endothelin-1 and Respiratory-Tract-Infections

Some patients with COPD are prone to frequent exacerbations, which are an important determinant of health status. Such patients have elevated airway cytokine levels, suggesting the presence of increased inflammation that may increase their susceptibility to exacerbation. The inflammatory response during a COPD exacerbation is variable, but increases in interleukin-6 levels during the exacerbation are related to the presence of a common cold. Rhinovirus infection is the most important etiologic factor in COPD exacerbations and is an important target for preventive therapy. The reduction of COPD exacerbations will have an important impact on the considerable morbidity and mortality associated with COPD.

Topics: Endothelin-1; Environmental Pollution; Humans; Inflammation; Interleukin-6; Interleukin-8; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Infections

We are interested in developing an airway explant culture system using sheep bronchi in which to establish respiratory viral infection and from which tissue can be used for functional, biochemical and immunohistochemical studies involving the endothelins (ETs). Freshly harvested sheep bronchial airway smooth muscle contains a homogeneous population of the ET(A) receptor. However, the potency of ET-1 and maximum contractile response of sheep bronchial explants to ET-1 increased with time in culture, despite these parameters remaining constant for carbachol in explants maintained for up to 48 h. The possibility that this was caused by changes in ET receptor density was assessed using light microscopic quantitative autoradiography. In view of the increased responsiveness to ET-1 in cultured explants, it was surprising to demonstrate a significant decrease in total ET receptor (59+/-6% compared with the initial value, n=4-5; P<0.01) and ET(A) receptor (51+/-2% compared with the initial value, n=4-5, P<0.01) density in sheep bronchial explants after 48 h. No ET(B) receptors were detected. Thus, the culture of sheep bronchial explants was associated with an increase in ET(A) receptor-mediated contractile function that was accompanied by a decrease in ET(A) receptor density. In addition, the structural integrity of the ciliated epithelium was preserved using this culture protocol, a feature that is critical to successful respiratory viral infection. The significant changes in ET receptor density and function in these bronchial explants must be carefully considered when assessing any effects of respiratory viral infection in this model.

Topics: Animals; Autoradiography; Bronchi; Endothelin-1; Female; Male; Models, Animal; Muscle Contraction; Muscle, Smooth; Organ Culture Techniques; Receptor, Endothelin A; Receptors, Endothelin; Respiratory Mucosa; Respiratory Tract Infections; Sheep

Respiratory syncytial virus (RSV) Infections that occur during the first three years of life have been demonstrated to be associated with the development of childhood asthma. The mechanism of virus-triggered airway inflammation Is not fully understood. Endothelin-1 is a potent bronchoconstrictor involved in many diseases including respiratory tract infections. Infants and young children diagnosed with either viral pneumonia or acute bronchiolitis, their age ranging between 2 months and 3 years, were recruited into this study. Nasopharyngeal aspirates were taken for detection of respiratory virus by antigen immunofluorescence stain, RT-PCR analysis and viral culture. Plasma endothelin-1 (ET-1) was measured by using a commercially available enzyme-linked immunosorbent assay (ELISA). Ten of the nineteen infants and children (52%) were positive for RSV infection, one co-infected with influenza A. Nine Infants (90%) were positive for RSV subtype A. There was only one infant with subtype B. One of the RSV negative individuals was positive for influenza A. In addition, we recruited 10 patients without chronic underlying or respiratory tract illness as controls. ET-1 levels were significantly increased in RSV infection compared to the controls (3.6 +/- 1.2 and 1.2 +/- 1 pg/ml, respectively (p < 0.05). In conclusion, infants and young children who are infected with RSV have an increase in circulating plasma endothelin-1. This in turn may contribute to the subsequent development of childhood asthma.

Topics: Bronchiolitis; Child; Child, Preschool; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Humans; Infant; Infant, Newborn; Male; Pneumonia, Viral; Prospective Studies; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Respiratory Tract Infections; Reverse Transcriptase Polymerase Chain Reaction

Endothelin (ET)-1 has been suggested to promote neutrophil adhesion to endothelium, migration to inflamed areas, and release of elastase. ET-1 might therefore play a role in the pathogenesis of bronchiectasis, a chronic inflammatory and infective airway disease which is still poorly understood. Thirty five patients with stable bronchiectasis (20 females, mean age+/-SD 49.1+/-15.0 yrs) and 18 control subjects (8 females, 49.4+/-11.3 yrs) were recruited prospectively. The ET-1 levels in serum and sputum were measured by commercially available enzyme linked immunosorbent assay (ELISA) kits. Patients with Pseudomonas aeruginosa in their sputum had a significantly higher serum level of ET-1 (median 25.8, interquartile range 13-43.9 pg x mL(-1)) than patients without P. aeruginosa (0, 0-10.5 pg x mL(-1); p=0.0004) and healthy control subjects (4.6, 0-16.3 pg x mL(-1); p=0.002). However, patients with and without P. aeruginosa infection had no significant difference in sputum ET-1 level (p=0.15). There was no correlation between serum or sputum ET-1 levels with the serum and sputum levels of the interleukin (IL)-1beta, IL-8 and tumour necrosis factor (TNF)-alpha; the number of bronchiectasis lung lobes; and spirometry. Serum ET-1 level correlated with 24 h sputum volume for the bronchiectasis patients (r=0.51, p=0.002). The results, therefore, suggest a significant pathogenic role for endothelin-1 among Pseudomonas aeruginosa-infected patients with bronchiectasis. Further studies should be performed to evaluate the clinico-pathological correlation and expression of endothelin-1 in bronchiectasis.

Topics: Bronchiectasis; Endothelin-1; Female; Humans; Interleukin-1; Interleukin-8; Leukocytes; Male; Middle Aged; Pancreatic Elastase; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Sputum; Tumor Necrosis Factor-alpha

Viral respiratory infections may increase the susceptibility of young animals to hypoxia-induced pulmonary edema. Because hypoxia stimulates endothelin production, we hypothesized that an increase in lung endothelin contributes to these alterations in lung water. Weanling rats were infected with Sendai virus, causing a mild respiratory infection. At day 7 after infection, animals were exposed to hypoxia (inspired O(2) fraction = 0.1) for 24 h. Exposure to virus plus hypoxia led to increases in lung water compared with control groups (P < 0.001). Lung endothelin levels were significantly higher in the virus plus hypoxia group than in control groups (P < 0.001). A second group of infected animals received bosentan, a nonselective endothelin receptor antagonist, during exposure to hypoxia. Bosentan-treated animals showed less lung water accumulation, less lung lavage fluid protein, and less perivascular fluid cuffing than untreated animals (P < 0.01). We conclude that the combination of a recent viral respiratory infection and exposure to moderate hypoxia led to increases in endothelin in the lungs of young rats and that endothelin receptor blockade ameliorates the hypoxia-induced increases in lung water found in these animals.

Topics: Animals; Aspartic Acid Endopeptidases; Body Water; Bronchoalveolar Lavage Fluid; Capillary Permeability; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Hypoxia; Lung; Male; Metalloendopeptidases; Protein Precursors; Proteins; Rats; Rats, Sprague-Dawley; Respiratory Tract Infections; Respirovirus; Respirovirus Infections; RNA, Messenger

The effects of endothelin-1 (ET-1) and sarafotoxin S6c (S6c) on cholinergic contractions elicited by electrical field stimulation (EFS) were examined in mouse tracheal preparations from healthy animals and from animals infected with parainfluenza-1 (P-1) virus. S6c (an ETB-selective agonist) and ET-1 caused marked ETA and/or ETB receptor-mediated potentiation of EFS-induced contraction in tracheal tissue from both groups. Despite the fact that such infection is known to markedly alter ET receptor density and function in mouse tracheal smooth muscle, no evidence for modulated neuronal ET receptor function was obtained. The reason for this differential sensitivity of smooth muscle and neuronal ET receptors to P-1 infection is unknown.

Topics: Animals; Electric Stimulation; Endothelin-1; Isometric Contraction; Male; Mice; Mice, Inbred CBA; Muscle, Smooth; Parasympathetic Nervous System; Receptors, Endothelin; Respiratory Tract Infections; Respirovirus; Respirovirus Infections; Trachea; Vasoconstrictor Agents; Viper Venoms

This study applied bronchoalveolar lavage (BAL) to children with congenital heart disease (CHD) prior to elective cardiac catheterization (n = 48), to determine the influence of pulmonary blood flow and viral infection on the alveolar epithelial lining fluid (ELF) concentration of leucocytes, protein and endothelin-1 (ET-1). Lower respiratory tract (LRT) viral infection was defined as either a positive immunofluorescence for virus, or a virus cultured from the bronchoalveolar lavage fluid (BALF). Haemodynamic status was determined at cardiac catheterization. Normative data for BALF, but not ELF parameters, were obtained from 26 asymptomatic, noninfected normal children undergoing elective surgery. In the absence of LRT infection, the BALF macrophage, lymphocyte and neutrophil differential in CHD was not significantly different from the normal controls. In CHD, both increased pulmonary-to-systemic flow ratio (Q'p/Q's) and increased pulmonary artery-to-left ventricular pressure ratio PAP/LVP were associated with a decrease in ELF protein (rs = -0.59; p < 0.0001; and rs = -0.50; p < 0.0001 respectively). A respiratory virus was isolated from the BALF in 8 (17%) of CHD children. Virus isolation was associated with an increased ELF total protein (p < 0.05 vs no infection), a decreased alveolar macrophage differential count (p < 0.01), and an increased neutrophil differential count (p < 0.05). ET-1 was detected in the BALF of 83% of the noninfected CHD children compared to only 23% of the controls (p < 0.001). ELF ET-1 concentrations did not correlate with haemodynamic status in CHD, but were up to 100 times higher than paired plasma levels. We conclude that, in congenital heart disease, both lower respiratory tract viral infection and increased pulmonary blood flow and/or pulmonary vascular pressure influence the alveolar milieu. High alveolar epithelial lining fluid concentrations of endothelin-1 occur in congenital heart disease, but the stimulus for pulmonary endothelin-1 production is unclear.

Topics: Bronchoalveolar Lavage Fluid; Cardiac Catheterization; Case-Control Studies; Cell Count; Endothelin-1; Heart Defects, Congenital; Humans; Infant; Leukocytes; Pulmonary Alveoli; Pulmonary Circulation; Respiratory Tract Infections; Virus Diseases

1. In this study we have compared the effects of parainfluenza-1 respiratory tract viral infection on the density and function of ETA and ETB receptors in rat and mouse tracheal airway smooth muscle. 2. The bronchoconstrictor effect of inhaled methacholine was significantly enhanced in virus-infected rats, at both 4 and 12 days post-inoculation. That is, the concentration of methacholine causing an increase in resistance of 100% (PC100 methacholine) was significantly lower in virus-infected animals at both 4 and 12 days post-inoculation (n = 6-8; P < 0.05). 3. Total specific binding of [125I]-endothelin-1 and the relative proportions of ETA and ETB binding sites for [125I]-endothelin-1 were assessed in tracheal airway smooth muscle in parainfluenza-1-infected rats and mice at days 2, 4 and 12 post-inoculation using the ligands BQ-123 (1 microM; ETA receptor-selective) and sarafotoxin S6c (100 nM; ETB receptor-selective). Total specific binding in mice was significantly reduced at day 2 post-inoculation (n = 5; P < 0.05) but not at days 4 and 12 post-inoculation (n = 5). In control mice, the proportions of ETA and ETB binding sites were 53%:47% at day 2 and 43%:57% at day 4 and these were significantly altered by parainfluenza-1 infection such that, the ratios were 81%:19% at day 2 and 89%:11% at day 4 (P < 0.05). By day 12 post-inoculation, the proportion of ETA and ETB binding sites in tracheal smooth muscle from mice infected with parainfluenza-1 was not significantly different from control. In rat tracheal airway smooth muscle, neither total specific binding nor the ETA and ETB binding site ratio (64%:36%) were significantly altered in virus-inoculated rats at days 2, 4 or 12 post-inoculation (n = 5). 4. Parainfluenza-1 infection in mice had no effect on the sensitivity or maximal contractile effect of endothelin-1 in tracheal smooth muscle at days 2, 4 or 12 post-inoculation (n = 4). In contrast, contraction in response to the ETB receptor-selective agonist sarafotoxin S6c was attenuated by 39% at day 2 and by 93% at day 4 post-inoculation (P < 0.05). However, by day 12 post-inoculation, contractions to sarafotoxin S6c were not significantly different between control and virus-infected mice. In parainfluenza-1-infected rats, there were small but significant reductions in the sensitivity to carbachol, endothelin-1 and sarafotoxin S6c whilst the maximal responses to the highest concentrations of these agonists were not significantly altered by virus inf

Topics: Animals; Endothelin Receptor Antagonists; Endothelin-1; In Vitro Techniques; Male; Methacholine Chloride; Mice; Mice, Inbred CBA; Muscle Contraction; Muscle, Smooth; Parainfluenza Virus 1, Human; Peptides, Cyclic; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Respiratory Tract Infections; Respirovirus Infections; Time Factors; Trachea; Vasoconstrictor Agents; Viper Venoms

1. This study examined the influence of respiratory tract infection with influenza A/PR-8/34 virus on endothelin receptor-mediated modulation of contraction induced by stimulation of cholinergic nerves in mouse isolated trachea. 2. The ETB receptor-selective agonist, sarafotoxin S6c (30 nM) induced large transient contractions (118 +/- 5% Cmax, n = 13; where Cmax is the contraction induced by 10 microM carbachol) of isolated tracheal segments from control mice. The peak contractile response to 30 nM sarafotoxin S6c was significantly lower in preparations from virus-inoculated mice at day 2 (57 +/- 8% Cmax, n = 3, P < 0.05) and 4 post-inoculation (90 +/- 8% Cmax, n = 9, P < 0.05), consistent with virus-induced attentuation of the ETB receptor-effector system linked to airway smooth muscle contraction. The mean peak contraction to 30 nM sarafotoxin S6c of preparations from virus-inoculated mice at day 8 post-inoculation (94 +/- 17% Cmax, n = 4) was not significantly different from that of control. 3. Electrical field stimulation (EFS; 90 V, 0.5 ms duration, 10 s train, 0.1-30 Hz) of preparations from control and virus-inoculated mice, caused contractions that were abolished by 0.1 microM atropine or 3 microM tetrodotoxin, indicating that these responses were mediated by neuronally released acetylcholine. Sarafotoxin S6c markedly potentiated contractions induced by a standard stimulus (0.3 Hz, every 3 min) in tracheal segments from control and virus-inoculated mice. In tracheal tissue from control mice, 30 nM sarafotoxin S6c significantly increased a standard EFS-induced contraction of 24 +/- 4% Cmax by a further 24 +/- 3% Cmax (i.e. 2 fold increase, n = 11). Sarafotoxin S6c (30 nM) also markedly potentiated standard EFS-induced contractions in preparations from virus-inoculated mice at day 2 (17 +/- 2% Cmax, n = 3), day 4 (17 +/- 5% Cmax, n = 9) and day 8 (26 +/- 5% Cmax, n = 4) post-inoculation. The level of potentiation of EFS-induced contractions in preparations from virus-inoculated mice was similar to that in tissue from control mice at days, 2, 4 and 8 post-inoculation. In contrast, sarafotoxin S6c (30 nM) did not enhance contractile responses of tracheal segments from control and virus-inoculated mice to exogenously applied acetylcholine (n = 3). 4. Endothelin-1 (1 nM) caused similar potentiations of standard EFS-induced contractions in tracheal segments from control (13 +/- 2% Cmax, n = 23) and virus-inoculated mice at day 2 (13 +/- 1% Cmax, n = 5),

Topics: Animals; Endothelin-1; In Vitro Techniques; Male; Mice; Mice, Inbred C3H; Muscle Contraction; Orthomyxoviridae Infections; Receptors, Cholinergic; Receptors, Endothelin; Respiratory Tract Infections; Trachea; Viper Venoms