title: Mast cell chymase modifies cell-matrix interactions and inhibits mitogen-induced proliferation of human airway smooth muscle cells.
abstract: The hallmarks of chronic, severe asthma include prominent airway inflammation and airway smooth muscle (ASM) hypertrophy and hyperplasia. One of the factors that contribute to the injury and repair process within the airway is activation of proteases and turnover of extracellular matrix components. Mast cells, which are present in increased numbers in the asthmatic airway, are a rich source of the neutral protease chymase, which can degrade several basement membrane components. Recent data suggest that proteases also play a critical role in regulating the expression of CD44, the primary receptor for the matrix glycosaminoglycan hyaluronan. In this study we investigated the effects of chymase treatment on human ASM cell function. We found that chymase degraded the smooth muscle cell pericellular matrix. This was accompanied by an increased release of fibronectin and soluble CD44, but not soluble ICAM-1 or soluble hyaluronan, into the conditioned medium. In addition, chymase inhibited T cell adhesion to ASM and dramatically reduced epidermal growth factor-induced smooth muscle cell proliferation. These data suggest that the local release of mast cell chymase may have profound effects on ASM cell function and airway remodeling.
authors.affiliation: Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. alazaar@mail.med.upenn.edu
authors.forename: Aili L
authors.initials: AL
authors.lastname: Lazaar
authors.forename: Michael I
authors.initials: MI
authors.lastname: Plotnick
authors.forename: Umberto
authors.initials: U
authors.lastname: Kucich
authors.forename: Irene
authors.initials: I
authors.lastname: Crichton
authors.forename: Shidan
authors.initials: S
authors.lastname: Lotfi
authors.forename: Susan K P
authors.initials: SK
authors.lastname: Das
authors.forename: Sibyl
authors.initials: S
authors.lastname: Kane
authors.forename: Joel
authors.initials: J
authors.lastname: Rosenbloom
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.forename: Norman M
authors.initials: NM
authors.lastname: Schechter
authors.forename: Ellen
authors.initials: E
authors.lastname: Puré
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D002478:Cells, Cultured; D053818:Chymases; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005109:Extracellular Matrix / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006131:Growth Inhibitors / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008407:Mast Cells / Q000201:enzymology*; D008934:Mitogens / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000166:cytology / Q000201:enzymology*; D012697:Serine Endopeptidases / Q000494:pharmacology / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D012995:Solubility; D014132:Trachea / Q000166:cytology / Q000201:enzymology*
chemical_list: D006131:Growth Inhibitors; D018960:Hyaluronan Receptors; D008934:Mitogens; D004815:Epidermal Growth Factor; D012697:Serine Endopeptidases; D053818:Chymases