Abstract:Arctigenin ameliorates monocrotaline-induced pulmonary arterial hypertension, at least in part, through exerting its anti-inflammatory, antioxidant, and antiproliferative effects, which inhibit the NLRP3 inflammasome signal pathway in rats.
“…NLRP3 inflammasome activation is reflected by increased numbers of NLRP3 positive cells in pulmonary arterioles, increased cleavage of caspase‐1, and the inflammasome products IL‐1β and IL‐18 in the whole lung tissue. Although the inflammasome has been suggested to be activated in several PH models, 14 , 15 , 24 , 25 , 26 , 27 human translational relevance of these models is limited.…”
Section: Discussionmentioning
confidence: 99%
“…This will have implications for progressive human PAH, including PAH associated with congenital heart disease. 14 , 15 , 20 , 24 , 25 , 26 , 27 …”
Section: Discussionmentioning
confidence: 99%
“…This will have implications for progressive human PAH, including PAH associated with congenital heart disease. 14,15,20,[24][25][26][27] The canakinumab anti-inflammatory thrombosis outcomes (CANTOS) study has shown that antagonism of IL-1β reduces recurrent myocardial infarction in patients with plasma C-reactive protein (CRP) levels >2 mg/L, suggesting an important role for IL-1β induced inflammation in CVD. 9 A small-scale pilot trial in adult PAH patients showed that IL-1 receptor blockade by anakinra reduced plasma CRP within 15 days of treatment, yet this did not result in significant hemodynamic or echocardiographic changes.…”
Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased pulmonary arterial pressure, inflammation, and neointimal remodeling of pulmonary arterioles. Serum levels of interleukin (IL)‐1β and IL‐18 are elevated in PAH patients and may enhance proinflammatory neointimal remodeling. NLRP3 inflammasome activation induces cleavage of the cytokines IL‐1β and IL‐18, required for their secretion. Pirfenidone (PFD), an antifibrotic and anti‐inflammatory drug, has been suggested to inhibit NLRP3 inflammasome activation. We hypothesized that PFD delays the progression of PAH by suppressing NLRP3 inflammasome activation. We assessed the effects of PFD treatment in a rat model for neointimal PAH induced by monocrotaline and aortocaval shunt using echocardiographic, hemodynamic, and vascular remodeling parameters. We measured inflammasome activation by NLRP3 immunostaining, Western blots for caspase‐1, IL‐1β, and IL‐18 cleavage, and macrophage IL‐1β secretion. PFD treatment ameliorated pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary vascular remodeling in PAH rats. In PAH rats, immunostaining of NLRP3 in pulmonary arterioles and caspase‐1, IL‐1β, and IL‐18 cleavage in lung homogenates were increased compared to controls, reflecting NLRP3 inflammasome activation in vivo. PFD decreased IL‐1β and IL‐18 cleavage, as well as macrophage IL‐1β secretion in vitro. Our studies show that PFD ameliorates pulmonary hemodynamics and vascular remodeling in experimental PAH. Although PFD did not affect all NLRP3 inflammasome parameters, it decreased IL‐1β and IL‐18 cleavage, the products of NLRP3 inflammasome activation that are key to its downstream effects. Our findings thus suggest a therapeutic benefit of PFD in PAH via suppression of NLRP3 inflammasome activation.
“…NLRP3 inflammasome activation is reflected by increased numbers of NLRP3 positive cells in pulmonary arterioles, increased cleavage of caspase‐1, and the inflammasome products IL‐1β and IL‐18 in the whole lung tissue. Although the inflammasome has been suggested to be activated in several PH models, 14 , 15 , 24 , 25 , 26 , 27 human translational relevance of these models is limited.…”
Section: Discussionmentioning
confidence: 99%
“…This will have implications for progressive human PAH, including PAH associated with congenital heart disease. 14 , 15 , 20 , 24 , 25 , 26 , 27 …”
Section: Discussionmentioning
confidence: 99%
“…This will have implications for progressive human PAH, including PAH associated with congenital heart disease. 14,15,20,[24][25][26][27] The canakinumab anti-inflammatory thrombosis outcomes (CANTOS) study has shown that antagonism of IL-1β reduces recurrent myocardial infarction in patients with plasma C-reactive protein (CRP) levels >2 mg/L, suggesting an important role for IL-1β induced inflammation in CVD. 9 A small-scale pilot trial in adult PAH patients showed that IL-1 receptor blockade by anakinra reduced plasma CRP within 15 days of treatment, yet this did not result in significant hemodynamic or echocardiographic changes.…”
Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased pulmonary arterial pressure, inflammation, and neointimal remodeling of pulmonary arterioles. Serum levels of interleukin (IL)‐1β and IL‐18 are elevated in PAH patients and may enhance proinflammatory neointimal remodeling. NLRP3 inflammasome activation induces cleavage of the cytokines IL‐1β and IL‐18, required for their secretion. Pirfenidone (PFD), an antifibrotic and anti‐inflammatory drug, has been suggested to inhibit NLRP3 inflammasome activation. We hypothesized that PFD delays the progression of PAH by suppressing NLRP3 inflammasome activation. We assessed the effects of PFD treatment in a rat model for neointimal PAH induced by monocrotaline and aortocaval shunt using echocardiographic, hemodynamic, and vascular remodeling parameters. We measured inflammasome activation by NLRP3 immunostaining, Western blots for caspase‐1, IL‐1β, and IL‐18 cleavage, and macrophage IL‐1β secretion. PFD treatment ameliorated pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary vascular remodeling in PAH rats. In PAH rats, immunostaining of NLRP3 in pulmonary arterioles and caspase‐1, IL‐1β, and IL‐18 cleavage in lung homogenates were increased compared to controls, reflecting NLRP3 inflammasome activation in vivo. PFD decreased IL‐1β and IL‐18 cleavage, as well as macrophage IL‐1β secretion in vitro. Our studies show that PFD ameliorates pulmonary hemodynamics and vascular remodeling in experimental PAH. Although PFD did not affect all NLRP3 inflammasome parameters, it decreased IL‐1β and IL‐18 cleavage, the products of NLRP3 inflammasome activation that are key to its downstream effects. Our findings thus suggest a therapeutic benefit of PFD in PAH via suppression of NLRP3 inflammasome activation.
“…A large body of evidence has demonstrated that inflammation plays a vital role in the pathogenesis of many diseases, including PAH. The recombinant NLR family pyrin domain containing protein 3 (NLRP3) inflammasome signalling pathway was blocked by administration of arctigenin to resist MCT-induced lung injury in rats [ 106 ]. In s chronic hypoxic environment, HIF-1 increases Ca 2+ influx and TRPC expression in PASMCs [ 107 ].…”
Pulmonary arterial hypertension (PAH) is a progressive and rare disease without obvious clinical symptoms that shares characteristics with pulmonary vascular remodeling. Right heart failure in the terminal phase of PAH seriously threatens the lives of patients. This review attempts to comprehensively outline the current state of knowledge on PAH its pathology, pathogenesis, natural medicines therapy, mechanisms and clinical studies to provide potential treatment strategies. Although PAH and pulmonary hypertension have similar pathological features, PAH exhibits significantly elevated pulmonary vascular resistance caused by vascular stenosis and occlusion. Currently, the pathogenesis of PAH is thought to involve multiple factors, primarily including genetic/epigenetic factors, vascular cellular dysregulation, metabolic dysfunction, even inflammation and immunization. Yet many issues regarding PAH need to be clarified, such as the “oestrogen paradox”. About 25 kinds monomers derived from natural medicine have been verified to protect against to PAH via modulating BMPR2/Smad, HIF-1α, PI3K/Akt/mTOR and eNOS/NO/cGMP signalling pathways. Yet limited and single PAH animal models may not corroborate the efficacy of natural medicines, and those natural compounds how to regulate crucial genes, proteins and even microRNA and lncRNA still need to put great attention. Additionally, pharmacokinetic studies and safety evaluation of natural medicines for the treatment of PAH should be undertaken in future studies. Meanwhile, methods for validating the efficacy of natural drugs in multiple PAH animal models and precise clinical design are also urgently needed to promote advances in PAH.
Graphical Abstract
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