title: Phosphoinositide 3-kinase-δ regulates fungus-induced allergic lung inflammation through endoplasmic reticulum stress.
abstract: BACKGROUND
  Sensitisation with Aspergillus fumigatus (Af) is known to be associated with severe allergic lung inflammation, but the mechanism remains to be clarified. Phosphoinositide 3-kinase (PI3K)-δ and endoplasmic reticulum (ER) stress are suggested to be involved in steroid-resistant lung inflammation. We aimed to elucidate the role of PI3K-δ and its relationship with ER stress in fungus-induced allergic lung inflammation.
  
  
  METHODS
  Using Af-exposed in vivo and in vitro experimental systems, we examined whether PI3K-δ regulates ER stress, thereby contributing to steroid resistance in fungus-induced allergic lung inflammation. Moreover, we checked expression of an ER stress marker in lung tissues isolated from patients with allergic bronchopulmonary aspergillosis.
  
  
  RESULTS
  Af-exposed mice showed that ER stress markers, unfolded protein response (UPR)-related proteins, phosphorylated Akt, generation of mitochondrial reactive oxygen species (mtROS), eosinophilic allergic inflammation, and airway hyperresponsiveness (AHR) were increased in the lung. Similarly, glucose-regulated protein 78 was increased in lung tissues of patients with ABPA. A PI3K-δ inhibitor reduced Af-induced increases in ER stress markers, UPR-related proteins, allergic inflammation and AHR in mice. However, dexamethasone failed to reduce Af-induced allergic inflammation, AHR and elevation of ER stress. Administration of an ER stress inhibitor or a mtROS scavenger improved Af-induced allergic inflammation. The PI3K-δ inhibitor reduced Af-induced mtROS generation and the mtROS scavenger ameliorated ER stress. In primary cultured tracheal epithelial cells, Af-induced ER stress was inhibited by blockade of PI3K-δ.
  
  
  CONCLUSIONS
  These findings suggest that PI3K-δ regulates Af-induced steroid-resistant eosinophilic allergic lung inflammation through ER stress.
authors.affiliation: Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea.
authors.forename: Kyung Sun
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Department of Immunology, Chonbuk National University Medical School, Jeonju, South Korea.
authors.forename: Jae Seok
authors.initials: JS
authors.lastname: Jeong
authors.affiliation: Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, South Korea.
authors.forename: So Ri
authors.initials: SR
authors.lastname: Kim
authors.affiliation: Division of Allergy and Immunology, Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
authors.forename: Seong Ho
authors.initials: SH
authors.lastname: Cho
authors.affiliation: Division of Allergy and Immunology, Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
authors.forename: Narasaiah
authors.initials: N
authors.lastname: Kolliputi
authors.affiliation: Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, South Korea.
authors.forename: Yun Hee
authors.initials: YH
authors.lastname: Ko
authors.affiliation: Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, South Korea.
authors.forename: Kyung Bae
authors.initials: KB
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, South Korea.
authors.forename: Suk Chul
authors.initials: SC
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, South Korea.
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, South Korea.
authors.forename: Yong Chul
authors.initials: YC
authors.lastname: Lee
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000201:enzymology* / Q000209:etiology*; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D018893:Bronchoalveolar Lavage; D022762:CCAAT-Enhancer-Binding Proteins / Q000032:analysis; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D005978:Glutathione / Q000032:analysis; D019803:Glutathione Disulfide / Q000032:analysis; D007073:Immunoglobulin E / Q000097:blood; D007249:Inflammation / Q000201:enzymology / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000032:analysis
chemical_list: D015415:Biomarkers; D022762:CCAAT-Enhancer-Binding Proteins; C477872:IC 87114; D011799:Quinazolines; D034741:RNA, Small Interfering; D007073:Immunoglobulin E; D019869:Phosphatidylinositol 3-Kinases; D005978:Glutathione; D000225:Adenine; D019803:Glutathione Disulfide
keywords: Allergic lung disease; Aspergillus Lung Disease; Asthma Mechanisms