endothelin-1 and Lung-Diseases--Interstitial

Scleroderma-associated interstitial lung disease (SSc-ILD) occurs frequently and for many patients SSc-ILD is a significant complication of their disease. SSc-ILD is now one of the leading causes of death among patients with SSc. SSc-ILD, classified most often as a non-specific interstitial pneumonia, may culminate in interstitial pulmonary fibrosis and end-stage lung disease. Fibrosis in the lung is the net result of fibroblast proliferation and deposition of excessive amounts of extracellular matrix proteins. Among the many cytokines and growth factors involved in the pathogenesis of SSc-ILD, ET-1 may be a central mediator. In vitro and in vivo studies of animals and SSc patients support the notion that ET-1 can enhance the proliferation of pulmonary mesenchymal cells and may also enhance the fibrogenic effects of TGF-beta. Two well-designed randomized controlled trials of the dual ET receptor blocker bosentan were negative in their primary (and for SSc also secondary) endpoints, although there might be explanations for this apparent lack of efficacy.

Topics: Animals; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Humans; Lung Diseases, Interstitial; Randomized Controlled Trials as Topic; Scleroderma, Systemic; Sulfonamides; Transforming Growth Factor beta; Treatment Failure

Angiogenesis has been implicated in the pathogenesis of idiopathic interstitial pneumonia (IIP). The aim of this study was to examine the relationship between plasma concentrations of the angiogenic cytokines interleukin 8 (IL-8), vascular endothelial growth factor (VEGF), and endothelin-1 (ET-1) and clinical parameters of disease progression over a 6 month period to identify potential aetiological mediators and prognostic markers of disease activity in patients with IIP.. Forty nine patients with IIP (40 men) were recruited to the study. Plasma cytokine measurements, pulmonary function tests, and high resolution computed tomography (HRCT) scans were performed on recruitment and after 6 months. Plasma cytokine measurements were also performed in 15 healthy volunteers for control purposes.. Patients with IIP had significantly higher median (IQR) baseline concentrations of IL-8 and ET-1 than controls (155 (77-303) pg/ml v 31 (0-100) pg/ml, p<0.001) and (1.21 (0.91-1.88) pg/ml v 0.84 (0.67-1.13) pg/ml, p<0.01), respectively. Baseline concentrations of IL-8, ET-1, and VEGF were significantly related to the baseline HRCT fibrosis score (r = 0.42, p<0.005; r = 0.39, p<0.01; and r = 0.42, p<0.005, respectively). Patients with IIP who developed progressive disease had significantly higher baseline levels of IL-8 (345 (270-497) pg/ml v 121 (73-266) pg/ml, p = 0.001) and VEGF (1048 (666-2149) pg/ml v 658 (438-837) pg/ml, p = 0.019). Over 6 months the change in VEGF was significantly related to the change in HRCT fibrosis score (r = 0.565, p = 0.035) and negatively related to the change in forced vital capacity (r = -0.353, p = 0.035).

Topics: Adult; Cytokines; Endothelin-1; Female; Forced Expiratory Volume; Humans; Interleukin-8; Lung; Lung Diseases, Interstitial; Male; Middle Aged; Neovascularization, Pathologic; Prospective Studies; ROC Curve; Total Lung Capacity; Vascular Endothelial Growth Factor A; Vital Capacity

The aim of this study was to determine the role of endothelin-1 (ET-1), a molecule involved in multiple vascular and fibrosing abnormalities, as a biomarker of interstitial lung disease (ILD), as well as its use for the differential diagnosis between idiopathic pulmonary fibrosis (IPF) and ILD associated with autoimmune diseases (AD-ILD), using a large and well-defined cohort of patients with ILD. A total of 112 patients with IPF, 91 patients with AD-ILD (28 rheumatoid arthritis (RA), 26 systemic sclerosis, 20 idiopathic inflammatory myositis and 17 interstitial pneumonia with autoimmune features) and 44 healthy controls were included. ET-1 serum levels were determined by enzyme-linked immunosorbent assay. A significant increase in ET-1 levels was found in patients with IPF compared to controls. Likewise, AD-ILD patients also showed higher ET-1 levels than controls when the whole cohort was stratified by the type of AD. Similar ET-1 levels were found in IPF and AD-ILD patients, regardless of the underlying AD. Interestingly, increased ET-1 levels were correlated with worse lung function in IPF and RA-ILD patients. Our study supports that serum ET-1 may be useful as a biomarker of ILD, although it could not help in the differential diagnosis between IPF and AD-ILD. Moreover, ET-1 levels may be associated with ILD severity.

Topics: Arthritis, Rheumatoid; Autoimmune Diseases; Biomarkers; Endothelin-1; Humans; Idiopathic Pulmonary Fibrosis; Lung Diseases, Interstitial

To determine serum and sputum Caveolin-1 (Cav-1) levels and their associations with transforming growth factor- ß (TGF-ß) and interstitial lung disease (ILD) in systemic sclerosis (SSc).. Serum and induced sputum samples from 55 patients with SSc, 25 asthma patients and 16 healthy volunteers (HC) were tested for Cav-1 and TGF-ß by the ELISA technique. As a possible downstream signaling regulator of TGF-ß, Endothelin-1 (ET-1), a potent profibrotic protein, was also measured in all serum and sputum samples and relations with Cav-1 and TGF-ß were sought. All scleroderma patients were evaluated for their clinical and laboratory parameters. Pulmonary function tests (PFT) and high resolution computerized tomography (HRCT) were performed for the diagnosis of ILD. The alveolitis-fibrosis index and the SSc disease severity scores were noted for each patient.. Serum Cav-1 levels were lower in SSc compared to HC (p<0.01). Cav-1 levels were significantly lower in the sputum of SSc patients compared to both control groups (p<0.001). It was also found significantly lower in SSc-ILD compared to those without ILD (0.19±0.04 vs 0.25±0.07, respectively, p<0.01). Although no difference was found in the serum TGF-ß levels among the groups, sputum TGF-ß levels correlated positively with the alveolitis index (r=0.34) and correlated inversely with FVC measurements (r=-0.44, p<0.05) among SSc patients. Serum ET-1 was significantly higher in SSc patients (p<0.01) but no association was found between ET-1 and Cav-1 or TGF-ß.. These results suggest that decreased sputum Cav-1 levels is associated with SSc related-ILD and may be used as a marker for the detection of SSc-ILD.

Topics: Adult; Aged; Case-Control Studies; Caveolin 1; Endothelin-1; Female; Humans; Lung Diseases, Interstitial; Male; Middle Aged; Prospective Studies; Scleroderma, Systemic; Sputum; Transforming Growth Factor beta

Development of pulmonary hypertension is a common and deadly complication of interstitial lung disease. Little is known regarding the cellular and molecular mechanisms that lead to pulmonary hypertension in patients with interstitial lung disease, and effective treatment options are lacking. The purpose of this study was to examine the adenosine 2B receptor (A(2B)R) as a regulator of vascular remodeling and pulmonary hypertension secondary to pulmonary fibrosis. To accomplish this, cellular and molecular changes in vascular remodeling were monitored in mice exposed to bleomycin in conjunction with genetic removal of the A(2B)R or treatment with the A(2B)R antagonist GS-6201. Results demonstrated that GS-6201 treatment or genetic removal of the A(2B)R attenuated vascular remodeling and hypertension in our model. Furthermore, direct A(2B)R activation on vascular cells promoted interleukin-6 and endothelin-1 release. These studies identify a novel mechanism of disease progression to pulmonary hypertension and support the development of A(2B)R antagonists for the treatment of pulmonary hypertension secondary to interstitial lung disease.

Topics: Adenosine-5'-(N-ethylcarboxamide); Animals; Bleomycin; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Interleukin-6; Lung Diseases, Interstitial; Male; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Purinergic P1 Receptor Agonists; Purines; Pyrazoles; Receptor, Adenosine A2B

The data obtained suggest an important role of the FRES and ET-1 in progressing of the lung interstitial diseases; they can be used as diagnostic criteria of the disease activity, risk of pulmonary hypertension, and extra-pulmonary manifestations.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Endothelial Growth Factors; Endothelin-1; Endothelium, Vascular; Female; Humans; Lung Diseases, Interstitial; Male; Middle Aged; Neovascularization, Pathologic

To study the plasma concentration of brain natriuretic peptide (BNP) and endothelin-1 (ET-1) as markers of pulmonary hypertension (PH) developed in interstitial lung diseases (ILD).. Along with physical examination, 97 patients with ILD underwent measurements of the plasma concentrations of BNP and ET-1, 6-minute walk test, external respiration function test, echocardiography, by measuring pulmonary artery systolic pressure (P(syst)), and chest multispiral computed tomography, by estimating the mean diameter of the pulmonary artery trunk.. The plasma concentration of ET-1 proved to be significantly higher in the presence of active lung lesion (5.2 +/- 3.9 and 2.8 +/- 1.8 pg/ml; p = 0.0001). In patients with ILD, persistent PH was associated with the significantly elevated plasma concentrations of BNP (69.3 +/- 341.35 and 23.7 +/- 26.69 pg/ml; p = 0.018). The increase of plasma BNP concentrations correlated with the shorter distance covered during a 6-minute walk test and diminished functional vital capacity.. The increased plasma levels of ET-1 in ILD reflects the transient pulmonary artery pressure elevation associated with the activity of the pulmonary process while those of BNP are indicative of developed persistent PH.

Topics: Biomarkers; Case-Control Studies; Data Interpretation, Statistical; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Middle Aged; Natriuretic Peptide, Brain; Severity of Illness Index

The endothelin system plays an important role in the development of pulmonary hypertension. Several studies have suggested that interfering with the function of the endothelin system will be helpful in pulmonary hypertension treatment. In the present study, we investigated the preventive and therapeutic effects of sildenafil on pulmonary hypertension in monocrotaline-treated rats. In the preventive study, the level of mean pulmonary arterial pressure, right ventricular divide, left ventricular and septum, small pulmonary arterial morphologic and elastic fiber changes were highly improved in the treated group (P<0.05). The expressions of endothelin-1 A type receptors on small pulmonary arterial hypertension were significantly reduced in the sildenafil-treated group (P<0.05). The ET-1 level in plasma was increased in the sildenafil-treated group, but did not reach significance. Emphysema, interstitial pneumonia were significantly improved in the sildenafil-treated group. The same findings were also observed in the therapeutic study. The present results suggest that sildenafil can prevent and reverse the development of pulmonary hypertension in monocrotaline-treated rats by improving the function of endothelin system in pulmonary arteries.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung; Lung Diseases, Interstitial; Male; Monocrotaline; Piperazines; Pulmonary Artery; Pulmonary Emphysema; Purines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Sildenafil Citrate; Sulfones; Time Factors; Vasodilator Agents

Polymyositis and dermatomyositis (PM/DM) are often complicated by interstitial pneumonitis (IP), which is an important cause of death. It has been reported that blood concentration of transforming growth factor-beta (TGF-beta), which is produced by a wide range of cells including endothelial cells and enhances the fibrotic changes in various tissues, is increased in PM/DM with IP. Endothelial damage is likely to exist in PM/DM. We studied the relationship between endothelial damage and IP in PM/DM.. Blood levels of sialylated carbohydrate antigen KL-6, TGF-beta, endothelin-1 (ET-1), thrombomodulin (TM), and plasminogen activator inhibitor-1 (PAI-1) were determined in 43 patients with PM or DM with or without IP, and the relationship between these measures was analyzed.. Blood levels of KL-6 and TGF-beta were higher in the patients with IP than those without, and these measures were well correlated with each other. Levels of ET-1, TM, and PAI-1, all known to reflect the extent of endothelial damage, were also increased in patients with IP, and these measures correlated well with TGF-beta.. Our data suggest that endothelial damage might play an important role through the production of fibrosis-enhancing factors such as TGF-beta or ET-1 in PM/DM.

Topics: Adult; Aged; Antigens, Neoplasm; Blood Cell Count; Dermatomyositis; Endothelin-1; Endothelium, Vascular; Humans; Lung Diseases, Interstitial; Middle Aged; Mucin-1; Mucins; Plasminogen Activator Inhibitor 1; Polymyositis; Thrombomodulin; Transforming Growth Factor beta

Hypoxemia stimulates endothelin-1 (ET-1) secretion. The reduction in alveolar ventilation during sleep is considered sufficient to account for the hypoxemia observed in patients with respiratory diseases.. The aim of this study was to evaluate the arterial ET-1 levels and their relationship with pulmonary hypertension in patients with interstitial lung disease (ILD) during sleep.. We examined 38 patients with ILD using formal polysomnography (electroencephalogram, electrocardiogram, airflow, respiratory muscle movement, oximeter) to detect the presence of nocturnal, nonapneic, oxyhemoglobin desaturation. All patients desaturated below a baseline sleep saturation of 90% for 5 minutes or more, reaching a nadir saturation of at least 85%. Each patient had already undergone right heart catheterization with a Swan-Ganz catheter for measuring hemodynamic parameters. Sampling of arterial blood from a radial artery line for determination of blood gases and ET-1 values was performed simultaneously, after 5 minutes of the first desaturation.. At rest, arterial ET-1 levels were higher in ILD patients (1.73 +/- 0.37 mgr/mL) than in controls (1.22 +/- 0.15 mgr/mL) ( p < 0.001). Also, the patients with pulmonary hypertension (Pa > 20 mm Hg) presented significantly higher arterial ET-1 levels (1.86 +/- 0.32 mgr/mL) than those without pulmonary hypertension (1.31 +/- 0.13 mgr/mL) ( p < 0.001). Arterial ET-1 levels were significantly correlated with mean pulmonary arterial pressure (PAP) (r = 0.749, p < 0.001), and arterial oxygen partial pressure (PaO2) (r = 0.79, p < 0.001). At sleep, during desaturation, arterial ET-1 levels significantly increased in all patients (2.46 +/- 0.13 mgr/mL) as compared with resting values ( p < 0.001). Arterial ET-1 levels were significantly correlated with PAP (r = 0.657, p < 0.001) and PaO2 (r = 0.93, p < 0.001).. According to our study, arterial ET-1 is markedly increased in ILD patients, especially in those with pulmonary hypertension.

Topics: Electrocardiography; Electroencephalography; Endothelin-1; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Lung Diseases, Interstitial; Male; Middle Aged; Oximetry; Polysomnography; Sleep

The aim of this study was to evaluate the plasma arterial levels of Endothelin-1 (ET-1) and their relationship with hypoxia and pulmonary hypertension (PH) in patients with interstitial lung disease (ILD). Incremental cycle ergometry was performed in all patients up to maximal capacity. ET-1 levels during exercise (2.2 +/- 0.36 pgr/ml) were significantly higher than at rest (1.73 +/- 0.37 pgr/ml) (p < 0.001). ET-1 levels were also significantly correlated with arterial oxygen (PaO2) (r = -0.935, p < 0.001) and mean pulmonary arterial pressure (Ppa) (r = 0.657, p < 0.001). Increased pulmonary and peripheral blood levels of ET-1 have been described in, and postulated to contribute to, the pathophysiology of several lung diseases. In agreement with this, in the current study, the plasma arterial levels of ET-1 were also found to be significantly elevated in patients with various interstitial lung disorders during exercise, especially in those with severe hypoxia and pulmonary hypertension.

Topics: Endothelin-1; Female; Humans; Hypertension, Pulmonary; Hypoxia; Lung Diseases, Interstitial; Male; Middle Aged

This study was undertaken to assess the arterial plasma levels of endothelin-1 (ET-1) and their relationship with pulmonary haemodynamic and gas exchange variables during exercise in patients with emphysema and interstitial lung disease (ILD). Incremental cycle ergometry was performed in all patients up to maximal capacity. At rest, arterial ET-1 levels were higher in emphysema (1.86 +/- 0.35 pg.mL-1; p < 0.02) and ILD (1.75 +/- 0.25 pg.mL-1; p < 0.03) patients than in controls (1.35 +/- 0.18 pg.mL-1). Emphysema (2.08 +/- 0.26 versus 1.70 +/- 0.40 pg.mL-1) and ILD (1.98 +/- 0.21 versus 1.67 +/- 0.02 pg.mL-1) patients with pulmonary hypertension (PH) presented significantly (p < 0.05) higher arterial ET-1 levels than those without. At rest, arterial ET-1 levels were significantly correlated with mean pulmonary arterial pressure (Ppa) in both ILD (r = 0.8, p = 0.01) and emphysema (r = 0.5, p = 0.03) patients. During exercise, the arterial ET-1 levels were significantly correlated with arterial oxygen (Pa,O2) (r = -0.6, p = 0.04), alveolar-arterial oxygen difference (r = 0.8, p = 0.01), and Ppa (r = 0.6, p = 0.04) in ILD patients, but not in those with emphysema. In brief, the results of this study suggest that arterial endothelin-1 is markedly increased in interstitial lung disease and emphysema patients, and that, it is related to the exercise-induced exacerbation of pulmonary hypertension in patients with interstitial lung disease, but not in those with emphysema.

Topics: Aged; Carbon Dioxide; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Middle Aged; Oxygen; Physical Exertion; Pulmonary Emphysema; Rest

Endothelin-1 (ET-1), a potent fibroblast/smooth muscle cells mitogen, has been implicated in the pathogenesis of systemic sclerosis lung disease (SSc). Since monocytes and macrophages are thought to be activated in SSc, we hypothesized that alveolar macrophages (AM) and their precursors blood monocytes from patients with SSc produced more ET-1 than cells from healthy subjects. ET-1 and big ET-1 concentrations were measured in plasma, in bronchoalveolar lavage (BAL) fluids and in cell culture supernatants from monocytes and alveolar macrophages derived from 13 patients with definite SSc with lung involvement and from 10 control subjects. Plasma and BAL fluid ET-1 and big ET-1 levels were similar in both controls and patients with SSc. ET-1 and big ET-1 concentrations in unstimulated alveolar macrophage supernatants were similar in both groups. In contrast, LPS-stimulated alveolar macrophages from patients with SSc secreted higher amounts of ET-1 and big ET-1 than control subjects. ET-1 and big ET-1 concentrations in monocyte supernatants (either LPS-stimulated or not) were not different in patients and controls. These results show that AM from patients with SSc are hyperresponsive to LPS in vitro in terms of ET-1 and big ET-1 production and suggest that AM could participate in vivo in the overproduction of this potentially profibrotic mediator in patients with SSc.

Topics: Adolescent; Adult; Aged; Bronchoalveolar Lavage Fluid; Cells, Cultured; Endothelin-1; Endothelins; Female; Humans; Lipopolysaccharides; Lung Diseases, Interstitial; Macrophages, Alveolar; Male; Middle Aged; Monocytes; Prospective Studies; Protein Precursors; Scleroderma, Systemic