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KMID : 0620920070390030367
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Experimental & Molecular Medicine
2007 Volume.39 No. 3 p.367 ~ p.375
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Potential use of an anticancer drug gefinitib, an EGFR inhibitor, on allergic airway inflammation
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Hur Gyu-Young
Lee Sung-Yong
Lee Seung-Hyeun
Kim Se-Joong
Lee Kyung-Joo
Jung Jin-Yong
Lee Eun-Joo
Kang Eun-Hae
Jung Ki-Hwan
Lee Sang-Yeub
Kim Je-Hyeong
Shin Chol
Shim Jae-Jeong
In Kwang-Ho
Kang Kyung-Ho
Yoo Se-Hwa
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Abstract
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The EGFR plays an essential role in goblet cell hyperplasia and mucus hypersecretion. EGFR has an intrinsic tyrosine kinase activity that, when activated, induces the production of MUC5AC through the signaling kinase cascade in the airway epithelium. We have investigated the effects of an EGFR tyrosine kinase inhibitor, gefitinib, on ovalbumin (OVA)-induced, allergic inflammation in airway epithelia of mice. OVA-sensitized mice were pretreated with gefitinib at two different doses (12.5 and 50 mg/kg) and then challenged with OVA. The OVA challenge increased the total cell count and eosinophil count in bronchoalveolar lavage fluid (BALF), as well as the concentrations of T-helper2 (Th2) cytokines, such as IL-4 and IL-13, overall eosinophil recruitment in the lung tissue and airway hyperresponsiveness (AHR). Pretreatment with gefitinib reduced the inflammatory cell counts and released cytokine concentrations (IL-4 and IL-13) in BALF, as well as eosinophil recruitment in the lungs and AHR, in a dose-dependent manner. This was associated with decreased EGFR and Akt phosphorylation. We showed that gefitnib inhibits EGFR and phosphoinositol 3’-kinase (PI3K)/Akt activation which were activated in OVA sensitized mice. These findings suggest that inhibitors of the EGFR cascade may have a role in the treatment of asthma.
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KEYWORD
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asthma, gefitinib, mucins, 1-phosphatidylinositol 3-kinase, proto-oncogene proteins c-akt, receptor, epidermal growth factor
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