M3 Pseudomonas aeruginosa induces inflammation in bronchial epithelial cells via the p38 MAP and Syk tyrosine kinase pathways

Objectives Pseudomonas aeruginosa (Pa) infection is a major cause of inflammation in cystic fibrosis airways, initially mediated by bronchial epithelial cells, which are vital for the immune response. Kinase activation, such as MAP and Tyrosine kinases, are integral to inflammatory responses to Pa, therefore are potential targets for novel anti-inflammatory therapies. This study aims to determine which kinases are involved in Pa-induced inflammation. Methods BEAS-2B bronchial epithelial cells were treated with kinase inhibitors against p38 MAPK (p38), MEK, JNK, Syk and c-Src at 1 µg/ml, for 2 hours, followed by Pa infection at 2.5 × 107 CFU/ml, for 5 hours. CXCL8 and IL-6 release were measured by sandwich ELISA. Combinations of inhibitors and novel narrow spectrum kinase inhibitors (NSKI) against p38, Src and/or Syk kinases were used to investigate synergistic effects of blocking multiple pathways. Synergy of compound combinations was calculated using the Chou-Talalay method. Results An inhibitor of p38 showed 85.8% (p Conclusion Pa-induced CXCL8 and IL-6 release is highly dependent on both p38 and Syk kinases, and inhibition of multiple selected pathways can lead to synergistic effects. Further investigation is planned to elucidate the possible role of Syk kinase in p38 activation. This study shows a potential for inhibitors of multiple specific kinases as potent anti-inflammatory therapies.