Transcriptional up-regulation of MMP12 and MMP13 by asbestos occurs via a PKCdelta-dependent pathway in murine lung.
Asbestos is a known inflammatory, carcinogenic, and fibrotic agent, but the mechanisms leading to asbestos-induced lung diseases are unclear. Using a murine inhalation model of fibrogenesis, we show that asbestos causes significant increases in mRNA levels of lung matrix metalloproteinases (MMPs 12 and 13) and tissue inhibitor of metalloproteinases (TIMP1), as well as increased activities of MMP 2, 9, and 12 in bronchoalveolar lavage fluids (BALF). Asbestos-exposed PKCdelta knockout (PKCdelta-/-) mice exhibited decreased expression of lung MMP12 and MMP13 compared with asbestos-exposed wild-type mice. Studies using small molecule inhibitors in murine alveolar epithelial type II cells (C10) and primary lung fibroblasts confirmed that asbestos transcriptionally up-regulates MMPs via an EGFR (or other growth factor receptors)/PI3K/PKCdelta/ERK1/2 pathway. Moreover, use of a broad-spectrum MMP inhibitor showed that MMPs play an important role in further enhancing asbestos-induced signaling events by activating EGFR. These data reveal a potentially important link between asbestos signaling and integrity of the extracellular matrix (ECM) that likely contributes to asbestos-induced lung remodeling and diseases.
Shukla
Arti
A
Department of Pharmacology, University of Vermont College of Medicine, 89 Beaumont Ave. Burlington, Vermont 05405, USA.
Barrett
Trisha F
TF
Nakayama
Keiichi I
KI
Nakayama
Kieko
K
Mossman
Brooke T
BT
Lounsbury
Karen M
KM
D000818:Animals; D001194:Asbestos / Q000494:pharmacology*; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D008168:Lung / Q000187:drug effects* / Q000201:enzymology*; D053508:Matrix Metalloproteinase 12; D053509:Matrix Metalloproteinase 13; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D001194:Asbestos; D051745:Protein Kinase C-delta; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D008666:Metalloendopeptidases; C507081:Mmp13 protein, mouse; D053508:Matrix Metalloproteinase 12