Departments of Physiology, Section of Pulmonary/Critical Care Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
Crit Care Med. 2011 Sep;39(9):2121-30. doi: 10.1097/CCM.0b013e31821e89dc.
Granulocytopenia frequently occurs in alcohol abusers with severe bacterial infection, which strongly correlates with poor clinical outcome. Knowledge of the molecular mechanisms underlying the granulopoietic response to bacterial infection remains limited. This study investigated the involvement of stem cell antigen-1 expression by granulocyte lineage-committed progenitors in the granulopoietic response to septicemia and how alcohol affected this response.
: Laboratory investigation.
University laboratory.
Male Balb/c mice.
Thirty mins after intraperitoneal injection of alcohol (20% ethanol in saline at 5 g of ethanol/kg) or saline, mice received an intravenous Escherichia coli challenge.
E. coli septicemia activated stem cell antigen-1 expression by marrow immature granulocyte differentiation antigen-1 precursors which correlated with an increase in proliferation, granulocyte macrophage colony-forming unit production, and expansion of this granulopoietic precursor cell pool. Acute alcohol treatment suppressed stem cell antigen-1 activation and inhibited the infection-induced increases in proliferation, granulocyte macrophage colony-forming unit production, and expansion the of immature granulocyte differentiation antigen-1 precursor cell population. Consequently, recovery of the marrow mature granulocyte differentiation antigen-1 cell population after E. coli challenge was impaired. Stem cell antigen-1 was induced in sorted granulocyte differentiation antigen-1, stem cell antigen-1' cells by lipopolysaccharide-stimulated C-Jun kinase activation that was also inhibited by alcohol. Furthermore, stem cell antigen-1 knockout mice failed to expand the marrow immature granulocyte differentiation antigen-1 cell pool and demonstrated fewer newly produced granulocytes in the circulation after the E. coli challenge.
Alcohol suppresses the stem cell antigen-1 response in granulocyte lineage-committed precursors and restricts granulocyte production during septicemia, which may serve as a novel mechanism underlying impaired host defense in alcohol abusers.
酗酒者发生严重细菌感染时常会出现粒细胞减少，这与不良临床结局密切相关。人们对细菌感染诱导粒细胞生成的分子机制知之甚少。本研究旨在探讨粒细胞系定向祖细胞中干细胞抗原-1表达在败血症粒细胞生成反应中的作用，以及酒精对这种反应的影响。
实验室研究。
大学实验室。
雄性 Balb/c 小鼠。
酒精（生理盐水 20%乙醇，5 g/kg 乙醇）或生理盐水腹腔注射 30 分钟后，小鼠接受静脉内大肠杆菌挑战。
大肠杆菌败血症激活骨髓不成熟粒细胞分化抗原-1前体细胞中的干细胞抗原-1表达，与增殖、粒细胞巨噬细胞集落形成单位生成和该粒细胞生成前体细胞库的扩增相关。急性酒精处理抑制干细胞抗原-1的激活，并抑制感染诱导的增殖、粒细胞巨噬细胞集落形成单位生成和不成熟粒细胞分化抗原-1前体细胞群的扩增。因此，大肠杆菌挑战后骨髓成熟粒细胞分化抗原-1细胞群的恢复受到损害。干细胞抗原-1在经脂多糖刺激的 C-Jun 激酶激活诱导的分选的粒细胞分化抗原-1、干细胞抗原-1'细胞中被诱导，该激活也被酒精抑制。此外，干细胞抗原-1 敲除小鼠未能扩增骨髓不成熟粒细胞分化抗原-1细胞池，并且在大肠杆菌挑战后循环中产生的新粒细胞较少。
酒精抑制粒细胞系定向祖细胞中的干细胞抗原-1反应，并限制败血症期间粒细胞的生成，这可能是酗酒者宿主防御受损的新机制。
