title: Fibroblast signal transducer and activator of transcription 4 drives cigarette smoke-induced airway fibrosis.
abstract: Cigarette smoke-induced emphysema and small airway remodeling are the anatomic bases of chronic obstructive pulmonary disease (COPD), but the pathogenesis of these changes is unclear, and current treatments for COPD are minimally effective. To evaluate the role of signal transducer and activator of transcription (STAT)-4 in cigarette smoke-induced small airway remodeling, we used C57BL/6J (wild type [WT]) and STAT4-/- mice exposed to air or cigarette smoke for 6 months and isolated airway and parenchymal fibroblasts. We also compared the results with those obtained with human fibroblasts. We found that STAT4-/- mice were protected against smoke-induced small airway remodeling but not emphysema. STAT4 is abundantly expressed in airway compared with parenchymal-derived fibroblasts isolated from normal human and murine lung. WT airway fibroblasts proliferate faster than STAT4-/- airway fibroblasts, whereas there is no difference between strains for parenchymal fibroblasts. IL-12 is up-regulated in the lung after smoke exposure, and IL-12 receptor B2 is expressed on airway and parenchymal fibroblasts in mouse and human lung. Treatment with IL-12 causes phosphorylation of STAT4 in WT airway fibroblasts. Exposure of WT airway, but not parenchymal, fibroblasts to IL-12 causes increased expression of collagen 1α1 and transforming growth factor β1, factors involved in small airway remodeling, whereas STAT4-/- fibroblasts are unresponsive to IL-12. These results indicate that IL-12 can drive small airway remodeling via STAT4 signaling and suggest that treatment with clinically available anti-IL-12p40 drugs might provide a new approach to preventing small airway remodeling in cigarette smokers.
authors.affiliation: 1 Department of Pathology and.
authors.forename: Tillie-Louise
authors.initials: TL
authors.lastname: Hackett
authors.forename: Furquan
authors.initials: F
authors.lastname: Shaheen
authors.forename: Steven
authors.initials: S
authors.lastname: Zhou
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Wright
authors.forename: Andrew
authors.initials: A
authors.lastname: Churg
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D049109:Cell Proliferation; D048430:Cell Shape; D002478:Cells, Cultured; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D050797:STAT4 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism*
chemical_list: D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D018664:Interleukin-12
keywords: chronic obstructive pulmonary disease; cigarette smoke; fibroblast; signal transducer and activator of transcription-4; small airway remodeling