leukotriene-b4 and Bronchitis--Chronic

Patients with COPD classically have neutrophilic bronchial inflammation and raised airway concentrations of the neutrophil chemoattractant leukotriene B(4) (LTB(4)). A small phase II trial was conducted to assess the effects of a leukotriene synthesis inhibitor on bronchial inflammation in patients with stable COPD.. A randomized, double-blind, placebo-controlled, parallel-group study.. Respiratory medicine department of a university hospital.. Seventeen patients with chronic bronchitis and COPD (mean FEV(1), 35.5% predicted; SD, 14.8% predicted) were randomized to receive 14 days of the oral leukotriene synthesis inhibitor BAYx1005 (500 mg bid) or placebo.. Spontaneous sputum samples obtained at baseline and at the end of treatment were assayed for LTB(4), myeloperoxidase (an indirect marker of neutrophil numbers and/or activation), and chemotactic activity (Boyden chamber). After 14 days, there were no significant differences (p > 0.05) in absolute LTB(4) concentrations between the two treatment groups. However, BAYx1005 treatment produced a significantly greater median reduction in LTB(4) of - 3.1 nM (interquartile range [IQR], - 9.6 to - 0.2 nM) vs 3.0 nM (IQR, - 0.3 to 8.5 nM) [p = 0.001], with concentrations decreasing from 8.0 nM (IQR, 4.3 to 24.4 nM) at baseline to 4.2 nM (IQR, 1.9 to 11.9 nM) at the end of treatment (p = 0.03). There were no changes in the placebo group and no differences in sputum myeloperoxidase concentration or chemotaxis between the two treatment arms (p > 0.05).. This small study suggests that a leukotriene synthesis inhibitor can produce modest reductions in some measures of neutrophilic bronchial inflammation in patients with COPD. This class of anti-inflammatory agent requires further study in larger numbers of patients to determine clinical benefit.

Topics: Aged; Bronchitis, Chronic; Double-Blind Method; Female; Humans; Leukotriene B4; Lipoxygenase Inhibitors; Male; Pulmonary Diffusing Capacity; Pulmonary Disease, Chronic Obstructive; Quinolines

The study was to evaluate the effect of triterpene acids of Eriobotrya japonica (thunb.) lindl. leaf (TAL) on inflammatory cytokine and mediator expression in alveolar macrophages (AM) of chronic bronchitic (CB) rats.. CB was induced by endotracheal instillation of lipopolysaccharide (LPS) followed by Bacillus Calmette Guerin (BCG) injection via the caudal vein one week later. Treatment groups received TAL at there different doses (50, 150, or 450 mg/kg daily i. g.), Ketotifen fumarate (5 mg/kg daily i. g.) or dexamethasone (1.2 mg/kg daily i. g.) for two weeks, 7 days after LPS injection. AM were then isolated and incubated for 24 h. IL-1, TNF-alpha and PGE2 levels in cultured supernatants were measured by thymocyte co-stimulating assay and radioimmunoassay. Immunocytochemistry staining and western-blot were used for intracellular location and activation of p65 subunit of NF-kB. LTB(4) level was analyzed by reverse-phase high performance liquid chromatography (RP-HPLC).. The levels of TNF-alpha, IL-1, NF-kB, PGE2 and LTB(4) expression in AM of TAL groups were significantly decreased compared to the CB group (P < 0.05 or P < 0.01), in a dose dependent manner.. TAL inhibited NF-kB activation in AM from CB rats and led to down regulation of TNF-alpha, IL-1, PGE(2) and LTB(4) expression, which might be a mechanism for its anti-inflammatory effects in CB rats.

Topics: Animals; Bronchitis, Chronic; Cell Nucleus; Cells, Cultured; Cytokines; Cytoplasm; Dinoprostone; Disease Models, Animal; Eriobotrya; Immunohistochemistry; Leukotriene B4; Macrophages, Alveolar; Male; Molecular Structure; NF-kappa B; Plant Extracts; Plant Leaves; Protein Subunits; Rats; Rats, Sprague-Dawley; Triterpenes; Ursolic Acid

Sputum analysis is used increasingly to assess airway inflammation in patients with chronic obstructive pulmonary disease, including those with chronic bronchitis and bronchiectasis. However, it is not known whether dithiothreitol (DTT), a reducing mucolytic agent regularly used to homogenise sputum, affects the detection of inflammatory mediators in the sputum soluble phase from such patients.. Thirty two spontaneous sputum samples were collected from 13 patients with chronic bronchitis and 17 with bronchiectasis. An aliquot from each sample was treated with either freshly prepared 0.1% DTT plus normal saline (NaCl) or NaCl alone, then ultracentrifuged to obtain the sputum sol phase. Interleukin (IL)-1beta, IL-6, IL-8, leukotriene B(4) (LTB(4)), secretory leukoprotease inhibitor (SLPI), alpha-1-antitrypsin (alpha(1)-AT), and tumour necrosis factor alpha (TNFalpha) were measured by ELISA, and neutrophil elastase (NE) and myeloperoxidase (MPO) by chromogenic substrate assay. The effect of DTT on the detection of assay standards was also determined.. Median levels of IL-1beta, IL-6, IL-8, SLPI, and NE were similar in the DTT and NaCl treated samples. There was a significant reduction in median (IQR) levels of detectable TNFalpha (0.07 (0.00-0.47) pM v 0.90 (0.06-6.98) pM, p<0.001), LTB(4) (1.67 (1.31-2.64) nM v 2.29 (0.95-4.22) nM, p<0.05) and MPO (0.00 (0.00-0.00) mg/l v 4.48 (0.00-33.66) mg/l, p<0.001) and a small increase in the median alpha(1)-AT concentration (0.05 (0.03-0.08) nM v 0.03 (0.02-0.08) nM, p<0.01) in the DTT treated samples. DTT had no effect on the assay standards for IL-1beta, IL-8 or TNFalpha, but at higher concentrations it did affect IL-6, SLPI, NE, and LTB(4) standards (43%, 70%, 76% and 643% of control value for top standard, respectively) and at all concentrations DTT completely abolished MPO activity.. Sputum processing with DTT significantly reduces the detectable concentration of TNFalpha, LTB(4) and MPO, and produces a small but significant increase in median alpha(1)-AT levels. To avoid this problem we recommend that an untreated aliquot of sputum be retained for cytokine analysis, unless the assay has been specifically validated.

Topics: alpha 1-Antitrypsin; Bronchiectasis; Bronchitis, Chronic; Dithiothreitol; Enzyme-Linked Immunosorbent Assay; Humans; Interleukins; Leukocyte Elastase; Leukotriene B4; Middle Aged; Peroxidase; Proteinase Inhibitory Proteins, Secretory; Proteins; Secretory Leukocyte Peptidase Inhibitor; Sodium Chloride; Sputum; Tumor Necrosis Factor-alpha