leukotriene-d4 and Lung-Neoplasms

Tumor-derived exosomes can modulate the cancer microenvironment and induce metastatic spread. Exosomes may carry enzymes for leukotriene (LT) biosynthesis, but the role of exosomal LTs has not been studied in cancer. We isolated exosomes and malignant cells from pleura exudates from 14 patients with non-small cell lung cancer. Lipidomic profiles, migration and apoptosis were determined. Both exosomes and primary cancer cells contained γ-glutamyl transpeptidase 1 (GGT-1) and avidly transformed exogenous LTC

Topics: Acetates; Adult; Aged; Aged, 80 and over; Apoptosis; Biomarkers, Tumor; Cell Movement; Cell Proliferation; Cyclopropanes; Exosomes; Female; Follow-Up Studies; Humans; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Lung Neoplasms; Male; Middle Aged; Pleural Neoplasms; Prognosis; Quinolines; Receptors, Leukotriene; Sulfides; Survival Rate; Tumor Cells, Cultured

Leukotrienes (LTs) play major roles in lung immune responses, and LTD4 is the most potent agonist for cysteinyl LT1, leading to bronchoconstriction and tissue remodeling. Here, we studied LT crosstalk between myeloid cells and pulmonary epithelial cells. Monocytic cells (Mono Mac 6 cell line, primary dendritic cells) and eosinophils produced primarily LTC4 In coincubations of these myeloid cells and epithelial cells, LTD4 became a prominent product. LTC4 released from the myeloid cells was further transformed by the epithelial cells in a transcellular manner. Formation of LTD4 was rapid when catalyzed by γ-glutamyl transpeptidase (GGT)1 in the A549 epithelial lung cancer cell line, but considerably slower when catalyzed by GGT5 in primary bronchial epithelial cells. When A549 cells were cultured in the presence of IL-1β, GGT1 expression increased about 2-fold. Also exosomes from A549 cells contained GGT1 and augmented LTD4 formation. Serine-borate complex (SBC), an inhibitor of GGT, inhibited conversion of LTC4 to LTD4 Unexpectedly, SBC also upregulated translocation of 5-lipoxygenase (LO) to the nucleus in Mono Mac 6 cells, and 5-LO activity. Our results demonstrate an active role for epithelial cells in biosynthesis of LTD4, which may be of particular relevance in the lung.

Topics: A549 Cells; Arachidonate 5-Lipoxygenase; Borates; Eosinophils; Epithelial Cells; Exosomes; gamma-Glutamyltransferase; Humans; Immunity, Cellular; Leukotriene C4; Leukotriene D4; Lung; Lung Neoplasms; Myeloid Cells; Serine

Mucin gene expression and mucin production are markedly increased in inflammatory airway disorders such as asthma, chronic bronchitis and rhinosinusitis. Cytokines, lipopolysaccharides and other inflammatory mediators such as prostaglandin and leukotriene are related to the secretion and production of mucin. However, the relationship of leukotrienes with mucin genes expression is not clear. The aim of this study is to evaluate MUC2/5AC gene expression and mucin secretion by the leukotriene receptor in human airway epithelial cells.. The effect of leukotriene D(4) and the leukotriene receptor antagonist, pranlukast hydrate (ONO-1078) on the regulation of MUC2/5AC gene expression and mucin secretion were observed in human airway NCI-H292 epithelial cells. The mRNA levels of MUC2/5AC and the amount of mucin were determined by reverse transcription-polymerase chain reaction (RT-PCR) and immunoassay.. Leukotriene D(4) upregulated MUC2/5AC gene expression and mucin secretion in a dose dependent pattern. Pranlukast hydrate (ONO-1078, 100 microM) downregulated the leukotriene D(4)-induced MUC2/5AC gene expression and mucin secretion.. These results suggest that the leukotriene receptor system is one of the mechanisms related to MUC2/5AC gene expression and mucin secretion in the human airway epithelium.

Topics: Carcinoma, Mucoepidermoid; Cell Line, Tumor; Chromones; Down-Regulation; Gene Expression; Humans; Leukotriene Antagonists; Leukotriene D4; Lung Neoplasms; Mucin 5AC; Mucin-2; Mucins; Receptors, Leukotriene; Respiratory Mucosa; Reverse Transcriptase Polymerase Chain Reaction; Up-Regulation

To ensure the suitable preservation of isolated lungs, a super-cooling system was used to cool water to temperatures as low as -5 degrees C without freezing.. After lung tissues were obtained from patients with lung cancer, they were kept at -5 degrees C or 4 degrees C for as many as 5 days, and then they were histologically and biochemically examined. To evaluate biochemical stability, tissues after storage were passively sensitized with immunoglobulin E and then incubated with anti-immunoglobulin-E antibody.. Although tissues preserved at -5 degrees C for 5 days had an almost normal appearance with intact cilia on bronchial epithelium and normal endothelium, tissues stored at 4 degrees C showed degradation of these structures. Single-stranded DNA, a sign of DNA cleavage, was frequently noted in tissues stored at 4 degrees C, but only rarely observed at -5 degrees C. A significant amount of cysteinyl-leukotrienes was generated from tissues stored at -5 degrees C for 3 days, but there was no response to antibody stimulation from tissues stored at 4 degrees C.. Super-cooling systems may provide useful applications as a novel preserving method.

Topics: Aged; Aged, 80 and over; Anaphylaxis; Antibodies, Anti-Idiotypic; Cryopreservation; DNA, Single-Stranded; Female; Humans; Hypertonic Solutions; Leukotriene C4; Leukotriene D4; Leukotriene E4; Lung; Lung Neoplasms; Lung Transplantation; Male; Middle Aged; Organ Preservation; Organ Preservation Solutions; Pneumonectomy; Refrigeration; Static Electricity; Temperature; Tissue and Organ Harvesting

Contractions induced by leukotriene and anti-IgE (sheep antiserum to human IgE) were antagonized by pretreatment of human airways with the cysteinyl leukotriene receptor antagonist BAY x7195 ((4S)-[4-carboxyphenylthio]-7-[4-(4-phenoxybutoxy)-phenyl]-h ept-5-(z)- enoic acid). However, this receptor antagonist did not inhibit either leukotriene D4- or leukotriene C4-induced contractions in human pulmonary veins. The pA2 value for BAY x7195 in human airways against leukotriene D4 was 7.83 +/- 0.16 with a slope of 1.07 +/- 0.15 (means +/- S.E.M; n = 11). The IC50 value for BAY x7195 in human airways contracted with anti-IgE was 0.31 +/- 0.08 microM (n = 11). These results were comparable to those obtained with ICI 204,219 (4-(5-cyclopentyl-oxycarbonylamino-1-methylindol-3-ylmeth yl)-3-methoxy-N-otolyl - sulfonylbenzamide). These data demonstrate that BAY x7195 is a potent selective leukotriene receptor antagonist which may block allergic reactions in the lung.

Topics: Antibodies, Anti-Idiotypic; Bronchodilator Agents; Female; Humans; Hydroxy Acids; Immunoglobulin E; Indoles; Leukotriene C4; Leukotriene D4; Lung Neoplasms; Male; Middle Aged; Muscle Contraction; Muscle, Smooth; Phenylcarbamates; Pulmonary Veins; Sulfonamides; Tosyl Compounds