Latent transforming growth factor-β1 protects against bleomycin-induced lung injury in mice

Am J Respir Cell Mol Biol. 2014 Dec;51(6):761-71. doi: 10.1165/rcmb.2013-0423OC.

Abstract

Transforming growth factor (TGF)-β1 is a potent mediator known to induce lung fibrosis. However, the role of latent TGF-β1 in lung inflammation and fibrosis is unclear. To investigate the role of circulating latent TGF-β1 in bleomycin-induced lung injury, lung disease was induced in keratin-5 promoter-driven TGF-β1(wt) transgenic (Tg) mice by bleomycin. The role of latent TGF-β1 in pulmonary inflammation and fibrosis was examined at Days 7 and 28 after administration of bleomycin. Compared with littermate wild-type (WT) mice, TGF-β1(wt) Tg mice had over twofold-higher levels of latent TGF-β1 in both plasma and lung tissue, and were protected from bleomycin-induced pulmonary inflammation, such as up-regulation of IL-1β, TNF-α, and macrophage chemotactic protein-1, and infiltration of CD3(+) T cells and F4/80(+) macrophages. In addition, the severity of lung fibrosis with massive collagen matrix accumulation was markedly reduced in TGF-β1(wt) Tg mice. These protective effects were associated with higher levels of Smad7 and inactivation of both NF-κB and TGF-β/Smad3 signaling pathways, in addition to an increase in forkhead box P3 (Foxp3)-dependent regulatory T cells, but inhibition of T helper 17-mediated lung injury. In summary, mice overexpressing latent TGF-β1 are protected from bleomycin-induced lung injury. Triggering the Smad7 negative feedback mechanism to inhibit both NF-κB and TGF-β/Smad signaling pathways, and enhancing the regulatory T cell response to counter-regulate T helper 17-mediated lung injury, are potential mechanisms by which latent TGF-β1 protects against bleomycin-induced lung injury.

Keywords: T helper 17; fibrosis; inflammation; latent transforming growth factor-β1; regulatory T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin
  • Female
  • Inflammation Mediators / blood
  • Lung / metabolism
  • Lung / pathology
  • Lung Injury / blood*
  • Lung Injury / chemically induced
  • Lung Injury / immunology
  • Macrophages, Alveolar / immunology
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Pneumonia / blood
  • Pneumonia / chemically induced
  • Pneumonia / immunology
  • Signal Transduction
  • Smad7 Protein / metabolism
  • Th17 Cells / immunology
  • Transforming Growth Factor beta1 / physiology*

Substances

  • Inflammation Mediators
  • Smad7 Protein
  • Smad7 protein, mouse
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1
  • Bleomycin