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This Article Full Text Full Text (PDF) All Versions of this Article: 297/2/L299    most recent 00008.2009v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Google Scholar Articles by Perl, A.-K. T. Articles by Gale, E. PubMed PubMed Citation Articles by Perl, A.-K. T. Articles by Gale, E.

FGF signaling is required for myofibroblast differentiation during alveolar regeneration

Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio

Submitted 13 January 2009 ; accepted in final form 3 June 2009

Normal alveolarization has been studied in rodents using detailed morphometric techniques and loss of function approaches for growth factors and their receptors. However, it remains unclear how these growth factors direct the formation of secondary septae. We have previously developed a transgenic mouse model in which expression of a soluble dominant-negative FGF receptor (dnFGFR) in the prenatal period results in reduced alveolar septae formation and subsequent alveolar simplification. Retinoic acid (RA), a biologically active derivative of vitamin A, can induce regeneration of alveoli in adult rodents. In this study, we demonstrate that RA induces alveolar reseptation in this transgenic mouse model and that realveolarization in adult mice is FGF dependent. Proliferation in the lung parenchyma, an essential prerequisite for lung regrowth was enhanced after 14 days of RA treatment and was not influenced by dnFGFR expression. During normal lung development, formation of secondary septae is associated with the transient presence of -smooth muscle actin (SMA)-positive interstitial myofibroblasts. One week after completion of RA treatment, SMA expression was detected in interstitial fibroblasts, supporting the concept that RA-initiated realveolarization recapitulates aspects of septation that occur during normal lung development. Expression of dnFGFR blocked realveolarization with increased PDGF receptor- (PDGFR)-positive cells and decreased SMA-positive cells. Taken together, our data demonstrate that FGF signaling is required for the induction of SMA in the PDGFR-positive myofibroblast progenitor and the progression of alveolar regeneration.

transgenic mouse model; interstitial myofibroblast; emphysema; platelet derived growth factor receptor