Pharmacological inhibition of focal adhesion kinase 1 (FAK1) and anaplastic lymphoma kinase (ALK) identified via kinome profile analysis attenuates lipopolysaccharide-induced endothelial inflammatory activation

Sepsis is a life-threatening condition often leading to multiple organ failure for which currently no pharmacological treatment available. Endothelial cells (EC) are among the first respond pathogens and inflammatory mediators in sepsis might be sentinel target prevent occurrence of failure. Lipopolysaccharide (LPS) Gram-negative bacterial component that induces endothelial expression adhesion molecules, cytokines, chemokines. This regulated by network kinases, result vivo enables leukocytes transmigrate from blood into underlying tissue, causing damage. We hypothesised besides known kinase pathways, other kinases involved regulation EC response LPS, these can pharmacologically targeted inhibit cell activation. Using kinome profiling, we identified 58 tyrosine (TKs) were active human umbilical vein (HUVEC) at various timepoints after stimulation with LPS. These included AXL (Axl), focal 1 (FAK1), anaplastic lymphoma (ALK). siRNA-based gene knock down, confirmed three TKs mediate LPS-induced Pharmacological inhibition FAK1 inhibitor FAK14 attenuated activation leukocyte partly via blockade NF-κB activity. Administration exposure LPS also resulted molecule expression. In contrast, ALK FDA-approved Ceritinib pathway was independent signalling while it did not affect adhesion. Furthermore, administration start Combined an additive manner, without affecting Summarising, our findings suggest involvement mediating EC. Since exposed represents promising follow up studies.