title: Relationship between matrix production by bronchial fibroblasts and lung function and AHR in asthma.
abstract: The reasons for enhanced deposition of extracellular matrix in the airways of asthmatic patients and the subsequent consequences on lung function are uncertain. Here, we investigated the synthesis of procollagen I and proteoglycans, the activity of various metalloproteinases (MMPs) and the production of their inhibitor TIMP-1 in biopsy-derived bronchial fibroblasts from eight patients with stable mild-to-moderate asthma, and how they are related to patients' lung function and airway hyperreactivity (AHR). Following 24-h fibroblast incubation in 0.4% serum, procollagen I carboxyterminal propeptide (PICP), TIMP-1 and MMP-1 in cell media were analysed by ELISA, MMP-2, MMP-3, MMP-9 by zymography and total proteoglycan production by [(35)S]-sulphate-incorporation/ion chromatography. Patients' FEV(1)% predicted and methacholine log PD(20) negatively correlated with PICP synthesized by patients' bronchial fibroblasts (r = -0.74 and r = -0.71, respectively). PICP and proteoglycan amounts positively correlated (0.8 ≤ r ≤ 0.9) with MMP-2 and MMP-3 activity. A positive correlation (r = 0.75) was also found between proteoglycan production and TIMP-1. There was no correlation between MMP-9 activity and PICP or proteoglycan production. MMP-9 activity positively correlated with patients' FEV(1)% predicted (r = 0.97) and methacholine log PD(20) (r = 0.86), whereas negative associations (-0.6 ≤ r ≤ -0.7) were observed for MMP-2 and MMP-3. In stable mild-to-moderate asthma, increased procollagen I synthesis and activity of MMP-2 and MMP-3 in bronchial fibroblasts may negatively affect patients' lung function and AHR. In contrast, MMP-9 activity was not associated with procollagen or proteoglycan production, or worsening of patients' lung function and AHR. An enhanced production of procollagen I and proteoglycans might be a result of a negative feedback from their degradation by MMP-2 and MMP-3.
authors.affiliation: Department of Experimental Medical Sciences, Lund University, BMC D12, Lund, Sweden.
authors.forename: Lizbet
authors.initials: L
authors.lastname: Todorova
authors.forename: Leif
authors.initials: L
authors.lastname: Bjermer
authors.forename: Anna
authors.initials: A
authors.lastname: Miller-Larsson
authors.forename: Gunilla
authors.initials: G
authors.lastname: Westergren-Thorsson
mesh_terms: D000328:Adult; D001249:Asthma / Q000378:metabolism* / Q000503:physiopathology; D001980:Bronchi / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D008875:Middle Aged; D011347:Procollagen / Q000096:biosynthesis*; D011509:Proteoglycans / Q000096:biosynthesis*; D012129:Respiratory Function Tests; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: D011347:Procollagen; D011509:Proteoglycans; D019715:Tissue Inhibitor of Metalloproteinase-1; D020781:Matrix Metalloproteinase 1