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The Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its sublineages pose a new challenge to healthcare systems worldwide due to its ability to efficiently spread in immunized populations and its resistance to currently available therapies. COVID-19, although targeting primarily the respiratory system, is also now well established that later affects every organ in the body. Most importantly, despite the available therapy and vaccine-elicited protection, the long-term consequences of viral infection in breakthrough and asymptomatic individuals are areas of concern. In the past two years, investigators accumulated evidence on how the virus triggers our immune system and the molecular signals involved in the cross-talk between immune cells and structural cells in the pulmonary vasculature to drive pathological lung complications such as endothelial dysfunction and thrombosis. In the review, we emphasize recent updates on the pathophysiological inflammatory and immune responses associated with SARS-CoV-2 infection and their potential long-term consequences that may consequently lead to the development of pulmonary vascular diseases.
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COVID-19 , Coinfección , Humanos , SARS-CoV-2 , Pulmón , Reacciones CruzadasRESUMEN
December 1, 2021, is "World AIDS Day," reminding us that HIV infection is still widespread and that many of its long-term effects can be deadly. One of these complications is its effect on the pulmonary vascular beds, leading to an increase in the pulmonary pressure, causing the clinical manifestation of "pulmonary hypertension." Unfortunately, we are still far from fully understanding the prevalence, mechanics, and pathobiology of "HIV pulmonary hypertension," especially in Africa and other developing countries where HIV is still common. In addition, the impact of other factors like coinfection and illicit drugs can add and modify the effect on the pulmonary vascular bed, complicating the pathological and clinical effects of HIV. Thus, "World AIDS Day" can be an impetus to pursue further research in this area.
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Síndrome de Inmunodeficiencia Adquirida , Infecciones por VIH , África , VIH , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , PrevalenciaRESUMEN
Human immunodeficiency virus (HIV) infection is an established risk factor for pulmonary arterial hypertension (PAH); however, the pathogenesis of HIV-related PAH remains unclear. Since K+ channel dysfunction is a common marker in most forms of PAH, our aim was to analyze whether the expression of HIV proteins is associated with impairment of K+ channel function in the pulmonary vascular bed. HIV transgenic mice (Tg26) expressing seven of the nine HIV viral proteins and wild-type (WT) mice were used. Hemodynamic assessment was performed by echocardiography and catheterization. Vascular reactivity was studied in endothelium-intact pulmonary arteries. K+ currents were recorded in freshly isolated pulmonary artery smooth muscle cells (PASMC) using the patch-clamp technique. Gene expression was assessed using quantitative RT-PCR. PASMC from Tg26 mice had reduced K+ currents and were more depolarized than those from WT. Whereas voltage-gated K+ channel 1.5 (Kv1.5) currents were preserved, pH-sensitive noninactivating background currents ( IKN) were nearly abolished in PASMC from Tg26 mice. Tg26 mice had reduced lung expression of Kv7.1 and Kv7.4 channels and decreased responses to the Kv7.1 channel activator L-364,373 assessed by vascular reactivity and patch-clamp experimental approaches. Although we found pulmonary vascular remodeling and endothelial dysfunction in Tg26 mice, this was not accompanied by changes in hemodynamic parameters. In conclusion, the expression of HIV proteins in vivo impairs pH-sensitive IKN and Kv7 currents. This negative impact of HIV proteins in K+ channels was not sufficient to induce PAH, at least in mice, but may play a permissive or accessory role in the pathophysiology of HIV-associated PAH.
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VIH-1/genética , Proteínas del Virus de la Inmunodeficiencia Humana/metabolismo , Hipertrofia Ventricular Derecha/patología , Músculo Liso Vascular/patología , Canales de Potasio con Entrada de Voltaje/metabolismo , Arteria Pulmonar/patología , Transgenes/fisiología , Animales , Infecciones por VIH/genética , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , Proteínas del Virus de la Inmunodeficiencia Humana/genética , Humanos , Hipertrofia Ventricular Derecha/metabolismo , Masculino , Potenciales de la Membrana , Ratones , Ratones Transgénicos , Músculo Liso Vascular/metabolismo , Canales de Potasio con Entrada de Voltaje/genética , Arteria Pulmonar/metabolismo , VasoconstricciónRESUMEN
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, 80 mg/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 75 ng/L and 6 mg/kg), 14 days after the injection of MCT (curative treatment: 6 mg/kg), or 5 days before the injection (preventive treatment: 6 mg/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 (75 ng/L or 6 mg/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.
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Antioxidantes/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/prevención & control , Melatonina/uso terapéutico , Animales , Hipertensión Pulmonar/inducido químicamente , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Hipertrofia Ventricular Derecha/prevención & control , Masculino , Monocrotalina/toxicidad , Ratas , Ratas Long-Evans , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/tratamiento farmacológico , Disfunción Ventricular Derecha/prevención & controlRESUMEN
BACKGROUND: The pathogenic mechanisms underlying pulmonary arterial hypertension resulting from schistosomiasis, one of the most common causes of pulmonary hypertension worldwide, remain unknown. We hypothesized that transforming growth factor-ß (TGF-ß) signaling as a consequence of Th2 inflammation is critical for the pathogenesis of this disease. METHODS AND RESULTS: Mice sensitized and subsequently challenged with Schistosoma mansoni eggs developed pulmonary hypertension associated with an increase in right ventricular systolic pressure, thickening of the pulmonary artery media, and right ventricular hypertrophy. Rho-kinase-dependent vasoconstriction accounted for ≈60% of the increase in right ventricular systolic pressure. The pulmonary vascular remodeling and pulmonary hypertension were dependent on increased TGF-ß signaling, as pharmacological blockade of the TGF-ß ligand and receptor, and mice lacking Smad3 were significantly protected from Schistosoma-induced pulmonary hypertension. Blockade of TGF-ß signaling also led to a decrease in interleukin-4 and interleukin-13 concentrations, which drive the Th2 responses characteristic of schistosomiasis lung pathology. Lungs of patients with schistosomiasis-associated pulmonary arterial hypertension have evidence of TGF-ß signaling in their remodeled pulmonary arteries. CONCLUSION: Experimental S mansoni-induced pulmonary vascular disease relies on canonical TGF-ß signaling.
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Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/parasitología , Schistosoma mansoni , Esquistosomiasis mansoni/metabolismo , Transducción de Señal/fisiología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Transgénicos , Circulación Pulmonar/fisiología , Vasoconstricción/fisiologíaRESUMEN
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 via whole-lung transcriptome analysis. Wild-type mice were experimentally exposed to Schistosoma mansoni ova by intraperitoneal sensitization followed by tail-vein augmentation, and the phenotype was assessed by right ventricular catheterization and tissue histology, as well as RNA and protein analysis. Whole-lung transcriptome analysis by microarray and RNA sequencing was performed, and RNA sequencing was analyzed according to two bioinformatics methods. Functional testing of the candidate IL-6 pathway was determined using IL-6 knockout mice and the signal transducers and activators of transcription protein-3 (STAT3) inhibitor S3I-201. Wild-type mice exposed to S. mansoni demonstrated increased right ventricular systolic pressure and thickness of the pulmonary vascular media. Whole-lung transcriptome analysis determined that the IL-6-STAT3-nuclear factor of activated T cells c2(NFATc2) pathway was up-regulated, as confirmed by PCR and the immunostaining of lung tissue from S. mansoni-exposed mice and patients who died of the disease. Mice lacking IL-6 or treated with S3I-201 developed pulmonary hypertension, associated with significant intima remodeling after exposure to S. mansoni. Whole-lung transcriptome analysis identified the up-regulation of the IL-6-STAT3-NFATc2 pathway, and IL-6 signaling was found to be protective against Schistosoma-induced intimal remodeling.
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Hipertensión Pulmonar/etiología , Interleucina-6/metabolismo , Schistosoma mansoni/patogenicidad , Animales , Modelos Animales de Enfermedad , Hipertensión Pulmonar Primaria Familiar , Perfilación de la Expresión Génica , Humanos , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Interleucina-6/deficiencia , Interleucina-6/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factores de Transcripción NFATC/metabolismo , Arteria Pulmonar/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Esquistosomiasis mansoni/complicaciones , Transducción de SeñalRESUMEN
OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
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Hipertensión Pulmonar/tratamiento farmacológico , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Familia-src Quinasas/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Becaplermina , Benzamidas , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Quimiotaxis/efectos de los fármacos , Dasatinib , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hemodinámica , Humanos , Hipertensión Pulmonar/enzimología , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/enzimología , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/prevención & control , Hipoxia/complicaciones , Mesilato de Imatinib , Monocrotalina , Músculo Liso Vascular/enzimología , Músculo Liso Vascular/patología , Músculo Liso Vascular/fisiopatología , Miocitos del Músculo Liso/enzimología , Miocitos del Músculo Liso/patología , Fosforilación , Piperazinas/farmacología , Proteínas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-sis/metabolismo , Pirimidinas/farmacología , Ratas , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Tiazoles/farmacología , Factores de Tiempo , Familia-src Quinasas/metabolismoRESUMEN
The microbiota refers to a plethora of microorganisms with a gene pool of approximately three million, which inhabits the human gastrointestinal tract or gut. The latter, not only promotes the transport of nutrients, ions, and fluids from the lumen to the internal environment but is linked with the development of diseases including coronary artery disease, heart failure, and lung diseases. The exact mechanism of how the microbiota achieves crosstalk between itself and distant organs/tissues is not clear, but factors released to other organs may play a role, like inflammatory and genetic factors, and now we highlight melatonin as a novel mediator of the gut-lung crosstalk. Melatonin is present in high concentrations in the gut and the lung and has recently been linked to the pathogenesis of pulmonary hypertension (PH). In this comprehensive review of the literature, we suggest that melatonin is an important link between the gut microbiota and the development of PH (where suppressed melatonin-crosstalk between the gut and lungs could promote the development of PH). More studies are needed to investigate the link between the gut microbiota, melatonin and PH. Studies could also investigate whether microbiota genes play a role in the epigenetic aspects of PH. This is relevant because, for example, dysbiosis (caused by epigenetic factors) could reduce melatonin signaling between the gut and lungs, reduce subcellular melatonin concentrations in the gut/lungs, or reduce melatonin serum levels secondary to epigenetic factors. This area of research is largely unexplored and further studies are warranted.
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RATIONALE: Schistosomiasis is the most common worldwide cause of pulmonary arterial hypertension. The anti-schistosome drug praziquantel has been shown to reverse the liver fibrosis associated with Schistosoma mansoni in mice. OBJECTIVES: We sought to determine whether praziquantel reverses established pulmonary vascular remodeling and pulmonary hypertension in a mouse model of S. mansoni. METHODS: Mice were infected percutaneously with S. mansoni. At 17 weeks after infection mice were either killed or received two doses of praziquantel or vehicle by oral gavage. Treated mice were studied at 25 weeks after infection. MEASUREMENTS AND MAIN RESULTS: Vehicle-treated mice demonstrated significant increases in right ventricular systolic pressures (RVSP) and right ventricular hypertrophy (RVH) at 25 weeks, accompanied by pulmonary vascular remodeling. The degree of vascular remodeling correlated with proximity to granulomas. The elevation of RVSP and RVH at 25 weeks was dependent on the presence of eggs in the lung. Praziquantel eliminated the production of eggs in feces and led to clearance of eggs from the lung and to a lesser extent from liver. Praziquantel prevented the rise in RVSP and RVH seen in vehicle-treated mice and reversed established pulmonary vascular remodeling. Praziquantel significantly reduced lung mRNA expression of IL-13, IL-8, and IL-4, but did not reduce serum cytokine levels. CONCLUSIONS: The development of pulmonary hypertension associated with S. mansoni infection can be prevented by praziquantel, and established vascular remodeling can be reversed. The mechanism involves clearance of lung eggs and reduced local expression of lung cytokines.
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Antihelmínticos/farmacología , Vasos Sanguíneos/efectos de los fármacos , Hipertensión Pulmonar/fisiopatología , Pulmón/irrigación sanguínea , Praziquantel/farmacología , Esquistosomiasis mansoni/complicaciones , Esquistosomiasis mansoni/fisiopatología , Animales , Presión Sanguínea , Citocinas/metabolismo , Regulación hacia Abajo , Femenino , Granuloma/parasitología , Granuloma/patología , Ventrículos Cardíacos/fisiopatología , Hipertensión Pulmonar/parasitología , Hipertrofia Ventricular Derecha/parasitología , Hipertrofia Ventricular Derecha/fisiopatología , Hipertrofia Ventricular Derecha/prevención & control , Mediadores de Inflamación/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucina-8/metabolismo , Hígado/parasitología , Pulmón/metabolismo , Pulmón/parasitología , Ratones , Ratones Endogámicos C57BL , Óvulo/efectos de los fármacos , ARN Mensajero/metabolismo , Schistosoma mansoni/efectos de los fármacos , Esquistosomiasis mansoni/patologíaRESUMEN
The lungs are the primary target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with severe hypoxia being the cause of death in the most critical cases. Coronavirus disease 2019 (COVID-19) is extremely heterogeneous in terms of severity, clinical phenotype and, importantly, global distribution. Although the majority of affected patients recover from the acute infection, many continue to suffer from late sequelae affecting various organs, including the lungs. The role of the pulmonary vascular system during the acute and chronic stages of COVID-19 has not been adequately studied. A thorough understanding of the origins and dynamic behaviour of the SARS-CoV-2 virus and the potential causes of heterogeneity in COVID-19 is essential for anticipating and treating the disease, in both the acute and the chronic stages, including the development of chronic pulmonary hypertension. Both COVID-19 and chronic pulmonary hypertension have assumed global dimensions, with potential complex interactions. In this Review, we present an update on the origins and behaviour of the SARS-CoV-2 virus and discuss the potential causes of the heterogeneity of COVID-19. In addition, we summarize the pathobiology of COVID-19, with an emphasis on the role of the pulmonary vasculature, both in the acute stage and in terms of the potential for developing chronic pulmonary hypertension. We hope that the information presented in this Review will help in the development of strategies for the prevention and treatment of the continuing COVID-19 pandemic.
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COVID-19 , Hipertensión Pulmonar , Humanos , Pulmón , Pandemias , SARS-CoV-2RESUMEN
HIV and Schistosoma infections have been individually associated with pulmonary vascular disease. Co-infection with these pathogens is very common in tropical areas, with an estimate of six million people co-infected worldwide. However, the effects of HIV and Schistosoma co-exposure on the pulmonary vasculature and its impact on the development of pulmonary vascular disease are largely unknown. Here, we have approached these questions by using a non-infectious animal model based on lung embolization of Schistosoma mansoni eggs in HIV-1 transgenic (HIV) mice. Schistosome-exposed HIV mice but not wild-type (Wt) counterparts showed augmented pulmonary arterial pressure associated with markedly suppressed endothelial-dependent vasodilation, increased endothelial remodeling and vessel obliterations, formation of plexiform-like lesions and a higher degree of perivascular fibrosis. In contrast, medial wall muscularization was similarly increased in both types of mice. Moreover, HIV mice displayed an impaired immune response to parasite eggs in the lung, as suggested by decreased pulmonary leukocyte infiltration, small-sized granulomas, and augmented residual egg burden. Notably, vascular changes in co-exposed mice were associated with increased expression of proinflammatory and profibrotic cytokines, including IFN-γ and IL-17A in CD4+ and γδ T cells and IL-13 in myeloid cells. Collectively, our study shows for the first time that combined pulmonary persistence of HIV proteins and Schistosoma eggs, as it may occur in co-infected people, alters the cytokine landscape and targets the vascular endothelium for aggravated pulmonary vascular pathology. Furthermore, it provides an experimental model for the understanding of pulmonary vascular disease associated with HIV and Schistosoma co-morbidity.
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Infecciones por VIH , Esquistosomiasis mansoni , Enfermedades Vasculares , Animales , Citocinas/metabolismo , Infecciones por VIH/complicaciones , Infecciones por VIH/patología , Humanos , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Schistosoma mansoni , Esquistosomiasis mansoni/complicaciones , Esquistosomiasis mansoni/patología , Enfermedades Vasculares/patologíaRESUMEN
COVID-19 infection primarily targets the lungs, which in severe cases progresses to cytokine storm, acute respiratory distress syndrome, multiorgan dysfunction, and shock. Survivors are now presenting evidence of cardiopulmonary sequelae such as persistent right ventricular dysfunction, chronic thrombosis, lung fibrosis, and pulmonary hypertension. This review will summarize the current knowledge on long-term cardiopulmonary sequelae of COVID-19 and provide a framework for approaching the diagnosis and management of these entities. We will also identify research priorities to address areas of uncertainty and improve the quality of care provided to these patients.
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Países en Desarrollo , Infecciones por VIH/complicaciones , Hipertensión Pulmonar/virología , Enfermedades Pulmonares/epidemiología , Enfermedades Vasculares/epidemiología , Terapia Antirretroviral Altamente Activa , Salud Global , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Hipertensión Pulmonar/epidemiología , Prevalencia , Factores de Riesgo , Resultado del TratamientoRESUMEN
The mechanisms underlying schistosomiasis-induced pulmonary hypertension (PH), one of the most common causes of PH worldwide, remain unclear. We sought to determine whether Schistosoma mansoni causes experimental PH associated with pulmonary vascular remodeling in an interleukin (IL)-13-dependent manner. IL-13Ralpha1 is the canonical IL-13 signaling receptor, whereas IL-13Ralpha2 is a competitive nonsignaling decoy receptor. Wild-type, IL-13Ralpha1(-/-), and IL-13Ralpha2(-/-) C57BL/6J mice were percutaneously infected with S. mansoni cercariae, followed by i.v. injection of eggs. We assessed PH with right ventricular catheterization, histological evaluation of pulmonary vascular remodeling, and detection of IL-13 and transforming growth factor-beta signaling. Infected mice developed pulmonary peri-egg granulomas and arterial remodeling involving predominantly the vascular media. In addition, gain-of-function IL-13Ralpha2(-/-) mice had exacerbated vascular remodeling and PH. Mice with loss of IL-13Ralpha1 function did not develop PH and had reduced pulmonary vascular remodeling. Moreover, the expression of resistin-like molecule-alpha, a target of IL-13 signaling, was increased in infected wild-type and IL-13Ralpha2(-/-) but not IL-13Ralpha1(-/-) mice. Phosphorylated Smad2/3, a target of transforming growth factor-beta signaling, was increased in both infected mice and humans with the disease. Our data indicate that experimental schistosomiasis causes PH and potentially relies on up-regulated IL-13 signaling.
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Granuloma/inmunología , Hipertensión Pulmonar/inmunología , Interleucina-13/inmunología , Pulmón/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis/complicaciones , Análisis de Varianza , Animales , Western Blotting , Granuloma/etiología , Granuloma/patología , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/patología , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación/fisiología , Esquistosomiasis/inmunología , Esquistosomiasis/patología , Transducción de Señal/fisiología , Proteína Smad2/inmunología , Proteína smad3/inmunología , Regulación hacia Arriba/fisiologíaRESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Pleiotropía Genética/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/fisiología , Arteria Pulmonar/efectos de los fármacos , Apoptosis/efectos de los fármacos , Apoptosis/genética , Atorvastatina , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Pleiotropía Genética/fisiología , Ácidos Heptanoicos/farmacología , Humanos , Masculino , Persona de Mediana Edad , Músculo Liso Vascular/citología , Músculo Liso Vascular/fisiología , Pravastatina/farmacología , Arteria Pulmonar/citología , Arteria Pulmonar/fisiología , Pirroles/farmacología , Simvastatina/farmacologíaRESUMEN
RATIONALE: Schistosomiasis is considered to be the most common worldwide cause of pulmonary hypertension. At present there is no well-characterized animal model to study the pathobiology of this important condition. OBJECTIVES: To develop a mouse model of schistosomiasis, characterize the extent of pulmonary vascular remodeling, and determine the potential role of inflammatory cytokines. METHODS: Mice (C57/Bl6) were infected transcutaneously with a high dose (approximately 75-100 cercariae) or a low dose (approximately 30 cercariae) of Schistosoma mansoni, and the development of lung and liver pathology was studied in the subacute (high-dose) and chronic (low-dose) settings. MEASUREMENTS AND MAIN RESULTS: In the subacute setting, mice showed few eggs in the lungs and no evidence of pulmonary vascular remodeling. In contrast, chronically infected animals had a much greater lung egg burden and developed marked pulmonary vascular remodeling accompanied by perivascular inflammation from 12 weeks onwards. In addition, we observed the presence of plexiform-like lesions in these mice. Lung egg burden correlated with both liver egg burden and right ventricular (RV) index in the chronic group, although significant RV hypertrophy was lacking. Plasma Th1 and Th2 cytokines increased with time in the chronic group and correlated with the degree of pulmonary vascular remodeling. CONCLUSIONS: This study provides evidence for extensive pulmonary vascular remodeling, despite the absence of RV hypertrophy, in a mouse model of schistosomiasis, including the formation of plexiform-like lesions. Inflammatory cytokines and lung egg burden may contribute to vascular lesion formation.
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Citocinas/metabolismo , Hipertensión Pulmonar/patología , Pulmón/parasitología , Arteria Pulmonar/patología , Schistosoma mansoni/aislamiento & purificación , Esquistosomiasis/patología , Resistencia Vascular/fisiología , Animales , Modelos Animales de Enfermedad , Femenino , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Inmunohistoquímica , Pulmón/patología , Pulmón/fisiopatología , Ratones , Ratones Endogámicos C57BL , Fotomicrografía , Esquistosomiasis/complicaciones , Esquistosomiasis/metabolismoRESUMEN
A wide variety of infectious diseases are major contributors to the causation of pulmonary vascular disease and, consequently, pulmonary hypertension, especially in the developing world. Schistosomiasis and human immunodeficiency virus are the most common infections that are known to contribute to pulmonary hypertension worldwide. The resultant inflammation and immunologic milieu caused by infection are the main pathologic processes affecting the pulmonary vasculature.
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Infecciones por VIH/complicaciones , Hipertensión Pulmonar , Inflamación , Esquistosomiasis/complicaciones , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Inflamación/etiología , Inflamación/patología , Inflamación/fisiopatologíaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a form of idiopathic interstitial pneumonia characterized by temporally and spatially heterogeneous fibroblast proliferation and poor prognosis. No therapies have been shown in randomized clinical trials (RCT) to influence survival. Twenty-nine subjects were assigned randomly in a pilot study to a double-blind, placebo-controlled, RCT to test sildenafil in patients with IPF with forced vital capacity 40-90% and diffusing capacity 30-90% of predicted. During the 6-month experimental treatment period, patients underwent 6-min walk tests and estimation of dyspnea using the Borg scale at baseline (0 months), 3 months, and 6 months. Participants had moderate impairment of pulmonary function, and there were no significant differences between placebo (n = 15) and sildenafil (n = 14)-treated groups. Sildenafil did not significantly increase 6-min walk test distance (mean distance +/- SD after 6-month protocol: placebo 355 +/- 82 m, sildenafil 324 +/- 41 m; p = 0.256) nor did it lessen dyspnea after exercise (mean Borg score after 6-month protocol: placebo 3.4 +/- 1.6, sildenafil 4.1 +/- 2.3; p = 0.492). Adverse reactions were few and minor in nature. In this trial, sildenafil did not significantly increase 6-min walk test distance or decrease the Borg dyspnea index in patients with clinically typical IPF. This trial was registered at clinicaltrials.gov as NCT00359736.
Asunto(s)
Tolerancia al Ejercicio/efectos de los fármacos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Piperazinas/uso terapéutico , Sulfonas/uso terapéutico , Vasodilatadores/uso terapéutico , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Disnea/tratamiento farmacológico , Disnea/etiología , Disnea/fisiopatología , Prueba de Esfuerzo , Femenino , Humanos , Fibrosis Pulmonar Idiopática/complicaciones , Fibrosis Pulmonar Idiopática/fisiopatología , Masculino , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa/efectos adversos , Proyectos Piloto , Piperazinas/efectos adversos , Capacidad de Difusión Pulmonar/efectos de los fármacos , Purinas/efectos adversos , Purinas/uso terapéutico , Citrato de Sildenafil , Sulfonas/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Vasodilatadores/efectos adversos , Capacidad Vital/efectos de los fármacosRESUMEN
OBJECTIVE: To evaluate the safety of intravenous (IV) sildenafil, an inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase, in treating near-term and term newborns with persistent pulmonary hypertension of the newborn (PPHN). STUDY DESIGN: This was an open-label, dose-escalation trial in newborns with PPHN and an oxygenation index (OI) > 15. Sildenafil was delivered by continuous IV infusion for at least 48 hours and up to 7 days. RESULTS: Five centers enrolled a total of 36 neonates with PPHN at a mean of 34 +/- 17 hours of age; 29 of these neonates were already receiving inhaled nitric oxide (iNO). A significant improvement in OI (28.7 to 19.3; P = .0002) was observed after 4 hours of sildenafil infusion in the higher dose cohorts. Thirty-five neonates survived; 1 neonate required extracorporeal membrane oxygenation (ECMO) support. In 4 neonates, sildenafil was stopped due to adverse events. Seven neonates were enrolled before developing the need for iNO. In these neonates, OI improved significantly by 4 hours after initiation of sildenafil infusion (24.6 to 14.7; P = .009); 6 neonates completed treatment without the need for iNO or ECMO. CONCLUSIONS: IV sildenafil was well tolerated, and acute and sustained improvements in oxygenation were noted in those neonates who received the higher infusion doses.
Asunto(s)
Síndrome de Circulación Fetal Persistente/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/administración & dosificación , Piperazinas/administración & dosificación , Sulfonas/administración & dosificación , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lactante , Recién Nacido , Infusiones Intravenosas , Masculino , Síndrome de Circulación Fetal Persistente/metabolismo , Síndrome de Circulación Fetal Persistente/fisiopatología , Inhibidores de Fosfodiesterasa/farmacocinética , Proyectos Piloto , Piperazinas/farmacocinética , Intercambio Gaseoso Pulmonar , Purinas/administración & dosificación , Purinas/farmacocinética , Citrato de Sildenafil , Sulfonas/farmacocinética , Resultado del TratamientoRESUMEN
RATIONALE: Iloprost is effective for the treatment of pulmonary hypertension. It acts through elevation of cAMP by binding to the prostacyclin receptor (IP receptor). However, there is evidence that patients with severe pulmonary hypertension have decreased expression of the IP receptor in the remodeled pulmonary arterial smooth muscle. OBJECTIVES: We hypothesized that prostanoid receptors other than the IP receptor are involved in signal transduction by iloprost. METHODS: Immunoblotting was used to detect the IP and prostanoid EP4 receptor in lung tissue from patients with idiopathic pulmonary arterial hypertension, and immunohistochemistry was used to detect these receptors in lung sections from rats treated with monocrotaline (MCT28d). Protein and mRNA were isolated from pulmonary arterial smooth muscle cells (PASMCs) from control and MCT28d rats treated with AH6809 (an EP2 receptor antagonist) and AH23848 (an EP4 receptor antagonist) in combination with iloprost. Intracellular cAMP was also assessed in these tissues. MEASUREMENTS AND MAIN RESULTS: IP receptor expression was reduced in idiopathic pulmonary arterial hypertension patient lung samples and MCT28d rat lungs compared with the controls. Reverse transcriptase-polymerase chain reaction and immunoblotting of MCT28d rat PASMC extracts revealed scant expression of the IP receptor but stable expression of EP4 receptor, compared with controls. Iloprost-induced elevation in intracellular cAMP in PASMCs was dose-dependently reduced by AH23848, but not by AH6809. CONCLUSIONS: Iloprost mediates vasodilatory functions via the EP4 receptor in the case of low IP receptor expression associated with pulmonary arterial hypertension. This is a previously unrecognized mechanism for iloprost, and illustrates that the EP4 receptor may be a novel therapeutic approach for the treatment of pulmonary arterial hypertension.