Exp Mol Med.  2007 Jun;39(3):367-375.

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

• Hur GY
• Lee SY
• Lee SH
• Kim SJ
• Lee KJ
• Jung JY
• Lee EJ
• Kang EH
• Jung KH
• Lee SY
• Kim JH
• Shin C
• Shim JJ
• In KH
• Kang KH
• Yoo SH

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 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.

Keyword

asthma; gefitinib; mucins; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; receptor, epidermal growth factor

MeSH Terms

Animals
Antineoplastic Agents/*therapeutic use
Bronchoalveolar Lavage Fluid/cytology
Cytokines/biosynthesis
Enzyme Activation
Eosinophils/cytology
Goblet Cells/pathology
Inflammation/drug therapy/metabolism
Male
Mice
Mice, Inbred BALB C
Ovalbumin
Phosphorylation
Proto-Oncogene Proteins c-akt/metabolism
Quinazolines/*therapeutic use
Receptor, Epidermal Growth Factor/*antagonists & inhibitors/metabolism
Respiratory Hypersensitivity/*drug therapy/etiology/metabolism
Respiratory Mucosa/drug effects/pathology