Progression of the PI3K/Akt signaling pathway in chronic obstructive pulmonary disease

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is a chronic respiratory disease characterized by a slow progression and caused by the inhalation of harmful particulate matter. Cigarette smoke and air pollutants are the primary contributing factors. Currently, the pathogenesis of COPD remains incompletely understood. The PI3K/Akt signaling pathway has recently emerged as a critical regulator of inflammation and oxidative stress response in COPD, playing a pivotal role in the disease's progression and treatment. This paper reviews the association between the PI3K/Akt pathway and COPD, examines effective PI3K/Akt inhibitors and novel anti-COPD agents, aiming to identify new therapeutic targets for clinical intervention in this disease.

Keywords: PI3K/Akt signalling pathway; chronic obstructive pulmonary disease; inflammation; inhibitor; oxidative stress.

FIGURE 1

Transduction and regulatory pathways of PI3K/Akt pathway. Activation of growth factor receptor tyrosine kinase (RTK) and G-protein-coupled receptors (GPCRs) led to the activation of the PI3K catalytic subunit. Activated PI3K promotes the conversion of PIP2 to PIP3 in the medial membrane, a function that can be reversed by phosphatase and tensin homologues (PTEN). PIP3 activates Akt signaling by specifically binding to the pleckstrin homlogy (PH) domain of both PDK-1 and Akt proteins. Protein phosphatase 2 (PP2A) and the PH domain are rich in leucine repeats of the protein phosphatase (PHLPP1/2), negatively regulating the PI3K/Akt pathway.

FIGURE 2

Role of PI3K /Akt in COPD regulation. The activation of PI3K/Akt is involved in COPD formation and can exacerbate COPD progression through inflammatory and oxidative stress. Specifically, activated PI3K/Akt promotes the release of ROS, as well as promotes the secretion of multiple pro-inflammatory cytokines by alveolar macrophages, neutrophils, T-lymphocytes, and epithelial cells to participate in COPD pathogenesis. Moreover, small molecule inhibitors targeting the PI3K/Akt signaling pathway can treat COPD through inhibiting oxidative stress and inflammation.