title: Bone morphogenetic protein receptor type II deficiency and increased inflammatory cytokine production. A gateway to pulmonary arterial hypertension.
abstract: BACKGROUND
  Mutations in bone morphogenetic protein receptor type II (BMPR-II) underlie most cases of heritable pulmonary arterial hypertension (PAH). However, disease penetrance is only 20-30%, suggesting a requirement for additional triggers. Inflammation is emerging as a key disease-related factor in PAH, but to date there is no clear mechanism linking BMPR-II deficiency and inflammation.
  
  
  OBJECTIVE
  To establish a direct link between BMPR-II deficiency, a consequentially heightened inflammatory response, and development of PAH.
  
  
  METHODS
  We used pulmonary artery smooth muscle cells from Bmpr2(+/-) mice and patients with BMPR2 mutations and compared them with wild-type controls. For the in vivo model, we used mice heterozygous for a null allele in Bmpr2 (Bmpr2(+/-)) and wild-type littermates.
  
  
  RESULTS
  Acute exposure to LPS increased lung and circulating IL-6 and KC (IL-8 analog) levels in Bmpr2(+/-) mice to a greater extent than in wild-type controls. Similarly, pulmonary artery smooth muscle cells from Bmpr2(+/-) mice and patients with BMPR2 mutations produced higher levels of IL-6 and KC/IL-8 after lipopolysaccharide stimulation compared with controls. BMPR-II deficiency in mouse and human pulmonary artery smooth muscle cells was associated with increased phospho-STAT3 and loss of extracellular superoxide dismutase. Chronic lipopolysaccharide administration caused pulmonary hypertension in Bmpr2(+/-) mice but not in wild-type littermates. Coadministration of tempol, a superoxide dismutase mimetic, ameliorated the exaggerated inflammatory response and prevented development of PAH.
  
  
  CONCLUSIONS
  This study demonstrates that BMPR-II deficiency promotes an exaggerated inflammatory response in vitro and in vivo, which can instigate development of pulmonary hypertension.
authors.affiliation: 1 Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom.|2 Pulmonary Vascular Diseases Unit, Papworth Hospital, Cambridge, United Kingdom.
authors.forename: Elaine
authors.identifier: http://orcid.org/0000-0002-5744-5014
authors.initials: E
authors.lastname: Soon
authors.affiliation: 1 Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Alexi
authors.initials: A
authors.lastname: Crosby
authors.affiliation: 2 Pulmonary Vascular Diseases Unit, Papworth Hospital, Cambridge, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Southwood
authors.affiliation: 1 Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Peiran
authors.initials: P
authors.lastname: Yang
authors.affiliation: 1 Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom.|3 James Black Centre, Cardiovascular Division, King's College London, London, United Kingdom; and.
authors.forename: Tamara
authors.initials: T
authors.lastname: Tajsic
authors.affiliation: 1 Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Toshner
authors.affiliation: 1 Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Appleby
authors.affiliation: 3 James Black Centre, Cardiovascular Division, King's College London, London, United Kingdom; and.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Shanahan
authors.affiliation: 4 Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.affiliation: 2 Pulmonary Vascular Diseases Unit, Papworth Hospital, Cambridge, United Kingdom.
authors.forename: Joanna
authors.initials: J
authors.lastname: Pepke-Zaba
authors.affiliation: 1 Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Upton
authors.affiliation: 1 Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000172:deficiency* / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000627:therapeutic use; D016207:Cytokines / Q000096:biosynthesis*; D005280:Fenoterol; D020022:Genetic Predisposition to Disease; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000503:physiopathology*; D007150:Immunohistochemistry; D008815:Mice, Inbred Strains; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000502:physiology
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D016207:Cytokines; D013113:Spin Labels; D005280:Fenoterol; C441642:SOD3 protein, human; D013482:Superoxide Dismutase; D052006:Bone Morphogenetic Protein Receptors, Type II; C001803:tempol
keywords: bone morphogenetic protein receptor type II; cytokine; inflammation; lipopolysaccharide; pulmonary hypertension