Potential use of an anticancer drug gefinitib, an EGFR inhibitor, on allergic airway inflammation

Gyu Young Hur,Ki Hwan Jung,Kyung Ho Kang,Chol Shin,Seung Hyeun Lee,Kwang Ho In,Jae Jeong Shim,Jin Yong Jung,Sung Yong Lee,Se Joong Kim,Sang Yeub Lee,Eun Joo Lee,Se Hwa Yoo,Je Hyeong Kim,Eun Hae Kang,Kyoung Ju Lee

doi:10.1038/emm.2007.41

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.

Highlights

Bronchial asthma is a chronic inflammatory disease of airways characterized by eosinophilic infiltration and airway hyperrespensiveness (AHR)
We have investigated whether the EGFR tyrosine kinase inhibitor, gefitinib can reduce allergic inflammation in the airway epithelial cells of mice
Our results show that exposure to OVA induces the recruitment of eosinophils, the release of IL-4 and IL-13, and an increase in airway hyperresponsiveness in mice

Summary

Introduction

Bronchial asthma is a chronic inflammatory disease of airways characterized by eosinophilic infiltration and airway hyperrespensiveness (AHR). Pathological features of asthma include pulmonary infiltration by eosinophils, lymphocytes, and mast cells, and structural changes of the airways, including bronchial wall thickening, subepithelial fibrosis, and goblet cell and airway smooth muscle hyperplasia (Cohn et al, 2004). Protein tyrosine kinases are essential for the activation and proliferation of inflammatory cells and airway-resident cells. Activated EGFR has an essential role in mucin production in airway epithelium (Takeyama et al, 1999, 2001; Nadel, 2001; Nadel and Burgel, 2001). It induces airway goblet cell hyperplasia and enhances the expression of mucin genes, such as MUC5AC.

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