Abstract
Hyperactivation of phosphoinositol 3-kinase (PI3K) has been suggested to be a potential mechanism for endoplasmic reticulum (ER) stress-enhanced airway hyperresponsiveness, and PI3K inhibitors have been examined as asthma therapeutics. However, the regulatory mechanism linking PI3K to ER stress and related pathological signals in asthma have not been defined. To elucidate these pathogenic pathways, we investigated the influence of a selective PI3Kδ inhibitor, IC87114, on airway inflammation in an ovalbumin/lipopolysaccharide (OVA/LPS)-induced asthma model. In OVA/LPS-induced asthmatic mice, the activity of PI3K, downstream phosphorylation of AKT and activation of nuclear factor-κB (NF-κB) were all significantly elevated; these effects were reversed by IC87114. IC87114 treatment also reduced the OVA/LPS-induced ER stress response by enhancing the intra-ER oxidative folding status through suppression of protein disulfide isomerase activity, ER-associated reactive oxygen species (ROS) accumulation and NOX4 activity. Furthermore, inositol-requiring enzyme-1α (IRE1α)-dependent degradation (RIDD) of IRE1α was reduced by IC87114, resulting in a decreased release of proinflammatory cytokines from bronchial epithelial cells. These results suggest that PI3Kδ may induce severe airway inflammation and hyperresponsiveness by activating NF-κB signaling through ER-associated ROS and RIDD–RIG-I activation. The PI3Kδ inhibitor IC87114 is a potential therapeutic agent against neutrophil-dominant asthma.
Highlights
Allergic asthma, one of the most common respiratory diseases, is characterized by chronic airway inflammation, reversible airway obstruction, increased mucus production and nonspecific airway hyperresponsiveness.[1]
Inositol-requiring enzyme-1α (IRE1α)-dependent degradation (RIDD) of inositol-requiring enzyme-1α (IRE1α) was reduced by IC87114, resulting in a decreased release of proinflammatory cytokines from bronchial epithelial cells. These results suggest that PI3Kδ may induce severe airway inflammation and hyperresponsiveness by activating nuclear factor-κB (NF-κB) signaling through endoplasmic reticulum (ER)-associated reactive oxygen species (ROS) and RIDD–RIG-I activation
OVA/LPS-treated mice exhibited increased total inflammatory cell counts in Bronchoalveolar lavage fluid (BALF), inflammatory cell infiltration in bronchioles and thickening of the airway epithelium compared with control (SAL) mice sensitized with saline, and these inflammatory responses persisted for up to 3 days after OVA challenge (Figures 1a and b)
Summary
One of the most common respiratory diseases, is characterized by chronic airway inflammation, reversible airway obstruction, increased mucus production and nonspecific airway hyperresponsiveness.[1]. Blockade of PI3δK as a therapeutic strategy against severe asthma was initially accomplished through development of the quinazolinone purine series of inhibitors, as exemplified by 2-[(6-aminopurin-9-yl)methyl]-5-methyl-3-(2-methylphenyl)quinazolin-4one (IC87114; ICOS Corporation, Bothell, WA, USA).[7]
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