p55PIK deficiency and its NH2-terminal derivative inhibit inflammation and emphysema in COPD mouse model

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-kappa B 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-kappa B 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-kappa B pathway.

Automated summary

Chronic obstructive pulmonary disease (COPD) is a combination of chronic airway inflammation and emphysema. Recent studies have found that Class IA phosphatidylinositol 3-kinases (PI3Ks) play a crucial role in controlling inflammation and emphysema. This study focuses on the regulatory subunit p55PIK of Class IA PI3Ks and its specific NH2-terminal, showing that p55PIK deficiency or TAT-N15 can inhibit cigarette smoke induced inflammation and prevent emphysema. The findings suggest that p55PIK is involved in the pathogenesis of COPD and TAT-N15 could be a potential drug for COPD treatment by inhibiting the Akt and NF-kappa B pathways.