leukotriene-a4 and Chronic-Disease

Neutrophils (PMNs) are key mediators of inflammatory processes throughout the body. In this study, we investigated the role of acrolein, a highly reactive aldehyde that is ubiquitously present in the environment and produced endogenously at sites of inflammation, in mediating PMN-mediated degradation of collagen facilitating proline-glycine-proline (PGP) production. We treated peripheral blood neutrophils with acrolein and analyzed cell supernatants and lysates for matrix metalloproteinase-9 (MMP-9) and prolyl endopeptidase (PE), assessed their ability to break down collagen and release PGP, and assayed for the presence of leukotriene A4 hydrolase (LTA4H) and its ability to degrade PGP. Acrolein treatment induced elevated production and functionality of collagen-degrading enzymes and generation of PGP fragments. Meanwhile, LTA4H levels and triaminopeptidase activity declined with increasing concentrations of acrolein thereby sparing PGP from enzymatic destruction. These findings suggest that acrolein exacerbates the acute inflammatory response mediated by neutrophils and sets the stage for chronic pulmonary and systemic inflammation.

Topics: Acrolein; Aminopeptidases; Chronic Disease; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Dose-Response Relationship, Drug; Humans; Inflammation; Leukotriene A4; Matrix Metalloproteinase 9; Neutrophils; Oligopeptides; Proline; Prolyl Oligopeptidases; Serine Endopeptidases

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Child; Chronic Disease; Cyclooxygenase Inhibitors; Diagnosis, Differential; Drug Hypersensitivity; Humans; Kartagener Syndrome; Leukotriene A4; Male; Skin Tests

Inflammatory cytokines and low-affinity Fcgamma receptor (FcgammaR) polymorphisms were investigated in 37 children with chronic immune thrombocytopenic purpura (cITP) and 218 controls. Genotype analysis included common variants in the regulatory regions of cytokines, TNF, LTA, IL1RN, IL1A, IL1B, IL4, IL6 and IL10, and structural variants of the low affinity FcgammaRs, FCGR2A, FCGR3A and FCGR3B. Associations were observed for TNF (P = 0.0032), LTA (P = 0.019), FCGR3A (P = 0.038) and FCGR3B (P = 0.0034). Two combinations of genotypes (TNF and FCGR3A; P = 0.0003, and LTA and FCGR3B; P = 0.011) were significantly associated with cITP. These results provide preliminary evidence that variant genotypes of FcgammaRs and cytokines contribute to cITP pathogenesis.

Topics: Case-Control Studies; Chi-Square Distribution; Child; Chronic Disease; Confidence Intervals; Cytokines; Genotype; Humans; Leukotriene A4; Odds Ratio; Pilot Projects; Polymorphism, Genetic; Purpura, Thrombocytopenic, Idiopathic; Receptors, IgG; Tumor Necrosis Factor-alpha