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Phosphoinositide 3-kinase-δ regulates fungus-induced allergic lung inflammation through endoplasmic reticulum stress

Kyung Sun Lee1, Jae Seok Jeong2, So Ri Kim3

  • 1Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju, South Korea.

Thorax
|November 7, 2015
PubMed
Abstract

Insights

Phosphoinositide 3-kinase-delta (PI3K-δ) drives steroid-resistant allergic lung inflammation in response to Aspergillus fumigatus by inducing endoplasmic reticulum (ER) stress. Targeting PI3K-δ or ER stress may offer new therapeutic strategies for severe allergic lung diseases.

Area of Science:

  • Immunology
  • Pulmonology
  • Molecular Biology

Background:

  • Aspergillus fumigatus (Af) sensitization is linked to severe allergic lung inflammation, with unclear mechanisms.
  • Phosphoinositide 3-kinase-delta (PI3K-δ) and endoplasmic reticulum (ER) stress are implicated in steroid-resistant lung inflammation.
  • The study investigates the roles of PI3K-δ and ER stress in fungus-induced allergic lung inflammation.

Purpose of the Study:

  • To elucidate the role of PI3K-δ in regulating ER stress.
  • To determine the contribution of PI3K-δ and ER stress to steroid resistance in allergic lung inflammation induced by Af.
  • To explore the relationship between PI3K-δ, ER stress, and mitochondrial reactive oxygen species (mtROS) in this context.

Main Methods:

  • Utilized Af-exposed in vivo (mice) and in vitro (tracheal epithelial cells) models.
  • Assessed ER stress markers, unfolded protein response (UPR) proteins, phosphorylated Akt, and mtROS generation.
  • Investigated the effects of PI3K-δ inhibitors, ER stress inhibitors, mtROS scavengers, and dexamethasone.
  • Examined ER stress markers in lung tissues from patients with allergic bronchopulmonary aspergillosis (ABPA).

Main Results:

  • Af exposure increased ER stress markers, UPR proteins, mtROS, allergic inflammation, and airway hyperresponsiveness (AHR) in mice.
  • Elevated glucose-regulated protein 78 was observed in ABPA patient lungs.
  • A PI3K-δ inhibitor reduced Af-induced inflammation and ER stress, while dexamethasone did not.
  • ER stress and mtROS inhibition improved allergic inflammation, with PI3K-δ inhibition reducing mtROS and mtROS scavenging ameliorating ER stress.

Conclusions:

  • PI3K-δ plays a critical role in regulating Af-induced, steroid-resistant eosinophilic allergic lung inflammation.
  • ER stress is a key mediator in the pathway linking PI3K-δ to allergic lung inflammation.
  • Targeting PI3K-δ or ER stress pathways presents potential therapeutic avenues for Af-induced allergic lung diseases.
Keywords:
Allergic lung diseaseAspergillus Lung DiseaseAsthma Mechanisms

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