Abstract
Several reports link cigarette smoking with leukemia. However, the effects of cigarette smoke extract (CSE) on bone marrow hematopoiesis remain unknown. The objective of this study was to elucidate the direct effects of cigarette smoke on human bone marrow hematopoiesis and characterize the inflammatory process known to result from cigarette smoking. Bone marrow mononuclear cells (BMCs) from healthy individuals when exposed to CSE had significantly diminished CFU-E, BFU-E and CFU-GM. We found increased nuclear translocation of the NF-κB p65 subunit and, independently, enhanced activation of AKT and ERK1/2. Exposure of BMCs to CSE induced IL-8 and TGF-β1 production, which was dependent on NF-κB and ERK1/2, but not on AKT. CSE treatment had no effect on the release of TNF-α, IL-10, or VEGF. Finally, CSE also had a significant induction of TLR2, TLR3 and TLR4, out of which, the up-regulation of TLR2 and TLR3 was found to be dependent on ERK1/2 and NF-κB activation, but not AKT. These results indicate that CSE profoundly inhibits the growth of erythroid and granulocyte-macrophage progenitors in the bone marrow. Further, CSE modulates NF-κB- and ERK1/2-dependent responses, suggesting that cigarette smoking may impair bone marrow hematopoiesis in vivo as well as induce inflammation, two processes that proceed malignant transformation.
Highlights
Cigarette smoking is a substantial contributor to the pathogenesis of many diseases, including cancer, predisposition to infections as well as a contributing factor to the failure of therapeutic modalities, such as HSCT transplants [1,2,3,4,5]
We examined the effects of cigarette smoke extract (CSE) on normal human granulocyte-macrophage (CFU-GM) and erythroid (CFU-E, BFU-E) cells
We discovered that the capacity of human Bone marrow mononuclear cells (BMCs) to form BFU-E, CFU-E, and CFUGM is impaired after treatment with CSE, indicating an in vitro ability to inhibit hematopoiesis
Summary
Cigarette smoking is a substantial contributor to the pathogenesis of many diseases, including cancer, predisposition to infections as well as a contributing factor to the failure of therapeutic modalities, such as HSCT transplants [1,2,3,4,5]. Recent studies have demonstrated the ability of bone marrowderived stem cells to respond to induced epithelial repair and are linked with cigarette smoke-induced lung cancer [9]. Apart from these observations, the mechanisms by which smoking impairs the hematopoietic system are not well understood. While some of the mechanisms by which cigarette smoke and CSE causes functional impairment have been studied in PBMC and non-immune cells, the direct behavior of such pathways in primary bone marrow cells remain poorly understood [11]
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