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Interleukin-6 and tumor necrosis factor-? are associated with quality of life-related symptoms in pulmonary arterial hypertension.

ABSTRACT: Inflammation is associated with symptoms in many chronic illnesses; however, this link has not been established in pulmonary arterial hypertension.The objective of this study was to investigate the association between inflammatory markers and quality of life-related symptoms in patients with pulmonary arterial hypertension. We hypothesized that higher circulating IL-6 and tumor necrosis factor-? levels would be associated with worse quality of life-related symptoms.We performed a secondary analysis using baseline and 3-month assessments of 62 subjects in a clinical trial of aspirin and simvastatin to determine the association between plasma IL-6 and tumor necrosis factor-? levels and the Medical Outcomes Study Short Form-36 subscales (pain, vitality, mental health).The mean age was 49.7±13.4 years; 87% were female. Higher IL-6 levels were significantly associated with lower Medical Outcomes Study Short Form-36 subscale scores, indicating worse bodily pain, vitality, and mental health (all P<0.01). Higher tumor necrosis factor-? levels were significantly associated with increased bodily pain, but better mental health scores.IL-6 and tumor necrosis factor-? levels are associated with certain quality of life domains in patients with pulmonary arterial hypertension. Clinical trial registered with www.clinicaltrials.gov (NCT00384865).

SUBMITTER: Matura LA

PROVIDER: S-EPMC4418312 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Interleukin-6 and tumor necrosis factor-α are associated with quality of life-related symptoms in pulmonary arterial hypertension.

Matura Lea Ann LA Ventetuolo Corey E CE Palevsky Harold I HI Lederer David J DJ Horn Evelyn M EM Mathai Stephen C SC Pinder Diane D Archer-Chicko Christine C Bagiella Emilia E Roberts Kari E KE Tracy Russell P RP Hassoun Paul M PM Girgis Reda E RE Kawut Steven M SM

Annals of the American Thoracic Society 20150301 3

<h4>Rationale</h4>Inflammation is associated with symptoms in many chronic illnesses; however, this link has not been established in pulmonary arterial hypertension.<h4>Objectives</h4>The objective of this study was to investigate the association between inflammatory markers and quality of life-related symptoms in patients with pulmonary arterial hypertension. We hypothesized that higher circulating IL-6 and tumor necrosis factor-α levels would be associated with worse quality of life-related sy ...[more]

PMID: 25615959

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Project description:Cold temperatures are associated with increased mortality and morbidity of cardiovascular and pulmonary disease. Cold exposure causes lung inflammation, pulmonary hypertension (PH), and right ventricle hypertrophy, but there is no effective therapy because of unknown mechanism. Here, we investigated whether RNA interference silencing of tumor necrosis factor (TNF)-α decreases cold-induced macrophage infiltration, PH, and pulmonary arterial (PA) remodeling. We found for the first time that continuous cold exposure (5.0°C) increased TNF-α expression and macrophage infiltration in the lungs and PAs right before elevation of right ventricle systolic pressure. The in vivo RNA interference silencing of TNF-α was achieved by intravenous delivery of recombinant AAV-2 carrying TNF-α short hairpin small-interfering RNA 24 hours before cold exposure. Cold exposure for 8 weeks significantly increased right ventricle pressure compared with the warm controls (40.19±4.9 versus 22.9±1.1 mm Hg), indicating that cold exposure caused PH. Cold exposure increased TNF-α, interleukin-6, and phosphodiesterase-1C protein expression in the lungs and PAs and increased lung macrophage infiltration. Notably, TNF-α short hairpin small-interfering RNA prevented the cold-induced increases in TNF-α, interleukin-6, and phosphodiesterase-1C protein expression, abolished lung macrophage infiltration, and attenuated PH (26.28±1.6 mm Hg), PA remodeling, and right ventricle hypertrophy. PA smooth muscle cells isolated from cold-exposed animals showed increased intracellular superoxide levels and cell proliferation along with decreased intracellular cGMP. These cold-induced changes were prevented by TNF-α short hairpin small-interfering RNA. In conclusions, upregulation of TNF-α played a critical role in the pathogenesis of cold-induced PH by promoting pulmonary macrophage infiltration and inflammation. AAV delivery of TNF-α short hairpin small-interfering RNA may be an effective therapeutic approach for cold-induced PH and PA remodeling.

Project description:ObjectiveConnective tissue disease (CTD)-associated pulmonary arterial hypertension (PAH) is the second most common etiology of PAH and carries a poor prognosis. Recently, it has been shown that female human tumor necrosis factor (TNF)-transgenic (Tg) mice die of cardiopulmonary disease by 6 months of age. This study was undertaken to characterize this pathophysiology and assess its potential as a novel model of CTD-PAH.MethodsHistologic analysis was performed on TNF-Tg and wild-type (WT) mice to characterize pulmonary vascular and right ventricular (RV) pathology (n = 40 [4-5 mice per group per time point]). Mice underwent right-sided heart catheterization (n = 29) and micro-computed tomographic angiography (n = 8) to assess vascular disease. Bone marrow chimeric mice (n = 12), and anti-TNF-treated mice versus placebo-treated mice (n = 12), were assessed. RNA sequencing was performed on mouse lung tissue (n = 6).ResultsTNF-Tg mice displayed a pulmonary vasculopathy marked by collagen deposition (P < 0.001) and vascular occlusion (P < 0.001) with associated RV hypertrophy (P < 0.001) and severely increased RV systolic pressure (mean ± SD 75.1 ± 19.3 mm Hg versus 26.7 ± 1.7 mm Hg in WT animals; P < 0.0001). TNF-Tg mice had increased α-smooth muscle actin (α-SMA) staining, which corresponded to proliferation and loss of von Willebrand factor (vWF)-positive endothelial cells (P < 0.01). There was an increase in α-SMA-positive, vWF-positive cells (P < 0.01), implicating endothelial-mesenchymal transition. Bone marrow chimera experiments revealed that mesenchymal but not bone marrow-derived cells are necessary to drive this process. Treatment with anti-TNF therapy halted the progression of disease. This pathology closely mimics human CTD-PAH, in which patient lungs demonstrate increased TNF signaling and significant similarities in genomic pathway dysregulation.ConclusionThe TNF-Tg mouse represents a novel model of CTD-PAH, recapitulates key disease features, and can serve as a valuable tool for discovery and assessment of therapeutics.

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Interleukin-6 and tumor necrosis factor-? are associated with quality of life-related symptoms in pulmonary arterial hypertension.

Publications

Interleukin-6 and tumor necrosis factor-α are associated with quality of life-related symptoms in pulmonary arterial hypertension.

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