title: Induction of pulmonary connective tissue growth factor in heart failure is associated with pulmonary parenchymal and vascular remodeling.
abstract: OBJECTIVE
  Pulmonary remodeling is a well recognized consequence of heart failure (HF). However, the cellular and molecular mechanisms orchestrating the structural alterations of the lungs in HF are poorly understood. We have previously reported induction of the profibrotic peptide connective tissue growth factor (CTGF) in myocardial tissue of rats with HF, suggesting a role of CTGF during myocardial remodeling. The aim of the present study was to explore the potential role of CTGF in pulmonary remodeling in HF.
  
  
  METHODS
  Pulmonary tissue samples were obtained from rats with myocardial infarction (MI) subsequent to ligation of the left coronary artery. Real-time quantitative RT-PCR was employed to investigate mRNA levels. The cellular distribution of CTGF was analysed by immunohistochemistry.
  
  
  RESULTS
  Seven days after induction of myocardial infarction (MI) and HF in rats we found 2.3-fold and 1.9-fold increase of pulmonary transforming growth factor-beta1 and procollagen alpha1(I) mRNA levels, respectively, and typical morphological characteristics of pulmonary remodeling including interstitial fibrosis and medial thickening of pulmonary arteries. Pulmonary CTGF mRNA levels were substantially elevated in HF rats compared to sham-operated rats (4-fold; P<0.05) and corresponded with similar increase (3-fold; P<0.05) of pulmonary CTGF protein contents. Immunohistochemical analysis revealed increased pulmonary anti-CTGF immunoreactivity in HF, with immunostaining predominantly localized to alveolar macrophages and interstitial fibroblasts. Isolated alveolar macrophages from HF rats demonstrated substantial induction of CTGF mRNA expression (16-fold; p<0.05). Interestingly, platelets caused robust induction of CTGF mRNA expression in alveolar macrophages upon co-culture in vitro.
  
  
  CONCLUSIONS
  Pulmonary CTGF was substantially increased in parallel with pulmonary remodeling in rats with HF. Our data indicate that alveolar macrophages are a major source of increased pulmonary CTGF in HF and that CTGF may be a player in the profibrotic mechanisms associated with HF.
authors.affiliation: Institute for Surgical Research, University of Oslo, and Department of Cardiology, Rikshospitalet University Hospital, Oslo, Norway.
authors.forename: Mohammad Shakil
authors.initials: MS
authors.lastname: Ahmed
authors.forename: Erik
authors.initials: E
authors.lastname: Øie
authors.forename: Leif Erik
authors.initials: LE
authors.lastname: Vinge
authors.forename: Thomas G
authors.initials: TG
authors.lastname: von Lueder
authors.forename: Toril
authors.initials: T
authors.lastname: Attramadal
authors.forename: Håvard
authors.initials: H
authors.lastname: Attramadal
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D055513:Connective Tissue Growth Factor; D016232:Endothelins / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006333:Heart Failure / Q000150:complications / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D011498:Protein Precursors / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014652:Vascular Diseases / Q000378:metabolism* / Q000473:pathology
chemical_list: C526316:CCN2 protein, rat; D016232:Endothelins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor