leukotriene-e4 and Pulmonary-Eosinophilia

Distinct receptors likely exist for leukotriene (LT)E(4), a potent mediator of airway inflammation. Purinergic receptor P2Y12 is needed for LTE(4)-induced airways inflammation, and P2Y12 antagonism attenuates house dust mite-induced pulmonary eosinophilia in mice. Although experimental data support a role for P2Y12 in airway inflammation, its role in human asthma has never been studied.. To test for association between variants in the P2Y12 gene (P2RY12) and lung function in human subjects with asthma, and to examine for gene-by-environment interaction with house dust mite exposure.. Nineteen single nucleotide polymorphisms (SNPs) in P2RY12 were genotyped in 422 children with asthma and their parents (n = 1266). Using family based methods, we tested for associations between these SNPs and five lung function measures. We performed haplotype association analyses and tested for gene-by-environment interactions using house dust mite exposure. We used the false discovery rate to account for multiple comparisons.. Five SNPs in P2RY12 were associated with multiple lung function measures (P-values 0.006–0.025). Haplotypes in P2RY12 were also associated with lung function (P-values 0.0055–0.046). House dust mite exposure modulated associations between P2RY12 and lung function, with minor allele homozygotes exposed to house dust mite demonstrating worse lung function than those unexposed (significant interaction P-values 0.0028–0.040).. The P2RY12 variants were associated with lung function in a large family-based asthma cohort. House dust mite exposure caused significant gene-by-environment effects. Our findings add the first human evidence to experimental data supporting a role for P2Y12 in lung function. P2Y12 could represent a novel target for asthma treatment.

Topics: Animals; Asthma; Child; Cohort Studies; Female; Gene-Environment Interaction; Humans; Leukotriene E4; Lung; Male; Mice; Polymorphism, Single Nucleotide; Pulmonary Eosinophilia; Pyroglyphidae; Receptors, Purinergic P2Y12; Respiratory Function Tests

The 3 cysteinyl leukotrienes (cysLTs), leukotriene (LT) C. We sought to determine whether LTD. We used 2 different in vivo models of CysLT. LTC. The conversion of LTC

Topics: Animals; Asthma; Blood Platelets; Cysteine; Cytokines; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Lung; Male; Mice; Mice, Inbred C57BL; Platelet Activation; Pulmonary Eosinophilia; Receptors, Leukotriene

Human type-2 CD8

Topics: A549 Cells; Asthma; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Chemokines; Cytokines; Humans; Hypersensitivity; Inflammation; Leukotriene E4; Lipids; Lymphocyte Count; Mast Cells; Prostaglandin D2; Pulmonary Eosinophilia; Th2 Cells

Leukotriene C4 (LTC4) and its extracellular metabolites, LTD4 and LTE4, mediate airway inflammation. They signal through three specific receptors (type 1 cys-LT receptor [CysLT1R], CysLT2R, and GPR99) with overlapping ligand preferences. In this article, we demonstrate that LTC4, but not LTD4 or LTE4, activates mouse platelets exclusively through CysLT2R. Platelets expressed CysLT1R and CysLT2R proteins. LTC4 induced surface expression of CD62P by wild-type mouse platelets in platelet-rich plasma (PRP) and caused their secretion of thromboxane A2 and CXCL4. LTC4 was fully active on PRP from mice lacking either CysLT1R or GPR99, but completely inactive on PRP from CysLT2R-null (Cysltr2(-/-)) mice. LTC4/CysLT2R signaling required an autocrine ADP-mediated response through P2Y12 receptors. LTC4 potentiated airway inflammation in a platelet- and CysLT2R-dependent manner. Thus, CysLT2R on platelets recognizes LTC4 with unexpected selectivity. Nascent LTC4 may activate platelets at a synapse with granulocytes before it is converted to LTD4, promoting mediator generation and the formation of leukocyte-platelet complexes that facilitate inflammation.

Topics: Adenosine Diphosphate; Animals; Autocrine Communication; Blood Platelets; Leukotriene C4; Leukotriene D4; Leukotriene E4; Mice; Mice, Knockout; Ovalbumin; P-Selectin; Platelet Activation; Platelet Factor 4; Platelet-Rich Plasma; Pulmonary Eosinophilia; Receptors, Leukotriene; Receptors, Purinergic P2; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2

Although eosinophils produce cysteinyl leukotrienes (CysLTs) in large quantities, information on the relationship between CysLTs and eosinophilic pneumonia (EP) is lacking. Inflammatory mediator concentrations in urine were quantified to clarify the relationship between CysLT concentrations and EP severity. Leukotriene (LT)E(4), eosinophil-derived neurotoxin (EDN), 9alpha,11beta-prostaglandin F2 and LTB(4) glucuronide concentrations were quantified in the urine of: EP patients during acute exacerbation and clinical remission; asthmatic patients during acute exacerbation and under stable conditions; and healthy control subjects. The urinary LTE(4) and EDN concentrations of EP patients during acute exacerbation were significantly higher than those of asthmatic patients and healthy subjects, and decreased immediately during clinical remission. The urinary LTE(4) concentration was associated with the urinary EDN concentration of EP patients during acute exacerbation. The urinary LTE(4) concentration significantly correlated with the diffusing capacity of the lung for carbon monoxide in EP patients during acute exacerbation. The increased urinary concentrations of leukotriene and eosinophil-derived neurotoxin were associated with acute exacerbation in eosinophilic pneumonia patients. The increased leukotriene concentration significantly correlated with diffusing capacity of the lung for carbon monoxide, suggesting that the monitoring of leukotriene concentration may aid in the management of eosinophilic pneumonia patients.

Topics: Adolescent; Adult; Aged; Asthma; Case-Control Studies; Female; Glucuronides; Humans; Inflammation; Leukotriene E4; Male; Middle Aged; Neurotoxins; Pulmonary Eosinophilia; Remission Induction