EGFR tyrosine kinase inhibition worsens acute lung injury in mice with repairing airway epithelium

Chika Harada, Tomonobu Kawaguchi, Saiko Ogata-Suetsugu, Mizuho Yamada, Naoki Hamada, Takashige Maeyama, Ryota Sozaki, Tatsuro Tajiri, Tomoaki Taguchi, Kazuyoshi Kuwano, Yoichi Nakanishi

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Rationale: Epidermal growth factor receptor (EGFR) and its ligands play important roles in the regeneration of damaged epithelium and proliferation of various epithelial tumors. Although the EGFRtyrosine kinase inhibitor gefitinib is effective against advanced non - small cell lung cancer with EGFR mutations, some patients treated with this agent develop severe acute interstitial pneumonia. Characteristics of patients who develop interstitial pneumonia include older age, smoking history, and preexisting interstitial pneumonia suggesting a connection between airway injury and alveolar dysfunction. Objectives: The purpose of this study was to investigate the effects of gefitinib on airway repair after injury. Methods: C57BL/6J mice received intraperitoneally naphthalene at Day 0. Gefitinib (20, 90, or 200 mg/kg) was given daily at Days21 to 13 after naphthalene administration. Bronchoalveolar lavage fluid and lung tissue were obtained at Days 7 and 14. Terminal bronchial epithelial cells from Days 7 and 14 were retrieved with laser capture microdissection, and gene expression analyzed using microarray. Measurements and Main Results: Gefitinib treatment after naphthalene prolonged neutrophil sequestration and worsened acute lung injury. We found 17 genes with more than a threefold increase in bronchiolar epithelial cells from mice treated with 200 mg/kg of gefitinib after naphthalene at Day 14 compared with those treated with naphthalene alone. Up-regulated genes included S100A8, S100A6, and StefinA3. These genes are known to participate in neutrophil sequestration, acute inflammation, and airway remodeling. Conclusions: EGFR inhibition in repairing airway epithelial cells modulated significant expression of genes involved in the airway microenvironment, prolonged inflammation, and potentiated acute lung injury.

Original languageEnglish
Pages (from-to)743-751
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume183
Issue number6
DOIs
Publication statusPublished - Mar 15 2011

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Acute Lung Injury
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Epithelium
Interstitial Lung Diseases
Epithelial Cells
Neutrophils
Genes
Laser Capture Microdissection
Inflammation
Airway Remodeling
Gene Expression
Bronchoalveolar Lavage Fluid
Wounds and Injuries
Inbred C57BL Mouse
Non-Small Cell Lung Carcinoma
Regeneration
Phosphotransferases
Smoking
History

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

EGFR tyrosine kinase inhibition worsens acute lung injury in mice with repairing airway epithelium. / Harada, Chika; Kawaguchi, Tomonobu; Ogata-Suetsugu, Saiko; Yamada, Mizuho; Hamada, Naoki; Maeyama, Takashige; Sozaki, Ryota; Tajiri, Tatsuro; Taguchi, Tomoaki; Kuwano, Kazuyoshi; Nakanishi, Yoichi.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 183, No. 6, 15.03.2011, p. 743-751.

Research output: Contribution to journalArticle

Harada, C, Kawaguchi, T, Ogata-Suetsugu, S, Yamada, M, Hamada, N, Maeyama, T, Sozaki, R, Tajiri, T, Taguchi, T, Kuwano, K & Nakanishi, Y 2011, 'EGFR tyrosine kinase inhibition worsens acute lung injury in mice with repairing airway epithelium', American Journal of Respiratory and Critical Care Medicine, vol. 183, no. 6, pp. 743-751. https://doi.org/10.1164/rccm.201002-0188OC
Harada, Chika ; Kawaguchi, Tomonobu ; Ogata-Suetsugu, Saiko ; Yamada, Mizuho ; Hamada, Naoki ; Maeyama, Takashige ; Sozaki, Ryota ; Tajiri, Tatsuro ; Taguchi, Tomoaki ; Kuwano, Kazuyoshi ; Nakanishi, Yoichi. / EGFR tyrosine kinase inhibition worsens acute lung injury in mice with repairing airway epithelium. In: American Journal of Respiratory and Critical Care Medicine. 2011 ; Vol. 183, No. 6. pp. 743-751.
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AU - Maeyama, Takashige

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N2 - Rationale: Epidermal growth factor receptor (EGFR) and its ligands play important roles in the regeneration of damaged epithelium and proliferation of various epithelial tumors. Although the EGFRtyrosine kinase inhibitor gefitinib is effective against advanced non - small cell lung cancer with EGFR mutations, some patients treated with this agent develop severe acute interstitial pneumonia. Characteristics of patients who develop interstitial pneumonia include older age, smoking history, and preexisting interstitial pneumonia suggesting a connection between airway injury and alveolar dysfunction. Objectives: The purpose of this study was to investigate the effects of gefitinib on airway repair after injury. Methods: C57BL/6J mice received intraperitoneally naphthalene at Day 0. Gefitinib (20, 90, or 200 mg/kg) was given daily at Days21 to 13 after naphthalene administration. Bronchoalveolar lavage fluid and lung tissue were obtained at Days 7 and 14. Terminal bronchial epithelial cells from Days 7 and 14 were retrieved with laser capture microdissection, and gene expression analyzed using microarray. Measurements and Main Results: Gefitinib treatment after naphthalene prolonged neutrophil sequestration and worsened acute lung injury. We found 17 genes with more than a threefold increase in bronchiolar epithelial cells from mice treated with 200 mg/kg of gefitinib after naphthalene at Day 14 compared with those treated with naphthalene alone. Up-regulated genes included S100A8, S100A6, and StefinA3. These genes are known to participate in neutrophil sequestration, acute inflammation, and airway remodeling. Conclusions: EGFR inhibition in repairing airway epithelial cells modulated significant expression of genes involved in the airway microenvironment, prolonged inflammation, and potentiated acute lung injury.

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