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- Title
Bone morphogenetic protein receptor type II deficiency and increased inflammatory cytokine production. A gateway to pulmonary arterial hypertension.
- Authors
Soon, Elaine; Crosby, Alexi; Southwood, Mark; Peiran Yang; Tajsic, Tamara; Toshner, Mark; Appleby, Sarah; Shanahan, Catherine M.; Bloch, Kenneth D.; Pepke-Zaba, Joanna; Upton, Paul; Morrell, Nicholas W.; Yang, Peiran
- Abstract
<bold>Rationale: </bold>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.<bold>Objectives: </bold>To establish a direct link between BMPR-II deficiency, a consequentially heightened inflammatory response, and development of PAH.<bold>Methods: </bold>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.<bold>Measurements and Main Results: </bold>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.<bold>Conclusions: </bold>This study demonstrates that BMPR-II deficiency promotes an exaggerated inflammatory response in vitro and in vivo, which can instigate development of pulmonary hypertension.
- Subjects
THERAPEUTIC use of antioxidants; OXIDES; ANIMAL experimentation; ANIMALS; CELL receptors; CYTOKINES; DISEASE susceptibility; FREE radicals; IMMUNOHISTOCHEMISTRY; MICE; PULMONARY hypertension; RESEARCH funding; SUPEROXIDE dismutase; ORCIPRENALINE; THERAPEUTICS
- Publication
American Journal of Respiratory & Critical Care Medicine, 2015, Vol 192, Issue 7, p859
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.201408-1509OC