title: Cigarette smoke (CS) and nicotine delay neutrophil spontaneous death via suppressing production of diphosphoinositol pentakisphosphate.
abstract: Diphosphoinositol 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.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 30020, China.
authors.forename: Yuanfu
authors.initials: Y
authors.lastname: Xu
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.forename: Besnik
authors.initials: B
authors.lastname: Bajrami
authors.forename: Hyunjeong
authors.initials: H
authors.lastname: Kwak
authors.forename: Shannan
authors.initials: S
authors.lastname: Cao
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Zhou
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhu
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
mesh_terms: D000818:Animals; D016923:Cell Death; D002462:Cell Membrane / Q000378:metabolism; D002469:Cell Separation; D005434:Flow Cytometry; D007295:Inositol Phosphates / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008168:Lung / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009538:Nicotine / Q000494:pharmacology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D012907:Smoking; D013997:Time Factors
chemical_list: D007295:Inositol Phosphates; C079849:1-diphosphoinositol pentakisphosphate; D009538:Nicotine; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt