title: Importance of mast cell Prss31/transmembrane tryptase/tryptase-γ in lung function and experimental chronic obstructive pulmonary disease and colitis.
abstract: Protease serine member S31 (Prss31)/transmembrane tryptase/tryptase-γ is a mast cell (MC)-restricted protease of unknown function that is retained on the outer leaflet of the plasma membrane when MCs are activated. We determined the nucleotide sequences of the Prss31 gene in different mouse strains and then used a Cre/loxP homologous recombination approach to create a novel Prss31(-/-) C57BL/6 mouse line. The resulting animals exhibited no obvious developmental abnormality, contained normal numbers of granulated MCs in their tissues, and did not compensate for their loss of the membrane tryptase by increasing their expression of other granule proteases. When Prss31-null MCs were activated with a calcium ionophore or by their high affinity IgE receptors, they degranulated in a pattern similar to that of WT MCs. Prss31-null mice had increased baseline airway reactivity to methacholine but markedly reduced experimental chronic obstructive pulmonary disease and colitis, thereby indicating both beneficial and adverse functional roles for the tryptase. In a cigarette smoke-induced model of chronic obstructive pulmonary disease, WT mice had more pulmonary macrophages, higher histopathology scores, and more fibrosis in their small airways than similarly treated Prss31-null mice. In a dextran sodium sulfate-induced acute colitis model, WT mice lost more weight, had higher histopathology scores, and contained more Cxcl-2 and IL-6 mRNA in their colons than similarly treated Prss31-null mice. The accumulated data raise the possibility that inhibitors of this membrane tryptase may provide additional therapeutic benefit in the treatment of humans with these MC-dependent inflammatory diseases.
authors.affiliation: From the Centre for Asthma and Respiratory Disease, University of Newcastle and Hunter Medical Research Institute, Newcastle, New South Wales 2308, Australia.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hansbro
authors.affiliation: the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hamilton
authors.affiliation: From the Centre for Asthma and Respiratory Disease, University of Newcastle and Hunter Medical Research Institute, Newcastle, New South Wales 2308, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Fricker
authors.affiliation: From the Centre for Asthma and Respiratory Disease, University of Newcastle and Hunter Medical Research Institute, Newcastle, New South Wales 2308, Australia.
authors.forename: Shaan L
authors.initials: SL
authors.lastname: Gellatly
authors.affiliation: From the Centre for Asthma and Respiratory Disease, University of Newcastle and Hunter Medical Research Institute, Newcastle, New South Wales 2308, Australia.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Jarnicki
authors.affiliation: the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Dominick
authors.initials: D
authors.lastname: Zheng
authors.affiliation: the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Frei
authors.affiliation: the Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and.
authors.forename: G William
authors.initials: GW
authors.lastname: Wong
authors.affiliation: the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Sahar
authors.initials: S
authors.lastname: Hamadi
authors.affiliation: the Department of Infectious Disease, Immunology, and Sexual Health, St. George Hospital and the University of New South Wales, Kogarah, New South Wales 2217, Australia.
authors.forename: Saijun
authors.initials: S
authors.lastname: Zhou
authors.affiliation: From the Centre for Asthma and Respiratory Disease, University of Newcastle and Hunter Medical Research Institute, Newcastle, New South Wales 2308, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.affiliation: the Department of Infectious Disease, Immunology, and Sexual Health, St. George Hospital and the University of New South Wales, Kogarah, New South Wales 2217, Australia.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Krilis
authors.affiliation: the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, rstevens@rics.bwh.harvard.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Stevens
mesh_terms: D000818:Animals; D003092:Colitis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology*; D008297:Male; D008407:Mast Cells / Q000201:enzymology* / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D053802:Tryptases / Q000235:genetics / Q000276:immunology*
chemical_list: D008565:Membrane Proteins; D053802:Tryptases; C000592404:Tpsg1 protein, Mouse
keywords: Chronic Obstructive Pulmonary Disease (COPD); Inflammation; Inflammatory Bowel Disease (IBD); Mast Cell; Protease