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Apical trypsin increases ion transport and resistance by a phospholipase C-dependent rise of Ca²⁺

Departments of ¹Anesthesiology, ²Physiology and Biophysics, ⁵Microbiology, and ⁴Medicine (Division of Nephrology), University of Alabama at Birmingham, Birmingham Alabama; and ³Section of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, New York

Submitted 25 October 2004 ; accepted in final form 27 December 2004

We investigated the mechanisms by which serine proteases alter lung fluid clearance in rat lungs and vectorial ion transport in airway and alveolar epithelial cells. Inhibition of endogenous protease activity by intratracheal instillation of soybean trypsin inhibitor (SBTI) or ₁-antitrypsin decreased amiloride-sensitive lung fluid clearance across rat fluid-filled lungs; instillation of trypsin partially restored this effect. Gelatin zymography demonstrated SBTI-inhibitable trypsin-like activity in rat lung lavage fluid. Apical trypsin and human neutrophil elastase, but not agonists of protease activated receptors, increased Na⁺ and Cl^– short-circuit currents (I_sc) and transepithelial resistance (R_TE) across human bronchial and nasal epithelial cells and rat alveolar type II cells, mounted in Ussing chambers, for at least 2 h. The increase in I_sc was fully reversed by amiloride and glibenclamide. The increase in R_TE was not prevented by ouabain, suggesting that trypsin decreased paracellular conductance. Apical trypsin also induced a transient increase in intracellular Ca²⁺ in human airway cells; treatment of these cells with BAPTA-AM mitigated the trypsin-induced increases of intracellular Ca²⁺ and of I_sc and R_TE. Increasing intracellular Ca²⁺ in airway cells with either ionomycin or thapsigargin reproduced the increase in I_sc, whereas inhibitors of phospholipase C (PLC) prevented the increases in both Ca²⁺ and I_sc. These data indicate trypsin-like proteases and elastase, either present in lung cells or released by inflammatory cells into the alveolar space, play an important role in the clearance of alveolar fluid by increasing ion transport and paracellular resistance via a PLC-initiated rise of intracellular Ca²⁺.

elastase; short-circuit current; sodium; chloride; lung fluid clearance

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