title: Matrix metalloproteinases and their tissue inhibitors in the lesions of cardiac and pulmonary sarcoidosis: an immunohistochemical study.
abstract: The pathogenesis of the tissue damage and fibrosis in sarcoidosis is poorly understood. The matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) must be considered in this regard, because they control the lysis of connective tissue components. Immunohistochemical studies (peroxidase and dual labeling for confocal microscopy) of reactivity for MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, and the 4 membrane-type-MMPs were made on tissues from patients with cardiac (n = 4) and pulmonary (n = 5) sarcoidosis. The granulomas were histochemically similar in both organs. The multinucleated giant cells (MGCs) showed moderate reactivity for MMP-1 and MMP-9 and variable reactivity for MMP-2 and MMP-3; in addition, they showed colocalization of MT-1-MMP, which activates MMP-2. The reactivity of epithelioid cells (ECs) was moderate for MMP-2 and mild for other MMPs. Macrophages showed weaker reactivity for MMPs than did MGCs and ECs. All 3 types of cells showed very low reactivity for TIMPs. Staining for type IV collagen showed focal damage to the basement membranes of cardiac myocytes and pulmonary alveoli near the granulomas. The cells in sarcoid granulomas contain an abundance of MMPs and a paucity of TIMPs. The MGCs also contain MT-1-MMP and thus can activate MMP-2 in the granulomas. The MMPs can cause damage to adjacent cardiac myocytes and pulmonary alveoli, leading to the interstitial fibrosis produced by sarcoidosis.
authors.affiliation: Pathology Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1518, USA.
authors.forename: A Adrián
authors.initials: AA
authors.lastname: González
authors.forename: Ana M
authors.initials: AM
authors.lastname: Segura
authors.forename: Koji
authors.initials: K
authors.lastname: Horiba
authors.forename: Sujuan
authors.initials: S
authors.lastname: Qian
authors.forename: Zu-Xi
authors.initials: ZX
authors.lastname: Yu
authors.forename: William
authors.initials: W
authors.lastname: Stetler-Stevenson
authors.forename: James T
authors.initials: JT
authors.lastname: Willerson
authors.forename: Hugh A
authors.initials: HA
authors.lastname: McAllister
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Ferrans
mesh_terms: D000328:Adult; D000368:Aged; D009202:Cardiomyopathies / Q000201:enzymology* / Q000473:pathology; D024141:Collagen Type IV / Q000032:analysis; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000032:analysis; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D019278:Matrix Metalloproteinase 3 / Q000032:analysis; D020783:Matrix Metalloproteinase 7 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D020782:Matrix Metalloproteinases / Q000032:analysis*; D018613:Microscopy, Confocal; D008875:Middle Aged; D012507:Sarcoidosis / Q000201:enzymology* / Q000473:pathology; D017565:Sarcoidosis, Pulmonary / Q000201:enzymology* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis; D019714:Tissue Inhibitor of Metalloproteinases / Q000032:analysis*
chemical_list: D024141:Collagen Type IV; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1