期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 192, 期 7, 页码 859-872出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.201408-1509OC
关键词
pulmonary hypertension; bone morphogenetic protein receptor type II; cytokine; lipopolysaccharide; inflammation
资金
- Medical Research Council training fellowship
- Sackler scholarship
- Wellcome Trust fellowship
- National Institute for Health Research (NIHR) Healthcare Scientist fellowship
- Fondation Leducq network award
- British Heart Foundation program grant
- Academy of Medical Sciences (AMS) [AMS-SGCL13-Soon] Funding Source: researchfish
- British Heart Foundation [PG/13/91/30579, RG/13/4/30107, PG/11/10/28724] Funding Source: researchfish
- Medical Research Council [G0802261, G0800784, G1000847, MR/K020919/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0514-10086, CL-2009-14-005(1)] Funding Source: researchfish
- MRC [MR/K020919/1, G0800784, G0802261, G1000847] Funding Source: UKRI
Rationale: 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. Objectives: 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. Measurements and Main 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.
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