A single dose of angiotensin-(1-7) resolves eosinophilic inflammation and protects the lungs from a secondary inflammatory challenge.

OBJECTIVE: Angiotensin-(1-7) [Ang-(1-7)] is a pro-resolving mediator. It is not known whether the pro-resolving effects of Ang-(1-7) are sustained and protect the lung from a subsequent inflammatory challenge. This study sought to investigate the impact of treatment in face of a second allergic or lipopolysaccharide (LPS) challenge. METHODS: Mice, sensitized and challenged with ovalbumin (OVA), received a single Ang-(1-7) dose at the peak of eosinophilic inflammation, 24 h after the final OVA challenge. Subsequently, mice were euthanized at 48, 72, 96, and 120 h following the OVA challenge, and cellular infiltrate, inflammatory mediators, lung histopathology, and macrophage-mediated efferocytic activity were evaluated. The secondary inflammatory stimulus (OVA or LPS) was administered 120 h after the last OVA challenge, and subsequent inflammatory analyses were performed. RESULTS: Treatment with Ang-(1-7) resulted in elevated levels of IL-10, CD4+Foxp3+, Mres in the lungs and enhanced macrophage-mediated efferocytic capacity. Moreover, in allergic mice treated with Ang-(1-7) and then subjected to a secondary OVA challenge, inflammation was also reduced. Similarly, in mice exposed to LPS, Ang-(1-7) effectively prevented the lung inflammation. CONCLUSION: A single dose of Ang-(1-7) resolves lung inflammation and protect the lung from a subsequent inflammatory challenge highlighting its potential therapeutic for individuals with asthma.

Factors associated with arterial stiffness assessed by pulse pressure amplification in healthy children and adolescents: a cross-sectional study.

BACKGROUND: Increasing evidence suggests that reducing pulse pressure amplification (PPA) plays an important role in pathogenesis and progression of cardiovascular disease. This is a cross-sectional, observational, and analytical study in which we evaluated the associated factors with a greater chance of reducing PPA in 136 healthy children and adolescents aged 8 to 19 years old stratified by gender and age group. METHODS: Arterial stiffness and vascular and hemodynamic parameters were non-invasively measured using Mobil-O-Graph® (IEM, Stolberg, Germany), a cuff-based oscillometric device. PPA was expressed as the peripheral-to-central pulse pressure ratio (PPp / PPc). Participants with PPA < 1.49 were considered as part of the arterial stiffness group. RESULTS: In a univariate model, the increase in total vascular resistance, the reflection coefficient and the augmentation pressure were more likely to have arterial stiffness in all groups. The factors most likely to have arterial stiffness (as assessed by the reduction of the PPA) in the multivariate model were increasing age, the reflection coefficient and cardiac index in the total sample, male group and child and adolescent groups. In addition to age in the female group, cardiac output, stroke volume, and AIx@75 were the factors most likely to present arterial stiffness. CONCLUSIONS: The results show for the first time in children and adolescents that the factors most likely to reduce PPA are related to the reflection wave, which determines aortic pressures and, therefore, left ventricular afterload.

Angiotensin-(1-7)/Mas receptor modulates anti-inflammatory effects of exercise training in a model of chronic allergic lung inflammation.

AIMS: Exercise training increases circulating and tissue levels of angiotensin-(1-7) [Ang-(1-7)], which was shown to attenuate inflammation and fibrosis in different diseases. Here, we evaluated whether Ang-(1-7)/Mas receptor is involved in the beneficial effects of aerobic training in a chronic model of asthma. MATERIAL AND METHODS: BALB/c mice were subjected to a protocol of asthma induced by ovalbumin sensitization (OVA; 4 i.p. injections) and OVA challenge (3 times/week for 4 weeks). Simultaneously to the challenge period, part of the animals was continuously treated with Mas receptor antagonist (A779, 1 µg/h; for 28 days) and trained in a treadmill (TRE; 60% of the maximal capacity, 1 h/day, 5 days/week during 4 weeks). PGC1-α mRNA expression (qRT-PCR), plasma IgE and lung cytokines (ELISA), inflammatory cells infiltration (enzymatic activity assay) and airway remodeling (by histology) were evaluated. KEY FINDINGS: Blocking the Mas receptor with A779 increased IgE and IL-13 levels and prevented the reduction in extracellular matrix deposition in airways in OVA-TRE mice. Mas receptor blockade prevented the reduction of myeloperoxidase activity, as well as, prevented exercise-induced IL-10 increase. These data show that activation of Ang-(1-7)/Mas receptor pathway is involved in the anti-inflammatory and anti-fibrotic effects of aerobic training in an experimental model of chronic asthma. SIGNIFICANCE: Our results support exercise training as a non-pharmacological tool to defeat lung remodeling induced by chronic pulmonary inflammation. Further, our result also supports development of new therapy based on Ang-(1-7) or Mas agonists as important tool for asthma treatment in those patients that cannot perform aerobic training.

Asthma: role of the angiotensin-(1-7)/Mas (MAS1) pathway in pathophysiology and therapy.

The incidence of asthma is a global health problem and requires studies aimed for the development of new treatments to improve its clinical management, reducing personal and economic burdens on the health system. Therefore, the discovery of mediators that promote anti-inflammatory and pro-resolutive effects are highly desirable to improve lung function and quality of life of asthmatic patients. In that regard, experimental studies have shown that the angiotensin-(1-7)/Mas receptor (MAS1) of the renin-angiotensin system is a potential candidate for the treatment of asthma. Therefore, we have reviewed findings related to the function of the angiotensin-(1-7)/Mas pathway in regulating the processes associated with inflammation, including leukocyte influx, fibrogenesis, pulmonary dysfunction and the resolution of inflammation in asthma. Thus, a knowledge of the role of the angiotensin-(1-7)/Mas can help pave the way for the development of new treatments for this disease, which has high morbidity and mortality, through new types of experiments and clinical trials.

Oral Formulation of Angiotensin-(1-7) Promotes Therapeutic Actions in a Model of Eosinophilic and Neutrophilic Asthma.

The presence of eosinophils and neutrophils in the lungs of asthmatic patients is associated with the severity of the disease and resistance to corticosteroids. Thus, defective resolution of eosinophilic and neutrophilic inflammation is importantly related to exacerbation of asthma. In this study, we investigated a therapeutic action of angiotensin-(1-7) (Ang-(1-7)) in a model of asthma induced by ovalbumin (OVA) and lipopolysaccharide (LPS). Balb-c mice were sensitized and challenged with OVA. Twenty-three hours after the last OVA challenge, experimental groups received LPS, and 1 h and 7 h later, mice were treated with oral formulation of Ang-(1-7). On the next day, 45 h after the last challenge with OVA, mice were subjected to a test of motor and exploratory behavior; 3 h later, lung function was evaluated, and bronchoalveolar lavage fluid (BALF) and lungs were collected. Motor and exploratory activities were lower in OVA + LPS-challenged mice. Treatment with Ang-(1-7) improved these behaviors, normalized lung function, and reduced eosinophil, neutrophil, myeloperoxidase (MPO), eosinophilic peroxidase (EPO), and ERK1/2 phosphorylation (p-ERK1/2) in the lungs. In addition, Ang-(1-7) decreased the deposition of mucus and extracellular matrix in the airways. These results extended those of previous studies by demonstrating that oral administration of Ang-(1-7) at the peak of pulmonary inflammation can be valuable for the treatment of neutrophil- and eosinophil-mediated asthma. Therefore, these findings potentially provide a new drug to reverse the natural history of the disease, unlike the current standards of care that manage the disease symptoms at best.

Predictors and reference equations for augmentation index, an arterial stiffness marker, in healthy children and adolescents.

OBJECTIVES: To investigate predictors and propose reference equations for the augmentation index normalized to 75 bpm heart rate (AIx@75) in healthy children and adolescents. METHODS: This was a cross-sectional, observational study involving 134 healthy children and adolescents aged 9 to 19 years old. Participants were categorized into child (n=53) and adolescent (n=81) groups, as well as into male (n=69) and female (n=65) groups. We evaluated AIx@75, vascular and hemodynamic parameters, anthropometric data, physical activity profile, and quality of life (Peds-QL4.0; physical, emotional, social and school domains). RESULTS: The predictors of AIx@75 in the whole sample were age, peripheral diastolic blood pressure (pDBP), mean arterial pressure, pulse pressure amplification (PPA), systolic volume (SV), cardiac index (CI), and pulse wave velocity (PWV; R2=80.47%). In the male group, the predictors of AIx@75 were SV, CI, total vascular resistence (TVR), and PWV (R2=78.56%), while in the female group, they were pDBP, PPA, SV, and PWV (R2=82.45%). In the children, they were pDBP, PPA, SV, and PWV (R2=79.17%), while in the adolescents, they were body mass index, pDBP, PPA, SV, TVR, and PWV (R2=81.57%). CONCLUSION: In the present study, we used a representative sample from Belo Horizonte to establish normality values of AIx@75. We also identified, for the first time, independent predictors of AIx@75 in healthy children and adolescents categorized by sex and age. Determining AIx@75 reference equations may facilitate the early diagnosis of preclinical atherosclerosis and allow an objective measure of the vascular effects of therapeutic interventions aimed at modifying cardiovascular risk factors.

Predictors and reference equations for augmentation index, an arterial stiffness marker, in healthy children and adolescents

OBJECTIVES: To investigate predictors and propose reference equations for the augmentation index normalized to 75 bpm heart rate (AIx@75) in healthy children and adolescents. METHODS: This was a cross-sectional, observational study involving 134 healthy children and adolescents aged 9 to 19 years old. Participants were categorized into child (n=53) and adolescent (n=81) groups, as well as into male (n=69) and female (n=65) groups. We evaluated AIx@75, vascular and hemodynamic parameters, anthropometric data, physical activity profile, and quality of life (Peds-QL4.0; physical, emotional, social and school domains). RESULTS: The predictors of AIx@75 in the whole sample were age, peripheral diastolic blood pressure (pDBP), mean arterial pressure, pulse pressure amplification (PPA), systolic volume (SV), cardiac index (CI), and pulse wave velocity (PWV; R2=80.47%). In the male group, the predictors of AIx@75 were SV, CI, total vascular resistence (TVR), and PWV (R2=78.56%), while in the female group, they were pDBP, PPA, SV, and PWV (R2=82.45%). In the children, they were pDBP, PPA, SV, and PWV (R2=79.17%), while in the adolescents, they were body mass index, pDBP, PPA, SV, TVR, and PWV (R2=81.57%). CONCLUSION: In the present study, we used a representative sample from Belo Horizonte to establish normality values of AIx@75. We also identified, for the first time, independent predictors of AIx@75 in healthy children and adolescents categorized by sex and age. Determining AIx@75 reference equations may facilitate the early diagnosis of preclinical atherosclerosis and allow an objective measure of the vascular effects of therapeutic interventions aimed at modifying cardiovascular risk factors.

Treatment with inhaled formulation of angiotensin-(1-7) reverses inflammation and pulmonary remodeling in a model of chronic asthma.

Asthma is characterized by inflammation, pulmonary remodeling and bronchial hyperresponsiveness. We have previously shown that treatment with angiotensin-(1-7) [Ang-(1-7)] promotes resolution of eosinophilic inflammation and prevents chronic allergic lung inflammation. Here, we evaluated the effect of treatment with the inclusion compound of Ang-(1-7) in hydroxypropyl ß-cyclodextrin (HPßCD) given by inhalation on pulmonary remodeling in an ovalbumin (OVA)-induced chronic allergic lung inflammation. Mice were sensitized to ovalbumin (OVA; 4 injections over 42 days, 14 days apart) and were challenged 3 times per week, for 4 weeks (days 21-46). After the 2nd week of challenge, mice were treated with Ang-(1-7) by inhalation (4.5 µg of Ang-(1-7) included in 6.9 µg of HPßCD for 14 days, i.e. days 35-48). Mice were killed 72 h after the last challenge and blood, bronchoalveolar lavage fluid (BALF) and lungs were collected. Histology and morphometric analysis were performed in the lung. Metalloproteinase (MMP)-9 and MMP-12 expression and activity, IL-5, CCL11 in the lung and plasma IgE were measured. After 2 weeks of OVA challenge there was an increase in plasma IgE and in inflammatory cells infiltration in the lung of asthmatic mice. Treatment with inhaled administration of Ang-(1-7)/HPßCD for 14 days reduced eosinophils, IL5, CCL11 in the lung and plasma IgE. Treatment of asthmatic mice with Ang-(1-7)/HPßCD by inhalation reversed pulmonary remodeling by reducing collagen deposition and MMP-9 and MMP-12 expression and activity. These results show for the first time that treatment by inhalation with Ang-(1-7) can reverse an installed asthma, inhibiting pulmonary inflammation and remodeling.

Oral formulation angiotensin-(1-7) therapy attenuates pulmonary and systemic damage in mice with emphysema induced by elastase.

Angiotensin-(1-7) [Ang-(1-7)], a peptide of the renin-angiotensin system, has anti-inflammatory, anti-fibrotic and antiproliferative effects in acute or chronic inflammatory disease of respiratory system. In this study, we evaluated the effect of treatment with Ang-(1-7) on pulmonary tissue damage and behavior of mice submitted to experimental model of elastase-induced pulmonary emphysema (PE). Initially, male C57BL/6 mice were randomly assigned into two main groups: control (CTRL) and PE. In the PE group, the animals received three intratracheal instillations of pancreatic porcine elastase (PPE) at 1-week intervals (0.2 IU in 50 µL of saline). The CTRL group received the same volume of saline solution (50 µL). Twenty-four hours after the last instillation, animals of the PE group were randomly divided into two groups: PE and PE + Ang-(1-7). The PE + Ang-(1-7) group was treated with 60 µg/kg of Ang-(1-7) and 92 µg kg of HPßCD in gavage distilled water, 100 µl. The CTRL and PE groups were treated with vehicle (HPßCD- 92 µg/kg in distilled water per gavage, 100 µl), orally daily for 3 weeks. On the 19th day of treatment, all groups were tested in relation to locomotor activity and exploratory behavior. After 48 h, the animals were euthanized and lungs were collected. The animals of PE group presented rupture of alveolar walls and consequently reduction of alveolar tissue area. Treatment with Ang-(1-7) partially restored the alveolar tissue area. The PE reduced the locomotor activity and the exploratory behavior of the mice in relation to the control group. Treatment with Ang-(1-7) attenuated this change. In addition, it was observed that Ang-(1-7) reduced lung levels of IL-1ß and increased levels of IL-10. These results show an anti-inflammatory effect of Ang-(1-7), inducing the return of pulmonary homeostasis and attenuation of the behavioral changes in experimental model of PE by elastase.

Changes in aortic pulse wave components, pulse pressure amplification, and hemodynamic parameters of children and adolescents with type 1 diabetes.

BACKGROUND/OBJECTIVE: Type 1 diabetes mellitus (DM1) presents important risk factors for cardiovascular events. OBJECTIVE: To compare the components of the aortic pulse wave (APW) and the hemodynamic parameters among children and adolescents with DM1 and healthy individuals. METHODS: This is a cross-sectional study, with 36 children and adolescents diagnosed with DM1 (11.9 ± 3.2 years) matched by sex and age with the control group (n = 36, 12.4 ± 2.9 years). The components of the APW and the hemodynamic parameters were evaluated non-invasively, using Mobil-O-Graph. RESULTS: On the week of the evaluation, DM1 patients presented glycated hemoglobin (hemoglobin A1C [HbA1c]) of 9.48 ± 2.22% and fasting glycemia of 222.58 ± 93.22 mg/dL. Augmentation index (AIx@75), reflection coefficient, and augmentation pressure (AP) were significantly higher in the DM1 group (29.0 ± 9.7%, 63.0 ± 7.9, and 7.8 ± 2.7 mm Hg, respectively) compared with the control group (20.6 ± 7.9%, 53.4 ± 9.1 and 4.9 ± 2.1 mm Hg, respectively). The systolic volume (52.6 ± 11.9 and 60 ± 12.4 mL) and the cardiac output (4.3 ± 0.5 and 4.6 ± 0.5 L/min) decreased in the DM1 group in relation to the control group. The pulse pressure amplification (PPA) was significantly lower in the DM1 group (1.4 ± 0.15) compared with the control group (1.6 ± 0.17). PPA correlated negatively with total vascular resistance (TVR), AP and reflection coefficient, and positively with cardiac index in both groups. In the DMI group, the AIx@75 correlated negatively with age, height, systolic volume, and PPA, and correlated positively with the TVR and reflection coefficient. CONCLUSIONS: These results confirm the presence of arterial stiffness in this population and extend the knowledge, showing, for the first time, the reduction of PPA in the DM1 group.

Echocardiographic Assessment of Ventricular Function in Young Patients with Asthma.

BACKGROUND: Despite significant advances in understanding the pathophysiology and management of asthma, some of systemic effects of asthma are still not well defined. OBJECTIVES: To compare heart function, baseline physical activity level, and functional exercise capacity in young patients with mild-to-moderate asthma and healthy controls. METHODS: Eighteen healthy (12.67 ± 0.39 years) and 20 asthmatics (12.0 ± 0.38 years) patients were enrolled in the study. Echocardiography parameters were evaluated using conventional and tissue Doppler imaging (TDI). RESULTS: Although pulmonary acceleration time (PAT) and pulmonary artery systolic pressure (PASP) were within normal limits, these parameters differed significantly between the control and asthmatic groups. PAT was lower (p < 0.0001) and PASP (p < 0.0002) was higher in the asthma group (114.3 ± 3.70 ms and 25.40 ± 0.54 mmHg) than the control group (135.30 ± 2.28 ms and 22.22 ± 0.40 mmHg). The asthmatic group had significantly lower early diastolic myocardial velocity (E', p = 0.0047) and lower E' to late (E'/A', p = 0.0017) (13.75 ± 0.53 cm/s and 1.70 ± 0.09, respectively) compared with control group (15.71 ± 0.34 cm/s and 2.12 ± 0.08, respectively) at tricuspid valve. In the lateral mitral valve tissue Doppler, the asthmatic group had lower E' compared with control group (p = 0.0466; 13.27 ± 0.43 cm/s and 14.32 ± 0.25 cm/s, respectively), but there was no statistic difference in the E'/A' ratio (p = 0.1161). Right isovolumetric relaxation time was higher (p = 0.0007) in asthmatic (57.15 ± 0.97 ms) than the control group (52.28 ± 0.87 ms), reflecting global myocardial dysfunction. The right and left myocardial performance indexes were significantly higher in the asthmatic (0.43 ± 0.01 and 0.37 ± 0.01, respectively) compared with control group (0.40 ± 0.01 and 0.34 ± 0.01, respectively) (p = 0.0383 and p = 0.0059, respectively). Physical activity level, and distance travelled on the six-minute walk test were similar in both groups. CONCLUSION: Changes in echocardiographic parameters, evaluated by conventional and TDI, were observed in mild-to-moderate asthma patients even with normal functional exercise capacity and baseline physical activity level. Our results suggest that the echocardiogram may be useful for the early detection and evoluation of asthma-induced cardiac changes.

Echocardiographic Assessment of Ventricular Function in Young Patients with Asthma / Avaliação Ecocardiográfica da Função Ventricular em Pacientes Jovens com Asma

Abstract Background: Despite significant advances in understanding the pathophysiology and management of asthma, some of systemic effects of asthma are still not well defined. Objectives: To compare heart function, baseline physical activity level, and functional exercise capacity in young patients with mild-to-moderate asthma and healthy controls. Methods: Eighteen healthy (12.67 ± 0.39 years) and 20 asthmatics (12.0 ± 0.38 years) patients were enrolled in the study. Echocardiography parameters were evaluated using conventional and tissue Doppler imaging (TDI). Results: Although pulmonary acceleration time (PAT) and pulmonary artery systolic pressure (PASP) were within normal limits, these parameters differed significantly between the control and asthmatic groups. PAT was lower (p < 0.0001) and PASP (p < 0.0002) was higher in the asthma group (114.3 ± 3.70 ms and 25.40 ± 0.54 mmHg) than the control group (135.30 ± 2.28 ms and 22.22 ± 0.40 mmHg). The asthmatic group had significantly lower early diastolic myocardial velocity (E', p = 0.0047) and lower E' to late (E'/A', p = 0.0017) (13.75 ± 0.53 cm/s and 1.70 ± 0.09, respectively) compared with control group (15.71 ± 0.34 cm/s and 2.12 ± 0.08, respectively) at tricuspid valve. In the lateral mitral valve tissue Doppler, the asthmatic group had lower E' compared with control group (p = 0.0466; 13.27 ± 0.43 cm/s and 14.32 ± 0.25 cm/s, respectively), but there was no statistic difference in the E'/A' ratio (p = 0.1161). Right isovolumetric relaxation time was higher (p = 0.0007) in asthmatic (57.15 ± 0.97 ms) than the control group (52.28 ± 0.87 ms), reflecting global myocardial dysfunction. The right and left myocardial performance indexes were significantly higher in the asthmatic (0.43 ± 0.01 and 0.37 ± 0.01, respectively) compared with control group (0.40 ± 0.01 and 0.34 ± 0.01, respectively) (p = 0.0383 and p = 0.0059, respectively). Physical activity level, and distance travelled on the six-minute walk test were similar in both groups. Conclusion: Changes in echocardiographic parameters, evaluated by conventional and TDI, were observed in mild-to-moderate asthma patients even with normal functional exercise capacity and baseline physical activity level. Our results suggest that the echocardiogram may be useful for the early detection and evoluation of asthma-induced cardiac changes.

Resumo Fundamento: Apesar de avanços significativos no entendimento da fisiopatologia e manejo da asma, alguns efeitos sistêmicos da asma ainda não são bem definidos. Objetivos: Comparar a função cardíaca, o nível de atividade física basal, e a capacidade funcional de pacientes jovens com asma leve a moderada com controles saudáveis. Métodos: Dezoito voluntários saudáveis (12,67 ± 0,39 anos) e 20 pacientes asmáticos (12,0 ± 0,38 anos) foram incluídos no estudo. Os parâmetros de ecocardiografia foram avaliados pelo exame de ecocardiogragia com Doppler convencional e tecidual (EDT). Resultados: Apesar de o tempo de aceleração pulmonar (TAP) e da pressão arterial sistólica pulmonar (PASP) encontrarem-se dentro da faixa de normalidade, esses parâmetros foram significativamente diferentes entre o grupo controle e o grupo asmático. O TAP foi menor (p < 0,0001) e a PASP maior (p < 0,0002) no grupo de indivíduos asmáticos (114,3 ± 3,70 ms e 25,40 ± 0,54 mmHg) que o grupo controle (135,30 ± 2,28 ms e 22,22 ± 0,40 mmHg). O grupo asmático apresentou velocidade diastólica inicial do miocárdio (E', p = 0,0047) e relação entre E' e velocidade tardia mais baixas (E'/A', p = 0,0017) (13,75 ± 0,53 cm/s e 1,70 ± 0,09, respectivamente) em comparação ao grupo controle (15,71 ± 0,34 cm/s e 2,12 ± 0,08, respectivamente) na valva tricúspide. No exame Doppler tecidual do anel mitral lateral, o grupo asmático apresentou menor E' em comparação ao grupo controle (p = 0,0466; 13,27 ± 0,43 cm/s e 14,32 ± 0,25 cm/s, respectivamente), mas não houve diferença estatística na razão E'/A' (p = 0,1161). O tempo de relaxamento isovolumétrico foi maior no grupo de pacientes asmáticos (57,15 ± 0,97 ms) que no grupo controle (52,28 ± 0,87 ms) (p = 0,0007), refletindo uma disfunção global do miocárdio. O índice de performance miocárdica direito e esquerdo foi significativamente maior no grupo asmático (0,43 ± 0,01 e 0,37 ± 0,01, respectivamente) que no grupo controle (0,40 ± 0,01 e 0,34 ± 0,01, respectivamente) (p = 0,0383 e p = 0,0059 respectivamente). O nível de atividade física e a distância percorrida no teste de caminhada de seis minutos foram similares entre os grupos. Conclusão: Mudanças nos parâmetros ecocardiográficos, avaliados pela ecocardiografia convencional e pela EDT foram observadas em pacientes com asma moderada a grave com capacidade funcional e nível de atividade física basal normais. Nossos resultados sugerem que o ecocardiograma pode ser útil para a detecção precoce e a evolução de alterações cardíacas induzidas pela asma. (Arq Bras Cardiol. 2018; 110(3):231-239)