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This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/L739    most recent 00294.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Buckley, S. Articles by Warburton, D. PubMed PubMed Citation Articles by Buckley, S. Articles by Warburton, D.

TGF-β signaling promotes survival and repair in rat alveolar epithelial type 2 cells during recovery after hyperoxic injury

¹Developmental Biology/Regenerative Medicine and Surgery and ²Research Immunology/Bone Marrow Transplant Programs, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California

Submitted 26 July 2007 ; accepted in final form 31 January 2008

Hyperoxic rats treated with inosine during oxygen exposure have increased levels of active transforming growth factor (TGF)-β in the bronchoalveolar lavage (BAL), yet alveolar epithelial type 2 cells (AEC2) isolated from these animals demonstrate less hyperoxia-induced DNA damage and increased expression of active Smad2. To determine whether TGF-β1 signaling per se protected AEC2 against hyperoxic damage, freshly isolated AEC2 from hyperoxic rats were incubated with TGF-β1 for 24 h and assayed for DNA damage by fluorescein-activated cell sorter analysis of TdT-mediated dUTP nick end labeling. TGF-β1 was protective over a concentration range similar to that in BAL of inosine-treated hyperoxic animals (50–5,000 pg/ml). TGF-β1 also augmented hyperoxia-induced DNA repair activity and cell migration, stimulated autocrine secretion of fibronectin, accelerated closure of a monolayer scratch wound, and restored hyperoxia-depleted VEGF secretion by AEC2 to normoxic levels. The TGF-β receptor type I activin-like kinase-4, -5, and -7 inhibitor peptide SB-505124 abolished the protective effect of TGF-β on hyperoxic DNA damage and increased TdT-mediated dUTP nick end labeling in normoxic cells. These data suggest that endogenous TGF-β-mediated Smad signaling is required for AEC2 homeostasis in vitro, while exogenous TGF-β1 treatment of hyperoxia-damaged AEC2 results in a cell that is equipped to survive, repair, migrate, secrete matrix, and induce new blood vessel formation more efficiently than AEC2 primed by hyperoxia alone.

TdT-mediated dUTP nick end labeling; Ku 70; VEGF; migration; fibronectin; activin-like kinase-5 inhibitor; in vitro wound healing