Matrix metalloproteinase induction in fibrosis and fibrotic nodule formation due to silica inhalation.
Matrix metalloproteinases (MMPs) are the principle enzymes that initiate degradation of collagen. We examined the role of MMPs during alveolar wall fibrosis and fibrotic nodule formation from silica exposure. Rats were exposed to filtered air or 15 mg/m(3) silica by inhalation for 5 days/wk, 6 h/day. Lungs were preserved by intratracheal instillation of fixative at 20, 40, 60, 79, and 116 days of exposure. Additional groups were fixed after 20, 40, and 60 days of exposure followed by 36 days of recovery. The number of nodules, defined by a collagenous core and a bounding cell layer detached from the alveolar wall, was determined by morphometry. Lungs showed increased alveolar wall collagen and fibrotic nodules at 79 and 116 days of exposure with increased collagenase and gelatinase activity. The number of nodules per lung in exposed groups increased from 619 +/- 447 at 40 days to 13,221 +/- 1,096 at 116 days (means +/- SE, n = 5). No nodules were seen in control lungs. Silica-exposed rats with a 36-day recovery in filtered air showed enhanced MMP activity over exposure to silica for the same duration with no recovery. MMP-2 and MMP-9 were significantly elevated in alveolar macrophages after 40-day exposure. Stromelysin expression was demonstrated in alveolar macrophages and cells within fibrotic nodules. TIMP-1 expression was not significantly altered. In summary, MMP activity was upregulated at 40 days of silica exposure and progressively increased during ensuing fibrotic responses. Early expression of stromelysin was found in fibrosing alveolar walls and fibrotic nodules.
Scabilloni
James F
JF
National Institute for Occupational Safety and Health, Pathology and Physiology Research Branch, 1095 Willowdale Rd., Morgantown, WV 26505, USA. zbc9@cdc.gov
Wang
Liying
L
Antonini
James M
JM
Roberts
Jenny R
JR
Castranova
Vincent
V
Mercer
Robert R
RR
D000818:Animals; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism; D004790:Enzyme Induction; D001239:Inhalation; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D019278:Matrix Metalloproteinase 3 / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D012822:Silicon Dioxide / Q000633:toxicity; D012829:Silicosis / Q000201:enzymology* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D015854:Up-Regulation
D019715:Tissue Inhibitor of Metalloproteinase-1; D012822:Silicon Dioxide; D003094:Collagen; D017364:Collagenases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9