Potential use of an anticancer drug gefinitib, an EGFR inhibitor, on allergic airway inflammation.
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.
Hur
Gyu Young
GY
Department of Internal Medicine, College of Medicine, Korea University, Seoul 152-703, Korea.
Lee
Sung Yong
SY
Lee
Seung Hyeun
SH
Kim
Se Joong
SJ
Lee
Kyoung Ju
KJ
Jung
Jin Yong
JY
Lee
Eun Joo
EJ
Kang
Eun Hae
EH
Jung
Ki Hwan
KH
Lee
Sang Yeub
SY
Kim
Je Hyeong
JH
Shin
Chol
C
Shim
Jae Jeong
JJ
In
Kwang Ho
KH
Kang
Kyung Ho
KH
Yoo
Se Hwa
SH
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
D000970:Antineoplastic Agents; D016207:Cytokines; D011799:Quinazolines; D010047:Ovalbumin; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib