Abstract
Phosphoinositide 3-kinase (PI3K) pathways play a critical role in orchestrating the chronic inflammation and the structural changes of the airways in patients with asthma. Recently, a great deal of progress has been made in developing selective and effective PI3K-targeted therapies on the basis of a vast amount of studies on the roles of specific PI3K isoforms and fine-tuned modulators of PI3Ks in a particular disease context. In particular, the pivotal roles of delta isoform of class I PI3Ks (PI3K-δ) in CD4-positive type 2 helper T cells-dominant disorders such as asthma have been consistently reported since the early investigations. Furthermore, there has been great advancement in our knowledge of the implications of PI3K-δ in various facets of allergic inflammation. This has involved the airway epithelial interface, adaptive T and B cells, potent effector cells (eosinophils and neutrophils), and, more recently, subcellular organelles (endoplasmic reticulum and mitochondria) and cytoplasmic innate immune receptors such as NLRP3 inflammasome, all of which make this PI3K isoform an important druggable target for treating asthma. Defining subpopulations of asthma patients with PI3K-δ activation, namely PI3K-δ-driven asthma endotype, may therefore provide us with a novel framework for the treatment of the disease, particularly for corticosteroid-resistant severe form, an important unresolved aspect of the current asthma management. In this review, we specifically summarize the recent advancement of our knowledge on the critical roles of PI3K-δ in the pathogenesis of bronchial asthma.
Highlights
Bronchial asthma is a representative allergic inflammatory disorder of the airways, wherein a spectrum of respiratory symptoms including cough, wheezing, chest tightness, and shortness of breath present variably over time in association with chronic airway inflammation and airway hyperresponsiveness (AHR)
Phosphoinositide 3-kinase (PI3K)-δ in airway epithelial cells is involved in the pathogenesis of allergic lung disorders through modulating the release of pro-inflammatory mediators such as hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF), all of which have been reported to play a crucial role in mediating vasodilation, increased permeability, and subsequent protein extravasation in allergic airway disease [25,26]
For the respiratory system, the critical roles of PI3K-δ, a dominant isoform in inflammatory cells such as leukocytes, have been consistently reported, given that the lung is equipped with abundant blood vessels and is continuously exposed to external environments
Summary
Bronchial asthma is a representative allergic inflammatory disorder of the airways, wherein a spectrum of respiratory symptoms including cough, wheezing, chest tightness, and shortness of breath present variably over time in association with chronic airway inflammation and airway hyperresponsiveness (AHR). Numerous recent clinical studies across human asthma cohorts in the United States and Europe have consistently demonstrated that the prevalence of atopy/allergy decreases in adult-onset and severe disease They have shown that asthma comprises diverse clinical and molecular phenotypes necessitating more precise and tailored treatment approaches according to causative pathobiologic mechanisms (i.e., endotype), in the severe form of the disease [1]. A pathobiologic mechanism that encompasses diverse physiological and pathological conditions involving various cell types may have the potential to integrate complex and heterogenous inflammation of bronchial asthma into a certain context as a novel endotype This approach enables us to develop more precise and tailored treatment options for individual patients (i.e., precision medicine), for a patient with severe asthma who has not responded well to the current maximal treatments. We summarize the recent advancement of our knowledge on the critical roles of the delta isoform of PI3Ks (PI3K-δ) in the pathogenesis of bronchial asthma, thereby suggesting a novel framework for the treatment of the PI3K-δ-driven asthma endotype
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