P55PIK deficiency and its NH2-terminal derivative inhibit inflammation and emphysema in COPD mouse model.

Abstract

Chronic obstructive pulmonary disease (COPD) is composed of chronic airway inflammation and emphysema. Recent studies show that Class IA phosphatidylinositol 3-kinases (PI3Ks) play an important role in the regulation of inflammation and emphysema. However, there are few studies on their regulatory subunits. p55PIK is a regulatory subunit of Class IA PI3Ks, and its unique NH2-terminal gives it special functions. p55PIK expression in the lungs of nonsmokers, smokers, and patients with COPD was examined. We established a fusion protein TAT-N15 from the NH2-terminal effector sequence of p55PIK and TAT (the transduction domain of HIV transactivator protein) and investigated the effects of silencing p55PIK or adding TAT-N15 on cigarette smoke exposure at the cellular and animal level. p55PIK expression was increased in patients with COPD. p55PIK deficiency and TAT-N15 significantly inhibited the cigarette smoke extract-induced IL-6, IL-8, and activation of the Akt and the NF-κB pathway in BEAS-2B. p55PIK deficiency and TAT-N15 intranasal administration prevented emphysema and the lung function decline in mice exposed to smoke for 6 mo. p55PIK deficiency and TAT-N15 significantly inhibited lung inflammatory infiltration, reduced levels of IL-6 and KC in mice lung homogenate, and inhibited activation of the Akt and the NF-κB signaling in COPD mice lungs. Our studies indicate that p55PIK is involved in the pathogenesis of COPD, and its NH2-terminal derivative TAT-N15 could be an effective drug in the treatment of COPD by inhibiting the activation of the Akt and the NF-κB pathway.