title: Pulmonary venous hypertension and mechanical strain stimulate monocyte chemoattractant protein-1 release and structural remodelling of the lung in human and rodent chronic heart failure models.
abstract: BACKGROUND
  The burden of chronic heart failure (HF) is rising owing to an increased survivorship after myocardial infarction (MI). Pulmonary structural remodelling in patients with HF may protect against oedema while causing dyspnoea, the predominant symptom associated with HF. The cellular and molecular mechanisms underlying these processes in HF are poorly understood. We hypothesised that pulmonary venous hypertension (PVH) following MI provides a mechanical stimulus for structural remodelling of the lung via monocyte chemoattractant protein-1 (MCP-1).
  
  
  METHODS
  Human lung microvascular endothelial cells (HLMVEC) and Ea.Hy 926 cells exposed to cyclic mechanical strain (CMS) in vitro were analysed for MCP-1 expression and activation of signalling intermediates. HF was induced in Sprague-Dawley rats 16 weeks after MI; a cohort was rescued with AAV9.SERCA2a gene therapy to reduce PVH.
  
  
  RESULTS
  HLMVEC and Ea.Hy 926 cells exposed to CMS upregulated MCP-1 gene expression and protein release in an extracellular-signal-regulated kinase (ERK) 1/2 dependent manner. Supernatants from these experiments stimulated fibroblast (human fetal lung fibroblast -1) and pulmonary artery smooth muscle cell proliferation and differentiation. Total lung collagen, a marker of structural remodelling, and MCP-1 gene expression were increased in the lungs of rats with post-MI HF. SERCA2a gene therapy that attenuated PVH after MI was associated with lower levels of lung collagen and MCP-1 gene expression in the lung.
  
  
  CONCLUSIONS
  Mechanical strain associated with PVH may stimulate pulmonary structural remodelling through ERK 1/2 dependent induction of MCP-1. These findings provide insights into the pathophysiology of lung remodelling in HF and highlight novel, potential therapeutic targets.
authors.affiliation: Department of Leukocyte Biology, National Heart and Lung Institute, Imperial College, London, UK.
authors.forename: John E S
authors.initials: JE
authors.lastname: Park
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, London, UK Myocardial Function Unit, National Heart and Lung Institute, Imperial College, London, UK.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Lyon
authors.affiliation: Department of Leukocyte Biology, National Heart and Lung Institute, Imperial College, London, UK NIHR Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, London, UK.
authors.forename: Dongmin
authors.initials: D
authors.lastname: Shao
authors.affiliation: Department of Leukocyte Biology, National Heart and Lung Institute, Imperial College, London, UK.
authors.forename: Lauren R
authors.initials: LR
authors.lastname: Hector
authors.affiliation: NIHR Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, London, UK.
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.affiliation: Myocardial Function Unit, National Heart and Lung Institute, Imperial College, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: O'Gara
authors.affiliation: Department of Leukocyte Biology, National Heart and Lung Institute, Imperial College, London, UK.
authors.forename: Liao
authors.initials: L
authors.lastname: Pinhu
authors.affiliation: Centre for Inflammation and Tissue Repair (CITR), University College London, Rayne Institute, London, UK.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Chambers
authors.affiliation: Department of Leukocyte Biology, National Heart and Lung Institute, Imperial College, London, UK NIHR Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, London, UK.
authors.forename: S John
authors.initials: SJ
authors.lastname: Wort
authors.affiliation: Department of Leukocyte Biology, National Heart and Lung Institute, Imperial College, London, UK NIHR Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, London, UK.
authors.forename: Mark J D
authors.initials: MJ
authors.lastname: Griffiths
mesh_terms: D056151:Airway Remodeling / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000502:physiology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D009203:Myocardial Infarction / Q000150:complications; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics; D013314:Stress, Mechanical; D015854:Up-Regulation / Q000502:physiology
chemical_list: C506948:Atp2a2 protein, rat; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: Pulmonary oedema; Systemic disease and lungs