title: Targeting phosphoinositide 3-kinase δ for the treatment of respiratory diseases.
abstract: Asthma and chronic obstructive pulmonary disease (COPD) are characterized in their pathogenesis by chronic inflammation in the airways. Phosphoinositide 3-kinase δ (PI3Kδ), a lipid kinase expressed predominantly in leukocytes, is thought to hold much promise as a therapeutic target for such inflammatory conditions. Of particular interest for the treatment of severe respiratory disease is the observation that inhibition of PI3Kδ may restore steroid effectiveness under conditions of oxidative stress. PI3Kδ inhibition may also prevent recruitment of inflammatory cells, including T lymphocytes and neutrophils, as well as the release of proinflammatory mediators, such as cytokines, chemokines, reactive oxygen species, and proteolytic enzymes. In addition, targeting the PI3Kδ pathway could reduce the incidence of pathogen-induced exacerbations by improving macrophage-mediated bacterial clearance. In this review, we discuss the potential and highlight the unknowns of targeting PI3Kδ for the treatment of respiratory disease, focusing on recent developments in the role of the PI3Kδ pathway in inflammatory cell types believed to be critical to the pathogenesis of COPD.
authors.affiliation: Refractory Respiratory Inflammation Discovery Performance Unit, Respiratory Therapy Area, GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom.
authors.forename: Srividya
authors.initials: S
authors.lastname: Sriskantharajah
authors.forename: Nicole
authors.initials: N
authors.lastname: Hamblin
authors.forename: Sally
authors.initials: S
authors.lastname: Worsley
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Calver
authors.forename: Edith M
authors.initials: EM
authors.lastname: Hessel
authors.forename: Augustin
authors.initials: A
authors.lastname: Amour
mesh_terms: D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009504:Neutrophils / Q000378:metabolism; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000201:enzymology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species