leukotriene-b4 and Respiratory-Tract-Diseases

Leukotriene A4 hydrolase (LTA4H) is a ubiquitously expressed enzyme that catalyzes the final step in the synthesis of leukotriene B4 (LTB4), a potent proinflammatory lipid mediator derived from arachidonic acid. Although LTB4 was identified 30 years ago, several recent findings have refocused attention on this mediator as a target for inflammatory and autoimmune diseases. While LTB4 was once thought to be a chemoattractant and activator only of leukocytes mediating acute, innate inflammatory responses, LTB4 receptors have since been discovered on multiple cell types, including T-lymphocytes and antigen-presenting dendritic cells. Thus, the inhibition of LTB4 synthesis demonstrates potential for targeting chronic, autoimmune-driven inflammation. In addition to genetic data in animals and humans linking the LTB4 pathway to cardiovascular disease, variants in the LTA4H gene have been linked with susceptibility to asthma. Several companies have initiated drug discovery efforts to identify potent, selective LTA4H inhibitors. Selected molecules have demonstrated oral efficacy in preclinical models of asthma, inflammatory bowel disease and arthritis, suggesting therapeutic potential for multiple indications. This review focuses on developments with therapeutic relevance for inhibitors of LTA4H as anti-inflammatory drugs, and particularly in the treatment of respiratory disease.

Topics: Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Dendritic Cells; Drug Design; Enzyme Inhibitors; Epoxide Hydrolases; Humans; Inflammation; Leukotriene B4; Respiratory Tract Diseases; T-Lymphocytes

Collection of exhaled breath (EB) and exhaled breath condensate (EBC) is a noninvasive method for obtaining samples from the lower airways. While this technique has been well established for the diagnosis of lower respiratory tract diseases in human medicine, only a few studies have been performed in veterinary medicine. This article critically reviews the collection methods and parameter values measured in various animal species published to date and points out directions for further research.

Topics: Animal Diseases; Animals; Breath Tests; Diagnosis, Differential; Hydrogen Peroxide; Hydrogen-Ion Concentration; Leukotriene B4; Nitric Oxide; Respiratory Tract Diseases; Species Specificity

Topics: Bacteria; Bacterial Infections; Environmental Exposure; Histamine Release; Humans; Immunoglobulin E; Leukotriene B4; Respiratory Tract Diseases

Topics: Animals; Asthma; Humans; Leukotriene B4; Lung; Muscle Tonus; Muscle, Smooth; Respiratory Physiological Phenomena; Respiratory Tract Diseases; SRS-A; Trachea

Acute respiratory failure in neonates (e.g. ARDS, meconium aspiration pneumonitis, pneumonia) is characterized by an excessive inflammatory response, governing the migration of polymorpho-nuclear leukocytes (PMNLs) into lung tissue and causing consecutive impairment of gas exchange and lung function. Critical to this inflammatory response is the activation of nuclear factor-kappaB (NF-kappaB) that is required for transcription of the genes for many pro-inflammatory mediators. We asked whether the inhibition of NF-kappaB activity using either a selective inhibitor (IKK-NBD peptide) or dexamethasone would be more effective in decreasing NF-kappaB activity and chemokine expression in pulmonary cells. Changes in lung function were repeatedly assessed for 24h following induction of acute respiratory failure and therapeutic intervention. We conducted a randomized, controlled, prospective animal study with mechanically ventilated newborn piglets which underwent repeated airway lavage (20+/-2 [SEM]) to remove surfactant and to induce lung inflammation. Admixed to 100 mg kg(-1) surfactant, piglets then received either IKK-NBD peptide (S+IKK), a selective inhibitor of NF-kappaB activation, its control peptide without intrinsic activity, dexamethasone (S+Dexa), its solvent aqua, or an air bolus only (all groups n=8). After 24h of mechanical ventilation, the following differences were measured: PaO(2)/FiO(2) (S+IKK 230+/-9 mm Hg vs. S+Dexa 188+/-14, p<0.05); ventilation efficiency index (0.18+/-0.01 [3800/(PIP-PEEP)(*)f(*)PaCO(2)] vs. 0.14+/-0.01, p<0.05); extravascular lung water (24+/-1 ml kg(-1) vs. 29+/-2, p<0.05); PMNL in BAL fluid (112+/-21 cells microl(-1) vs. 208+/-34, p<0.05), IL-8 (351+/-117 pg ml(-1) vs. 491+/-144, p=ns) and leukotriene B(4) (23+/-7 pg ml(-1) vs. 71+/-11, p<0.01) in BAL fluid. NF-kappaB activity in the nucleus of pulmonary cells differed by 32+/-5% vs. 55+/-3, p<0.001. Differences between these two intervention groups were more pronounced in the second half of the observation period (hours 12-24). At 24h of mechanical ventilation, inhibition of NF-kappaB activity by IKK-NBD peptide admixed to surfactant as a carrier caused improved gas exchange, lung function and reduced pulmonary inflammation, as evidenced by reduction in PMNL migration into lung tissue due to reduced nuclear NF-kappaB activity. We conclude that IKK-NBD admixture to surfactant in acute neonatal respiratory failure is superior to dexamethasone administration within the fir

Topics: Acute Disease; Animals; Animals, Newborn; Anti-Inflammatory Agents; Blood Cell Count; Bronchoalveolar Lavage Fluid; Dexamethasone; Inflammation; Interleukin-8; Leukotriene B4; Lung Diseases; Neutrophils; NF-kappa B; Organ Size; Pulmonary Gas Exchange; Pulmonary Surfactants; Respiration, Artificial; Respiratory Tract Diseases; Swine

Exhaled breath condensate (EBC) analysis is a noninvasive method to assess the lower respiratory tract. In human subjects, EBC hydrogen peroxide (H. To determine associations between EBC biomarkers and cytological and endoscopic definitions of lower airway inflammation (LAI) while controlling for sampling and environmental variables.. Prospective, cross-sectional study.. EBC pH and H. LAI is challenging to categorise due to a variety of clinical and cytological phenotypes. Although the study was designed to overcome this limitation, numbers of horses were small in some categories.

Topics: Analysis of Variance; Animals; Biomarkers; Breath Tests; Bronchoalveolar Lavage Fluid; Bronchoscopy; Cross-Sectional Studies; Eosinophils; Female; Hemorrhage; Horse Diseases; Horses; Hydrogen Peroxide; Hydrogen-Ion Concentration; Inflammation; Leukotriene B4; Linear Models; Male; Multivariate Analysis; Neutrophils; Prospective Studies; Respiratory System; Respiratory Tract Diseases

Aspirin-exacerbated respiratory disease (AERD) is an inflammatory condition of the respiratory tract and is characterized by overproduction of leukotrienes (LT) and large numbers of circulating granulocyte-platelet complexes. LT production can be suppressed by prostaglandin E(2) (PGE(2)) and the cyclic AMP-dependent protein kinase A (PKA).. To determine if PGE(2)-dependent control of LT production by granulocytes is dysregulated in AERD.. Granulocytes from well-characterized patients with and without AERD were activated ex vivo and subjected to a range of functional and biochemical analyses.. Granulocytes from subjects with AERD generated more LTB4 and cysteinyl LTs than did granulocytes from controls with aspirin-tolerant asthma and controls without asthma. When compared with controls, granulocytes from subjects with AERD had comparable levels of EP(2) protein expression and PGE(2)-mediated cAMP accumulation, yet were resistant to PGE(2)-mediated suppression of LT generation. Percentages of platelet-adherent neutrophils correlated positively with LTB4 generation and inversely with responsiveness to PGE(2)-mediated suppression of LTB(4). The PKA inhibitor H89 potentiated LTB4 generation by control granulocytes but was inactive in granulocytes from individuals with AERD and had no effect on platelet P-selectin induction. Both tonic PKA activity and levels of PKA catalytic gamma subunit protein were significantly lower in granulocytes from individuals with AERD relative to those from controls.. Impaired granulocyte PKA function in AERD may lead to dysregulated control of 5-lipoxygenase activity by PGE(2), whereas adherent platelets lead to increased production of LTs, which contributes to the features of persistent respiratory tract inflammation and LT overproduction.

Topics: Adult; Aged; Aspirin; Blood Platelets; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dinoprostone; Female; Granulocytes; Humans; Leukotriene B4; Leukotrienes; Male; Middle Aged; Neutrophils; Receptors, Prostaglandin E, EP2 Subtype; Respiratory Tract Diseases; Young Adult

Collection of exhaled breath condensate (EBC) and the measurement of inflammatory markers contained therein (eg, hydrogen peroxide [H2O2], leukotriene B4 [LTB4], and pH) have been reported to be noninvasive tools for the investigation of respiratory disease in various species. In this study, the EBC of clinically healthy psittacine birds (n = 15) and psittacine birds with respiratory tract disease (n = 19) was examined, and inflammatory markers contained in the EBC were analyzed and compared. Awake birds were placed in an acrylic container from which the outflow passed through a condensation system that collected the EBC. All samples were analyzed for pH, H2O2, and LTB4. The mean values for each of these components, as well as the mean volume of the total EBC, measured from the apparently healthy birds did not differ significantly from those measured in birds with signs of respiratory tract disease. However, LTB4 in the EBC of diseased birds was higher than that of the apparently healthy birds and showed a trend toward significance. The study demonstrated the establishment of a standardized method for collecting and analyzing EBC in psittacine birds and a measurement protocol for pH, H2O2, and LTB4.

Topics: Animals; Bird Diseases; Breath Tests; Female; Hydrogen Peroxide; Hydrogen-Ion Concentration; Leukotriene B4; Male; Psittaciformes; Respiratory Tract Diseases

Cineole (eucalyptol) is the isolated active agent of eucalyptus oil. Traditionally, it is recommended for treating the symptoms of airway diseases exacerbated by infection. We have examined the inhibitory effect of 1.8-cineole on LPS-and IL1beta-stimulated mediator production by human monocytes in vitro. For the first time, we report on a dose-dependent and highly significant inhibition of production of tumor necrosis factor-alpha, interleukin-1beta, leukotriene B4 and thromboxane B2 by 1.8-cineole. In summary, this is the first report on a new mechanism of action of monoterpenes suggesting 1.8-cineole as a strong inhibitor of cytokines that might be suitable for longterm treatment of airway inflammation in bronchial asthma and other steroid-sensitive disorders.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Asthma; Cyclohexanols; Cytokines; Eucalyptol; Female; Humans; In Vitro Techniques; Inflammation; Inflammation Mediators; Interleukin-1; Leukotriene B4; Lipopolysaccharides; Male; Menthol; Monocytes; Monoterpenes; Respiratory Tract Diseases; Terpenes; Thromboxane B2; Tumor Necrosis Factor-alpha

The role of lipoxygenase products was studied in children suffering from chronic diseases of the lung. Leukotrienes C4, D4, E4 and B4 were measured by high performance liquid chromatography (HPLC) and a specific radioimmunoassay (RIA) for C4. Elevated levels (up to 40 ng/ml), especially for leukotriene E4, were found in plasma of asthmatic and bronchitic patients (leukotriene C4 concentrations varied between 0.05 and 40 ng/ml, mean 4.9 +/- 7.8 ng/ml). In healthy donors the concentrations were below the detection limits of HPLC, leukotriene C4 ranging between 5 +/- 4 ng/ml (RIA data). The conversion of leukotriene C4 to D4 and E4 was observed by incubating the samples with synthetic leukotriene C4. The half-life of leukotriene C4 in plasma varied greatly, ranging from less than 12 min to 72 min (mean 39 +/- 16 min). Bronchial lavages yielded leukotriene C4 concentrations of 0.2 to 7 ng. Leukotriene E4 was detected in 10 of 41 cases. Conversion of leukotriene C4 did not occur in 50% of all cases, but was regularly observed in putrid lavages. These data suggest that leukotrienes play an important role in allergic and infectious lung diseases.

Topics: Adolescent; Asthma; Bronchitis; Child; Child, Preschool; Chromatography, High Pressure Liquid; Chronic Disease; Humans; Infant; Leukotriene B4; Leukotriene E4; Radioimmunoassay; Respiratory Tract Diseases; SRS-A

Topics: Arachidonic Acid; Arachidonic Acids; Cyclooxygenase Inhibitors; Humans; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Leukotriene B4; Lipoxygenase Inhibitors; Lung; Mast Cells; Models, Biological; Prostaglandin D2; Prostaglandins D; Respiratory Tract Diseases; SRS-A