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

被引:48
作者
Hur, Gyu Young [1 ]
Lee, Sung Yong [1 ]
Lee, Seung Hyeun [1 ]
Kim, Se Joong [1 ]
Lee, Kyoung Ju [1 ]
Jung, Jin Yong [1 ]
Lee, Eun Joo [1 ]
Kang, Eun Hae [1 ]
Jung, Ki Hwan [1 ]
Lee, Sang Yeub [1 ]
Kim, Je Hyeong [1 ]
Shin, Choi [1 ]
Shim, Jae Jeong [1 ]
In, Kwang Ho [1 ]
Kang, Kyung Ho [1 ]
Yoo, Se Hwa [1 ]
机构
[1] Korea Univ, Coll Med, Dept Internal Med, Seoul 152703, South Korea
关键词
asthma; gefitinib; mucins; 1-phosphatidylinositol; 3-kinase; proto-oncogene proteins c-akt; receptor; epidermal growth factor;
D O I
10.1038/emm.2007.41
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (Pl3K)/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.
引用
收藏
页码:367 / 375
页数:9
相关论文
共 48 条
  • [1] Expression of epidermal growth factor and epidermal growth factor receptor immunoreactivity in the asthmatic human airway
    Amishima, M
    Munakata, M
    Nasuhara, Y
    Sato, A
    Takahashi, T
    Homma, Y
    Kawakami, Y
    [J]. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1998, 157 (06) : 1907 - 1912
  • [2] Regulation of mucin expression: Mechanistic aspects and implications for cancer and inflammatory diseases
    Andrianifahanana, Mahefatiana
    Moniaux, Nicolas
    Batra, Surinder K.
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER, 2006, 1765 (02): : 189 - 222
  • [3] Epidermal growth factor receptor signaling
    Bogdan, S
    Klämbt, C
    [J]. CURRENT BIOLOGY, 2001, 11 (08) : R292 - R295
  • [4] Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium
    Burgel, PR
    Nadel, JA
    [J]. THORAX, 2004, 59 (11) : 992 - 996
  • [5] The phosphoinositide 3-kinase pathway
    Cantley, LC
    [J]. SCIENCE, 2002, 296 (5573) : 1655 - 1657
  • [6] Immunostimulatory DNA inhibits transforming growth factor-β expression and airway remodeling
    Cho, JY
    Miller, M
    Baek, KJ
    Han, JW
    Nayar, J
    Rodriguez, M
    Lee, SY
    McElwain, K
    McElwain, S
    Raz, E
    Broide, DH
    [J]. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2004, 30 (05) : 651 - 661
  • [7] Inhibitor of p42/44 mitogen-activated protein kinase, but nto p38 MAPK, attenuated antigen challenge of guinea pig airways in vitro
    Chue, SC
    Seow, CJ
    Duan, W
    Yeo, KSL
    Koh, AHM
    Wong, WSF
    [J]. INTERNATIONAL IMMUNOPHARMACOLOGY, 2004, 4 (08) : 1089 - 1098
  • [8] Ciardiello F, 2001, CLIN CANCER RES, V7, P2958
  • [9] IL-13 INDUCES PROLIFERATION AND DIFFERENTIATION OF HUMAN B-CELLS ACTIVATED BY THE CD40-LIGAND
    COCKS, BG
    MALEFYT, RD
    GALIZZI, JP
    DEVRIES, JE
    AVERSA, G
    [J]. INTERNATIONAL IMMUNOLOGY, 1993, 5 (06) : 657 - 663
  • [10] ASTHMA: Mechanisms of disease persistence and progression
    Cohn, L
    Elias, JA
    Chupp, GL
    [J]. ANNUAL REVIEW OF IMMUNOLOGY, 2004, 22 : 789 - 815