N-Acetylcysteine Increases the Frequency of Bone Marrow Pro-B/Pre-B Cells, but Does Not Reverse Cigarette Smoking-Induced Loss of This Subset

Abstract

BackgroundWe previously showed that mice exposed to cigarette smoke for three weeks exhibit loss of bone marrow B cells at the Pro-B-to-pre-B cell transition, but the reason for this is unclear. The antioxidant N-acetylcysteine (NAC), a glutathione precursor, has been used as a chemopreventive agent to reduce adverse effects of cigarette smoke exposure on lung function. Here we determined whether smoke exposure impairs B cell development by inducing cell cycle arrest or apoptosis, and whether NAC treatment prevents smoking-induced loss of developing B cells.Methodology/Principal FindingsGroups of normal mice were either exposed to filtered room air or cigarette smoke with or without concomitant NAC treatment for 5 days/week for three weeks. Bone marrow B cell developmental subsets were enumerated, and sorted pro-B (B220+CD43+) and pre-B (B220+CD43−) cell fractions were analyzed for cell cycle status and the percentage of apoptotic cells. We find that, compared to sham controls, smoke-exposed mice have ∼60% fewer pro-B/pre-B cells, regardless of NAC treatment. Interestingly, NAC-treated mice show a 21–38% increase in total bone marrow cellularity and lymphocyte frequency and about a 2-fold increase in the pro-B/pre-B cell subset, compared to sham-treated controls. No significant smoking- or NAC-dependent differences were detected in frequency of apoptotic cells or the percentage cells in the G1, S, or G2 phases of the cycle.Conclusions/SignificanceThe failure of NAC treatment to prevent smoking-induced loss of bone marrow pre-B cells suggests that oxidative stress is not directly responsible for this loss. The unexpected expansion of the pro-B/pre-B cell subset in response to NAC treatment suggests oxidative stress normally contributes to cell loss at this developmental stage, and also reveals a potential side effect of therapeutic administration of NAC to prevent smoking-induced loss of lung function.

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

“…Consistent with the aforementioned findings regarding lower percentages of B cells in blood, cigarette smoke exposure can suppress B-cell differentiation process at a very early stage, as a significant down-regulation of pre-B and pro-B cells was identified in murine bone marrow [ 295 , 296 ].…”

Impacts of cigarette smoking on immune responsiveness: Up and down or upside down?

“…They developed from bone marrow-derived hematopoietic stem cells that first differentiated into precursor and progenitor B cells and then immature B cells [ 82 ]. It was found that tobacco smoke exposure led to obvious downregulation of murine marrow B220 + CD34 − pre-B cells and/or B220 + CD34 + pro-B cells without significant changes in cell apoptosis and cell cycle [ 83 , 84 ].…”

Serum and Salivary Immunoglobulins levels in Tobacco Smokers of Baghdad Governorate

“…Alteration in the immunological functions for both antibody and cell mediated immunity might be due to the inhalation of tobacco smoke (12,13) .Several previous studies in other countries authorized that serum levels of Igs were lower in smokers by 10-20% as compared with non-smokers individuals (14) .Depending on the results of the current study, non-significant increase in terms of serum IgM was found in smokers which came in agreement with the results of Arinola et al (15) and Gonzalez-Quintela et al (16) who stated that this increased may be attributable to the ability of IgM in neutralizing the harmful toxins found in tobacco smoke by complement activation, conversely, Tarbiah et al (13) reported a significant increased while Olayanju et al (17) reported a significant decreased in the serum IgM in smokers as compared with non-smokers. In addition results of this research showed that both serum IgG and IgA levels were decreased significantly in smokers which were similar to the findings of Tarbiah et al (13) in terms of IgG and Aula and Fikry (18) in terms of IgA level, however, IgG and IgA levels were found to be higher in smokers according to Prajapati and Jyoti study (19) .Various investigations have concentrated on the possible mechanisms by which tobacco smoke might alter B-cells (which responsible for the production of Igs after their differentiation into plasma cells) development, functioning and distribution, it was found that tobacco smoke might cause down regulation of murine marrow B220+CD34-pre-B cells and/or B220+CD34+ pro-B cells which they effect on B-cells development (20) . In addition several molecular studies have stated that nicotinic receptors such as α 4 and α7 subunits which have essential roles in B-cells lines show elevated expression after long term exposure to nicotine which suppress B-cells secretions (21) .Furthermore, it was found that proliferative ability of T-cells and T-cells dependent antibody responses were decreased in smokers which subsequently suppress B-cells functions and causes reduction in the production of serum Igs (22) .Moreover low number and impaired functions of regulatory B-cells in smokers infected by Helicobacter pylori had been improved by Li et al (23) .It was found that after smoking cessation the levels of serum IgM and IgG were increased significantly, however the level of IgA remained the same (24) .Despite the fact that blood considered as an essential sample for disease diagnosis; saliva reveals the mucosal and systemic expression of many biomarkers in the human body, salivary IgA initiate from the plasma cells found in salivary glands, while salivary IgM and IgG are mainly originate from the serum (25) .Regarding the results of the present study, salivary IgM revealed non-significant increase in smokers which analogs with the results of Barton et al …”