RT Journal Article
SR Electronic
T1 Phosphoinositide 3-kinase-δ regulates fungus-induced allergic lung inflammation through endoplasmic reticulum stress
JF Thorax
JO Thorax
FD BMJ Publishing Group Ltd and British Thoracic Society
SP 52
OP 63
DO 10.1136/thoraxjnl-2015-207096
VO 71
IS 1
A1 Kyung Sun Lee
A1 Jae Seok Jeong
A1 So Ri Kim
A1 Seong Ho Cho
A1 Narasaiah Kolliputi
A1 Yun Hee Ko
A1 Kyung Bae Lee
A1 Suk Chul Park
A1 Hae Jin Park
A1 Yong Chul Lee
YR 2016
UL http://thorax.bmj.com/content/71/1/52.abstract
AB 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.