Repetitive schistosoma exposure causes perivascular lung fibrosis and persistent pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) can occur as a complication of schistosomiasis. In humans, schistosomiasis-PH persists despite antihelminthic therapy and parasite eradication. We hypothesized that persistent disease arises as a consequence of exposure repetition. METHODS: Following intraperitoneal sensitization, mice were experimentally exposed to Schistosoma eggs by intravenous injection, either once or three times repeatedly. The phenotype was characterized by right heart catheterization and tissue analysis. RESULTS: Following intraperitoneal sensitization, a single intravenous Schistosoma egg exposure resulted in a PH phenotype that peaked at 7-14 days, followed by spontaneous resolution. Three sequential exposures resulted in a persistent PH phenotype. Inflammatory cytokines were not significantly different between mice exposed to one or three egg doses, but there was an increase in perivascular fibrosis in those who received three egg doses. Significant perivascular fibrosis was also observed in autopsy specimens from patients who died of this condition. CONCLUSIONS: Repeatedly exposing mice to schistosomiasis causes a persistent PH phenotype, accompanied by perivascular fibrosis. Perivascular fibrosis may contribute to the persistent schistosomiasis-PH observed in humans with this disease.

Associação entre a notificação compulsória de violência e o índice de desenvolvimento humano municipal

The aim of the present study is to verify if the Human Development Index (HDI) of Brazilian municipalities is associated with the compulsory notification of violence in the Health Services. This is an observational study, with an ecological design, using data from 5,565 Brazilian municipalities, both from the notification of violence, extracted from DATASUS, and from HDI, extracted from the United Nations Development Program (UNDP). The results demonstrate there is a positive correlation between the compulsory notification of violence in general and the HDI. The exception was the Southeast macro-region where the coefficient was negative. There is a positive correlation with HDI for most types of violence in the compulsory notification of violence against women, except by the Southeast macro-region which keeps the negative correlation. The results on compulsory notification against men, in the same way, indicate a positive correlation with the HDI for most types of violence, except, again, by the Southeast macro-region. Regarding to financial violence the coefficient was negative both in Brazil and in all macro-regions, whether for violence against men or women. Psychological violence was negative when analyzed in the compulsory notification of violence against men. The study has concluded that compulsory notification of violence is present in municipalities that have better human development indices. Financial violence is still unknown, and little addressed in primary health care services, as well as the psychological violence suffered by men is not recognized, demonstrating a culture of tolerance to this type of violence.

El presente estudio tiene como objetivo verificar si el Índice de Desarrollo Humano (IDH) de los municipios brasileños está asociado a la notificación obligatoria de la violencia en los Servicios de Salud. Se trata de un estudio observacional, con diseño ecológico, utilizando datos de 5.565 municipios brasileños, tanto de la notificación de violencia, extraídos del DATASUS, como del IDH, extraído del Programa de las Naciones Unidas para el Desarrollo (PNUD). Los resultados demuestran que existe una correlación positiva entre la notificación obligatoria de la violencia en general y el IDH. La excepción fue la macrorregión Sudeste donde el coeficiente fue negativo. Existe una correlación positiva con el IDH para la mayoría de los tipos de violencia en la notificación obligatoria de violencia contra las mujeres, excepto por la macrorregión Sudeste que mantiene la correlación negativa. Los resultados sobre notificación obligatoria contra los hombres, del mismo modo, indican una correlación positiva con el IDH para la mayoría de los tipos de violencia, excepto, nuevamente, por parte de la macrorregión Sudeste. En cuanto a la violencia financiera, el coeficiente fue negativo tanto en Brasil como en todas las macrorregiones, ya sea para la violencia contra hombres o mujeres. La violencia psicológica fue negativa cuando se analizó en la notificación obligatoria de violencia contra los hombres. El estudio concluyó que la notificación obligatoria de la violencia está presente en los municipios que presentan mejores índices de desarrollo humano. La violencia financiera aún es desconocida y poco abordada en los servicios de atención primaria de salud, así como no se reconoce la violencia psicológica que sufren los hombres, demostrando una cultura de tolerancia a este tipo de violencia.

Objetivando conhecer se o índice de desenvolvimento humano dos municípios brasileiros (IDHM) está associado com a notificação compulsória de violência nos serviços de saúde realizou-se o presente estudo. Trata-se de um estudo observacional, com delineamento ecológico, utilizando dados dos 5565 municípios brasileiros, tanto da notificação de violência, extraídos do DATASUS como do IDHM, extraídos do Programa das Nações Unidas para o Desenvolvimento (PNUD). Os resultados demonstram que existe correlação positiva entre a notificação compulsória de violência em geral e o IDHM. A exceção foi a macrorregião Sudeste onde o coeficiente foi negativo. Na notificação compulsória de violência contra as mulheres existe correlação positiva com IDHM para a maioria das violências, exceto a macrorregião Sudeste, que se mantém negativa. Os resultados sobre a notificação compulsória contra homens, da mesma forma, indicam correlação positiva com o IDHM para a maioria das violências, com exceção da macrorregião Sudeste, que também foi negativa. O quesito tipo de violência financeira apresentou coeficiente negativo tanto no Brasil, como em todas as macrorregiões, seja para violência contra homens, seja contra mulheres. A violência psicológica apresentou-se negativa quando analisada na notificação compulsória de violência contra homens. O estudo concluiu que a notificação compulsória de violência está presente em municípios que possuem melhores índices de desenvolvimento humano. A violência financeira ainda se mostra desconhecida e pouco abordada nos serviços de atenção primária à saúde, como, também, a violência psicológica sofrida por homens não é reconhecida, demonstrando uma cultura de tolerância a esse tipo de violência.

TGF-ß activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-ß signalling with idiopathic, heritable and autoimmune-associated etiologies; moreover, TGF-ß blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. TGF-ß is regulated at the level of activation, but how TGF-ß is activated in this disease is unknown. Here we show TGF-ß activation by thrombospondin-1 (TSP-1) is both required and sufficient for the development of PH in Schistosoma-exposed mice. Following Schistosoma exposure, TSP-1 levels in the lung increase, via recruitment of circulating monocytes, while TSP-1 inhibition or knockout bone marrow prevents TGF-ß activation and protects against PH development. TSP-1 blockade also prevents the PH in a second model, chronic hypoxia. Lastly, the plasma concentration of TSP-1 is significantly increased in subjects with scleroderma following PAH development. Targeting TSP-1-dependent activation of TGF-ß could thus be a therapeutic approach in TGF-ß-dependent vascular diseases.

Estudo ecocardiográfico do ventrículo direito em pacientes com hipertensão pulmonar por esquistossomose mansoni / Echocardiography of right ventricle in patients with schistosomiasis-induced pulmonary hypertension

Introdução: A esquistossomose, parasitose tropical, pode provocar hipertensão pulmonar grave (HAPE), que leva a remodelamento e disfunção do ventrículo direito (VD), que pode ser detectada pela diminuição da excursão sistólica do anel tricúspide (TAPSE) e da variação de áreas do VD. No VD normal, rico em fibras longitudinais, predomina o strain longitudinal, sendo menor o strain transversal. Objetivo: Avaliar, com ecocardiografia convencional e com strain bidimensional do VD, pacientes portadores de HAPE, comparando os resultados com dados clínicos, hemodinâmicos e com parâmetros ecocardiográficos obtidos em controles sadios. Material: Trinta e dois pacientes com HAPE, média etária de 45 ± 12 anos. Vinte e três controles sadios, média etária de 48 ± 18 anos.Métodos: Foram avaliados os parâmetros de função do VD (variação de áreas e TAPSE) e o gradiente de refluxo tricúspide. Foi determinado o strain longitudinal e transversal do VD em pacientes com HAPE e em controles sadios. Resultados: Entre os pacientes com HAPE e os controles sadios, a variação das áreas foi, respectivamente, 28% e 46% (p = 0,0001), o TAPSE, 1,9 cm e 2,2 cm (p = 0,02); gradiente de regurgitação tricúspide, 76 mmHg e 28 mmHg (p = 0,0001); deformação longitudinal da parede lateral do VD -22% e -37% (p = 0,0001); e deformação transversal 39% e 21% (p = 0,001). Conclusão: Pacientes com HAPE modificaram o padrão de deformação do VD, com aumento do strain transversal, provavelmente por adaptação do VD à sobrecarga pressórica. O ecocardiograma convencional também foi útil paraavaliar a função do VD na HAPE.

Introduction: Schistosomiasis is a tropical parasitic disease may cause severe pulmonary hypertension (SIPH), which leads to right ventricular (RV) remodeling and dysfunction, which can be detected by decreased tricuspid annular plane systolic excursion (TAPSE) and variation of RV areas. In normal RV, rich in longitudinal fibers, longitudinal strain prevails, and transverse strain is smaller. Objective: To assess, using conventional echocardiography and two-dimensional RV strain, patients with SIPH, comparing the results with clinical and hemodynamic data and echocardiographic parameters obtained from healthy controls. Material: Thirty-two patients with SIPH, mean age 45 ± 12 years old. Twenty-three healthy controls, mean age 48 ± 18 years old. Methods: RV function parameters (range of areas and TAPSE) and the tricuspid regurgitation gradient were evaluated. Longitudinal and transverse RV strain RV were determined in patients with SIPH and in healthy controls. Results: Among SIPH patients and healthy controls, the variation of areas was 28% and 46%, respectively (p = 0.0001), TAPSE was 1.9 cm and 2.2 cm (p = 0.02); tricuspid regurgitation gradient was 76 mmHg and 28 mmHg (p = 0.0001); RV sidewall longitudinal strain -22% and -37%(p = 0.0001); and transverse strain of 39% and 21% (p = 0.001). Conclusion: Patients with SIPH changed the RV strain pattern with increased transverse strain, probably due to RV adaptation to pressure overload. Conventional echocardiography was also useful to assess RV function in SIPH.

Portal vein thrombosis associated with protein C deficiency and elevated Factor VIII in hepatosplenic schistosomiasis.

Portal vein thrombosis is considered a vaso-occlusive process that can appear during the course of hepatosplenic Schistosoma mansoni, but may result from impaired portal blood flow or be associated with acquired or inherited thrombophilic factors. Here, we report the case of a 67-year-old woman who developed thrombocytopenia as a result of hypersplenism. Following the diagnosis of hepatosplenic schistosomiasis, portal vein thrombosis was detected by ultrasound examination, while haematological tests revealed low levels of protein C (43.3%) and high levels of factor VIII (183.1%). The pathogenesis of portal vein thrombosis remains unclear in some patients with S. mansoni. We recommend, therefore, that early clinical and haemostatic investigations are done to evaluate risk of portal vein thrombosis and hence avoid further complications.

The Causal Role of IL-4 and IL-13 in Schistosoma mansoni Pulmonary Hypertension.

RATIONALE: The etiology of schistosomiasis-associated pulmonary arterial hypertension (PAH), a major cause of PAH worldwide, is poorly understood. Schistosoma mansoni exposure results in prototypical type-2 inflammation. Furthermore, transforming growth factor (TGF)-ß signaling is required for experimental pulmonary hypertension (PH) caused by Schistosoma exposure. OBJECTIVES: We hypothesized type-2 inflammation driven by IL-4 and IL-13 is necessary for Schistosoma-induced TGF-ß-dependent vascular remodeling. METHODS: Wild-type, IL-4(-/-), IL-13(-/-), and IL-4(-/-)IL-13(-/-) mice (C57BL6/J background) were intraperitoneally sensitized and intravenously challenged with S. mansoni eggs to induce experimental PH. Right ventricular catheterization was then performed, followed by quantitative analysis of the lung tissue. Lung tissue from patients with schistosomiasis-associated and connective tissue disease-associated PAH was also systematically analyzed. MEASUREMENTS AND MAIN RESULTS: Mice with experimental Schistosoma-induced PH had evidence of increased IL-4 and IL-13 signaling. IL-4(-/-)IL-13(-/-) mice, but not single knockout IL-4(-/-) or IL-13(-/-) mice, were protected from Schistosoma-induced PH, with decreased right ventricular pressures, pulmonary vascular remodeling, and right ventricular hypertrophy. IL-4(-/-)IL-13(-/-) mice had less pulmonary vascular phospho-signal transducer and activator of transcription 6 (STAT6) and phospho-Smad2/3 activity, potentially caused by decreased TGF-ß activation by macrophages. In vivo treatment with a STAT6 inhibitor and IL-4(-/-)IL-13(-/-) bone marrow transplantation also protected against Schistosoma-PH. Lung tissue from patients with schistosomiasis-associated and connective tissue disease-associated PAH had evidence of type-2 inflammation. CONCLUSIONS: Combined IL-4 and IL-13 deficiency is required for protection against TGF-ß-induced pulmonary vascular disease after Schistosoma exposure, and targeted inhibition of this pathway is a potential novel therapeutic approach for patients with schistosomiasis-associated PAH.

TGF beta and IL13 in Schistosomiasis mansoni associated pulmonary arterial hypertension; a descriptive study with comparative groups.

BACKGROUND: It is suggested that interleukin (IL)-13 and transforming growth factor (TGF)-beta play a role in the pulmonary vascular changes found in animal models of schistosomiasis. The aim of this study was to assess and compare the serum levels of total TGF-beta and IL-13 of patients with schistosomiasis with pulmonary arterial hypertension (PAH) and patients with schistosomiasis without PAH. METHODS: 34 patients from the schistosomiasis outpatient clinic of the Hospital das Clinicas, Recife, Pernambuco, Brazil, without PAH assessed by echocardiography and 34 patients from the Reference Centre of Pulmonary Hypertension of Pronto Socorro Cardiológico de Pernambuco, Recife, Brazil with PAH, confirmed by right heart catheterization, were enrolled on the study. Both groups presented with schistosomal periportal fibrosis after abdominal ultrasound. Serum levels of TGF-beta1 and IL-13 were determined by ELISA. Student t test to independent samples, Mann-Whitney test to nonparametric variables, Pearson correlation test for correlation analyses and Fisher Chi-squared test to compare categorical analyses were used. RESULTS: The median value of TGF-beta1 was significantly higher in patients with PAH (22496.9 pg/ml, interquartile range [IR] 15936.7 - 32087.8) than in patients without PAH (13629.9 pg/ml, IR: 10192.2- 22193.8) (p = 0.006). There was no difference in the median value of IL-13 in the group with Sch-PAH compared to patients without Sch-PAH (p > 0.05). CONCLUSION: Our results suggest that TGF-beta possibly plays a role in the pathogenesis of schistosomiasis-associated PAH.

Transforming growth factor-ß signaling promotes pulmonary hypertension caused by Schistosoma mansoni.

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.

Relação da pressão sistólica em artéria pulmonar com gênero, menopausa e gravidez em portadores de hipertensão arterial pulmonar associada à esquistossomose / Pulmonary artery pressure, gender, menopause, and pregnancy in schistosomiasis-associated pulmonary hypertension

FUNDAMENTO: A hipertensão arterial pulmonar associada à esquistossomose (HPAE) é uma grande preocupação no mundo todo. No entanto, o papel de fatores contribuintes específicos do gênero em HPAE é desconhecido. OBJETIVO: Investigamos os valores da pressão arterial pulmonar sistólica (PAPS) e a presença de elevação grave na PAPS relacionado ao gênero, presença de menopausa e histórico de gravidez em pacientes com HPAE. MÉTODOS: Setenta e nove pacientes diagnosticados com HPAE de 2000 a 2009 foram avaliados e 66 foram incluídos no estudo. As informações referentes à idade, status da menopausa, gravidez, PAPS derivada da ecocardiografia, e pressão arterial pulmonar média invasiva (PAPm) foram coletadas de registros médicos. A relação entre os valores de PAPS e PAPm e a correlação para doença grave foram avaliados. Os modelos de regressão avaliaram a associação de gênero, status da menopausa e histórico de gravidez com valores de PAPS e a presença de PAPS severa. RESULTADOS: Houve correlação moderada entre PAPm e PAPS, com boa concordância para classificação de doença grave. Os valores de PAPS foram semelhantes para homens e mulheres. Uma tendência a valores maiores de PAPS foi encontrada para mulheres não menopausadas em comparação a homens. Valores superiores de PAPS foram encontrados para mulheres menopausadas em comparação a mulheres não menopausadas; os valores não foram significativos após o ajuste de idade. O histórico de gravidez não teve relação com a PAPS. Presença de menopausa e passado de gravidez não mostraram associação com valores de PAPS. CONCLUSÃO: Em pacientes com HPAE, nem o gênero, nem o status da menopausa nem o histórico de gravidez apresentou uma correlação independente com valores de HPAE avaliados pela ecocardiografia.

BACKGROUND: Schistosomiasis-associated pulmonary arterial hypertension (SPAH) is a major concern worldwide. However, the role of gender-specific contributing factors in SPAH is unknown. OBJECTIVE: We investigated how systolic pulmonary artery pressure (SPAP) values and the presence of severe SPAP relate to gender, menopausal status, and pregnancy history in SPAH patients. METHODS: Seventy-nine patients diagnosed with SPAH from 2000 to 2009 were assessed and 66 were enrolled in the study. Information about age, menopausal status, pregnancy, echocardiography-derived SPAP, and invasive mean pulmonary artery pressure (mPAP) was collected from medical records. The relation between values of SPAP and mPAP and their agreement for severe disease were assessed. Regression models assessed the association of gender, menopausal status, and pregnancy history with SPAP values and the presence of severe SPAP. RESULTS: Moderate correlation and good agreement for severe disease were found between mPAP and SPAP. Mean SPAP values were similar for men and women. A trend toward higher values of SPAP was found for non-menopausal women compared to men. Higher SPAP values were found for menopausal compared to non-menopausal women; the values were non-significant after adjustment for age. Pregnancy history had no association with SPAP. Menopause and positive pregnancy had no association with severe SPAP. CONCLUSION: In SPAH patients, neither gender, nor menopausal status, nor pregnancy history showed independent correlation with SPAP values assessed by echocardiography.

Pulmonary artery pressure, gender, menopause, and pregnancy in schistosomiasis-associated pulmonary hypertension.

BACKGROUND: Schistosomiasis-associated pulmonary arterial hypertension (SPAH) is a major concern worldwide. However, the role of gender-specific contributing factors in SPAH is unknown. OBJECTIVE: We investigated how systolic pulmonary artery pressure (SPAP) values and the presence of severe SPAP relate to gender, menopausal status, and pregnancy history in SPAH patients. METHODS: Seventy-nine patients diagnosed with SPAH from 2000 to 2009 were assessed and 66 were enrolled in the study. Information about age, menopausal status, pregnancy, echocardiography-derived SPAP, and invasive mean pulmonary artery pressure (mPAP) was collected from medical records. The relation between values of SPAP and mPAP and their agreement for severe disease were assessed. Regression models assessed the association of gender, menopausal status, and pregnancy history with SPAP values and the presence of severe SPAP. RESULTS: Moderate correlation and good agreement for severe disease were found between mPAP and SPAP. Mean SPAP values were similar for men and women. A trend toward higher values of SPAP was found for non-menopausal women compared to men. Higher SPAP values were found for menopausal compared to non-menopausal women; the values were non-significant after adjustment for age. Pregnancy history had no association with SPAP. Menopause and positive pregnancy had no association with severe SPAP. CONCLUSION: In SPAH patients, neither gender, nor menopausal status, nor pregnancy history showed independent correlation with SPAP values assessed by echocardiography.

Protective role of IL-6 in vascular remodeling in Schistosoma pulmonary hypertension.

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.

Perfil hemodinâmico de gravidade ao teste de vasorreatividade pulmonar em esquistossomóticos / Hemodynamic profile of severity at pulmonary vasoreactivity test in schistosomiasis patients

FUNDAMENTO: A taxa de vasorreatividade pulmonar da Hipertensão Arterial Pulmonar Esquistossomótica (HAPE) não é conhecida. Dados hemodinâmicos obtidos pelo cateterismo cardíaco associam-se aos critérios clínicos de gravidade mais utilizados. OBJETIVO: Estimar o percentual de vasorreatividade positiva ao óxido nítrico em hipertensão arterial pulmonar esquistossomótica; verificar nesses pacientes a associação de parâmetros hemodinâmicos com a classificação funcional da OMS e teste de caminhada de seis minutos. MÉTODOS: Foram selecionados 84 pacientes portadores de hipertensão pulmonar de etiologia esquistossomótica de um banco de dados, submetidos ao cateterismo cardíaco direito e esquerdo com realização do teste de vasorreatividade pulmonar com óxido nítrico. Foram coletados os dados da classificação funcional da OMS e do teste de caminhada de seis minutos para fim de comparação com os dados invasivos. RESULTADOS: Dos 84 pacientes portadores de HAPE, três (3,5%) apresentaram os critérios para vasorreatividade pulmonar positivo. O aumento da resistência vascular pulmonar esteve associado significativamente à menor capacidade de esforço aferida pelo teste de caminhada de seis minutos (p = 0,045) e maiores sintomas de gravidade por meio de maiores classificações funcionais da OMS (classes III/IV) (p = 0,013). A diminuição da saturação de oxigênio na artéria pulmonar esteve associada significativamente a maiores classificações funcionais (p = 0,041). CONCLUSÃO: A taxa de resposta pulmonar ao teste de vasodilatação dos pacientes esquistossomóticos encontra-se abaixo dos valores encontrados para hipertensão pulmonar de etiologia idiopática. A resistência vascular pulmonar e a saturação de oxigênio na artéria pulmonar são dados hemodinâmicos que podem ser utilizados como marcadores de gravidade na hipertensão pulmonar esquistossomótica.

BACKGROUND: The pulmonary vasoreactivity rate of Schistosomal Pulmonary Artery Hypertension (SPAH) is not known. Hemodynamic data obtained by cardiac catheterization are associated with the most commonly used clinical criteria of severity. OBJECTIVE: To estimate the percentage of positive vasoreactivity to nitric oxide in schistosomal pulmonary arterial hypertension and verify the association of hemodynamic parameters with WHO functional classification and the six-minute walk test in these patients. METHODS: A total of 84 patients with schistosomal pulmonary hypertension were selected from a database, who had been submitted to the right and left cardiac catheterization and pulmonary vasoreactivity test with nitric oxide. Data on WHO functional classification and six-minute walk test were collected for comparison with invasive data. RESULTS: Of the 84 patients with SPAH, 3 (3.5%) had positive criteria for pulmonary vasoreactivity. The increase in pulmonary vascular resistance was significantly associated with lower exercise capacity measured by the six-minute walk test (p = 0.045) and greater symptom severity by higher functional classifications (WHO class III/IV) (p = 0.013). The decrease in oxygen saturation in the pulmonary artery was significantly associated with higher functional classifications (p = 0.041). CONCLUSION: The pulmonary response rate to the vasodilation test of schistosomiasis patients is below the values found for idiopathic pulmonary hypertension. Pulmonary vascular resistance and oxygen saturation in the pulmonary artery are hemodynamic data that can be used as markers of severity in schistosomal pulmonary hypertension.

Hemodynamic profile of severity at pulmonary vasoreactivity test in schistosomiasis patients.

BACKGROUND: The pulmonary vasoreactivity rate of Schistosomal Pulmonary Artery Hypertension (SPAH) is not known. Hemodynamic data obtained by cardiac catheterization are associated with the most commonly used clinical criteria of severity. OBJECTIVE: To estimate the percentage of positive vasoreactivity to nitric oxide in schistosomal pulmonary arterial hypertension and verify the association of hemodynamic parameters with WHO functional classification and the six-minute walk test in these patients. METHODS: A total of 84 patients with schistosomal pulmonary hypertension were selected from a database, who had been submitted to the right and left cardiac catheterization and pulmonary vasoreactivity test with nitric oxide. Data on WHO functional classification and six-minute walk test were collected for comparison with invasive data. RESULTS: Of the 84 patients with SPAH, 3 (3.5%) had positive criteria for pulmonary vasoreactivity. The increase in pulmonary vascular resistance was significantly associated with lower exercise capacity measured by the six-minute walk test (p = 0.045) and greater symptom severity by higher functional classifications (WHO class III/IV) (p = 0.013). The decrease in oxygen saturation in the pulmonary artery was significantly associated with higher functional classifications (p = 0.041). CONCLUSION: The pulmonary response rate to the vasodilation test of schistosomiasis patients is below the values found for idiopathic pulmonary hypertension. Pulmonary vascular resistance and oxygen saturation in the pulmonary artery are hemodynamic data that can be used as markers of severity in schistosomal pulmonary hypertension.

Significant intrapulmonary Schistosoma egg antigens are not present in schistosomiasis-associated pulmonary hypertension.

Schistosomiasis-associated pulmonary arterial hypertension (PAH) is one of the most common causes of pulmonary hypertension worldwide. A potential contributing mechanism to the pathogenesis of this disease is a localized immune reaction to retained and persistent parasite-derived antigens. We sought to identify Schistosoma-derived egg antigens present in the lungs of individuals who died of the disease. We obtained 18 lung samples collected at autopsy from individuals who died of schistosomiasis-associated PAH in Brazil. A rabbit polyclonal antibody was created to known Schistosoma mansoni-soluble egg antigen (SEA). Histologic assessment and immunostaining of the human tissue was performed, along with immunostaining and immunoblotting of lung tissue from mice experimentally infected with S. mansoni. All 18 lung samples had evidence of pulmonary vascular remodeling with plexiform lesions and arterial medial thickening, but no visible eggs were seen. The anti-SEA antibody detected S. mansoni egg antigens in visible eggs in mouse lung and human intestine specimens, but did not identify a significant amount of egg antigen in the human lung specimens. In mouse granulomas containing degraded eggs, we observed colocalization of egg antigens and macrophage lysosomes. In conclusion, there is unlikely to be a significant amount of persistent parasite-derived antigens within the lungs of individuals who die of schistosomiasis-associated PAH. This suggests that retained and persistent parasite proteins are not contributing to a localized immune response in the pathogenesis of this disease.

Schistosomiasis-induced experimental pulmonary hypertension: role of interleukin-13 signaling.

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.

Schistosomiasis-associated pulmonary hypertension: pulmonary vascular disease: the global perspective.

Inflammation is likely a critical underlying etiology in many forms of severe pulmonary hypertension (PH), and schistosomiasis-associated PH, one of the most common causes of PH worldwide, is likely driven by the host response to parasite antigens. More than 200 million people are infected with schistosomiasis, the third most common parasitic disease, and approximately 1% of those chronically infected develop PH. Acute cutaneous infection causes inflammation at the site of parasite penetration followed by a subacute immune complex-mediated hypersensitivity response as the parasite migrates through the lungs. Chronic schistosomiasis infection induces a granulomatous inflammation around ova deposited in the tissue. In particular, Schistosoma mansoni migrates to the portal venous system and causes preportal fibrosis in a subset of individuals and appears to be a prerequisite for PH. Portal hypertension facilitates shunting of ova from the portal system to the pulmonary arterial tree, resulting in localized periovular pulmonary granulomas. The pulmonary vascular remodeling is likely a direct consequence of the host inflammatory response, and portopulmonary hypertension may be a significant contributor. New specific therapies available for PH have not been widely tested in patients with schistosomiasis and often are unavailable for those infected in resource-poor areas of the world where schistosomiasis is endemic. Furthermore, the current PH therapies in general target vasodilation rather than vascular remodeling and inflammation. Further research is needed into the pathogenic mechanism by which this parasitic infection results in pulmonary vascular remodeling and PH, which also may be informative regarding the etiology of other types of PH.

Pulmonary hypertension in Latin America: pulmonary vascular disease: the global perspective.

Latin America is here defined as all of the Americas south of the United States. In the setting of pulmonary hypertension, there are social inequalities and geophysical aspects in this region that account for a high prevalence of certain etiologies. This review aimed to analyze some of these factors. Data were collected from the existing literature. Information also was obtained from local tertiary-care centers to where patients with pulmonary hypertension generally are referred. Further, local experience and expertise was taken into consideration. Three etiologies of pulmonary hypertension were found to be the most prevalent: schistosomiasis (approximately 1 million affected people in Brazil), high altitude (particularly in the Andes), and congenital heart disease (late diagnosis of congenital left-to-right shunts leading to development of pulmonary vasculopathy). The diversity in terms of ancestries and races probably accounts for the differences in phenotype expression of pulmonary hypertension when a given region is considered (eg, schistosomiasis-, high-altitude-, or congenital heart disease-associated pulmonary hypertension). Governmental measures are needed to improve social and economic inequalities with an obvious impact on certain etiologies, such as schistosomiasis and congenital heart disease. Early diagnosis of pulmonary hypertension and access to medication remain important challenges all over Latin America.