atrial-natriuretic-factor and Pulmonary-Fibrosis

Pulmonary fibrosis is a life-threatening disease characterized by progressive dyspnea and worsening pulmonary function. Atrial natriuretic peptide (ANP), a heart-derived secretory peptide used clinically in Japan for the treatment of acute heart failure, exerts a wide range of protective effects on various organs, including the heart, blood vessels, kidneys, and lungs. Its therapeutic properties are characterized by anti-inflammatory and anti-fibrotic activities mediated by the guanylyl cyclase-A (GC-A) receptor. We hypothesized that ANP would have anti-fibrotic and anti-inflammatory effects on bleomycin (BLM)-induced pulmonary fibrosis in mice.. Mice were divided into three groups: normal control, BLM with vehicle, and BLM with ANP. ANP (0.5 μg/kg/min via osmotic-pump, subcutaneously) or vehicle administration was started before BLM administration (1 mg/kg) and continued until the mice were sacrificed. At 7 or 21 days after BLM administration, fibrotic changes and infiltration of inflammatory cells in the lungs were assessed based on histological findings and analysis of bronchoalveolar lavage fluid. In addition, fibrosis and inflammation induced by BLM were evaluated in vascular endothelium-specific GC-A overexpressed mice. Finally, attenuation of transforming growth factor-β (TGF-β) signaling by ANP was studied using immortalized mouse endothelial cells stably expressing GC-A receptor.. ANP significantly decreased lung fibrotic area and infiltration of inflammatory cells in lungs after BLM administration. Furthermore, similar effects of ANP were observed in vascular endothelium-specific GC-A overexpressed mice. In cultured mouse endothelial cells, ANP reduced phosphorylation of Smad2 after TGF-β stimulation.. ANP exerts protective effects on BLM-induced pulmonary fibrosis via vascular endothelial cells.

Topics: Animals; Atrial Natriuretic Factor; Bleomycin; Endothelial Cells; Immunologic Factors; Lung; Male; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Treatment Outcome

Expression of miR-154 is upregulated in the diseased heart and was previously shown to be upregulated in the lungs of patients with pulmonary fibrosis. However, the role of miR-154 in a model of sustained pressure overload-induced cardiac hypertrophy and fibrosis had not been assessed. To examine the role of miR-154 in the diseased heart, adult male mice were subjected to transverse aortic constriction for four weeks, and echocardiography was performed to confirm left ventricular hypertrophy and cardiac dysfunction. Mice were then subcutaneously administered a locked nucleic acid antimiR-154 or control over three consecutive days (25 mg/kg/day) and cardiac function was assessed 8 weeks later. Here, we demonstrate that therapeutic inhibition of miR-154 in mice with pathological hypertrophy was able to protect against cardiac dysfunction and attenuate adverse cardiac remodelling. The improved cardiac phenotype was associated with attenuation of heart and cardiomyocyte size, less cardiac fibrosis, lower expression of atrial and B-type natriuretic peptide genes, attenuation of profibrotic markers, and increased expression of p15 (a miR-154 target and cell cycle inhibitor). In summary, this study suggests that miR-154 may represent a novel target for the treatment of cardiac pathologies associated with cardiac fibrosis, hypertrophy and dysfunction.

Topics: Animals; Aorta; Atrial Natriuretic Factor; Cyclin-Dependent Kinase Inhibitor p15; Disease Models, Animal; Echocardiography; Hypertension; Hypertrophy, Left Ventricular; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Natriuretic Peptide, Brain; Oligonucleotides; Pulmonary Fibrosis; Ventricular Remodeling

Idiopathic pulmonary fibrosis (IPF) is a progressive fibro-proliferative disorder refractory to current therapy commonly complicated by the development of pulmonary hypertension (PH); the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti-fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and myocardial fibrosis. Here, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function preventing the development of pulmonary fibrosis and associated PH, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life-threatening disorder.. Pulmonary haemodynamics, right ventricular function and markers of lung fibrosis were determined in wild-type (WT) and natriuretic peptide receptor (NPR)-A knockout (KO) mice exposed to bleomycin (1 mg·kg(-1) ). Human myofibroblast differentiation was studied in vitro.. Exacerbated cardiac, vascular and fibrotic pathology was observed in NPR-A KO animals, compared with WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels (ecadotril) and potentiated natriuretic peptide-dependent signalling (sildenafil) reduced indices of disease progression, whether administered prophylactically or to animals with established lung disease. This positive pharmacodynamic effect was diminished in NPR-A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced TGFβ-induced human myofibroblast differentiation, a key driver of remodelling in IPF patients.. These data highlight an endogenous host-defence capacity of natriuretic peptides in lung fibrosis and PH. A combination of ecadotril and sildenafil reversed the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in patients with IPF.

Topics: Animals; Atrial Natriuretic Factor; Bleomycin; Cell Differentiation; Dose-Response Relationship, Drug; Humans; Hypertension, Pulmonary; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myofibroblasts; Natriuretic Peptide, C-Type; Natriuretic Peptides; Protein Precursors; Pulmonary Fibrosis; Structure-Activity Relationship; Transforming Growth Factor beta

The purpose of this study was to evaluate the pathophysiologic role of atrial natriuretic peptide (ANP) as a pulmonary artery vasodilator in patients with acute respiratory failure receiving artificial ventilation. Twenty-one consecutive patients were studied, 12 without and 9 with preexisting cardiopulmonary disease. Pulmonary artery plasma ANP levels were significantly higher than the levels obtained in the superior vena cava and radial artery. Plasma ANP levels correlated significantly with the plasma levels of its second messenger, guanosine 3',5'-cyclic monophosphate (cGMP). In the 12 patients without prior cardiopulmonary disease, plasma ANP levels correlated significantly with mean pulmonary arterial pressure (MPAP). This correlation was not found in the nine patients with preexisting cardiopulmonary disease. The cGMP/ANP ratio, indicating the biologic effect of ANP, was also higher in the patients without preexisting cardiopulmonary disease. These results are compatible with clearance and vasodilator activity of ANP in the pulmonary vascular bed, but only in patients without preexisting cardiopulmonary disease.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Atrial Function, Right; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Female; Heart Failure; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Pulmonary Artery; Pulmonary Fibrosis; Radial Artery; Respiration, Artificial; Respiratory Insufficiency; Vena Cava, Superior

Plasma levels of the atrial natriuretic factor were prospectively measured in 15 patients suffering from connective tissue disease with alveolar-interstitial lung lesions. The mean level was significantly higher in these patients than in 12 patients without known lung lesions (74.8 +/- 20.7 pg/ml versus 30.8 +/- 12 pg/ml; P less than 0.01) and in 18 healthy subjects (25.4 +/- 12.6 pg/ml). There was no correlation between these levels and lung function tests. Three patients with isolated lymphocytosis in the alveolar lavage fluid had a high level of atrial natriuretic factor.

Topics: Atrial Natriuretic Factor; Female; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Fibrosis; Rheumatic Diseases

Human atrial natriuretic peptide (hANP) is stored by granules of both human atria. Atrial distension appears to be a major stimulus for hANP secretion. Precapillary pulmonary hypertension increases right ventricular afterload and may thus cause right atrial distension. We therefore hypothesized that hANP plasma concentrations (1) are higher in the right atrium than in the peripheral vein, (2) are increased in patients with precapillary pulmonary hypertension, and (3) correlate with right atrial pressure. Thirty-three adult patients with chronic obstructive pulmonary disease (COPD) or interstitial fibrosis were examined by right heart catheterization. Mean pressures were measured in the right atrium, pulmonary artery, and pulmonary capillary wedge position, and blood was drawn from the right atrium and from a peripheral vein for determination of hANP levels. In general, hANP plasma levels in the right atrium were significantly higher than in a peripheral vein. Seventeen out of 33 patients had pulmonary hypertension, whereas 16 patients exhibited normal pulmonary artery mean pressures. In all patients, pulmonary arterial wedge pressure was normal. Plasma hANP concentrations were significantly higher in patients with pulmonary hypertension than in patients with normal pulmonary artery pressure. A strong correlation between central or peripheral hANP plasma levels (or both) and mean right atrial pressure could be observed (r = 0.75; p less than 0.001). From these data, we conclude that the increased secretion of hANP in our patients with precapillary pulmonary hypertension appears to be mediated by right atrial distension.

Topics: Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Female; Heart Atria; Humans; Hypertension, Pulmonary; Lung Diseases, Obstructive; Lung Volume Measurements; Male; Middle Aged; Pulmonary Artery; Pulmonary Fibrosis; Pulmonary Ventilation; Pulmonary Wedge Pressure; Vascular Resistance