title: Latent transforming growth factor-β1 protects against bleomycin-induced lung injury in mice.
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.
authors.affiliation: 1 Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, the Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yong-Jiang
authors.initials: YJ
authors.lastname: Tang
authors.forename: Jun
authors.initials: J
authors.lastname: Xiao
authors.forename: Xiao Ru
authors.initials: XR
authors.lastname: Huang
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chen
authors.initials: C
authors.lastname: Yang
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Meng
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Feng
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.forename: David S C
authors.initials: DS
authors.lastname: Hui
authors.forename: Cheuk-Man
authors.initials: CM
authors.lastname: Yu
authors.forename: Hui Yao
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000818:Animals; D001761:Bleomycin; D005260:Female; D018836:Inflammation Mediators / Q000097:blood; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000097:blood* / Q000139:chemically induced / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D011014:Pneumonia / Q000097:blood / Q000139:chemically induced / Q000276:immunology; D015398:Signal Transduction; D051906:Smad7 Protein / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: D018836:Inflammation Mediators; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D001761:Bleomycin
keywords: T helper 17; fibrosis; inflammation; latent transforming growth factor-β1; regulatory T cells