title: Role of α1 and α2 chains of type IV collagen in early fibrotic lesions of idiopathic interstitial pneumonias and migration of lung fibroblasts.
abstract: Early fibrotic lesions are thought to be the initial findings of fibrogenesis in idiopathic interstitial pneumonias, but little is known about their properties. Type IV collagen comprises six gene products, α1-α6, and although it is known as a major basement membrane component, its abnormal deposition is seen in fibrotic lesions of certain organs. We studied the expression of type I and III collagen and all α chains of type IV collagen in lung specimens from patients with usual interstitial pneumonia (UIP) or organizing pneumonia (OP) via immunohistochemistry. With cultured lung fibroblasts, we analyzed the expression and function of all α chains of type IV collagen via immunohistochemistry, western blotting, real-time quantitative PCR, and a Boyden chamber migration assay after the knockdown of α1 and α2 chains. Although we observed type I and III collagens in early fibrotic lesions of both UIP and OP, we found type IV collagen, especially α1 and α2 chains, in early fibrotic lesions of UIP but not OP. Fibroblasts enhanced the expression of α1 and α2 chains of type IV collagen after transforming growth factor-β1 stimulation. Small interfering RNA against α1 and α2 chains increased fibroblast migration, with upregulated phosphorylation of focal adhesion kinase (FAK), and adding medium containing fibroblast-produced α1 and α2 chains reduced the increased levels of fibroblast migration and phosphorylation of FAK. Fibroblasts in OP were positive for phosphorylated FAK but fibroblasts in UIP were not. These results suggest that fibroblasts in UIP with type IV collagen deposition, especially α1 and α2 chains, have less ability to migrate from early fibrotic lesions than fibroblasts in OP without type IV collagen deposition. Thus, type IV collagen deposition in early fibrotic lesions of UIP may be implicated in refractory pathophysiology including migration of lesion fibroblasts via a FAK pathway.
authors.affiliation: Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Urushiyama
authors.affiliation: Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Terasaki
authors.affiliation: Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Nagasaka
authors.affiliation: Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Terasaki
authors.affiliation: Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Kunugi
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Nagase
authors.affiliation: Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Yuh
authors.initials: Y
authors.lastname: Fukuda
authors.affiliation: Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
mesh_terms: D000368:Aged; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism*; D008168:Lung / Q000166:cytology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation
chemical_list: C547475:COL4A1 protein, human; C502625:COL4A2 protein, human; D024141:Collagen Type IV; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human