Matrix metalloproteinases promote inflammation and fibrosis in asbestos-induced lung injury in mice.
Inhalation of asbestos fibers causes pulmonary inflammation and eventual pulmonary fibrosis (asbestosis). Although the underlying molecular events are poorly understood, protease/antiprotease and oxidant/antioxidant imbalances are believed to contribute to the disease. Implicated in other forms of pulmonary fibrosis, the matrix metalloproteinases (MMPs) have not been examined in asbestosis. We therefore hypothesized that MMPs play a pathogenic role in asbestosis development. Wild-type C57BL/6 mice were intratracheally instilled with 0.1 mg crocidolite asbestos, causing an inflammatory response at 1 d and a developing fibrotic response at 7, 14, and 28 d. Gelatin zymography demonstrated an increase in MMP-9 (gelatinase B) during the inflammatory phase, while MMP-2 (gelatinase A) was profoundly increased in the fibrotic phase. Immunohistochemistry revealed MMP-9 in and around bronchiolar and airspace neutrophils that were often associated with visible asbestos fibers. MMP-2 was found in fibrotic regions at 7, 14, and 28 d. No increases in RNA levels of MMP-2, MMP-9, or MMP-8 were found, but levels of MMP-7, MMP-12, and MMP-13 RNA did increase at 14 d. The MMP inhibitors, TIMP-1 and TIMP-2, were also increased at 7-28 d after asbestos exposure. To confirm the importance of MMP activity in disease progression, mice exposed to asbestos were given daily injections of the MMP inhibitor, GM6001. MMP inhibition reduced inflammation and fibrosis in asbestos-treated mice. Collectively, these data suggest that MMPs contribute to the pathogenesis of asbestosis through effects on inflammation and fibrosis development.
Department of Pathology, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Roderick J
RJ
Tan
Cheryl L
CL
Fattman
Laura M
LM
Niehouse
Jacob M
JM
Tobolewski
Lana E
LE
Hanford
Qinglang
Q
Li
Federico A
FA
Monzon
William C
WC
Parks
Tim D
TD
Oury
D000818:Animals; D017638:Asbestos, Crocidolite / Q000633:toxicity*; D004151:Dipeptides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000139:chemically induced* / Q000201:enzymology* / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000201:enzymology* / Q000473:pathology
D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D017638:Asbestos, Crocidolite; D020782:Matrix Metalloproteinases