Role of Oxidative Stress in the Suppression of Immune Responses in Peripheral Blood Mononuclear Cells Exposed to Combustible Tobacco Product Preparation

Abstract

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.

Effect of the thymine‐DNA glycosylase rs4135050 variant on Saudi smoker population

“…Genes in DNA repair pathways are vital in protecting DNA from multiple types of damage initiated by tobacco's chemical carcinogens (Hoeijmakers, ). Genetic variations, such as SNPs of DNA repair genes, modify DNA repair efficiency by changing protein function and therefore increase the risk for various cancers (de Boer, ; Xi et al, ), such as chronic pulmonary disease and lung malignancy (Arimilli, Schmidt, Damratoski, & Prasad, ; Kheradmand et al, ). Among DNA repair genes, the TDG gene was identified as the first mismatch‐specific enzyme playing a key role in recognizing and correcting a variety of damaged and/or mismatched nucleotides (Cortazar et al, ; Da & Yu, ).…”

Tobacco Smoke Induces and Alters Immune Responses in the Lung Triggering Inflammation, Allergy, Asthma and Other Lung Diseases: A Mechanistic Review

“…Although the number of alveolar macrophages is increased in BAL of smokers, a vast body of evidence suggests that these cells are functionally impaired [ 189 , 190 , 191 , 192 , 193 , 194 ]. Specifically, the ability to release pro-inflammatory cytokines (e.g., Il-1, IL-5, Il-6, IL-8, IL-12, TNF-α, IP-10, MCP-1, MIP-1α, and VEGF) seems to be substantially reduced following CSE and oxidative stress appears to be implied [ 195 , 196 ]. This explains, at least in part, why AMs from smokers elaborate a blunted inflammatory response after LPS stimulation, which results in increased susceptibility to infections [ 193 , 197 , 198 , 199 ].…”

Association of modifiable risk factors and IL-6, CRP, and adiponectin: Findings from the 1993 Birth Cohort, Southern Brazil

“…Most findings in the literature are consistent regarding the association of obesity and higher levels of IL-6 and CRP, corroborating our results. For smoking, several authors have also found an association with inflammatory biomarkers [43, 44], but this has not been as consistent as for obesity [45, 46].…”