[Show abstract][Hide abstract] ABSTRACT: Pulmonary hypertension (PH) is characterized by elevated pulmonary arterial pressure, which leads to right ventricular (RV) hypertrophy and failure. The pathophysiological mechanisms of PH remain unclear but oxidative stress is believed to contribute to RV dysfunction. Melatonin is a powerful antioxidant and is cardioprotective against ischemia-reperfusion injury and hypertension. Therefore, we hypothesized that a chronic treatment with melatonin, given as a curative or preventive therapy, may confer cardiovascular benefits in PH. PH was induced in Long Evans rats (n≥6 per group), with a single subcutaneous injection of monocrotaline (MCT, 80mg/kg). Melatonin was given daily in the drinking water, with the treatment starting either on the day of the injection of MCT (dose-testing: melatonin 75ng/L and 6mg/kg), 14 days after the injection of MCT (curative treatment: 6mg/kg) or five days before the injection (preventive treatment: 6mg/kg). The development of PH was assessed by measuring RV hypertrophy, RV function, cardiac interstitial fibrosis and plasma oxidative stress. Compared with controls, MCT-treated rats displayed RV hypertrophy and dysfunction, increased interstitial fibrosis and elevated plasma oxidative stress. A chronic melatonin treatment (75ng/L or 6mg/kg) reduced RV hypertrophy, improved RV-function and reduced plasma oxidative stress. Curative and preventive treatment improved RV functional and plasma oxidative stress parameters and reduced cardiac interstitial fibrosis. Our data demonstrate that melatonin confers cardioprotection in this model of PH. As melatonin is an inexpensive and safe drug, we propose that clinical investigation of the effects of melatonin on RV function in patients with PH should be considered. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Journal of Pineal Research 07/2015; DOI:10.1111/jpi.12263 · 9.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Phosphodiesterase inhibitors (PDE) can be used as therapeutic agents for various diseases such as dementia, depression, schizophrenia and erectile dysfunction in men, as well as congestive heart failure, chronic obstructive pulmonary disease, rheumatoid arthritis, other inflammatory diseases, diabetes and various other conditions. In this review we will concentrate on one type of PDE, mainly PDE5 and its role in pulmonary vascular diseases.
[Show abstract][Hide abstract] ABSTRACT: The extent to which pulmonary arterial hypertension (PAH) experts share common practice patterns that are in alignment with published expert consensus recommendations is unknown. Our objective was to characterize the clinical management strategies used by an international cohort of self-identified PAH experts. A 32-item questionnaire composed mainly of rank order or Likert scale questions was distributed via the Internet (August 5, 2013, through January 20, 2014) to four international pulmonary vascular disease organizations. The survey respondents (N = 105) were field experts reporting 11.6 ± 8.7 years of PAH experience. Likert scale responses (1 = disagree, 7 = agree) were 3.0-5.0, indicating a disparity in opinions, for 78% of questions. Respondent (dis)agreement scores were 4.4 ± 2.2 for use of expert recommendations to determine catheterization timing in PAH. For PAH patients without cardiogenic shock or known vasoreactivity status, the most and least preferred first-line therapies (1 = most preferred, 5 = least preferred) were phosphodiesterase type 5 inhibitors (PDE-Vi) and subcutaneous prostacyclin analogues, respectively (1.4 ± 0.8 vs. 4.0 ± 1.1; P < 0.05). Compared with US-practicing clinicians (N = 46), non-US-practicing clinicians (N = 57) favored collaboration between cardiology and pulmonary medicine for clinical decision making (1 = disagree, 7 = agree; 3.1 ± 2.2 vs. 4.8 ± 2.2; P < 0.0001) and PDE-Vi (6.5% vs. 22.4%) as first-line therapy for PAH patients with cardiogenic shock but were less likely to perform vasoreactivity testing in patients with lung disease-induced pulmonary hypertension (4.3 ± 2.1 vs. 2.2 ± 1.6; P < 0.0001). In conclusion, practice patterns among PAH experts diverge from consensus recommendations and differ by practice location, suggesting that opportunity may exist to improve care quality for this highly morbid cardiopulmonary disease.
[Show abstract][Hide abstract] ABSTRACT: Schistosomiasis is caused by infection with the parasite Schistosoma, which is a flat-worm or fluke. The dominant species are Schistosoma mansoni, Schistosoma japonicum, and Schistosoma haematobium. Schistosomiasis is the third most common parasitic disease in the world after malaria and amoebiasis. It is endemic in more than 70 countries affecting about 200 million people worldwide, of whom 80% are in sub-Saharan Africa. There are pockets of infection in north-eastern Brazil, near the Yangtze River in China, and some pockets in south East Asia. In the East Mediterranean regions, the Schistosoma have been reported in Iraq and Egypt as well as in Sudan. The latter has the highest infection rate nowadays, particularly in the Al Jazeera area, due to the poor Schistosoma control program. In the Arabian peninsula, schistosomiasis has been reported in southwest part of Saudi Arabia, mainly in the Asir province and Jizan province, which lay in the southwest corner of Saudi Arabia and directly north of the border with Yemen. The efforts to control schistosomiasis have been very successful in Saudi Arabia due to the irrigation system control. However, the infection is prone in Yemen, where the schistosomiasis control is much less strict. Thus as a result, the problem still exists due to transmigration of the populations from both countries.
As a cause of pulmonary arterial hypertension (PAH), schistosomiasis is still under diagnosed and undertreated. This article with give a highlight about the pathophysiology of the disease and both diagnostic and therapeutic strategies.
Annals of Thoracic Medicine 07/2014; 9(Suppl 1):S38-41. DOI:10.4103/1817-1737.134019 · 1.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Saudi Association for Pulmonary Hypertension (previously called Saudi Advisory Group for Pulmonary Hypertension) has published the first Saudi Guidelines on Diagnosis and Treatment of Pulmonary Arterial Hypertension back in 2008. That guideline was very detailed and extensive and reviewed most aspects of pulmonary hypertension (PH). One of the disadvantages of such detailed guidelines is the difficulty that some of the readers who just want to get a quick guidance or looking for a specific piece of information might face.
All efforts were made to develop this guideline in an easy-to-read form, making it very handy and helpful to clinicians dealing with PH patients to select the best management strategies for the typical patient suffering from a specific condition. This Guideline was designed to provide recommendations for problems frequently encountered by practicing clinicians involved in management of PH. This publication targets mainly adult and pediatric PH-treating physicians, but can also be used by other physicians interested in PH.
Annals of Thoracic Medicine 07/2014; 9(Suppl 1):S1-S15. DOI:10.4103/1817-1737.134006 · 1.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pulmonary hypertension (PH) is a disorder that develops as a result of remodeling of the pulmonary vasculature and is characterized by narrowing/obliteration of small pulmonary arteries, leading to increased mean pulmonary artery pressure and pulmonary vascular resistance. Subsequently, PH increases the right ventricular afterload, which leads to right ventricular hypertrophy and eventually right ventricular failure. The pathophysiology of PH is not fully elucidated, and current treatments have only a modest impact on patient survival and quality of life. Thus, there is an urgent need for improved treatments or a cure. The use of animal models has contributed extensively to the current understanding of PH pathophysiology and the investigation of experimental treatments. However, PH in current animal models may not fully represent current clinical observations. For example, PH in animal models appears to be curable with many therapeutic interventions, and the severity of PH in animal models is also believed to correlate poorly with that observed in humans. In this review, we discuss a variety of animal models in PH research, some of their contributions to the field, their shortcomings, and how these have been addressed. We highlight the fact that the constant development and evolution of animal models will help us to more closely model the severity and heterogeneity of PH observed in humans.
[Show abstract][Hide abstract] ABSTRACT: The pathogenic mechanisms underlying pulmonary arterial hypertension (PAH) due to schistosomiasis, one of the most common causes of pulmonary hypertension (PH) worldwide, remains unknown. We hypothesized that TGF-β signaling as a consequence of Th2 inflammation is critical for the pathogenesis of this disease.
Mice sensitized and subsequently challenged with S. mansoni eggs developed PH associated with an increase in right ventricular systolic pressure (RVSP), thickening of the pulmonary artery media, and right ventricular hypertrophy. Rho-kinase dependent vasoconstriction accounted for about 60% of the increase in RVSP. The pulmonary vascular remodeling and PH were dependent on increased TGF-β signaling, as pharmacological blockade of the TGF-β ligand and receptor, and mice lacking Smad3 were significantly protected from Schistosoma-induced PH. Blockade of TGF-β signaling also led to a decrease in IL4 and IL13 concentrations, which drive the Th2 responses characteristic of schistosomiasis lung pathology. Lungs of patients with schistosomiasis-associated PAH have evidence of TGF-β signaling in their remodeled pulmonary arteries.
Experimental S. mansoni-induced pulmonary vascular disease relies on canonical TGF-β signaling.
[Show abstract][Hide abstract] ABSTRACT: Rationale: Schistosomiasis is one of the most common causes of pulmonary arterial hypertension worldwide, but the pathogenic mechanism by which the host inflammatory response contributes to vascular remodeling is unknown. We sought to identify signaling pathways that play protective or pathogenic roles in experimental Schistosoma-induced pulmonary vascular disease by whole-lung transcriptome analysis. Methods: Wildtype mice were experimentally exposed to S. mansoni ova by intraperitoneal sensitization followed by tail vein augmentation, and the phenotype assessed by right ventricular catheterization and tissue histology, RNA and protein analysis. Whole-lung transcriptome analysis by microarray and RNA sequencing was performed, the latter analyzed using 2 bioinformatic methods. Functional testing of the candidate IL-6 pathway was determined using IL6-knockout mice and the STAT3 inhibitor STI-201. Results: Wild-type mice exposed to S. mansoni had increased right ventricular systolic pressure and thickness of the pulmonary vascular media. Whole lung transcriptome analysis identified the IL6-STAT3-NFATc2 pathway as being upregulated, which was confirmed by PCR and immunostaining of lung tissue from S. mansoni-exposed mice and patients who died of the disease. Mice lacking IL6 or treated with STI-201 developed pulmonary hypertension associated with significant intima remodeling after exposure to S. mansoni. Conclusions: Whole lung transcriptome analysis identified upregulation of the IL6-STAT3-NFATc2 pathway, and IL6 signaling was found to be protective against Schistosoma-induced intimal remodeling.
American Journal of Respiratory Cell and Molecular Biology 07/2013; DOI:10.1165/rcmb.2012-0532OC · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Schistosomiasis is a global parasitic disease with high impact on public health in tropical areas. Schistosomiasis is a well-described cause of pulmonary arterial hypertension (PAH). The exact pathogenesis is still unclear, though inflammatory mechanisms are suspected. Another unknown is whether the changes in the pulmonary vasculature are generalized or localized. We studied 13 mice infected with cercariae for 12 weeks compared with 10 control mice. In our model, we observed that the liver was a target during infection and was enlarged more than two-fold after infection. However, right heart hypertrophy as measured by RV/(LV + S) ratio was not observed at this time point. Moreover, we noticed that 72% of the sampled lobes (92% of the lungs) harvested from these animals costained evidence of granulomatous changes, secondary to egg deposition. We systemically mapped the distribution of granulomatous lesions in right lung lobes (n = 43) of infected mice. We observed that the distribution of the granulomatous lesions was heterogeneous. Remodeled pulmonary vessels were seen in 26% of the lobes (46% of the lungs) and were observed only in close proximity to the granuloma. No remodeling was observed in the absence of granulomas. These findings support the view that pulmonary vascular remodeling is caused by the local presence of granulomas in PAH associated with schistosomiasis. The heterogeneous nature of the remodeling partly explains why many patients with schistosomiasis do not develop pulmonary hypertension.
[Show abstract][Hide abstract] ABSTRACT: Pulmonary arterial hypertension is a progressive pulmonary vascular disorder with high morbidity and mortality. Compelling evidence suggests that receptor tyrosine kinases, such as platelet-derived growth factor (PDGF) are closely involved in the pathogenesis of pulmonary arterial hypertension. We investigated the effects of 2 novel PDGF inhibitors, nilotinib/AMN107 (Abl kinases/PDGF receptor inhibitor) and dasatinib/BMS-354825 (Abl kinases/PDGF receptor/Src inhibitor), on the proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) and on the hemodynamics and pulmonary vascular remodeling in experimental pulmonary hypertension, and determined the expression and regulation of Src family kinases.
Human PASMCs were stimulated by PDGF alone or multiple growth factors to induce proliferation and migration in vitro. Dasatinib (0.03 μmol/L), nilotinib (0.3 μmol/L), and imatinib (1 μmol/L) potently inhibited PDGF-induced signal transducer and activator of transcription 3 and Akt phosphorylation. All 3 inhibitors decreased PDGF-induced proliferation, cell cycle gene regulation, and migration. In contrast, only dasatinib inhibited multiple growth factor-induced PASMC proliferation, and this was associated with the inhibition of Src phosphorylation. Combination of specific Src inhibitors (phosphoprotein phosphatase 1, phosphoprotein phosphatase 2) with either imatinib or nilotinib reduced multiple growth factor-induced proliferation to a similar extent as dasatinib. Importantly, Src phosphorylation increased in pulmonary arterial hypertension PASMCs compared with control PASMCs. Finally, in vivo dasatinib (15 mg/kg per body weight) treatment caused a complete reversal of pulmonary vascular remodeling and achieved similar effectiveness as imatinib (100 mg/kg per body weight) in both monocrotaline- and hypoxia-induced pulmonary hypertension models.
We suggest that dual inhibition of PDGF receptor and Src kinases potently inhibits mitogenic and motogenic responses to growth factors in PASMCs and pulmonary vascular remodeling in vivo so that dual inhibition may represent an alternative therapeutic approach for pulmonary arterial hypertension.
[Show abstract][Hide abstract] ABSTRACT: Recent clinical data suggest statins have transient but significant effects in patients with pulmonary arterial hypertension. In this study we explored the molecular effects of statins on distal human pulmonary artery smooth muscle cells (PASMCs) and their relevance to proliferation and apoptosis in pulmonary arterial hypertension.
Primary distal human PASMCs from patients and controls were treated with lipophilic (simvastatin, atorvastatin, mevastatin and fluvastatin), lipophobic (pravastatin) and nitric-oxide releasing statins and studied in terms of their DNA synthesis, proliferation, apoptosis, matrix metalloproteinase-9 and endothelin-1 release.
Treatment of human PASMCs with selected statins inhibited DNA synthesis, proliferation and matrix metalloproteinase-9 production in a concentration-dependent manner. Statins differed in their effectiveness, the rank order of anti-mitogenic potency being simvastatin > atorvastatin > > pravastatin. Nevertheless, a novel nitric oxide-releasing derivative of pravastatin (NCX 6550) was effective. Lipophilic statins, such as simvastatin, also enhanced the anti-proliferative effects of iloprost and sildenafil, promoted apoptosis and inhibited the release of the mitogen and survival factor endothelin-1. These effects were reversed by mevalonate and the isoprenoid intermediate geranylgeranylpyrophosphate and were mimicked by inhibitors of the Rho and Rho-kinase.
Lipophilic statins exert direct effects on distal human PASMCs and are likely to involve inhibition of Rho GTPase signalling. These findings compliment some of the recently documented effects in patients with pulmonary arterial hypertension.
Respiratory research 10/2011; 12(1):137. DOI:10.1186/1465-9921-12-137 · 3.09 Impact Factor