Purpose: Peptidylarginine deiminase (PAD) catalyzes citrullination, a post-translational modification that can alter structure, function and antigenicity of proteins. Citrullination in the lungs due to smoking is believed to initiate an anti-citrulline immune response in rheumatoid arthritis. Citrullination in other inflamed organs has also been demonstrated, but it is not known whether smoking or inflammatory processes in general result in release of relevant amounts of PAD into the circulation with potential to cause citrullination of proteins at various anatomical sites. Coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) induces an acute systemic inflammation response. In the present study, we investigate whether smoking or acute systemic inflammation causes release of PAD into the circulation.
Patients and methods: This study included 36 patients with coronary heart disease (16 smokers and 20 non-smokers) undergoing CABG surgery with CPB. Circulating levels of PAD2 and PAD4, PAD activity, the neutrophil activation markers MPO, MMP-9 and lipocalin-2, the cytokines IL-6 and IL-10, and the chemokine CXCL8 were measured 2 hrs preoperatively and 2 hrs postoperatively.
Results: At baseline, serum PAD2 and PAD4 concentration did not differ between smokers and non-smokers. However, serum from non-smokers contained higher PAD activity than serum from smokers. Circulating PAD2 levels and PAD activity increased markedly in both groups after surgery, as did all neutrophil activation markers, cytokines and chemokine. PAD2 levels correlated with neutrophil activation markers, but not with cytokine and chemokine levels.
Conclusion: Blood levels of PAD2 did not differ significantly between smokers and non-smokers, but smokers had decreased PAD activity in the circulation. PAD2 levels and PAD activity increased in blood during inflammation induced by CABG with CPB. This suggests that acute inflammation, ischemia or reperfusion, or a combination of these, leads to systemic spreading of enzymatically active PAD, which may affect protein function and induce generation of citrullinated self-antigens.

Keywords: citrullination, peptidylarginine deiminase, PAD, inflammation, coronary artery bypass grafting, CABG, cardiopulmonary bypass, CPB



中文翻译：

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在冠状动脉搭桥手术引起的急性炎症过程中，活性肽酰精氨酸脱氨酶释放到循环系统中。


目的：肽基精氨酸脱亚氨酶（PAD）催化瓜氨酸化，翻译后修饰可以改变蛋白质的结构，功能和抗原性。认为由于吸烟引起的肺瓜氨酸在类风湿性关节炎中引发抗瓜氨酸免疫反应。还已经证明了在其他发炎器官中的瓜氨酸化，但是尚不清楚吸烟或炎症过程是否通常导致相关量的PAD释放到循环中，并可能在各个解剖部位引起蛋白质的瓜氨酸化。使用体外循环（CPB）的冠状动脉搭桥术（CABG）引起急性全身性炎症反应。在本研究中，我们调查吸烟或急性全身性炎症是否会导致PAD释放进入循环系统。
患者和方法：本研究包括36例接受CPB的CABG手术的冠心病患者（16名吸烟者和20名非吸烟者）。术前2小时和术后2小时测量了PAD2和PAD4的循环水平，PAD活性，中性粒细胞激活标记MPO，MMP-9和lipocalin-2，细胞因子IL-6和IL-10以及趋化因子CXCL8。
结果：在基线时，吸烟者和非吸烟者的血清PAD2和PAD4浓度没有差异。但是，非吸烟者的血清比吸烟者的血清具有更高的PAD活性。两组术后循环PAD2水平和PAD活性显着增加，所有中性粒细胞激活标志物，细胞因子和趋化因子也升高。PAD2水平与中性粒细胞活化标志物相关，但与细胞因子和趋化因子水平无关。
结论：吸烟者和非吸烟者之间的PAD2血液水平没有显着差异，但是吸烟者的循环中PAD活性降低。在CABG和CPB诱导的炎症过程中，血液中PAD2水平和PAD活性增加。这表明急性发炎，局部缺血或再灌注或它们的组合会导致酶活性PAD的全身扩散，这可能会影响蛋白质功能并诱导瓜氨酸化自身抗原的产生。

关键字：瓜氨酸化，肽酰精氨酸脱亚氨酶，PAD，炎症，冠状动脉搭桥术，CABG，体外循环，CPB