title: VCAM-1 is a TGF-β1 inducible gene upregulated in idiopathic pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic lethal interstitial lung disease of unknown etiology. We previously reported that high plasma levels of vascular cell adhesion molecule 1 (VCAM-1) predict mortality in IPF subjects. Here we investigated the cellular origin and potential role of VCAM-1 in regulating primary lung fibroblast behavior. VCAM-1 mRNA was significantly increased in lungs of subjects with IPF compared to lungs from control subjects (p=0.001), and it negatively correlated with two markers of lung function, forced vital capacity (FVC) and pulmonary diffusion capacity for carbon monoxide (DLCO). VCAM-1 protein levels were highly expressed in IPF subjects where it was detected in fibrotic foci and blood vessels of IPF lung. Treatment of human lung fibroblasts with TGF-β1 significantly increased steady-state VCAM1 mRNA and protein levels without affecting VCAM1 mRNA stability. Further, cellular depletion of VCAM-1 inhibited fibroblast cell proliferation and reduced G2/M and S phases of the cell cycle suggestive of cell cycle arrest. These effects on cell cycle progression triggered by VCAM1 depletion were associated with reductions in levels of phosphorylated extracellular regulated kinase 1/2 and cyclin D1. Thus, these observations suggest that VCAM-1 is a TGF-β1 responsive mediator that partakes in fibroblast proliferation in subjects with IPF.
authors.affiliation: Dorothy P and Richard P Simmons Center for Interstitial Lung Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Marianna
authors.initials: M
authors.lastname: Agassandian
authors.affiliation: Dorothy P and Richard P Simmons Center for Interstitial Lung Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Tedrow
authors.affiliation: Dorothy P and Richard P Simmons Center for Interstitial Lung Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: John
authors.initials: J
authors.lastname: Sembrat
authors.affiliation: Dorothy P and Richard P Simmons Center for Interstitial Lung Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Kass
authors.affiliation: Dorothy P and Richard P Simmons Center for Interstitial Lung Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Goncharova
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, School of Medicine, Yale University, New Heaven, CT, United States.
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Medical Specialty Service Line, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, United States. Electronic address: mallampallirk@upmc.edu.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mallampalli
authors.affiliation: Dorothy P and Richard P Simmons Center for Interstitial Lung Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States. Electronic address: vugalj@upmc.edu.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Vuga
mesh_terms: D000368:Aged; D000818:Animals; D049109:Cell Proliferation; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D021381:Protein Transport; D015533:Transcriptional Activation; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D053773:Transforming Growth Factor beta1; D019010:Vascular Cell Adhesion Molecule-1
keywords: IPF; Lung fibroblasts; TGF-β1; VCAM-1