FGF signaling is required for myofibroblast differentiation during alveolar regeneration

Am J Physiol Lung Cell Mol Physiol. 2009 Aug;297(2):L299-308. doi: 10.1152/ajplung.00008.2009. Epub 2009 Jun 5.

Abstract

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 alpha-smooth muscle actin (alphaSMA)-positive interstitial myofibroblasts. One week after completion of RA treatment, alphaSMA 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-alpha (PDGFRalpha)-positive cells and decreased alphaSMA-positive cells. Taken together, our data demonstrate that FGF signaling is required for the induction of alphaSMA in the PDGFRalpha-positive myofibroblast progenitor and the progression of alveolar regeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Age Factors
  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Division / drug effects
  • Cell Division / physiology
  • Elastin / metabolism
  • Fibroblast Growth Factors / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / physiology*
  • Green Fluorescent Proteins / genetics
  • Humans
  • Mice
  • Mice, Transgenic
  • Pulmonary Alveoli / cytology*
  • Pulmonary Alveoli / growth & development
  • Pulmonary Alveoli / physiology*
  • Pulmonary Surfactant-Associated Protein C / genetics
  • Pulmonary Surfactant-Associated Protein C / metabolism
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Regeneration / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Tretinoin / pharmacology

Substances

  • Actins
  • Antineoplastic Agents
  • Pulmonary Surfactant-Associated Protein C
  • SFTPC protein, human
  • Green Fluorescent Proteins
  • Tretinoin
  • Fibroblast Growth Factors
  • Elastin
  • Fgfr1 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, Platelet-Derived Growth Factor alpha