Tyrosine kinase inhibitors: a new approach for asthma.
The pathogenesis of allergic asthma involves the interplay of inflammatory cells and airway-resident cells, and of their secreted mediators including cytokines, chemokines, growth factors and inflammatory mediators. Receptor tyrosine kinases are important for the pathogenesis of airway remodeling. Activation of epidermal growth factor (EGF) receptor kinase and platelet-derived growth factor (PDGF) receptor kinase leads to hyperplasia of airway smooth muscle cells, epithelial cells and goblet cells. Stimulation of non-receptor tyrosine kinases (e.g. Lyn, Lck, Syk, ZAP-70, Fyn, Btk, Itk) is the earliest detectable signaling response upon antigen-induced immunoreceptor activation in inflammatory cells. Cytokine receptor dimerization upon ligand stimulation induces activation of Janus tyrosine kinases (JAKs), leading to recruitment and phosphorylation of signal transducer and activator of transcription (STAT) for selective gene expression regulation. Activation of chemokine receptors can trigger JAK-STAT pathway, Lck, Fyn, Lyn, Fgr, and Syk/Zap-70 to induce chemotaxis of inflammatory cells. Inhibitors of tyrosine kinases have been shown in vitro to block growth factor-induced hyperplasia of airway-resident cells; antigen-induced inflammatory cell activation and cytokine synthesis; cytokine-mediated pro-inflammatory gene expression in inflammatory and airway cells; and chemokine-induced chemotaxis of inflammatory cells. Recently, anti-inflammatory effects of tyrosine kinase inhibitors (e.g. genistein, tyrphostin AG213, piceatannol, tyrphostin AG490, WHI-P97, WHI-P131, Syk antisense) in animal models of allergic asthma have been reported. Therefore, development of inhibitors of tyrosine kinases can be a very attractive strategy for the treatment of asthma.
Wong
W S Fred
WS
Department of Pharmacology, Faculty of Medicine, National University of Singapore, MD2 18 Medical Drive, Singapore 117597, Singapore. phcwong@nus.edu.sg
Leong
Khai Pang
KP
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D018121:Receptors, Cytokine / Q000502:physiology; D015398:Signal Transduction
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D018121:Receptors, Cytokine; D011505:Protein-Tyrosine Kinases