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Phosphatidylinositol 3-kinase-δ controls endoplasmic reticulum membrane fluidity and permeability in fungus-induced allergic inflammation in mice.

Authors
  • Lee, Hwa-Young1
  • Lee, Geum-Hwa2
  • Kim, Hyung-Ryong3
  • Lee, Yong-Chul4
  • Chae, Han-Jung1
  • 1 Department of Pharmacology and Institute of New Drug Development, Chonbuk National University Medical School, Jeonju, Republic of Korea. , (North Korea)
  • 2 Non-Clinical Evaluation Center, Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk, Republic of Korea. , (North Korea)
  • 3 College of Dentistry, Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, Republic of Korea. , (North Korea)
  • 4 Department of Internal Medicine, Chonbuk National University Medical School, Chonbuk, Republic of Korea. , (North Korea)
Type
Published Article
Journal
British Journal of Pharmacology
Publisher
Wiley (Blackwell Publishing)
Publication Date
Apr 01, 2020
Volume
177
Issue
7
Pages
1556–1567
Identifiers
DOI: 10.1111/bph.14917
PMID: 31713846
Source
Medline
Language
English
License
Unknown

Abstract

Phosphatidylinositol 3-kinase (PI3K), especially PI3K-δ, and endoplasmic reticulum (ER) stress play important roles in refractory asthma induced by the fungus Aspergillus fumigatus through mechanisms that are not well understood. Here we have investigated these mechanisms, using BEAS-2B human bronchial epithelial cells and a mouse model of A. fumigatus-induced allergic lung inflammation. A selective PI3K-δ inhibitor, IC87114, and an ER folding chaperone, 4-phenylbutyric acid (4-PBA), were applied to a model of A. fumigatus-induced asthma in female C57BL/6 mice. The therapeutic potential of IC87114 and 4-PBA was assessed in relevant primary cell, tissue, and disease models, using immunohistochemistry, western blotting and assessment of ER redox state and membrane fluidity. Treatment with IC87114 or 4-PBA alleviated pulmonary inflammation and airway remodelling and reduced ER stress and inflammation-associated intra-ER hyperoxidation, disrupting protein disulfide isomerase (PDI) chaperone activity. IC87114 and 4-PBA also reversed changes in ER membrane fluidity and permeability and the resultant mitochondrial hyperactivation (i.e., Ca2+ accumulation) under hyperoxidation, thereby restoring the physiological state of the ER and mitochondria. These compounds also abolished mitochondria-associated ER membrane (MAM) formation caused by the physical contact between these subcellular organelles. PI3K-δ and ER stress mediate A. fumigatus-induced allergic lung inflammation by altering the ER redox state, PDI chaperone function, and ER membrane fluidity and permeability and by amplifying ER signalling to mitochondria through MAM formation. Thus, therapeutic strategies that target the PI3K-δ-ER stress axis could be an effective treatment for allergic asthma caused by fungi. © 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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