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 EGFR-tyrosine 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 Days--1 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.
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 EGFR-tyrosine 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 Days--1 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.
Authors: James H Finigan; Rangnath Mishra; Vihas T Vasu; Lori J Silveira; David E Nethery; Theodore J Standiford; Ellen L Burnham; Marc Moss; Jeffrey A Kern Journal: Eur Respir J Date: 2012-05-17 Impact factor: 16.671
Authors: Stefan H Gorissen; Milena Hristova; Aida Habibovic; Lynne M Sipsey; Page C Spiess; Yvonne M W Janssen-Heininger; Albert van der Vliet Journal: Am J Respir Cell Mol Biol Date: 2012-12-13 Impact factor: 6.914
Authors: Jack Wellmerling; Rachael E Rayner; Sheng-Wei Chang; Elizabeth L Kairis; Sun Hee Kim; Amit Sharma; Prosper N Boyaka; Estelle Cormet-Boyaka Journal: FASEB J Date: 2022-05 Impact factor: 5.191
Authors: Sina A Gharib; Daniel Mar; Karol Bomsztyk; Oleg Denisenko; Shireesha Dhanireddy; W Conrad Liles; William A Altemeier Journal: Shock Date: 2016-02 Impact factor: 3.454
Authors: Siang-Boon Koh; Kenneth Ross; Steven J Isakoff; Nsan Melkonjan; Lei He; Karina J Matissek; Andrew Schultz; Erica L Mayer; Tiffany A Traina; Lisa A Carey; Hope S Rugo; Minetta C Liu; Vered Stearns; Adam Langenbucher; Srinivas Vinod Saladi; Sridhar Ramaswamy; Michael S Lawrence; Leif W Ellisen Journal: Clin Cancer Res Date: 2021-06-24 Impact factor: 12.531