ABSTRACT
BACKGROUND AND PURPOSE: AVE 0991 (AVE) is a non-peptide compound, mimic of the angiotensin (Ang)-(1-7) actions in many tissues and pathophysiological states. Here, we have investigated the effect of AVE on pulmonary remodelling in a murine model of ovalbumin (OVA)-induced chronic allergic lung inflammation. EXPERIMENTAL APPROACH: We used BALB/c mice (6-8 weeks old) and induced chronic allergic lung inflammation by OVA sensitization (20 µg·mouse(-1) , i.p., four times, 14 days apart) and OVA challenge (1%, nebulised during 30 min, three times per·week, for 4 weeks). Control and AVE groups were given saline i.p and challenged with saline. AVE treatment (1 mg·kg(-1) ·per day, s.c.) or saline (100 µL·kg(-1) ·per day, s.c.) was given during the challenge period. Mice were anaesthetized 72 h after the last challenge and blood and lungs collected. In some animals, primary bronchi were isolated to test contractile responses. Cytokines were evaluated in bronchoalveolar lavage (BAL) and lung homogenates. KEY RESULTS: Treatment with AVE of OVA sensitised and challenged mice attenuated the altered contractile response to carbachol in bronchial rings and reversed the increased airway wall and pulmonary vasculature thickness and right ventricular hypertrophy. Furthermore, AVE reduced IL-5 and increased IL-10 levels in the BAL, accompanied by decreased Ang II levels in lungs. CONCLUSIONS AND IMPLICATIONS: AVE treatment prevented pulmonary remodelling, inflammation and right ventricular hypertrophy in OVA mice, suggesting that Ang-(1-7) receptor agonists are a new possibility for the treatment of pulmonary remodelling induced by chronic asthma.
Subject(s)
Airway Remodeling/drug effects , Angiotensin I/pharmacology , Anti-Asthmatic Agents/pharmacology , Asthma/drug therapy , Imidazoles/pharmacology , Lung/drug effects , Peptide Fragments/pharmacology , Pulmonary Artery/drug effects , Pulmonary Veins/drug effects , Angiotensin II/metabolism , Animals , Asthma/chemically induced , Asthma/immunology , Asthma/metabolism , Asthma/physiopathology , Bronchoalveolar Lavage Fluid/immunology , Bronchoconstriction/drug effects , Chronic Disease , Cytokines/metabolism , Disease Models, Animal , Hypertrophy, Right Ventricular/metabolism , Hypertrophy, Right Ventricular/prevention & control , Lung/blood supply , Lung/immunology , Lung/metabolism , Lung/physiopathology , Male , Mice , Mice, Inbred BALB C , Molecular Mimicry , Ovalbumin , Proto-Oncogene Mas , Proto-Oncogene Proteins/drug effects , Proto-Oncogene Proteins/metabolism , Pulmonary Artery/immunology , Pulmonary Artery/metabolism , Pulmonary Artery/physiopathology , Pulmonary Veins/immunology , Pulmonary Veins/metabolism , Pulmonary Veins/physiopathology , Receptors, G-Protein-Coupled/drug effects , Receptors, G-Protein-Coupled/metabolism , Time FactorsABSTRACT
UNLABELLED: Alveolar hypoxia is the most powerful pulmonary vasoconstrictor. In a previous work, we did not demonstrate significant changes in vascular reactivity and edema formation in an isolated canine lobe model during alveolar hypoxia. The purpose of this study is to define vascular pulmonary reactivity and edema formation after induction of pulmonary vasoconstriction using a prostaglandin inhibitor like tiaprofenic acid and alveolar hypoxia. Six isolated canine pulmonary lobules were instrumented and studied, all of them under two conditions (normoxia FIO2 21% and hypoxia FIO2 5%) four starting in normoxia condition and 2 starting in hypoxia condition. RESULTS: No significant changes in filtration rate were found, normoxia 0.42 +/- 0.41, hypoxia 0.37 +/- 0.51 ml/min/100 g pulmonary tissue P = NS. The arterial pressure in basal conditions was 25.1 +/- 6.21, and during hypoxia increased to 37 +/- 7.19 cm H2O (Delta 12.0 +/- 1.2 cm H2O). P < 0.001. CONCLUSION: Hypoxia vascular reactivity was significantly increased in tiaprofenic acid pretreated isolated canine lobes, no changes in pulmonary permeability was found nor increased rate in edema formation.
Subject(s)
Propionates/pharmacology , Prostaglandin Antagonists/pharmacology , Pulmonary Artery/drug effects , Pulmonary Edema/etiology , Pulmonary Veins/drug effects , Animals , Calibration , Dogs , Female , Hypoxia/physiopathology , In Vitro Techniques , Male , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/physiopathology , Pulmonary Artery/physiopathology , Pulmonary Edema/physiopathology , Pulmonary Veins/physiopathology , Vasoconstriction/drug effects , Vasoconstriction/physiologyABSTRACT
Alteraçöes respiratórias já foram descritas após escleroterapia endoscópica de varizes esofágicas. O oleato de etanolamina, agente esclerosante gorduroso, atingindo a circulaçäo sistêmica, possibilita o desenvolvimento de lesäo de vasos pulmonares nos pacientes submetidos a escleroterapia. Foram estudados 17 pacientes (grupo I) com hipertensäo portal e varizes esofágicas, sendo 13 com diagnóstico compatível com esquistossomose e quatro com doença crónica parenquimatosa do fígado. O grupo controle constou de dez pacientes (grupo II) com hipertensäo portal e varizes esofágicas, sendo oito com diagnóstico compatível com esquistossomose e dois com doença crónica parenquimatosa do fígado. O grupo I submeteu-se a escleroterapia com oleato de etanolamina pela técnica intravasal, enquanto no grupo controle (grupo II) foi feito procedimento endoscópico idêntico, sem o tratamento escleroterápico. Os dois grupos (I e II) foram submetidos, previamente e durante o estudo, a radiografia de tórax, espirometria, gasometria arterial e cintilografia pulmonar de inalaçäo e perfusäo. No grupo I, a média da pressäo parcial de oxigênio no sangue arterial (pO2) antes da escleroterapia foi de 81,8mmHg, reduzindo-se para 78,9mmHg duas horas após e tornando-se significativamente baixa quatro e oito horas após, 73,8mmHg (p < 0,05) e 70,1mmHg (p < 0,05), respectivamente. Com 24 horas, a pO2 estava em 77,03mmHg. Neste grupo, um paciente desenvolveu embolia pulmonar. Nos pacientes do grupo controle, a pO2 antes da endoscopia foi de 82,7mmHg, reduzindo-se para 68,9mmHg duas horas após (p < 0,05), para 67,6mmHg quatro horas após (p < 0,05), para 71,8mmHg oito horas após (p < 0,05) e para 75,2mmHg 24 horas após. Nossos resultados sugerem que o procedimento da endoscopia digestiva alta sob sedaçäo produz hipoxemia arterial e que talvez a escleroterapia com oleato de etanolamina pela técnica intravasal pode causar embolia pulmonar.