Inhibitors of the tyrosine kinase signaling cascade for asthma.
The pathogenesis of allergic asthma involves the interplay of inflammatory cells and resident airway cells, and of their secreted mediators including cytokines, chemokines, growth factors and inflammatory mediators. Tyrosine kinase signaling cascades play a critical role in the pathogenesis of allergic airway inflammation. Receptor tyrosine kinases (e.g. epidermal growth factor receptor [EGFR] and platelet-derived growth factor receptor) are important for the pathogenesis of airway remodeling. Stimulation of non-receptor tyrosine kinases (e.g. Lyn, Lck, Syk, ZAP-70, Btk, Itk and JAK) is the earliest detectable signaling response upon activation of immune receptors (T cell receptor, B cell receptor and FCepsilonR1), cytokine receptors and chemokine receptors in inflammatory cells. Activation of tyrosine kinases invokes multiple downstream signaling pathways, including phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB), leading to cell differentiation, survival, proliferation, degranulation and chemotaxis. Inhibitors targeted at different enzyme molecules of the tyrosine kinase signaling cascade might afford therapeutic potential for asthma. Anti-inflammatory effects of pharmacological agents targeted at tyrosine kinases, Syk, Itk, signal transducer and activator of transcription-1, NF-kappaB, GATA3, EGFR, PI3K, MEK1/2, p38 MAPK and JNK have been reported in animal models of allergic airway inflammation. Therefore, development of inhibitors targeted at the tyrosine kinase signaling cascade is an attractive strategy for the treatment of asthma.
Wong
W S Fred
WS
Department of Pharmacology, Faculty of Medicine, Immunology Program, National University of Singapore, MD2 18 Medical Drive, 117597 Singapore. phcwongf@nus.edu.sg
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*
D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases