scholarly journals Obesity-Related Pulmonary Arterial Hypertension in Rats Correlates with Increased Circulating Inflammatory Cytokines and Lipids and with Oxidant Damage in the Arterial Wall but not with Hypoxia

2014 ◽  
Vol 4 (4) ◽  
pp. 638-653 ◽  
Author(s):  
David C. Irwin ◽  
Chrystelle V. Garat ◽  
Joseph T. Crossno ◽  
Paul S. MacLean ◽  
Timothy M. Sullivan ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Inflammatory Cytokines ◽  
Arterial Wall ◽  
Oxidant Damage ◽  
Pulmonary Arterial

scholarly journals Lack of elevation in plasma levels of pro-inflammatory cytokines in common rodent models of pulmonary arterial hypertension: questions of construct validity for human patients

2017 ◽  
Vol 7 (2) ◽  
pp. 476-485 ◽  
Author(s):  
Kenny Schlosser ◽  
Mohamad Taha ◽  
Yupu Deng ◽  
Baohua Jiang ◽  
Lauralyn A McIntyre ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Animal Models ◽  
Arterial Hypertension ◽  
Inflammatory Cytokines ◽  
Plasma Levels ◽  
Rodent Models ◽  
Plasma Cytokine ◽  
Cytokine Levels ◽  
Pulmonary Arterial ◽  
Pro Inflammatory Cytokines

Translational research depends on the relevance of animal models and how well they replicate human disease. Here, we investigated plasma levels of three important pro-inflammatory cytokines (TNFα, IL-6, and MCP-1), known to be elevated in human pulmonary arterial hypertension (PAH), and systematically assessed their levels in PAH patients compared to five different rodent models of pulmonary hypertension (PH). A consistent immunoassay platform (Luminex xMAP) and source (Millipore) was used to measure all specimens. PAH patients (n = 29) exhibited significant elevations in all three cytokines (median [IQR] pg/mL; TNFα, 7.0 [4.8–11.7]; IL-6, 9.2 [3.8–17.2]; MCP-1, 109 [65–142]) versus healthy participants (n = 20) (median [IQR] pg/mL; TNFα, 3.0 [2.0–3.6]; IL-6, 1.7 [0.5–7.2]; MCP-1, 79 [49–93]. In contrast, mice with PH established after three weeks of hypoxia (n = 18) or SU5416 plus hypoxia (n = 20) showed no significant change in their plasma cytokine levels versus controls (n = 16), based on three to four independent experiments per group. Similarly, plasma cytokine levels were not elevated in rats with PH established three weeks after monocrotaline (n = 23), eight weeks after SU5416 alone (n = 10) or six to eight weeks after SU5416 plus hypoxia (n = 21) versus controls (n = 36 rats), based on three to eight independent experiments per group. Positive biologic control specimens from sepsis patients (n = 9), cecal-ligation and puncture (CLP)-induced septic mice (n = 6), and lipopolysaccharide-induced septic rats (n = 4) showed robust elevations in all three cytokines. This study suggests that animal models commonly used for the development of novel diagnostic and therapeutic approaches for PAH may have limited construct validity with respect to markers of systemic immune activation seen in human patients.

scholarly journals Elevated Levels of Inflammatory Cytokines Predict Survival in Idiopathic and Familial Pulmonary Arterial Hypertension

Circulation ◽  
2010 ◽  
Vol 122 (9) ◽  
pp. 920-927 ◽  
Author(s):  
Elaine Soon ◽  
Alan M. Holmes ◽  
Carmen M. Treacy ◽  
Natalie J. Doughty ◽  
Laura Southgate ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Inflammatory Cytokines ◽  
Pulmonary Arterial

Hypoxia-Induced Pulmonary Arterial Hypertension: The Role of TLR4

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1146-1146
Author(s):  
Liping Ma ◽  
Jianxing Chang ◽  
Hui Wu ◽  
Yabing Chen
Keyword(s):  
Reactive Oxygen Species ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Wall Thickness ◽  
Arterial Wall ◽  
Pulmonary Vasculature ◽  
Oxygen Species ◽  
Arterial Wall Thickness ◽  
Pulmonary Arterial

Abstract Abstract 1146 Pulmonary arterial hypertension (PAH) is often as a result of COPD and contributes to morbidity and mortality of chronic cor pulmonale. Hypoxemia is its main clinical features. The toll-like receptors are a group of type I transmembrane proteins that play a central role in specific recognition of pathagen-associated molecular patterns and are critical for the induction of innate immunity and inflammation. Expression of these innate immune receptors, especially TLR4 in healthy and pathological arteries has implicated its role in the homeostasis of vasculature. Chronic hypoxia-induced PAH is mediated by increased production of reactive oxygen species (ROS). ROS have been linked to activation of toll-like receptor 4 (TLR4) signaling. The present studies investigated the role of TLR4 in the pathogenesis PAH and the underlying mechanisms. In vitro, pulmonary arterial smooth muscle cells (PASMC) derived from TLR4−/− mice exhibited increased production of intracellular reactive oxygen species (ROS). Furthermore, under hypoxia, the expression of TLR4 in PASMC from WT mice was decreased, ROS production in PASMC from WT mice were increased, suggesting down-regulation of TLR4 may contribute to hypoxia-induced PAH. Using a hypoxia-induced PAH model, we found that hypoxia induced PAH and increased pulmonary arterial wall thickness in wild type (WT) mice. In contrast, mice deficient in TLR4 spontaneously developed PAH and increased pulmonary arterial wall thickness, which were not further enhanced by hypoxia. Consistent with the development of PAH in TLR4−/− mice, echocardiography confirmed right ventricular hypertrophy and decreased pulmonary arterial acceleration time compared to WT mice. Above results suggest that TLR4 plays an important role in maintaining normal pulmonary vasculature, and that hypoxia induces PAH via TLR4. In short, these studies demonstrate an important role of TLR4 in maintaining normal pulmonary vasculature and in the development of hypoxia-induced PAH. Genetic ablation of TLR4 and inhibition of TLR4 expression by hypoxia induces PASMC proliferation and vascular remodeling, in association with redox signaling in the pathogenesis of PAH. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Epigenetic Targets for Oligonucleotide Therapies of Pulmonary Arterial Hypertension

2020 ◽  
Vol 21 (23) ◽  
pp. 9222
Author(s):  
William Gerthoffer
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Small Molecules ◽  
Vascular Remodeling ◽  
Arterial Wall ◽  
Vascular Wall ◽  
Wall Structure ◽  
Wall Thickening ◽  
Pulmonary Arterial

Arterial wall remodeling underlies increased pulmonary vascular resistance and right heart failure in pulmonary arterial hypertension (PAH). None of the established vasodilator drug therapies for PAH prevents or reverse established arterial wall thickening, stiffening, and hypercontractility. Therefore, new approaches are needed to achieve long-acting prevention and reversal of occlusive pulmonary vascular remodeling. Several promising new drug classes are emerging from a better understanding of pulmonary vascular gene expression programs. In this review, potential epigenetic targets for small molecules and oligonucleotides will be described. Most are in preclinical studies aimed at modifying the growth of vascular wall cells in vitro or normalizing vascular remodeling in PAH animal models. Initial success with lung-directed delivery of oligonucleotides targeting microRNAs suggests other epigenetic mechanisms might also be suitable drug targets. Those targets include DNA methylation, proteins of the chromatin remodeling machinery, and long noncoding RNAs, all of which act as epigenetic regulators of vascular wall structure and function. The progress in testing small molecules and oligonucleotide-based drugs in PAH models is summarized.

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