TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment?
Fibroblast proliferation and extracellular matrix accumulation characterize idiopathic pulmonary fibrosis (IPF). We evaluated the presence of tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, and -4; collagenase-1, -2, and -3; gelatinases A and B; and membrane type 1 matrix metalloproteinase (MMP) in 12 IPF and 6 control lungs. TIMP-1 was found in interstitial macrophages and TIMP-2 in fibroblast foci. TIMP-3 revealed an intense staining mainly decorating the elastic lamina in vessels. TIMP-4 was expressed in IPF lungs by epithelial and plasma cells. TIMP-2 colocalized with Ki67 in fibroblasts, whereas TIMP-3 colocalized with p27 in inflammatory and epithelial cells. Collagenase-1 was localized in macrophages and alveolar epithelial cells, collagenase-2 was localized in a few neutrophils, and collagenase-3 was not detected. MMP-9 was found in neutrophils and subepithelial myofibroblasts. Myofibroblast expression of MMP-9 was corroborated in vitro by RT-PCR. MMP-2 was noticed in myofibroblasts, some of them close to areas of basement membrane disruption, and membrane type 1 MMP was noticed in interstitial macrophages. These findings suggest that in IPF there is higher expression of TIMPs compared with collagenases, supporting the hypothesis that a nondegrading fibrillar collagen microenvironment is prevailing.
Selman
M
M
Instituto Nacional de Enfermedades Respiratorias, México DF CP 14080, Mexico.
Ruiz
V
V
Cabrera
S
S
Segura
L
L
Ramírez
R
R
Barrios
R
R
Pardo
A
A
D000368:Aged; D017364:Collagenases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism; D008875:Middle Aged; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014018:Tissue Distribution; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism*
D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; D020033:Protein Isoforms; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; C413374:p27 antigen; D017364:Collagenases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9