Cigarette Smoke (CS) and Nicotine Delay Neutrophil Spontaneous Death via Suppressing Production of Diphosphoinositol Pentakisphosphate
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CitationXu, Yuanfu, Hongmei Li, Besnik Bajrami, Hyunjeong Kwak, Shannan Cao, Peng Liu, Jiaxi Zhou, et al. 2013. “Cigarette Smoke (CS) and Nicotine Delay Neutrophil Spontaneous Death via Suppressing Production of Diphosphoinositol Pentakisphosphate.” Proceedings of the National Academy of Sciences 110 (19) (April 22): 7726–7731. doi:10.1073/pnas.1302906110. http://dx.doi.org/10.1073/pnas.1302906110.
AbstractDiphosphoinositol pentakisphosphate (InsP7), a higher inositol phosphate containing energetic pyrophosphate bonds, is beginning to emerge as a key cellular signaling molecule. However, the various physiological and pathological processes that involve InsP7 are not completely understood. Here we report that cigarette smoke (CS) extract and nicotine reduce InsP7 levels in aging neutrophils. This subsequently leads to suppression of Akt deactivation, a causal mediator of neutrophil spontaneous death, and delayed neutrophil death. The effect of CS extract and nicotine on neutrophil death can be suppressed by either directly inhibiting the PtdIns(3,4,5)P3/Akt pathway, or increasing InsP7 levels via overexpression of InsP6K1, an inositol hexakisphosphate (InsP6) kinase responsible for InsP7 production in neutrophils. Delayed neutrophil death contributes to the pathogenesis of CS-induced chronic obstructive pulmonary disease. Therefore, disruption of InsP6K1 augments CS-induced neutrophil accumulation and lung damage. Taken together, these results suggest that CS and nicotine delay neutrophil spontaneous death by suppressing InsP7 production and consequently blocking Akt deactivation in aging neutrophils. Modifying neutrophil death via this pathway provides a strategy and therapeutic target for the treatment of tobacco-induced chronic obstructive pulmonary disease.
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