Department of Microbiology & Immunology, Wake Forest University Health Sciences, Room 2N-052, 575 Patterson Avenue, Winston-Salem, NC, 27101, USA.
RAI Services Company, Winston-Salem, NC, USA.
Inflammation. 2017 Oct;40(5):1622-1630. doi: 10.1007/s10753-017-0602-9.
Cigarette smoking is a major risk factor for several human diseases. Chronic inflammation, resulting from increased oxidative stress, has been suggested as a mechanism that contributes to the increased susceptibility of smokers to cancer and microbial infections. We have previously shown that whole-smoke conditioned medium (WS-CM) and total particulate matter (TPM) prepared from Kentucky 3R4F reference cigarettes [collectively called as combustible tobacco product preparations (TPPs)] potently suppressed agonist-stimulated cytokine secretion and target cell killing in peripheral blood mononuclear cells (PBMCs). Here we have investigated the role of oxidative stress from TPPs, which alters inflammatory responses in vitro. Particularly, we investigated the mechanisms of WS-CM-induced suppression of select cytokine secretions in Toll-like receptor (TLR) agonist-stimulated cells and target cell killing by effector cells in PBMCs. Pretreatment with N-acetyl cysteine (NAC), a precursor of reduced glutathione and an established anti-oxidant, protected against DNA damage and cytotoxicity caused by exposure to WS-CM. Similarly, secretion of tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8 in response to TLR-4 stimulation was restored by pretreatment with NAC. Target cell killing, a functional measure of cytolytic cells in PBMCs, is suppressed by WS-CM. Pretreatment with NAC restored the target cell killing in WS-CM treated PBMCs. This was accompanied by higher perforin levels in the effector cell populations. Collectively, these data suggest that reducing oxidative stress caused by cigarette smoke components restores select immune responses in this ex vivo model.
吸烟是多种人类疾病的主要危险因素。氧化应激增加导致的慢性炎症，被认为是增加吸烟者易患癌症和微生物感染的机制之一。我们之前已经表明，来自肯塔基 3R4F 参考香烟的全烟条件培养基（WS-CM）和总颗粒物（TPM）[统称为可燃烟草制品制剂（TPP）]可强烈抑制外周血单个核细胞（PBMC）中激动剂刺激的细胞因子分泌和靶细胞杀伤。在这里，我们研究了 TPP 引起的氧化应激在体外改变炎症反应的作用。特别是，我们研究了 WS-CM 诱导的 TLR 激动剂刺激细胞中选择细胞因子分泌和 PBMC 中效应细胞对靶细胞杀伤的抑制作用的机制。用 N-乙酰半胱氨酸（NAC）预处理，NAC 是还原型谷胱甘肽的前体和一种已建立的抗氧化剂，可以防止 WS-CM 暴露引起的 DNA 损伤和细胞毒性。类似地，用 NAC 预处理可以恢复 TLR-4 刺激引起的肿瘤坏死因子（TNF）、白细胞介素（IL）-6 和 IL-8 的分泌。WS-CM 抑制 PBMC 中靶细胞的杀伤，这是一种细胞毒性细胞的功能测量。用 NAC 预处理可以恢复 WS-CM 处理的 PBMC 中的靶细胞杀伤。这伴随着效应细胞群中穿孔素水平的升高。总的来说，这些数据表明，减少香烟烟雾成分引起的氧化应激可以恢复该体外模型中的某些免疫反应。
