interleukin-8 and pyrimidine

We aimed to use serum metabolomics to discriminate infants with severe respiratory syncytial virus (RSV) bronchiolitis who later developed subsequent recurrent wheezing from those who did not and to investigate the relationship between serum metabolome and host immune responses with regard to the subsequent development of recurrent wheezing. Fifty-one infants who were hospitalized during an initial episode of severe RSV bronchiolitis at 6 months of age or less were included and followed for up to the age of 3 years. Of them, 24 developed subsequent recurrent wheezing and 27 did not. Untargeted serum metabolomics was performed by ultraperformance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-MS/MS). Cytokines were measured by multiplex immunoassay. Difference in serum metabolomic profiles was observed between infants who developed recurrent wheezing and those who did not. L-lactic acid level was significantly higher in infants with recurrent wheezing than those without. Pyrimidine metabolism, glycerophospholipid metabolism, and arginine biosynthesis were identified as the most significant changed pathways between the two groups. Moreover, L-lactic acid level was positively associated with serum CXCL8 level. This exploratory study showed that differential serum metabolic signatures during severe RSV bronchiolitis in early infancy were associated with the development of subsequent recurrent wheezing in later childhood.

Topics: Bronchiolitis; Child, Preschool; Chromatography, High Pressure Liquid; Cytokines; Female; Follow-Up Studies; Humans; Infant; Interleukin-8; Lactic Acid; Male; Metabolomics; Pyrimidines; Respiratory Sounds; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Serum; Tandem Mass Spectrometry

Chemokine receptor CXCR2 is expressed on various immune cells and is essential for neutrophil recruitment and angiogenesis at sites of acute and chronic inflammation caused by tissue injury or infection. Because of its role in inflammation, it has been implicated in a number of immune-mediated inflammatory diseases such as psoriasis, arthritis, COPD, cystic fibrosis, asthma, and various types of cancer. CXCR2 and its ligands are up-regulated in cancer cells as well as the tumor microenvironment, promoting tumor growth, angiogenesis, and invasiveness. Although pharmaceutical companies have pursued the development of CXCR2-specific small-molecule inhibitors as anti-inflammatory agents within the last decades, there are currently no clinically approved CXCR2 inhibitors. Using a high-throughput, cell-based assay specific for CXCR2, we screened an in-house library of structurally diverse compounds and identified a class of pyrimidine-based compounds that alter CXCR2-mediated second messenger signaling. Our lead compound, CX797, inhibited IL8-mediated cAMP signaling and receptor degradation while specifically up-regulating IL8-mediated β-arrestin-2 recruitment. CX797 also inhibited IL8-mediated cell migration. Mechanistic comparison of CX797 and a previously reported CXCR2 inhibitor, SB265610, show these two classes of compounds have a distinct mechanism of action on CXCR2.

Topics: Anti-Inflammatory Agents; Arrestins; beta-Arrestin 2; beta-Arrestins; Cell Line, Tumor; Cell Movement; Cyclic AMP; HL-60 Cells; Humans; Inflammation; Interleukin-8; Jurkat Cells; Pyrimidines; Receptors, Interleukin-8B; Signal Transduction; Tumor Microenvironment