Transcriptional up-regulation of MMP12 and MMP13 by asbestos occurs via a PKCδ-dependent pathway in murine lung

Arti Shukla, Trisha F. Barrett, Keiichi I. Nakayama, Kieko Nakayama, Brooke T. Mossman, Karen M. Lounsbury

研究成果: Contribution to journalArticle査読

33 被引用数 (Scopus)

抄録

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 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 upregulates MMPs via an EGFR (or other growth factor receptors)/PI3K/PKCδ/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.

本文言語英語
ページ(範囲)E160-E169
ジャーナルFASEB Journal
20
7
DOI
出版ステータス出版済み - 5 2006

All Science Journal Classification (ASJC) codes

  • バイオテクノロジー
  • 生化学
  • 分子生物学
  • 遺伝学

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