title: Activated alveolar epithelial cells initiate fibrosis through autocrine and paracrine secretion of connective tissue growth factor.
abstract: Fibrogenesis involves a pathological accumulation of activated fibroblasts and extensive matrix remodeling. Profibrotic cytokines, such as TGF-β, stimulate fibroblasts to overexpress fibrotic matrix proteins and induce further expression of profibrotic cytokines, resulting in progressive fibrosis. Connective tissue growth factor (CTGF) is a profibrotic cytokine that is indicative of fibroblast activation. Epithelial cells are abundant in the normal lung, but their contribution to fibrogenesis remains poorly defined. Profibrotic cytokines may activate epithelial cells with protein expression and functions that overlap with the functions of active fibroblasts. We found that alveolar epithelial cells undergoing TGF-β-mediated mesenchymal transition in vitro were also capable of activating lung fibroblasts through production of CTGF. Alveolar epithelial cell expression of CTGF was dramatically reduced by inhibition of Rho signaling. CTGF reporter mice demonstrated increased CTGF promoter activity by lung epithelial cells acutely after bleomycin in vivo. Furthermore, mice with lung epithelial cell-specific deletion of CTGF had an attenuated fibrotic response to bleomycin. These studies provide direct evidence that epithelial cell activation initiates a cycle of fibrogenic effector cell activation during progressive fibrosis. Therapy targeted at epithelial cell production of CTGF offers a novel pathway for abrogating this progressive cycle and limiting tissue fibrosis.
authors: 109 Zina Pitcher Place, BSRB 4061, Ann Arbor, MI 48109. kevkim@med.umich.edu.
authors: Jibing
authors: J
authors: Yang
authors: Miranda
authors: M
authors: Velikoff
authors: Ernesto
authors: E
authors: Canalis
authors: Jeffrey C
authors: JC
authors: Horowitz
authors: Kevin K
authors: KK
authors: Kim
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D019898:Autocrine Communication; D001761:Bleomycin / Q000494:pharmacology; D015153:Blotting, Western; D018893:Bronchoalveolar Lavage; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006909:Hydroxyproline / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019899:Paracrine Communication; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000099222:betaIG-H3 Protein
chemical_list: D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D055513:Connective Tissue Growth Factor; D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins; D006909:Hydroxyproline; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein; C526318:CCN2 protein, mouse
keywords: connective tissue growth factor; epithelial; epithelial-mesenchymal transition; fibrosis; lung