title: Fibroblasts that resist cigarette smoke-induced senescence acquire profibrotic phenotypes.
abstract: This study assessed the effect of extended exposure to cigarette smoke extract (CSE) on tissue repair functions in lung fibroblasts. Human fetal (HFL-1) and adult lung fibroblasts were exposed to CSE for 14 days. Senescence-associated β-galactosidase (SA β-gal) expression, cell proliferation, and tissue repair functions including chemotaxis and gel contraction were assessed. HFL-1 proliferation was inhibited by CSE and nearly half of the CSE-exposed cells were SA β-gal positive after 14 days exposure, whereas 33% of adult lung fibroblasts were SA β-gal positive in response to 10% CSE exposure. The SA β-gal-positive cells did not proliferate as indicated by bromodeoxyuridine incorporation. In contrast, cells negative for SA β-gal after CSE exposure proliferated faster than cells never exposed to CSE. These nonsenescent cells migrated more and contracted collagen gels more than control cells. CSE exposure stimulated TGF-β1 production, and both inhibition of TGF-β receptor kinase and TGF-β1 siRNA blocked CSE modulation of fibroblast function. Extended exposure to CSE might induce two different fibroblast phenotypes, a senescent and a profibrotic phenotype. The fibroblasts that resist CSE-induced cellular senescence may contribute to the pathogenesis of idiopathic pulmonary fibrosis and could contribute to fibrotic lesions in chronic obstructive pulmonary disease acting through a TGF-β1-mediated pathway. In contrast, the senescent cells may contribute to the pathogenesis of emphysema.
authors.affiliation: Division of Endocrinology and Metabolism, Hematology, Rheumatology and Respiratory Medicine, Kagawa University, Kagawa, Japan;
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kanaji
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Hesham
authors.initials: H
authors.lastname: Basma
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Amy
authors.initials: A
authors.lastname: Nelson
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Maha
authors.initials: M
authors.lastname: Farid
authors.affiliation: Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan;
authors.forename: Tadashi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan;
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakanishi
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Xingqi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Joel
authors.initials: J
authors.lastname: Michalski
authors.affiliation: Department of Hygiene and Public Health, Nippon Medical School, Tokyo, Japan;
authors.forename: YingJi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Yoko
authors.initials: Y
authors.lastname: Gunji
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Carol
authors.initials: C
authors.lastname: Feghali-Bostwick
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska;
authors.forename: Xiangde
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; srennard@unmc.edu.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D002633:Chemotaxis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005333:Fetus; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D010641:Phenotype; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D012906:Smoke / Q000009:adverse effects*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D012906:Smoke; D053773:Transforming Growth Factor beta1; D001616:beta-Galactosidase
keywords: fibroblast; fibrotic phenotype; senescence