Degradation of airway neuropeptides by human lung tryptase.
Several lines of evidence suggest a possible role for mast cell proteases in modulating the biologic effects of neuropeptides. To explore the potential of such interactions in human airway, we examined the activity of human tryptase, the major secretory protease of human lung mast cells, against several neuropeptides with proposed regulatory functions in human airway. Using highly purified tryptase obtained from extracts of human lung, we determined the sites and rats of hydrolysis of vasoactive intestinal peptide (VIP), peptide histidine-methionine (PHM), calcitonin gene-related peptide (CGRP), and the tachykinins substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). Tryptase hydrolyzes VIP rapidly at several sites (Arg12, Arg14, Lys20, and Lys21) with an overall kcat/Km of 1.5 x 10(5) M-1 s-1 and hydrolyzes PHM primarily at a single site (Lys20) with a kcat/Km of 1.9 x 10(4) M-1 s-1. Tryptase also rapidly hydrolyzes CGRP at two sites (Arg18 and Lys24) with a kcat/Km of 2.7 x 10(5) M-1 s-1. The tachykinins are not hydrolyzed by tryptase. These observations raise the possibility that tryptase-mediated degradation of the bronchodilators VIP and PHM combined with exaggerated mast cell release of tryptase may contribute to the increase in bronchial responsiveness and the decrease in immunoreactive VIP in airway nerves associated with asthma. The favorable rates of hydrolysis of CGRP suggest that tryptase may also terminate the effects of CGRP on bronchial and vascular smooth muscle tone and permeability.
Cardiovascular Research Institute, University of California, San Francisco 94143-0130.
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D000595:Amino Acid Sequence; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000201:enzymology*; D008407:Mast Cells / Q000201:enzymology; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D010451:Peptide PHI / Q000378:metabolism; D013373:Substance P / Q000378:metabolism; D015320:Tachykinins / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism
D009479:Neuropeptides; D010451:Peptide PHI; D015320:Tachykinins; D013373:Substance P; D014660:Vasoactive Intestinal Peptide; D010447:Peptide Hydrolases; C023073:tosylarginine methyl ester hydrolase; D015740:Calcitonin Gene-Related Peptide