title: Potential use of an anticancer drug gefinitib, an EGFR inhibitor, on allergic airway inflammation.
abstract: 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 gefinitib 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.
authors.affiliation: Department of Internal Medicine, College of Medicine, Korea University, Seoul 152-703, Korea.
authors.forename: Gyu Young
authors.initials: GY
authors.lastname: Hur
authors.forename: Sung Yong
authors.initials: SY
authors.lastname: Lee
authors.forename: Seung Hyeun
authors.initials: SH
authors.lastname: Lee
authors.forename: Se Joong
authors.initials: SJ
authors.lastname: Kim
authors.forename: Kyoung Ju
authors.initials: KJ
authors.lastname: Lee
authors.forename: Jin Yong
authors.initials: JY
authors.lastname: Jung
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Lee
authors.forename: Eun Hae
authors.initials: EH
authors.lastname: Kang
authors.forename: Ki Hwan
authors.initials: KH
authors.lastname: Jung
authors.forename: Sang Yeub
authors.initials: SY
authors.lastname: Lee
authors.forename: Je Hyeong
authors.initials: JH
authors.lastname: Kim
authors.forename: Chol
authors.initials: C
authors.lastname: Shin
authors.forename: Jae Jeong
authors.initials: JJ
authors.lastname: Shim
authors.forename: Kwang Ho
authors.initials: KH
authors.lastname: In
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Kang
authors.forename: Se Hwa
authors.initials: SH
authors.lastname: Yoo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation; D004804:Eosinophils / Q000166:cytology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D020397:Goblet Cells / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use*; D012130:Respiratory Hypersensitivity / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D011799:Quinazolines; D010047:Ovalbumin; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib