Increased Levels of ER Stress and Apoptosis in A Sheep Model for Pulmonary Fibrosis Are Alleviated by in Vivo Blockade of the KCa3.1 Ion Channel
| Autor: | Udari Eshani Perera, Kenneth J. Snibson, Habtamu B Derseh, Louise Organ, Andrew Stent, Sasika N. Vithana Dewage |
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| Rok vydání: | 2020 |
| Předmět: |
Pulmonary and Respiratory Medicine
Article Subject Bleomycin Diseases of the respiratory system 03 medical and health sciences Idiopathic pulmonary fibrosis chemistry.chemical_compound 0302 clinical medicine Pulmonary fibrosis Medicine 030304 developmental biology 0303 health sciences Lung TUNEL assay RC705-779 business.industry Interstitial lung disease respiratory system medicine.disease respiratory tract diseases medicine.anatomical_structure chemistry Apoptosis Unfolded protein response Cancer research business 030217 neurology & neurosurgery |
| Zdroj: | Canadian Respiratory Journal, Vol 2021 (2021) |
| DOI: | 10.21203/rs.3.rs-97842/v1 |
| Popis: | Background Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease, characterized by progressive damage to the lung tissues. Apoptosis and endoplasmic reticulum stress (ER stress) in type II alveolar epithelial cells (AECs) and lung macrophages has been linked with the development of IPF. Therefore, apoptosis- and ER stress-targeted therapies have drawn attention as potential avenues for treatment of IPF. The calcium-activated potassium ion channel KCa3.1 has been proposed as a potential therapeutic target for fibrotic diseases including IPF. While KCa3.1 is expressed in AECs and macrophages, its influence on ER stress and apoptosis during the disease process is unclear. Methods We utilized a novel sheep model of pulmonary fibrosis to demonstrate that apoptosis and ER stress occurs in type II AECs and macrophages in sheep with bleomycin-induced lung fibrosis. Apoptosis in type II AEC and macrophages was identified using the TUNEL method of tagging fragmented nuclear DNA, while ER stress was characterized by increased expression of GRP-78 ER chaperone proteins. Results We demonstrated that apoptosis and ER stress in type II AECs and macrophages increased significantly 2 weeks after the final bleomycin infusion and remained high for up to 7 weeks post-bleomycin injury. Senicapoc treatment significantly reduced the rates of ER stress in type II AECs and macrophages that were resident in bleomycin-infused lung segments. There were also significant reductions in the rates of apoptosis of type II AECs and macrophages in the lung segments of senicapoc-treated sheep. Conclusion In-vivo blockade of the KCa3.1 ion channel alleviates the ER stress and apoptosis in type II AECs and macrophages, and this effect potentially contributes to the antifibrotic effects of senicapoc. |
| Databáze: | OpenAIRE |
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