Challenges and opportunities in treating inflammation associated with pulmonary hypertension

Voelkel, Norbert F.; Tamošiūnienė, Rasa; Nicolls, Mark R.

doi:10.1080/14779072.2016.1180976

Cited by 68 publications

(63 citation statements)

References 154 publications

(145 reference statements)

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“…Macrophages can potentiate smooth muscle cell proliferation associated with PAH through the secretion of cytokines, chemokines and leukotrienes [ 16 , 17 ] Based on reported potent anti-inflammatory effects of CDCs, we assessed macrophage infiltration in the lungs, via immunohistochemistry, at 35 days post CDC or Sham treatments ( Fig 4 ). Sham animals had increased macrophages throughout the peri-vascular areas of the lung and within vessel walls (p< 0.003 vs. control), but macrophage infiltration was attenuated in CDC-treated animals (p<0.02 vs. Sham, Fig 4 ).…”

Section: Resultsmentioning

confidence: 99%

Therapeutic benefits of intravenous cardiosphere-derived cell therapy in rats with pulmonary hypertension

Middleton

Fournier

et al. 2017

PLoS ONE

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Pulmonary arterial hypertension (PAH) is a progressive condition characterized by occlusive pulmonary arteriopathy, in which survival remains poor despite pharmacologic advances. The aim of this study was to evaluate the ability of cardiosphere-derived cells (CDCs), cardiac progenitor cells with potent anti-inflammatory and immunomodulatory properties, to attenuate hemodynamic and morphometric remodeling of the right ventricle (RV) and pulmonary arterioles in rats with established monocrotaline (MCT)-induced PAH. Animals were divided into 3 groups: 1) Control (CTL), 2) PAH in which CDCs were centrally infused (CDC) and 3) PAH in which saline was given (Sham). Significant increments in RV systolic pressure (RVSP) and RV hypertrophy were noted in Sham animals compared to CTL. In CDC rats at day 35, RSVP fell (- 38%; p< 0.001) and RV hypertrophy decreased (-26%; p< 0.01). TAPSE and cardiac output were preserved in all 3 groups at day 35. Pulmonary arteriolar wall thickness was greater in Sham rats compared to CTL, and reduced in CDC animals for vessels 20–50 μm (P<0.01; back to CTL levels) and 50–80μm (P<0.01) in diameter. The macrophage population was increased in Sham animals compared to CTL (P< 0.001), but markedly reduced in CDC rats. In conclusion, infusion of CDCs markedly attenuated several key pathophysiologic features of PAH. As adjunctive therapy to PAH-specific agents, CDCs have the potential to impact on the pathobiology of adverse pulmonary arteriolar remodeling, by acting on multiple mechanisms simultaneously.

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Section: Resultsmentioning

confidence: 99%

Therapeutic benefits of intravenous cardiosphere-derived cell therapy in rats with pulmonary hypertension

Middleton

Fournier

et al. 2017

PLoS ONE

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“…rape seed oil), and parasitic infections (e.g. schistosomiasis) with pathogenesis thought to include underlying inflammation in pulmonary arterial segments accompanied by local cytokine production [3,6]. Indeed, an unusual example of acquired PAH occurs in patients, mainly women, who have been administered Type I interferons (IFNs).…”

Section: Introductionmentioning

confidence: 99%

MxA Is a Novel Regulator of Endosome-Associated Transcriptional Signaling by Bone Morphogenetic Proteins 4 and 9 (BMP4 and BMP9)

Yuan

Sehgal

2016

PLoS ONE

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There is confusion about the role that IFN-α plays in the pathogenesis of pulmonary arterial hypertension (PAH) with different investigators reporting a causative or a protective role. There is now clear evidence in PAH pathogenesis for the involvement of BMP4 and BMP9 signaling, and its disruption by mutations in BMPR2. In the present study, we investigated MxA, an IFN-α-inducible cytoplasmic dynamin-family GTPase for effects on BMP4/9 signaling, including in the presence of PAH-disease-associated mutants of BMPR2. In human pulmonary arterial endothelial cells (HPAECs), IFN-α-induced endogenous as well as exogenously expressed MxA was associated with endosomes that aligned alongside microtubules and tubules of the endoplasmic reticulum (ER). Moreover, IFN-α and MxA stimulated basal and BMP4/9 signaling to a Smad1/5/8-responsive pBRE-Luc reporter. In HEK293T cells, immunoelectron microscopy confirmed the association of MxA with endosomes, and immunofluorescence methods showed these to be positive for early endosome markers (early endosomal antigen 1, clathrin light chain and Rab5) and RSmad1/5/8. Functionally, using different genetic and inhibitor approaches, we observed that clathrin-mediated endocytosis enhanced and caveolin-mediated endocytosis inhibited the transcriptional response to BMP4 and BMP9. MxA produced a further 3-4-fold enhancement of the BMP-induced response in a clathrin-endocytosis dependent manner. The microtubule inhibitor nocodazole and stabilizer paclitaxel respectively attenuated and enhanced the effect of MxA, implicating microtubule integrity in this process. MxA enhanced BMP-induced signaling in the presence of wild-type BMPR2, and partially rescued signaling from some PAH-disease-associated BMPR2 mutants. Taken together, the data identify MxA as a novel stimulator of BMP4 and BMP9 transcriptional signaling, and suggest it to be a candidate IFN-α-inducible mechanism that might have a protective role against development of PAH and other vascular diseases.

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“…Inflammation likely plays an important role in pathogenesis and progression of PAH , as well as in the development of RV failure (Kherbeck et al 2013;Price et al 2012;Rabinovitch et al 2014;Voelkel et al 2016). In patients with PAH, there is histologic evidence of accumulation of inflammatory cells and elevated levels of cytokines and chemokines (Huertas et al 2014;Humbert et al 2019), both around pulmonary vessels (Nicolls and Voelkel 2017) as well as in the failing RV (Sun et al 2017).…”

Section: Pathophysiology Of Pahmentioning

confidence: 99%

Pulmonary arterial hypertension: the case for a bioelectronic treatment

et al. 2019

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Pulmonary arterial hypertension (PAH) is a rare disease of unknown etiology that progresses to right ventricular failure. It has a complex pathophysiology, which involves an imbalance between vasoconstrictive and vasodilative processes in the pulmonary circulation, pulmonary vasoconstriction, vascular and right ventricular remodeling, systemic inflammation, and autonomic imbalance, with a reduced parasympathetic and increased sympathetic tone. Current pharmacological treatments for PAH include several classes of drugs that target signaling pathways in vascular biology and cardiovascular physiology, but they can have severe unwanted effects and they do not typically stop the progression of the disease. Pulmonary artery denervation has been tested clinically as a method to suppress sympathetic overactivation, however it is a nonspecific and irreversible intervention. Bioelectronic medicine, in particular vagus nerve stimulation (VNS), has been used in cardiovascular disorders like arrhythmias, heart failure and arterial hypertension and could, in principle, be tested as a treatment in PAH. VNS can produce pulmonary vasodilation and renormalize right ventricular function, via activation of pulmonary and cardiac vagal fibers. It can suppress systemic inflammation, via activation of fibers that innervate the spleen. Finally, VNS can gradually restore the balance between parasympathetic and sympathetic tone by regulating autonomic reflexes. Preclinical studies support the feasibility of using VNS in PAH. However, there are challenges with such an approach, arising from the need to affect a relatively small number of relevant vagal fibers, and the potential for unwanted cardiac and noncardiac effects of VNS in this sensitive patient population.

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Challenges and opportunities in treating inflammation associated with pulmonary hypertension

Cited by 68 publications

References 154 publications

Therapeutic benefits of intravenous cardiosphere-derived cell therapy in rats with pulmonary hypertension

Therapeutic benefits of intravenous cardiosphere-derived cell therapy in rats with pulmonary hypertension

MxA Is a Novel Regulator of Endosome-Associated Transcriptional Signaling by Bone Morphogenetic Proteins 4 and 9 (BMP4 and BMP9)

Pulmonary arterial hypertension: the case for a bioelectronic treatment

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