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.
Highlights
Cigarette smoking is known to adversely impact innate and adaptive immunity through its pro-inflammatory and immunosuppressive effects on host defense systems [1]
We have recently shown that developing B cells in the bone marrow are affected by cigarette smoking: mice exposed to a mixture of mainstream and sidestream smoke for three weeks showed a significant reduction in the percentage of bone marrow B220+CD432 B cells, but not B220+CD43+ B cells [2]
The duration of smoke exposure was chosen based on our previous study which demonstrated that mice exposed to cigarette smoke for three weeks showed a significant decrease in bone marrow B220+CD432 B cells, but earlier precursor B220+CD43+ B cells and splenic transitional and mature B cells were not significantly affected by smoke exposure [2]
Summary
Cigarette smoking is known to adversely impact innate and adaptive immunity through its pro-inflammatory and immunosuppressive effects on host defense systems [1]. The role of oxidative stress in smoking-induced pathologies has prompted efforts to investigate whether compounds with antioxidant properties can be used therapeutically to counteract the oxidative stress associated with cigarette smoke exposure [5]. We wished to test whether NAC administered during a smoke exposure regimen in mice could counteract the negative effects of smoking on B cell development under these conditions. We sought to determine whether the loss of bone marrow B220+CD432 B cells observed in mice exposed to cigarette smoke could be attributed to a smokinginduced arrest of cell cycle or an increase in apoptosis in this cell population. We 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. 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
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