Acute and chronic alcohol exposure impair the phagocytosis of apoptotic cells and enhance the pulmonary inflammatory response.
Acute and chronic alcohol exposure impair the phagocytosis of apoptotic cells and enhance the pulmonary inflammatory response.
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DOI：
10.1111/j.1530-0277.2010.01259.x
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发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Vandivier RW
中科院分区：
文献类型：
--
作者：
Boé DM;Richens TR;Horstmann SA;Burnham EL;Janssen WJ;Henson PM;Moss M;Vandivier RW
酒精滥用会增加急性呼吸窘迫综合征（ARDS）的风险。胞饮作用（清除凋亡细胞）在炎症消退中非常重要，并受到RhoA和rho激酶（ROCK）激活的调节。尚未确定酒精对肺Rho通路激活和红细胞增多的影响。我们假设急性和慢性酒精暴露损害肺红细胞增多症，导致ARDS时炎症反应加剧。在体内实验中，C57 BL/6小鼠接受单次腹膜内注射酒精或慢性乙醇水溶液8周，然后向腹膜内滴注凋亡细胞或脂多糖（LPS）。进行支气管肺泡灌洗（BAL）以进行细胞计数、计算吞噬指数（PI）和Rho活性测量。对于体外研究，将原代肺泡巨噬细胞在酒精（25 - 100mM）中培养，然后与凋亡细胞共培养。在酒精暴露后测定RhoA活性，并在用ROCK抑制剂Y27632处理之前和之后测定PI。急性酒精暴露与红细胞增多症受损有关。LPS暴露后，急性酒精暴露也与BAL中性粒细胞增加相关。慢性酒精暴露单独不改变红细胞增多症。然而，暴露于LPS后，慢性酒精暴露与受损的红细胞增多和BAL中性粒细胞增加有关。在体外酒精暴露引起剂量依赖性减少红细胞增多症。尽管事实上，RhoA活性降低酒精暴露和RhoA抑制并没有改变酒精对红细胞增多症的影响，治疗与Rho激酶抑制剂，Y27632，逆转酒精对红细胞增多症的影响。急性酒精暴露损害肺红细胞增多症，而慢性酒精暴露仅与LPS诱导的肺损伤后红细胞增多症受损相关。两种形式的酒精暴露都与肺泡中性粒细胞数量增加有关。酒精对红细胞增多症的急性影响似乎是由ROCK的RhoA非依赖性激活介导的，至少部分是这样。需要进一步的研究来剖析急性和慢性酒精暴露对红细胞增多症的影响之间的差异，并确定酒精对ROCK替代激活剂的影响。
Alcohol abuse increases the risk for acute respiratory distress syndrome (ARDS). Efferocytosis, the clearance of apoptotic cells, is important in the resolution of inflammation and is regulated by RhoA and rho kinase (ROCK) activation. The effects of alcohol on pulmonary Rho pathway activation and efferocytosis have not been determined. We hypothesize that acute and chronic alcohol exposure impair pulmonary efferocytosis, leading to heightened inflammation during ARDS. For in vivo experiments, C57BL/6 mice received either a single, intraperitoneal injection of alcohol or chronic ethanol-in-water for 8 weeks prior to intratracheal instillation of apoptotic cells or lipopolysaccharide (LPS). Bronchoalveolar lavage (BAL) was performed for cells counts, calculation of the phagocytic index (PI), and Rho activity measurements. For in vitro studies, primary alveolar macrophages were cultured in alcohol (25-100mM) and then co-cultured with apoptotic cells. RhoA activity was determined following alcohol exposure, and the PI was determined before and after treatment with the ROCK inhibitor, Y27632. Acute alcohol exposure was associated with impaired efferocytosis. Following LPS exposure, acute alcohol exposure was also associated with increased BAL neutrophils. Chronic alcohol exposure alone did not alter efferocytosis. However, following exposure to LPS, chronic alcohol exposure was associated with both impaired efferocytosis and increased BAL neutrophils. In vitro alcohol exposure caused a dose-dependent decrease in efferocytosis. Despite the fact that RhoA activity was decreased by alcohol exposure and RhoA inhibition did not alter the effects of alcohol on efferocytosis, treatment with the Rho kinase inhibitor, Y27632, reversed the effects of alcohol on efferocytosis. Acute alcohol exposure impairs pulmonary efferocytosis, while exposure to chronic alcohol is only associated with impaired efferocytosis following LPS-induced lung injury. Both forms of alcohol exposure are associated with increased alveolar neutrophil numbers in response to LPS. The acute effects of alcohol on efferocytosis appear to be mediated, at least in part, by RhoA-independent activation of ROCK. Further studies are needed to dissect the differences between the effects of acute and chronic alcohol exposure on efferocytosis and to determine the effects of alcohol on alternative activators of ROCK.
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影响因子：
4
作者：
Miñambres, R;Guasch, RM;Guerri, C
通讯作者：
Guerri, C
影响因子：
4.4
作者：
Morimoto, Konosuke;Janssen, William J.;Vandivier, R. William
通讯作者：
Vandivier, R. William
影响因子：
4.4
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM
影响因子：
2.3
作者：
Li, X;Grossman, CJ;Gartside, P
通讯作者：
Gartside, P
影响因子：
3.7
作者：
Lee, S;Rivier, C
通讯作者：
Rivier, C