypsin Inhibitor (IαI) is a serum protease inhibitor which is present in the alveolar spaces following lung injury. We therefore tested whether IαI decreased ENaC activity. In the first series of experiments we measured the open probability (Po) of ENaC channel in alveolar epithelial cells of mouse lung slices by patching them in the cell attached mode. Incubation of lung slices with IαI (0.1 mg/ml) for 2 h decreased the Po of both ENaC and cation channels by about 50%. Incubation of lung slices with an antibody against IαI, had no effect. In the second set of experiments, we incubated Xenopus laevis oocytes, injected with human α, β, and γ‐ENaC cRNAs for two days, with IαI and measured amiloride‐sensitive current‐voltage relationships. IαI (0.1 mg/ml) decreased amiloride‐sensitive ENaC currents by about 70% with a half‐time of inhibition of about 12 min. Trypsin (2 μM), added after IαI, reversed the effects of the IαI indicating that IαI decreased the number of active ENaC channels but not total protein levels. These data suggest, that IαI may contribute to ENaC down‐regulation in various forms of inflammatory and oxidative lung injury.