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.

Neutrophils and emerging targets for treatment in chronic obstructive pulmonary disease

“…Especially NE and MMP-9 are targeted, together with neutrophil infiltration. For example, inhibiting PI3Kd decreases neutrophil infiltration in murine models of acute lung damage, and might therefore also be a target for the treatment of COPD [128]. However, it seems that neutrophil signaling pathways are altered in COPD, which makes research much more difficult and has led to many of such promising targets yielding no results.…”

Advanced Role of Neutrophils in Common Respiratory Diseases

“…PI3K γ deficiency could significantly reduce the influx of neutrophils into BALF [52]. PI3K δ inhibition may also prevent recruitment of neutrophils [53]. The PI3K-related inflammation and steroid insensitivity should partly be attributed to microRNA-21/PI3K/histone deacetylase 2 (HDAC2) axis as Kim et al reported [54].…”

Therapeutic Potential of Medicinal Plants and Their Constituents on Lung Inflammatory Disorders

“…Although TG100-115, PI3Kγ and -δ inhibitor, was proven to be effective in the mouse smoke-induced lung inflammation model (Doukas et al ., 2009), the clinical development has been discontinued at present. Recent study suggested that targeting PI3Kδ was beneficial for the treatment of respiratory diseases (Sriskantharajah et al ., 2013). GSK2269557, an inhaled PI3Kδ inhibitor, is currently undergoing clinical trial for COPD.…”