Matrix metalloproteinases regulation by asbestos in murine lung:Role of protein kinase C delta

• Published in: The FASEB journal 2006-03, Vol.20 (4), p.A226-A226
• Main Authors: Shukla, Arti, Barrett, Trisha F, Lounsbury, Karen M, Mossman, Brooke T
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.20.4.A226-c

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 PKCδ knockout (PKCδ‐/‐) mice exhibited decreased expression of lung MMP12 and 13 as compared to asbestos‐exposed wildtype mice. Studies using small molecule inhibitors in murine alveolar epithelial type II cells (C10) and primary lung fibroblasts confirmed that asbestos transcriptionally upregulates TIMP1 and MMP via an EGFR(or other growth factor receptors)/PI3K/PKCδ/ERK1/2 pathway. Asbestos‐induced MMP and TIMP expression was altered by addition of N‐acetyl‐L‐cysteine (NAC), suggesting a role for intracellular redox balance in these processes. 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 that likely contributes to asbestos‐induced lung remodeling and diseases. Supported by PO1 HL67004 from NHLBI.