MECHANISMS OF BIOLOGICAL EFFECTS OF HUMAN AIRWAY TRYPSIN-LIKE PROTEASE (HAT) ON BRONCHIAL CELLS AND PATHOLOGICAL ROLES OF HAT IN THE AIRWAY DISEASES

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1. Contents of human airway trypsin-like protease (HAT) in sputum : There was no difference between HAT concentration in sputum from healthy volunteers and that from patients with chronic airway diseases. Because the patients have more abundance of secretion of bronchial lavage fluid than healthy volunteers, it is considered that the production of HAT in airway of patients is enhanced and HAT causes the progress and amplification of disease2. Mechanisms of proliferation enhanced by HAT on normal human bronchial fibroblasts : HAT enhanced proliferation of bronchial fibroblasts in serum-free medium with or without transferrin. Protease-activated receptor-2 agonist peptide (PAR2AP) enhanced proliferation of bronchial fibroblasts in serum-supplemented medium with transferrin. Leupeptin (serine protease inhibitor) and U0126 (MEK inhibitor) inhibited HAT induced proliferation of bronchial fibroblasts. Western blot analysis showed that HAT promoted the phosphorylation of MAP kinase. It was concluded that HAT enhanced the proliferation of fibroblasts through MAP kinase signal transduction, but not through PAR23. Enhanced synthesis of IL-8 by HAT on human bronchial epithelial cells (HBEC) : PAR2 mRNA was detected in HBEC with reverse PCR. Induction of IL-8 mRNA and release of IL-8 were increased by addition of HAT and PAR2 agonist peptide on HBEC. It was concluded that enhancement of IL-8 synthesis by HAT on HBEC was resulted from a sequential activation process : PAR2 activation by HAT, EGFR activation by transactivation and MAP kinase activation4. Activation of PAR2 by HAT on bronchial epithelial cells : Activation of PAR which coupled with G-protein increases the concentration of free Ca^<2+> in cells. Concentration of free Ca^<2+> in HBEC was increased by stimulation of HAT and PAR2 agonist peptide. It was concluded that HAT controlled the metabolic function of HBEC through activation of PAR2