BackgroundThe role of bronchiolar epithelial cells in the pathogenesis of pulmonary fibrosis has not been clarified. We previously demonstrated DNA damage in murine bronchioles in the early stages of bleomycin-induced pulmonary fibrosis that subsequently extended to alveolar cells at the advanced stages of the disease. Club cells are progenitor cells for bronchioles and are known to play protective roles against lung inflammation and damage. The aim of the present study was to elucidate the role of club cells in the development of pulmonary fibrosis.MethodsC57BL/6 J mice received naphthalene intraperitoneally on day −2 to deplete club cells and were given intratracheal bleomycin or a vehicle on day 0. Lung tissues were obtained on days 1, 7, and 14, and bronchoalveolar lavage was performed on day 14. Bronchiolar epithelial cells sampled by laser capture microdissection were analyzed by gene expression microarray analysis on day 14.ResultsClub cell depletion induced by naphthalene protected mice from bleomycin-induced lung injury and fibrosis. Bleomycin-triggered bronchiolar TGF-β1 expression was reduced. Gene expression microarray analysis revealed that genes associated with inflammatory response and chemokine activity were downregulated in the bleomycin-injured bronchiolar epithelium with club cell injury compared to that in bronchiolar epithelium without cell injury.ConclusionsClub cells are involved in the development of lung injury and fibrosis.
Gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is an effective therapeutic agent for non-small cell lung cancer with EGFR mutations. It can cause severe acute pneumonitis in some patients. We previously demonstrated that mice with naphthalene-induced airway epithelial injury developed severe gefitinib-induced pneumonitis and that neutrophils played important roles in the development of the disease. This study aimed to investigate the effects of the neutrophil elastase inhibitor sivelestat on gefitinib-induced pneumonitis in mice. C57BL/6J mice received naphthalene (200 mg/kg) intraperitoneally on day 0. Gefitinib (250 or 300 mg/kg) was orally administered to mice from day -1 until day 13. Sivelestat (150 mg/kg) was administered intraperitoneally from day 1 until day 13. Bronchoalveolar lavage fluid (BALF) and lung tissues were sampled on day 14. Sivelestat treatment significantly reduced the protein level, neutrophil count, neutrophil elastase activity in BALF, and severity of histopathologic findings on day 14 for mice administered with 250 mg/kg of gefitinib. Moreover, sivelestat treatment significantly improved the survival of mice administered with 300 mg/kg of gefitinib. These results indicate that sivelestat is a promising therapeutic agent for severe acute pneumonitis caused by gefitinib.
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