Effects of Phosphoinositide 3-Kinase on Protease-Induced Acute and Chronic Lung Inflammation, Remodeling, and Emphysema in Rats

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Abstract

Background:

Phosphoinositide 3-kinase (PI3K) plays an important role in tissue inflammatory reactions and fibrotic processes. The objective of this study was to evaluate the potential mechanism and therapeutic effects of PI3K inhibitor on pancreatic elastase (PE)-induced acute and chronic lung inflammation, edema, and injury.

Methods:

Rats were terminated at 7 or 28 days after an intratracheal challenge with PE and intranasal instillation with a PI3K inhibitor, SHBM1009. Alterations of airway epithelial cells and myofibroblasts were studied in vitro.

Measurements:

Lung inflammation, edema, and injury; emphysema; and tissue remodeling were measured after PE instillation with or without treatment with PI3K inhibitor and budesonide. Cellular biologic functions were monitored.

Results:

SHBM1009 could prevent PE-induced acute lung inflammation, edema, and injury, and chronic lung inflammation, remodeling, and emphysema. Different patterns of inhibitory effects of SHBM1009 and BEZ235, a dual PI3K/mechanistic target of rapamycin inhibitor, on PE-challenged epithelial cells were observed. PE per se reduced epithelial cell proliferation and stability through the inhibition of cell division rather than promoting cell death, in dose- and time-dependent patterns. Effects of PI3K inhibitors on cells were associated with the severity of PE challenges.

Conclusions:

PI3K plays a critical role in the development of acute and chronic lung injury, including the process of tissue remodeling and emphysema. PI3K inhibitors could be new therapeutic alternatives for chronic lung diseases.

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