Increased levels of plasma CXC-Chemokine Ligand 10, 12 and 16 are associated with right ventricular function in patients with idiopathic pulmonary arterial hypertension

Yang, Tao; Li, Zhennan; Guo, Chuan Fei; Gu, Qing; Ni, Xin‐Hai; Zhao, Zhi-hui; Ye, Jue; Meng, Xia; Liu, Zhihong; Xiong, Chang-ming; He, Jian‐Guo

doi:10.1016/j.hrtlng.2014.04.016

Cited by 36 publications

(24 citation statements)

References 30 publications

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“…Although the CXCL12/CXCR4 axis plays an important role in the onset and progression of the disease [4][5][6][7][8][9][10][11][12] , little is known about the role of CXCR7 in PAH. Interestingly, CXCR7 appears to be critical for both the cardiovascular system development and vascular homeostasis in animal models.…”

Section: Discussionmentioning

confidence: 99%

Neutralization of CXCL12 attenuates established pulmonary hypertension in rats

Bordenave

Thuillet

et al. 2019

Cardiovascular Research

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Aims The progressive accumulation of cells in pulmonary vascular walls is a key pathological feature of pulmonary arterial hypertension (PAH) that results in narrowing of the vessel lumen, but treatments targeting this mechanism are lacking. The C-X-C motif chemokine 12 (CXCL12) appears to be crucial in these processes. We investigated the activity of two CXCL12 neutraligands on experimental pulmonary hypertension (PH), using two complementary animal models. Methods and results Male Wistar rats were injected with monocrotaline (MCT) or were subjected to SU5416 followed by 3-week hypoxia to induce severe PH. After PH establishment, assessed by pulsed-wave Doppler echocardiography, MCT-injected or SU5416 plus chronic hypoxia (SuHx) rats were randomized to receive CXCL12 neutraligands chalcone 4 or LIT-927 (100 mg/kg/day), the C-X-C motif chemokine receptor 4 (CXCR4) antagonist AMD3100 (5 mg/kg/day), or vehicle, for 2 or 3 weeks, respectively. At the end of these treatment periods, echocardiographic and haemodynamic measurements were performed and tissue samples were collected for protein expression and histological analysis. Daily treatment of MCT-injected or SuHx rats with established PH with chalcone 4 or LIT-927 partially reversed established PH, reducing total pulmonary vascular resistance, and remodelling of pulmonary arterioles. Consistent with these observations, we found that neutralization of CXCL12 attenuates right ventricular hypertrophy, pulmonary vascular remodelling, and decreases pulmonary artery smooth muscle cell (PA-SMC) proliferation in lungs of MCT-injected rats and SuHx rats. Importantly, CXCL12 neutralization with either chalcone 4 or LIT-927 inhibited the migration of PA-SMCs and pericytes in vitro with a better efficacy than AMD3100. Finally, we found that CXCL12 neutralization decreases vascular pericyte coverage and macrophage infiltration in lungs of both MCT-injected and SuHx rats. Conclusion We report here a greater beneficial effect of CXCL12 neutralization vs. the conventional CXCR4 blockade with AMD3100 in the MCT and SuHx rat models of severe PH, supporting a role for CXCL12 in the progression of vascular complications in PH and opening to new therapeutic options.

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Section: Discussionmentioning

confidence: 99%

Neutralization of CXCL12 attenuates established pulmonary hypertension in rats

Bordenave

Thuillet

et al. 2019

Cardiovascular Research

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“…The CXCL10, ligand of CXCR3, was also found to be elevated in IPAH lungs and blood samples, which might favor the recruitment of CXCR3 + effector T cells [13, 28]. These inflammatory processes might therefore be inextricably linked to a specific (presumably a Th1/Th17-predominant) (peri-) vascular inflammation found in IPAH.…”

Section: Discussionmentioning

confidence: 99%

Acute effects of exercise on the inflammatory state in patients with idiopathic pulmonary arterial hypertension

et al. 2016

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BackgroundExercise training positively influences exercise tolerance and functional capacity of patients with idiopathic pulmonary arterial hypertension (IPAH). However, the underlying mechanisms are unclear. We hypothesized that exercise modulates the activated inflammatory state found in IPAH patients.MethodsSingle cardiopulmonary exercise testing was performed in 16 IPAH patients and 10 healthy subjects. Phenotypic characterization of peripheral blood mononuclear cells and circulating cytokines were assessed before, directly after and 1 h after exercise.ResultsBefore exercise testing, IPAH patients showed elevated Th2 lymphocytes, regulatory T lymphocytes, IL-6, and TNF-alpha, whilst Th1/Th17 lymphocytes and IL-4 were reduced. In IPAH patients but not in healthy subject, exercise caused an immediate relative decrease of Th17 lymphocytes and a sustained reduction of IL-1-beta and IL-6. The higher the decrease of IL-6 the higher was the peak oxygen consumption of IPAH patients.ConclusionsExercise seems to be safe from an immune and inflammatory point of view in IPAH patients. Our results demonstrate that exercise does not aggravate the inflammatory state and seems to elicit an immune-modulating effect in IPAH patients.

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“…Remarkably, significantly more inflammatory cells were found in RV tissue samples from SSc-PAH patients as compared to those from patients with idiopathic PAH thus confirming increased local inflammation in these patients ( Overbeek et al, 2010 ). Contribution of inflammatory pathways to the pathogenesis of RV adverse remodeling and dysfunction is further supported by the association of circulatory mediators of inflammation with RV function in patients with PAH ( Sztrymf et al, 2010 ; Yang et al, 2014 ; Prins et al, 2017 ). Interestingly, a recent magnetic resonance imaging investigation in individuals free of clinical cardiovascular disease has demonstrated that plasma levels of pro-inflammatory C-reactive protein (CRP) and interleukin-6 (IL-6) are independently associated with RV morphology, suggesting that systemic inflammation may contribute to RV structural changes ( Harhay et al, 2013 ).…”

Section: Introductionmentioning

confidence: 91%

Inflammatory Mediators Drive Adverse Right Ventricular Remodeling and Dysfunction and Serve as Potential Biomarkers

et al. 2018

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Adverse right ventricular (RV) remodeling leads to ventricular dysfunction and failure that represents an important determinant of outcome in patients with pulmonary hypertension (PH). Recent evidence indicates that inflammatory activation contributes to the pathogenesis of adverse RV remodeling and dysfunction. It has been shown that accumulation of inflammatory cells such as macrophages and mast cells in the right ventricle is associated with maladaptive RV remodeling. In addition, inhibition of inflammation in animal models of RV failure ameliorated RV structural and functional impairment. Furthermore, a number of circulating inflammatory mediators have been demonstrated to be associated with RV performance. This work reviews the role of inflammation in RV remodeling and dysfunction and discusses anti-inflammatory strategies that may attenuate adverse structural alterations while promoting improvement of RV function.

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Increased levels of plasma CXC-Chemokine Ligand 10, 12 and 16 are associated with right ventricular function in patients with idiopathic pulmonary arterial hypertension

Cited by 36 publications

References 30 publications

Neutralization of CXCL12 attenuates established pulmonary hypertension in rats

Neutralization of CXCL12 attenuates established pulmonary hypertension in rats

Acute effects of exercise on the inflammatory state in patients with idiopathic pulmonary arterial hypertension

Inflammatory Mediators Drive Adverse Right Ventricular Remodeling and Dysfunction and Serve as Potential Biomarkers

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