Baclofen, a GABABR agonist, ameliorates immune-complex mediated acute lung injury by modulating pro-inflammatory mediators.
Baclofen, a GABABR agonist, ameliorates immune-complex mediated acute lung injury by modulating pro-inflammatory mediators.
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DOI：
10.1371/journal.pone.0121637
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Rane MJ
中科院分区：
文献类型：
--
作者：
Jin S;Merchant ML;Ritzenthaler JD;McLeish KR;Lederer ED;Torres-Gonzalez E;Fraig M;Barati MT;Lentsch AB;Roman J;Klein JB;Rane MJ
免疫复合物在肺部炎症性疾病中起重要作用。中性粒细胞活化介导免疫复合物（IC）沉积诱导的急性肺损伤（ALI）。γ氨基丁酸（GABA）信号传导的组分，包括GABA B受体2（GABABR 2）、GAD 65/67和GABA转运蛋白，存在于肺和中性粒细胞中。然而，肺GABABR激活在嗜中性粒细胞介导的ALI中的作用尚未确定。因此，本研究的目的是确定给予GABABR激动剂巴氯芬是否会改善或加重ALI。我们假设巴氯芬通过保护肺GABABR表达来调节IC诱导的ALI。对大鼠进行假损伤或IC诱导的ALI，两小时后，用盐水或lmg/kg巴氯芬对大鼠进行再2小时的气管内处理并处死。通过血管渗漏、组织学、TUNEL和肺caspase-3裂解来评估ALI。支气管肺泡灌洗液（BALF）中总蛋白、肿瘤坏死因子α（TNF-α）和白细胞介素1受体相关蛋白（IL-1 R AcP）均明显升高。肺组织GABABR 2表达减少，磷酸化p38 MAPK表达增加，IκB降解增加，中性粒细胞内流增加。巴氯芬的管理，开始后的ALI，恢复GABABR的表达，这是抑制GABABR拮抗剂，CGP 52432的存在。巴氯芬激活肺磷酸化ERK，抑制p38 MAPK磷酸化和IκB降解。此外，巴氯芬显著抑制促炎性TNF-α和IL-1βAcP的释放，并促进BAL中性粒细胞凋亡。巴氯芬对ALI的保护作用可能是通过抑制TNF-α和IL-1β介导的炎症信号传导而实现的。有趣的是，GABABR 2表达在来自肺损伤患者的肺组织切片中的II型肺细胞中受到调节，进一步表明GABABR 2在肺损伤的修复过程中的生理作用。GABABR 2激动剂可能在ALI中发挥潜在的治疗作用。
Immune-complexes play an important role in the inflammatory diseases of the lung. Neutrophil activation mediates immune-complex (IC) deposition-induced acute lung injury (ALI). Components of gamma amino butyric acid (GABA) signaling, including GABA B receptor 2 (GABABR2), GAD65/67 and the GABA transporter, are present in the lungs and in the neutrophils. However, the role of pulmonary GABABR activation in the context of neutrophil-mediated ALI has not been determined. Thus, the objective of the current study was to determine whether administration of a GABABR agonist, baclofen would ameliorate or exacerbate ALI. We hypothesized that baclofen would regulate IC-induced ALI by preserving pulmonary GABABR expression. Rats were subjected to sham injury or IC-induced ALI and two hours later rats were treated intratracheally with saline or 1 mg/kg baclofen for 2 additional hours and sacrificed. ALI was assessed by vascular leakage, histology, TUNEL, and lung caspase-3 cleavage. ALI increased total protein, tumor necrosis factor α (TNF-α and interleukin-1 receptor associated protein (IL-1R AcP), in the bronchoalveolar lavage fluid (BALF). Moreover, ALI decreased lung GABABR2 expression, increased phospho-p38 MAPK, promoted IκB degradation and increased neutrophil influx in the lung. Administration of baclofen, after initiation of ALI, restored GABABR expression, which was inhibited in the presence of a GABABR antagonist, CGP52432. Baclofen administration activated pulmonary phospho-ERK and inhibited p38 MAPK phosphorylation and IκB degradation. Additionally, baclofen significantly inhibited pro-inflammatory TNF-α and IL-1βAcP release and promoted BAL neutrophil apoptosis. Protective effects of baclofen treatment on ALI were possibly mediated by inhibition of TNF-α- and IL-1β-mediated inflammatory signaling. Interestingly, GABABR2 expression was regulated in the type II pneumocytes in lung tissue sections from lung injured patients, further suggesting a physiological role for GABABR2 in the repair process of lung damage. GABABR2 agonists may play a potential therapeutic role in ALI.
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影响因子：
3.6
作者：
Duthey, Beatrice;Huebner, Anita;Boehncke, Wolf-Henning
通讯作者：
Boehncke, Wolf-Henning
影响因子：
4.4
作者：
Gao, Hongwei;Hoesel, L. Marco;Ward, Peter A.
通讯作者：
Ward, Peter A.
影响因子：
5.8
作者：
Benke, Dietmar
通讯作者：
Benke, Dietmar
DOI：
10.1073/pnas.0915139107
发表时间：
2010-02-09
影响因子：
11.1
作者：
Bhat, Roopa;Axtell, Robert;Steinman, Lawrence
通讯作者：
Steinman, Lawrence
影响因子：
9.6
作者：
DICPINIGAITIS, PV;SPUNGEN, AM;ALMENOFF, PL
通讯作者：
ALMENOFF, PL