title: Extra-cellular matrix proteins induce matrix metalloproteinase-1 (MMP-1) activity and increase airway smooth muscle contraction in asthma.
abstract: Airway remodelling describes the histopathological changes leading to fixed airway obstruction in patients with asthma and includes extra-cellular matrix (ECM) deposition. Matrix metalloproteinase-1 (MMP-1) is present in remodelled airways but its relationship with ECM proteins and the resulting functional consequences are unknown. We used airway smooth muscle cells (ASM) and bronchial biopsies from control donors and patients with asthma to examine the regulation of MMP-1 by ECM in ASM cells and the effect of MMP-1 on ASM contraction. Collagen-I and tenascin-C induced MMP-1 protein expression, which for tenascin-C, was greater in asthma derived ASM cells. Tenascin-C induced MMP-1 expression was dependent on ERK1/2, JNK and p38 MAPK activation and attenuated by function blocking antibodies against the β1 and β3 integrin subunits. Tenascin-C and MMP-1 were not expressed in normal airways but co-localised in the ASM bundles and reticular basement membrane of patients with asthma. Further, ECM from asthma derived ASM cells stimulated MMP-1 expression to a greater degree than ECM from normal ASM. Bradykinin induced contraction of ASM cells seeded in 3D collagen gels was reduced by the MMP inhibitor ilomastat and by siRNA knockdown of MMP-1. In summary, the induction of MMP-1 in ASM cells by tenascin-C occurs in part via integrin mediated MAPK signalling. MMP-1 and tenascin-C are co-localised in the smooth muscle bundles of patients with asthma where this interaction may contribute to enhanced airway contraction. Our findings suggest that ECM changes in airway remodelling via MMP-1 could contribute to an environment promoting greater airway narrowing in response to broncho-constrictor stimuli and worsening asthma symptoms.
authors.affiliation: Division of Respiratory Medicine and Respiratory Research Unit, University of Nottingham, Nottingham, England, United Kingdom.
authors.forename: Natasha K
authors.initials: NK
authors.lastname: Rogers
authors.affiliation: Division of Respiratory Medicine and Respiratory Research Unit, University of Nottingham, Nottingham, England, United Kingdom.
authors.forename: Debbie
authors.initials: D
authors.lastname: Clements
authors.affiliation: Division of Respiratory Medicine and Respiratory Research Unit, University of Nottingham, Nottingham, England, United Kingdom.
authors.forename: Arundhati
authors.initials: A
authors.lastname: Dongre
authors.affiliation: Division of Respiratory Medicine and Respiratory Research Unit, University of Nottingham, Nottingham, England, United Kingdom.
authors.forename: Tim W
authors.initials: TW
authors.lastname: Harrison
authors.affiliation: Division of Respiratory Medicine and Respiratory Research Unit, University of Nottingham, Nottingham, England, United Kingdom.
authors.forename: Dominic
authors.initials: D
authors.lastname: Shaw
authors.affiliation: Division of Respiratory Medicine and Respiratory Research Unit, University of Nottingham, Nottingham, England, United Kingdom.
authors.forename: Simon R
authors.initials: SR
authors.lastname: Johnson
mesh_terms: D001249:Asthma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D001920:Bradykinin / Q000494:pharmacology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D019012:Integrin beta1 / Q000378:metabolism; D039661:Integrin beta3 / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D034622:RNA Interference; D012137:Respiratory System / Q000187:drug effects / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019063:Tenascin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D024042:Collagen Type I; D016326:Extracellular Matrix Proteins; D006877:Hydroxamic Acids; D007211:Indoles; D019012:Integrin beta1; D039661:Integrin beta3; D019063:Tenascin; D014665:Vasodilator Agents; D020928:Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; C119203:ilomastat; D001920:Bradykinin