title: Lung-specific loss of α3 laminin worsens bleomycin-induced pulmonary fibrosis.
abstract: Laminins are heterotrimeric proteins that are secreted by the alveolar epithelium into the basement membrane, and their expression is altered in extracellular matrices from patients with pulmonary fibrosis. In a small number of patients with pulmonary fibrosis, we found that the normal basement membrane distribution of the α3 laminin subunit was lost in fibrotic regions of the lung. To determine if these changes play a causal role in the development of fibrosis, we generated mice lacking the α3 laminin subunit specifically in the lung epithelium by crossing mice expressing Cre recombinase driven by the surfactant protein C promoter (SPC-Cre) with mice expressing floxed alleles encoding the α3 laminin gene (Lama3(fl/fl)). These mice exhibited no developmental abnormalities in the lungs up to 6 months of age, but, compared with control mice, had worsened mortality, increased inflammation, and increased fibrosis after the intratracheal administration of bleomycin. Similarly, the severity of fibrosis induced by an adenovirus encoding an active form of transforming growth factor-β was worse in mice deficient in α3 laminin in the lung. Taken together, our results suggest that the loss of α3 laminin in the lung epithelium does not affect lung development, but plays a causal role in the development of fibrosis in response to bleomycin or adenovirally delivered transforming growth factor-β. Thus, we speculate that the loss of the normal basement membrane organization of α3 laminin that we observe in fibrotic regions from the lungs of patients with pulmonary fibrosis contributes to their disease progression.
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and the Department of Cell and Molecular Biology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois.
authors.forename: Luisa I
authors.initials: LI
authors.lastname: Morales-Nebreda
authors.forename: Micah R
authors.initials: MR
authors.lastname: Rogel
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Eisenberg
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Hamill
authors.forename: Saul
authors.initials: S
authors.lastname: Soberanes
authors.forename: Recep
authors.initials: R
authors.lastname: Nigdelioglu
authors.forename: Monica
authors.initials: M
authors.lastname: Chi
authors.forename: Takugo
authors.initials: T
authors.lastname: Cho
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Radigan
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ridge
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Misharin
authors.forename: Alex
authors.initials: A
authors.lastname: Woychek
authors.forename: Susan
authors.initials: S
authors.lastname: Hopkinson
authors.forename: Harris
authors.initials: H
authors.lastname: Perlman
authors.forename: Gokhan M
authors.initials: GM
authors.lastname: Mutlu
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
authors.forename: Moises
authors.initials: M
authors.lastname: Selman
authors.forename: Jonathan C R
authors.initials: JC
authors.lastname: Jones
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
mesh_terms: D000818:Animals; D001761:Bleomycin; D006801:Humans; D007797:Laminin / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D007797:Laminin; D016212:Transforming Growth Factor beta; D001761:Bleomycin; C095567:laminin alpha 3
keywords: development; laminin; matrix; pulmonary fibrosis