Concentrations of Cysteinyl Leukotrienes in Various Biological Fluids of Children with Bronchial Asthma, Atopic Dermatitis and Food Protein Induced Enterocolitis

Clinical manifestation of food allergy is characterized by polymorphic cutaneous, respiratory and gastrointestinal syndromes. Leukotrienes occupy a key place in the pathogenesis of a wide range of inflammatory diseases, including bronchial asthma, allergic rhinitis, atopic dermatitis, hives, allergic conjunctivitis, atherosclerotic cardio-vascular lesions system, inflammatory bowel disease, multiple sclerosis, cancer, etc. Better understanding of general pathophysiological mechanisms of allergic realization put the focus on the studying of cysteinyl leukotrienes biological effects in infants with atopic dermatitis and food-protein induced enterocolitis important.Aim. To optimize the diagnosis of allergic lesions of the gastrointestinal tract in children.Methods. The study was conducted in the allergy center and children clinic of the «Institute Pediatrics, Obstetrics and Gynecology named after academician O. Lukyanova of NAMS of Ukraine». Children were included from September 2017 to June 2018.We examined 60 patients aged from 3 months to 3 years old, including 22 patients with atopic dermatitis, 18 children with food-protein induced enterocolitis, 8 patients with bronchial asthma in the stage of aggravation and 12 practically healthy children (control group).Medical examination have been perfomed, general IG E and specific serum IG E were defined by ImmunoCAP (Phadia, 100), as well as concentrations of cysteinyl leukotrienes (LTB4, LTC4, LTE4) in biological liquids (serum, saliva, urine) using immunoenzyme method using the production sets of the "Enzolifescience" (USA) company on the analyzer-photometer Multiskan Plus "Labsystems". The results of the received data were processed statistically. The probability of differences was estimated with Student's t-test and Tau Kendall rank correlation test. The difference was considered significant at p <0.05.Results. A significant increase in the concentrations of cysteinyl leukotrienes (C4, D4, E4) in the blood, urine and saliva was found in infants with allergic skin diseases, gastro-intestinal and respiratory tract surveyed during manifestation the disease compared with the control group.Comparison of concentrations of leukotrienes in urine and saliva of children with atopic dermatitis (AD), food-protein induced enterocolitis (FPIE) and asthma did not find credible. However, in the serum of patients with asthma, the concentration of cysteinyl leukotrienes was significantly higher (703.9±68.7) pg / ml than in children with enterocolitis induced by dietary proteins (509.3±57.4) pg / ml and significantly did not differ from patients with atopic dermatitis (695.2±46.3) pg / ml.According to the results of Kendall Tau correlation test, no significant Spearman rank correlation was found between the cysteinyl leukotrienes concentration in blood and urine – r=0.14 (p>0.05), blood and saliva r=0.07 (p>0.05), urine and saliva r=–0.52 (p>0.05).Conclusions. Increase in cysteinyl leukotrienes concentrations in serum, urine and saliva of children of early age with allergic skin diseases, respiratory and gastrointestinal tract was found. The absence of significant Spearman rank correlation between concentrations of leukotrienes in blood and urine, blood and saliva, saliva and urine shows that it is possible to select any biological fluid, saliva or urine, as a non-invasive way to determine the leukotriene concentrations for monitoring activity of allergic inflammation

Concentrations of Cysteinyl Leukotrienes in Various Biological Fluids of Children with Bronchial Asthma, Atopic Dermatitis and Food Protein Induced Enterocolitis

Clinical manifestation of food allergy is characterized by polymorphic cutaneous, respiratory and gastrointestinal syndromes. Leukotrienes occupy a key place in the pathogenesis of a wide range of inflammatory diseases, including bronchial asthma, allergic rhinitis, atopic dermatitis, hives, allergic conjunctivitis, atherosclerotic cardio-vascular lesions system, inflammatory bowel disease, multiple sclerosis, cancer, etc. Better understanding of general pathophysiological mechanisms of allergic realization put the focus on the studying of cysteinyl leukotrienes biological effects in infants with atopic dermatitis and food-protein induced enterocolitis important.Aim. To optimize the diagnosis of allergic lesions of the gastrointestinal tract in children.Methods. The study was conducted in the allergy center and children clinic of the «Institute Pediatrics, Obstetrics and Gynecology named after academician O. Lukyanova of NAMS of Ukraine». Children were included from September 2017 to June 2018.We examined 60 patients aged from 3 months to 3 years old, including 22 patients with atopic dermatitis, 18 children with food-protein induced enterocolitis, 8 patients with bronchial asthma in the stage of aggravation and 12 practically healthy children (control group).Medical examination have been perfomed, general IG E and specific serum IG E were defined by ImmunoCAP (Phadia, 100), as well as concentrations of cysteinyl leukotrienes (LTB4, LTC4, LTE4) in biological liquids (serum, saliva, urine) using immunoenzyme method using the production sets of the "Enzolifescience" (USA) company on the analyzer-photometer Multiskan Plus "Labsystems". The results of the received data were processed statistically. The probability of differences was estimated with Student's t-test and Tau Kendall rank correlation test. The difference was considered significant at p <0.05.Results. A significant increase in the concentrations of cysteinyl leukotrienes (C4, D4, E4) in the blood, urine and saliva was found in infants with allergic skin diseases, gastro-intestinal and respiratory tract surveyed during manifestation the disease compared with the control group.Comparison of concentrations of leukotrienes in urine and saliva of children with atopic dermatitis (AD), food-protein induced enterocolitis (FPIE) and asthma did not find credible. However, in the serum of patients with asthma, the concentration of cysteinyl leukotrienes was significantly higher (703.9±68.7) pg / ml than in children with enterocolitis induced by dietary proteins (509.3±57.4) pg / ml and significantly did not differ from patients with atopic dermatitis (695.2±46.3) pg / ml.According to the results of Kendall Tau correlation test, no significant Spearman rank correlation was found between the cysteinyl leukotrienes concentration in blood and urine – r=0.14 (p>0.05), blood and saliva r=0.07 (p>0.05), urine and saliva r=–0.52 (p>0.05).Conclusions. Increase in cysteinyl leukotrienes concentrations in serum, urine and saliva of children of early age with allergic skin diseases, respiratory and gastrointestinal tract was found. The absence of significant Spearman rank correlation between concentrations of leukotrienes in blood and urine, blood and saliva, saliva and urine shows that it is possible to select any biological fluid, saliva or urine, as a non-invasive way to determine the leukotriene concentrations for monitoring activity of allergic inflammation

LTD4 and TGF-β1 induce the expression of metalloproteinase-1 in chronic rhinosinusitis via a cysteinyl leukotriene receptor 1-related mechanism

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Involvement of leukotriene pathway in the pathogenesis of ischemia-reperfusion injury and septic and non-septic shock.

The 5-lipoxygenase (5-LO) pathway is responsible for the production of leukotrienes (LTs), inflammatory lipid mediators which play a role in innate immunity. More recently, a pivotal role of LTs in ischemia-reperfusion and shock injury has been suggested. In fact, these pathological conditions are characterized by a severe neutrophil infiltration that gives rise to tissue injury and 5-LO metabolites control neutrophil recruitment in injured tissue by the modulation of adhesion molecule expression. The aim of this review is to analyze the results reported in the literature on the role of 5-LO pathway, with particular regard to LTs, in these pathological conditions. A better understanding of the mechanisms underlying the role of the 5-LO enzyme and/or its metabolites in the regulation of neutrophil trafficking, might open new perspectives in the therapy of organ dysfunction and/or injury associated with shock and ischemia-reperfusion injury

The treatment of asthma with leukotriene receptor antagonists

Over the past three decades the pharmacotherapy of asthma has been based on glucocorticoids, ß2 agonists and theophyllines. Research conducted over the past 10 years has led to greater understanding of the cellular and molecular basis of asthma, particularly the role of the underlying inflammatory process.peer-reviewe

Mercapturate Pathway in the Tubulocentric Perspective of Diabetic Kidney Disease

BACKGROUND: The recent growing evidence that the proximal tubule underlies the early pathogenesis of diabetic kidney disease (DKD) is unveiling novel and promising perspectives. This pathophysiological concept links tubulointerstitial oxidative stress, inflammation, hypoxia, and fibrosis with the progression of DKD. In this new angle for DKD, the prevailing molecular mechanisms on proximal tubular cells emerge as an innovative opportunity for prevention and management of DKD as well as to improve diabetic dysmetabolism. SUMMARY: The mercapturate pathway (MAP) is a classical metabolic detoxification route for xenobiotics that is emerging as an integrative circuitry detrimental to resolve tubular inflammation caused by endogenous electrophilic species. Herein we review why and how it might underlie DKD. Key Messages: MAP is a hallmark of proximal tubular cell function, and cysteine-S-conjugates might represent targets for early intervention in DKD. Moreover, the biomonitoring of urinary mercapturates from metabolic inflammation products might be relevant for the implementation of preventive/management strategies in DKD.info:eu-repo/semantics/publishedVersio

Cysteinyl-leukotrienes contribute to sputum eosinophil chemotactic activity in asthmatics

Background: Cysteinyl-leukotrienes are lipid derived mediators involved in asthma. They are able to stimulate eosinophil chemotaxis in vitro. Induced sputum from asthmatics has been shown to contain eosinophil chemotactic activity. The purpose of our study was to evaluate the contribution of cysteinyl-leukotrienes to sputum eosinophil chemotactic activity in asthmatics and to seek whether there might be differences between asthmatics free of inhaled corticosteroids vs those regularly receiving this treatment. Methods: Twenty-two patients (11 corticosteroid free, mean FEV1 99% predicted, 11 corticosteroid-treated, mean FEV1 77% predicted) recruited from our asthma clinic underwent a sputum induction. Sputum was processed according to standard procedure. Eosinophil chemotactic activity contained in the fluid phase was assessed using Boyden microchamber model and expressed as chemotaxis index (CI). Cysteinyl-leukotrienes were measured in sputum supernatant by ELISA and their role in sputum eosionophil chemotactic activity was evaluated by using montelukast, a selective antagonist of a cys-LT1 receptor. Results: Cysteinyl-leukotrienes were well detectable in sputum supernatants from both steroid-naive (247 +/- 42 pg/ml) and steroid-treated (228 +/- 26 pg/ml) asthmatics. Sputum eosinophil chemotactic activity was indiscriminately present in both corticosteroid-naive (CI: 2.61 +/- 0.22) and corticosteroid-treated (2.98 +/- 0.35) asthmatics. Montelukast (100 mu M) significantly inhibited the eosinophil chemotactic activity in both groups achieving a mean inhibition of 54.2 +/- 9.2% (P < 0.001) and 64.7 +/- 7.8% (P < 0.001) in steroid-naive and steroid-treated asthmatics respectively. Conclusion: Cysteinyl-leukotrienes actively participate in sputum eosinophil chemotactic activity found in asthmatics irrespective of whether they are or not under treatment with inhaled corticoids.Peer reviewe

Taurocholate-stimulated leukotriene C4 biosynthesis and leukotriene C4-stimulated choleresis in isolated rat liver

BACKGROUND/AIMS: Cysteinyl-containing leukotrienes seem to exert a cholestatic effect. However, leukotriene inhibitors were found to reduce bile salt efflux in isolated rat hepatocytes, suggesting a role for leukotrienes in bile flow formation. METHODS: In the isolated rat liver, the effects of two different concentrations of leukotriene C4 on bile flow and bile salt excretion are analyzed, as well as the possible effect of taurocholate on the hepatic production of cysteinyl-containing leukotrienes. RESULTS: Leukotriene C4 (0.25 fmol) increased bile salt excretion (+22.2%; P < 0.05), whereas a much higher dose (0.25 x 10(6) fmol) showed the known cholestatic effect, reducing bile salt excretion (-25.9%; P < 0.01). These dose-dependent biphasic effects were specific because they could be prevented by the simultaneous administration of cysteinyl-containing leukotriene antagonists. On the other hand, taurocholate administration induced a dose-dependent increase in biliary excretion of cysteinyl-containing leukotrienes. Furthermore, taurocholate increased messenger RNA levels of 5-lipoxygenase, a key enzyme in leukotriene biosynthesis. Taurocholate increase of hepatocyte intracellular calcium was not significant, suggesting that taurocholate effects are not mediated by stimulation of calcium metabolism. CONCLUSIONS: These results constitute evidence for the existence of a positive feedback mechanism by which bile salts stimulate the synthesis of leukotrienes that, in turn, stimulate bile salt excretion

Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s.

Group 2 innate lymphoid cells (ILC2s) and type 2 helper T cells (Th2 cells) are the primary source of interleukin 5 (IL-5) and IL-13 during type 2 (allergic) inflammation in the lung. In Th2 cells, T cell receptor (TCR) signaling activates the transcription factors nuclear factor of activated T cells (NFAT), nuclear factor κB (NF-κB), and activator protein 1 (AP-1) to induce type 2 cytokines. ILC2s lack a TCR and respond instead to locally produced cytokines such as IL-33. Although IL-33 induces AP-1 and NF-κB, NFAT signaling has not been described in ILC2s. In this study, we report a nonredundant NFAT-dependent role for lipid-derived leukotrienes (LTs) in the activation of lung ILC2s. Using cytokine reporter and LT-deficient mice, we find that complete disruption of LT signaling markedly diminishes ILC2 activation and downstream responses during type 2 inflammation. Type 2 responses are equivalently attenuated in IL-33- and LT-deficient mice, and optimal ILC2 activation reflects potent synergy between these pathways. These findings expand our understanding of ILC2 regulation and may have important implications for the treatment of airways disease

Cysteinyl Leukotriene Receptor Type 1 (CysLT1) Mediates Contraction of the Guinea Pig Lower Esophageal Sphincter

AbstractObjectiveLeukotriene D4 (LTD4) causes contraction of the cat lower esophageal sphincter. The effects of leukotrienes in the guinea pig lower esophageal sphincter and the cysteinyl leukotriene receptor (CysLT) subtype that mediate this contraction are not known. The purpose of the present study was to characterize the CysLT receptors in the guinea pig lower esophageal sphincter.Materials and MethodsWe measured the contractions of transverse strips from the guinea pig lower esophageal sphincter caused by cysteinyl leukotrienes, LTC4, LTD4 and LTE4, and the dihydroxy leukotriene, LTB4. We also measured LTD4-induced contraction inhibited by CysLT receptor antagonists, tetrodotoxin and atropine.ResultsIn the guinea pig lower esophageal sphincter strips, LTC4, LTD4 and LTE4, but not LTB4, caused concentration-dependent contractions. The relative potencies for cysteinyl leukotrienes to cause contraction were LTD4 = LTC4 > LTE4. LTE4 was a partial agonist. The LTD4-induced contraction was inhibited by two selective CysLT1 receptor antagonists, montelukast and zafirlukast, and by the dual CysLT1 and CysLT2 receptor antagonist BAY u9773. The combination of both montelukast and BAY u9773 did not potentiate the inhibition caused by montelukast alone. These findings indicate that CysLT1 mediates the contraction in the lower esophageal sphincter. Furthermore, LTD4-induced contraction was not affected by tetrodotoxin or atropine, suggesting a direct effect.ConclusionThese results demonstrate that cysteinyl leukotrienes, but not the dihydroxy leukotriene LTB4, cause contraction of the guinea pig lower esophageal sphincter. The CysLT1 receptor mediates this contraction