Abstract 973: A Novel Anti-Inflammatory Therapeutic Approach for Pulmonary Arterial Hypertension: Blockade of NF-kB by Nano-DDS of NF-kB decoy to the lung ameliorates monocrotaline-induced PAH

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Satoshi Kimura ◽  
Kensuke Egashira ◽  
Chen Ling ◽  
Hiroyuki Tsujimoto ◽  
Kaori Hara ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Cross Sections ◽  
Animal Studies ◽  
Nuclear Factor Κb ◽  
Therapeutic Benefit ◽  
Pulmonary Vasculature ◽  
Pulmonary Arterial ◽  
Anti Inflammatory ◽  
Intratracheal Injection

Background: Inflammatory mechanisms are implicated in the pathogenesis of pulmonary arterial hypertension (PAH), and thus can be a promising therapeutic target of the devastating disease. Nuclear factor-κB (NF-κB) is a redox-sensitive transcription factor that controls expression of important inflammatory cytokines. However, no prior study addressed the role of NF-κB in PAH. We have developed nanotechnology-based drug delivery system (Nano-DDS) to the lung using intratracheal injection of bioabsorbable polymeric PLGA nanoparticle (NP, a mean diameter of 50 nm) for clinical application. Hypothesis: Blockade of NF-κB by Nano-DDS of NF-κB decoy to the lung ameliorates monocrotaline (MCT)-induced PAH. Methods and Results: [Immunohistochemical studies in human samples from autopsy] Immunohistochemical study using an antibody against activated form (α-p65) showed that activation of NF-κB was noted in the alveolar macrophage and pulmonary vasculature with medial hypertrophy from lung cross-sections from patients with severe PAH. These pathologic changes were associated with increased staining of IL-6 and MCP-1. [Experimental animal studies] Single intratracheal injection of NP incorporated with fluorescence labeled NF-κB decoy in rats resulted in sustained intracellular delivery into macrophages and pulmonary vasculature until 7 days. After MCT injection, rats were divided into no treatment (No Tx) group, and those received single intratracheal decoy alone (50 μg), blank NPs alone, or decoy NP (n=6 – 8, each). No Tx group developed significant PAH, pulmonary arterial remodeling, and increased infiltration of macrophages 3 weeks after MCT injection. These pathologic changes were ameliorated by treatment with decoy NP, but not with decoy only or blank NP only. Increased activity of NF-κB in alveolar macrophages in No Tx group was attenuated by intratracheal decoy NP, but not by decoy only or blank NP only. Conclusions: We have developed a novel Nano-DDS of NF-κB decoy into the lung using bioabsorbable NP, and demonstrated its therapeutic benefit associated with anti-inflammatory effects in MCT-induced PAH. This study provides an innovative future direction of less invasive and dependable Nano-DDS for patients with severe PAH.

scholarly journals Gender, Sex Hormones, and Pulmonary Arterial Hypertension

2011 ◽  
Vol 10 (3) ◽  
pp. 160-166 ◽  
Author(s):  
Eric D. Austin
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Animal Studies ◽  
Pulmonary Arteries ◽  
Connective Tissue Diseases ◽  
World Health ◽  
Pulmonary Vasculature ◽  
Diverse Range ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary vascular remodeling of the distal pulmonary vasculature, ultimately leading to destruction and loss of the smallest pulmonary arteries.1 The ensuing syndrome of PAH is clinically characterized by reduced pulmonary arterial circulatory flow, resulting in increased pulmonary vascular resistance, which ultimately results in failure of the right heart.2 In both children and adults, PAH presents as a primary disease or in association with a diverse range of diseases such as connective tissue diseases, portal hypertension, and congenital heart disease.3 Nearly all forms of World Health Organization (WHO) Group 1 PAH demonstrate a skewed gender ratio with significantly more females diagnosed with PAH than males.4–6 While the mechanistic details behind the female predominance remain unclear, this gender discrepancy may represent an opportunity for advanced biologic understanding and future therapeutic development. This article will briefly discuss the intersection of human, in vitro, and animal studies of PAH, and highlight the conflicting data that others have discussed and elegantly elaborated upon as the “estrogen paradox” in PAH.7–9

Abstract 18587: Downregulation of Pulmonary Artery Endothelial Catechol-o-methyltransferase Activity by Aldosterone Increases Norepinephrine Levels in Pulmonary Arterial Hypertension

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Samantha Torquato ◽  
Kiyotake Ishikawa ◽  
Jaume Aguerro ◽  
Bradley A Maron ◽  
Joseph Loscalzo ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Right Heart Failure ◽  
Therapeutic Interventions ◽  
Pulmonary Vasculature ◽  
Methyltransferase Activity ◽  
Comt Activity ◽  
Pulmonary Arterial

Elevated levels of norepinephrine (NE) occur in pulmonary arterial hypertension (PAH) and are determined, in part, by the activity of catechol- O -methyltransferase (COMT). COMT degrades catecholamines, is negatively regulated by calcium, and is expressed by pulmonary artery endothelial cells (PAEC). As hyperaldosteronism occurs in PAH and aldosterone (ALDO) influences calcium levels, we hypothesized that ALDO decreases COMT activity to increase NE levels in PAH. Accordingly, human PAEC were treated with ALDO (10 -7 mol/L), a level that is achieved clinically in PAH, for up to 72 h. Compared to vehicle-treated PAEC, ALDO decreased COMT activity by 59.2 ± 6.2% (p<0.01) to increase NE levels in the medium (122.4 ± 11.8 vs. 210.7 ± 15.5 pg/mL/mg protein, p<0.01). This occurred as a result of an ALDO-mediated decrease in COMT protein expression by 52.6 ± 9.3% (p<0.01) as well as an increase in intracellular calcium levels (102.9 ± 21.0 vs. 167.7 ± 17.8 nmol/L, p<0.05) to inhibit activity. These effects were abrogated by coincubation with spironolactone. To determine the in vivo relevance of these findings, COMT was examined in the rat monocrotaline model of PAH with confirmed hyperALDO. COMT was decreased (47.6 ± 10.2 %control, p<0.05) in remodeled pulmonary arterioles with a concomitant increase in lung NE levels (432.8 ± 44.5 vs. 899.7 ± 34.2 pg/mL, p<0.01) compared to control rats. In the porcine pulmonary vein banding model of pulmonary hypertension (PH-pigs) with elevated mean pulmonary artery pressure (15[13-15] vs. 35[27-43], p<0.01) and pulmonary vascular resistance (PVR) index (1.97[1.74-2.28] vs. 5.78[2.61-8.75], p <0.05), ALDO levels were also increased (27.1 ± 5.1 vs. 60.8 ± 10.6 pg/mL, p<0.03) in advance of right heart failure as compared to sham controls. PH-pigs demonstrated a 48.3 ± 9.9% (p<0.02) decrease in pulmonary vascular COMT expression and an increase in NE levels (114.6 ± 20.2 vs. 1,622.6 ± 489.2 pg/mL, p<0.02) that correlated positively with ALDO levels (R 2 =0.58, p<0.02). These findings were confirmed in patients with PAH. Together, these data indicate that there is crosstalk in the pulmonary vasculature between ALDO and the sympathetic nervous system to regulate NE levels in PAH, and thus, have implications for therapeutic interventions.

Abstract 382: Cyclophilin A (CypA) is a Pathogenic Mediator of Pulmonary Arterial Hypertension

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Chao Xue
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Specific Inhibitor ◽  
Cyclophilin A ◽  
Pulmonary Vasculature ◽  
Tunel Staining ◽  
Mesenchymal Transition ◽  
Pulmonary Arterial

Rationale: Pulmonary arterial hypertension (PAH) is a devastating disease in which oxidative stress has been proposed to mediate pathological changes to the pulmonary vasculature such as endothelial cell (EC) apoptosis, endothelial to mesenchymal transition (EndMT), vascular smooth muscle cell (VSMC) proliferation, and inflammation. Our previous study showed that cyclophilin A (CypA) was secreted from EC and VSMC in response to oxidative stress, and much of the secreted CypA was acetylated (AcK-CypA). Furthermore, CypA was increased in the plasma of patients with PAH. Objective: To evaluate the cell- s pecific role of CypA in PAH and compare the relative effects of AcK-CypA and CypA on EC apoptosis, development of an inflammatory EC phenotype and EndMT. Methods and Results: Transgenic overexpression of CypA in EC, but not SMC, caused a PAH phenotype including increased pulmonary artery pressure, α-smooth muscle actin expression in small arteries, and CD45 positive cells in the lungs. Mechanistic analysis using cultured mouse lung microvascular EC showed that CypA and AcK-CypA increased apoptosis measured by caspase 3 cleavage and TUNEL staining. MM284, a specific inhibitor of extracellular CypA, prevented EC apoptosis. In addition, CypA and AcK-CypA promoted an EC inflammatory phenotype assessed by increased VCAM1 and ICAM1 expression, phosphorylation of p65, and degradation of IkB. Furthermore, CypA and AcK-CypA promoted EndMT assayed by change in cell morphology, increased mesenchymal markers and EndMT related transcription factors. At all concentrations, AcK-CypA stimulated greater increases in apoptosis, inflammation and EndMT than CypA. Conclusions: EC-derived CypA (especially AcK-CypA) causes PAH by a presumptive mechanism involving increased EC apoptosis, inflammation and EndMT. Our results suggest that inhibiting extracellular secreted CypA is a novel therapeutic approach for PAH.

scholarly journals Novel Therapeutic Approaches of Pulmonary Arterial Hypertension

2019 ◽  
Vol 28 (02) ◽  
pp. 112-117
Author(s):  
Sanjay Tyagi ◽  
Vishal Batra
Keyword(s):  
Nitric Oxide ◽  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Endothelin Receptors ◽  
Pulmonary Vasculature ◽  
Therapeutic Approaches ◽  
Uncommon Disease ◽  
Pulmonary Arterial ◽  
Novel Therapeutic

AbstractPulmonary arterial hypertension (PAH) is an uncommon disease characterized progressive remodeling of pulmonary vasculature. Although treatment for PAH have improved in last two decades but the outcome remains fatal. Currently, the therapies for PAH target three well-established pathways the nitric oxide (NO) pathway, endothelin receptors, and prostanoids. There are multiple potential targets for development of newer drugs in PAH which requires meticulous research and clinical trials.

scholarly journals Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for Pulmonary Arterial Hypertension

2020 ◽  
pp. 1902061
Author(s):  
David Macias ◽  
Stephen Moore ◽  
Alexi Crosby ◽  
Mark Southwood ◽  
Xinlin Du ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Target Genes ◽  
Right Heart Failure ◽  
Pulmonary Vasculature ◽  
Pulmonary Arterial ◽  
The Impact

Pulmonary Arterial Hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant HIF2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades.Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from IPAH patients were used to determine the impact of HIF2α-inhibition on endothelial function.Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyper-proliferative phenotype and over-active arginase activity in blood outgrowth endothelial cells from IPAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population.

Pulmonary vasculature

2017 ◽  
Author(s):  
Sophie Vergnaud ◽  
David Dobarro ◽  
John Wort
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Treatment Strategies ◽  
Symptomatic Improvement ◽  
Pulmonary Vasculature ◽  
History Of ◽  
Diffuse Cutaneous Systemic Sclerosis ◽  
Pulmonary Arterial ◽  
Phosphodiesterase 5 ◽  
Haemodynamic Improvement

A 16-year-old girl with a diagnosis of diffuse cutaneous systemic sclerosis is referred to a specialist pulmonary hypertension centre with a history of progressive breathlessness, reduced exercise tolerance, and raised pulmonary pressures on transthoracic echocardiogram. She is found to have pulmonary arterial hypertension on right cardiac catheterization and is started on sildenafil, a phosphodiesterase-5 inhibitor, which stabilizes her condition. An endothelin receptor antagonist is added, which provides some initial symptomatic improvement. She continues to deteriorate over a period of 5 years, ultimately requiring intravenous prostanoids, the only treatment to provide a real symptomatic and haemodynamic improvement. This chapter explores the physiology and pathophysiology of pulmonary arterial hypertension, its classification, the means of investigation and diagnosis, who to refer to specialist centres, and the concepts behind current and future treatment strategies.

Differential expression of vasoactive mediators in microparticle-challenged lungs of chickens that differ in susceptibility to pulmonary arterial hypertension

2010 ◽  
Vol 298 (1) ◽  
pp. R235-R242 ◽  
Author(s):  
Krishna R. Hamal ◽  
Robert F. Wideman ◽  
Nicholas B. Anthony ◽  
Gisela F. Erf
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Broiler Chickens ◽  
Breeding Population ◽  
Pulmonary Vasculature ◽  
Pulmonary Hypertension Syndrome ◽  
Vasoactive Mediators ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
Pulmonary Arterial Smooth Muscle

Pulmonary hypertension syndrome (PHS; ascites) in fast growing meat-type chickens (broilers) is characterized by the onset of idiopathic pulmonary arterial hypertension (IPAH) leading to right-sided congestive heart failure and terminal ascites. Intravenous microparticle (MP) injection is a tool used by poultry geneticists to screen for the broilers that are resistant (RES) or susceptible (SUS) to IPAH in a breeding population. MPs occlude pulmonary arterioles and initiate focal inflammation, causing local tissues and responding leukocytes to release vasoactive mediators such as serotonin (5-HT), endothelin-1 (ET-1), and nitric oxide (NO). RT-PCR was used to examine the differences between RES and SUS broilers in terms of gene expression of ET-1, ET receptor types A and B (ETA and ETB), the serotonin transporter (SERT), serotonin receptors (5-HT1A, 5-HT2A, 5-HT1B, 5-HT2B), endothelial NO synthase (eNOS), and inducible NOS (iNOS) in the lungs of these broilers before (0 h) and after (2, 6, 12, 24, and 48 h) MP injection. In SUS broilers MP injection elicited higher ( P < 0.05) pulmonary expression of 5-HT1A, 5-HT2B, and ET-1, which promote vasoconstriction and proliferation of pulmonary arterial smooth muscle cells (PASMC). In RES broilers the MP injection elicited higher expression of eNOS, iNOS, and ETB, which promote vasodilation and inhibit PASMC proliferation. These observations support the hypothesis that the resistance of broiler chickens to IPAH may be due to the higher expression of vasoactive mediators that favor enhanced vasodilation and attenuated vasoconstriction during MP injection challenges to the pulmonary vasculature.

scholarly journals Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities

Blood ◽  
2011 ◽  
Vol 117 (13) ◽  
pp. 3485-3493 ◽  
Author(s):  
Samar Farha ◽  
Kewal Asosingh ◽  
Weiling Xu ◽  
Jacqueline Sharp ◽  
Deepa George ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Hypoxia Inducible Factor ◽  
Pulmonary Arteries ◽  
Disease Process ◽  
Pulmonary Vasculature ◽  
Normal Numbers ◽  
Pulmonary Arterial

AbstractPulmonary arterial hypertension (PAH) is a proliferative vasculopathy characterized by high circulating CD34+CD133+ proangiogenic progenitors, and endothelial cells that have pathologic expression of hypoxia-inducible factor 1 α (HIF-1α). Here, CD34+CD133+ progenitor cell numbers are shown to be higher in PAH bone marrow, blood, and pulmonary arteries than in healthy controls. The HIF-inducible myeloid-activating factors erythropoietin, stem cell factor (SCF), and hepatocyte growth factor (HGF) are also present at higher than normal levels in PAH blood, and related to disease severity. Primary endothelial cells harvested from human PAH lungs produce greater HGF and progenitor recruitment factor stromal-derived factor 1 α (SDF-1α) than control lung endothelial cells, and thus may contribute to bone marrow activation. Even though PAH patients had normal numbers of circulating blood elements, hematopoietic alterations in myeloid and erythroid lineages and reticulin fibrosis identified a subclinical myeloproliferative process. Unexpectedly, evaluation of bone marrow progenitors and reticulin in nonaffected family members of patients with familial PAH revealed similar myeloid abnormalities. Altogether, the results show that PAH is linked to myeloid abnormalities, some of which may be related to increased production of HIF-inducible factors by diseased pulmonary vasculature, but findings in nonaffected family suggest myeloid abnormalities may be intrinsic to the disease process.

Sign in / Sign up

Export Citation Format

Share Document