endothelin-1 and montelukast

Endothelin-1 (ET-1) is produced by vascular endothelial cells and epithelial cells, T-lymphocytes and phagocytes. Increased ET-1 levels have been demonstrated in the bronchial epithelium of asthma patients. In vitro, ET-1 stimulates mucus secretion, activates proinflammatory cells - macrophages and mast cells - and serves as a mitogenic stimulus for fibroblasts and smooth muscle. In addition, ET-1 activates phospholipase 2. Compared with healthy individuals, asthma patients have increased ET-1 levels during an attack and following stabilisation. Our study was designed to examine plasma ET-1 (P-ET) levels in paediatric atopic patients newly diagnosed with persistent mild bronchial asthma and 1 month after initiation of montelukast therapy.. Patients' histories were examined, and their blood eosinophil leucocyte count and levels of total serum immunoglobulin E (S-IgE), serum eosinophil cationic protein (S-ECP) and P-ET were determined. Thirty-six patients with persistent mild bronchial asthma were treated with the leukotriene receptor antagonist montelukast, administered once a day for 4 weeks. Second P-ET and S-ECP level determinations were made 4 weeks later with all the children included in the study. P-ET levels were also determined in a group of 27 healthy children who had no atopy in their medical histories and were taking no drugs (including montelukast), and who served as controls.. The mean +/- SD pretreatment P-ET level in the 36 study children was 11.542 +/- 6.408 pg/L, and this decreased to 5.636 +/- 4.419 pg/L after 1 month's therapy with montelukast (statistically significant difference; p < 0.0001). Both of these values were significantly higher (p < 0.0001 and p < 0.031, respectively) than the mean level in the control group of 27 children (3.543 +/- 2.497 pg/L). The mean pretreatment S-ECP level was 35.78 +/- 19.58 microg/L, and this decreased to 19.54 +/- 13.86 microg/L after 1 month's therapy (p < 0.001).. This study demonstrated a decrease in P-ET levels in children with mild asthma receiving montelukast. This indicates a reduction in the severity of the inflammatory response and, hence, provides evidence for the anti-inflammatory effect of montelukast. Monitoring both ET-1 and ECP levels at regular follow-up may be useful in assessing these two facets of activity of chronic inflammation in bronchial asthma.

Topics: Acetates; Administration, Intranasal; Adolescent; Albuterol; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Child; Cyclopropanes; Drug Administration Schedule; Endothelin-1; Eosinophil Cationic Protein; Female; Humans; Leukotriene Antagonists; Male; Quinolines; Severity of Illness Index; Sulfides; Time Factors

Airway inflammation is accompanied by structural changes, termed remodeling, that lead to lung dysfunction over the long term. Although both endothelin-1 (ET-1) and cysteinyl leukotrienes (CysLTs) appear to be involved in airway remodeling in several lung diseases, how these molecules interact remains largely unknown. In this study, we examined the effects of leukotriene (LT) D(4) on the function of ET-1-primed fibroblasts. ET-1 at 10(-7) M up-regulated the expression of the CysLT receptors at both the mRNA and protein levels in human lung fibroblasts. LTD(4) enhanced matrix metalloproteinase-2 and pro-collagen production, and alpha-smooth muscle actin expression of ET-1-primed fibroblasts, but had little or no effect on unprimed fibroblasts. The CysLT1 receptor antagonist montelukast completely abrogated the effects of LTD(4). Our data suggested that LTD(4) may act as a precipitating factor during ET-1-mediated airway remodeling and that CysLT1 receptor antagonists may have a role in preventing aberrant extracellular matrix degradation.

Topics: Acetates; Actins; Cyclopropanes; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Fetus; Fibroblasts; Flow Cytometry; Humans; Leukotriene Antagonists; Leukotriene D4; Lung; Matrix Metalloproteinases; Membrane Proteins; Peptide Fragments; Procollagen; Quinolines; Receptors, Leukotriene; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfides; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta1

The cysteinyl leukotrienes (cysLTs) and the peptide hormone endothelin (ET)-1 are potent bronchoconstrictor substances, and these mediators are also claimed to be implicated in the development of eosinophilic airway inflammation. In the present study, we have investigated the effect of the cysLT1 receptor antagonist montelukaston the development of an eosinophilic airway inflammation 24 h after intratracheal Sephadex (SDX) provocation in rats. Furthermore, the effect of montelukast treatment on the generation of ET-1 and other pro-inflammatory mediators has been studied. The inflammatory response was significantly reduced in the animals receiving SDX + montelukast compared to animals receiving solely SDX, as evaluated by a decrease in bronchoalveolar lavage fluid total cell count (10.3 +/- 1.2 vs. 18.5 +/- 1.8 x 10(4) ml(-1), P<0.001), number of eosinophils (299.7 +/- 43.8 vs. 577.6 +/- 46.6 x 10(2) ml(-1), P<0.001), and lymphocytes (116.8 +/- 20 vs. 222.0 +/- 34.8 x 10(2) ml(-1), P<0.05), as well as the degree of tissue inflammation (P<0.05). Montelukast also inhibited the increase in the concentration of the pro-inflammatory mediators ET-1 (28.5 +/- 75 vs. 40.9 +/- 7.3 x pg ml(-1), P<0.05) and interferon (IFN)-gamma (4.3 +/- 2.2 vs. 15.6+/-8.7 x pg ml(-1), P<0.05), but not tumor necrosis factor-gamma or interleukin-8. In summary, treatment with the cysLT1 receptor antagonist montelukast reduced the inflammatory response during development of an eosinophilic airway inflammation, possibly by inhibiting the release of pro-inflammatory mediators like ET-1 and IFN-gamma.

Topics: Acetates; Animals; Bronchoalveolar Lavage Fluid; Cell Count; Cyclopropanes; Endothelin-1; Eosinophils; Interferon-gamma; Interleukin-8; Leukotriene Antagonists; Lung; Male; Quinolines; Rats; Rats, Wistar; Sulfides; Tumor Necrosis Factor-alpha