【作者】 洪小杨；

【导师】 封志纯；

【作者基本信息】 南方医科大学 ， 儿科学， 2014， 博士

【摘要】 第一部分ECMO在儿童重症医学中的应用研究目的：体外膜肺氧合技术(Extracorporeal Membrane Oxygenation, ECMO)是能够在较长时间内对严重的心肺功能衰竭患者进行长时间心肺支持的一种体外生命支持技术,是儿童重症医学体外生命支持系统中最重要的一环。目前ECMO技术在中国大陆在儿童重症医学领域的开展严重滞后。本研究通过回顾近年来本单位开展儿科ECMO病例资料,对接受ECMO支持患儿的临床应用指征、预后情况、儿科ECPR的开展情况及ECMO期间出现并发症的CRRT处理进行分析总结,希望对中国大陆儿童重症医学领域ECMO的开展提供可靠的临床参考资料,为完善儿童重症医学体外生命支持技术体系提供重要依据。方法：收集并回顾2010年至2013年因呼吸循环衰竭于本单位接受ECMO支持重症患儿病历资料并对ECMO应用的情况进行分析。研究对象纳入标准为出现心肺功能衰竭并接受ECMO支持患儿。计量资料中连续变量呈正态分布者表示为均数±标准差,所有统计分析均采用SPSS19.0软件进行处理。P<O.05表示差异有统计学意义。结果：1.临床情况及预后12例ECMO辅助患儿支持时间为81.2±46.5h,最短时间为12h,最长时间为173h,监护室停留时间为10.9±6.4d。其中成功撤离ECMO7例,撤机率58.3%,近期存活5例,存活率41.6%,死亡7例。2. ECMO支持应用指征与禁忌征呼吸支持指征：本组资料中根据主要患儿氧合指数及pH值评估是否具有呼吸支持适应征。4例呼吸支持患儿中,氧合指数分别为117、40、100和33,前3例是在吸入NO的情况下；所有pH值也小于7.25,低氧血症已经造成机体氧供和氧耗失衡,导致机体的内环境酸碱平衡紊乱。循环支持指征：8例循环支持患儿中,有5例是心肺复苏同时建立的ECMO,2例是心脏术后无法脱离体外循环而进行ECMO支持,1例是术中代替体外循环。禁忌症：心肺功能不可逆损伤是ECMO禁忌症；本组资料中根据ECMO支持前的胸片、肺部CT检查及呼吸机参数和应用时间评估肺功能；心功能的评估主要根据心跳停博持续时间和心脏畸形纠正情况；神经功能的评估主要是床旁头颅超声检查,尽量了解是否有颅内出现,脑积水等情况；坏死性小肠结肠炎,将是ECMO支持的绝对禁忌症。3.ECMO的治疗模式与建立方式本组资料中所有患儿均采用V-A模式ECMO进行呼吸或循环支持。6例经右心房、升主动脉插管建立ECMO,占50%。4例为经右颈内静脉、右颈总动脉插管建立ECMO,占33.3%。2例经右侧股静脉至股动脉建立ECMO,占16.7%。4.ECMO对重要生命体征及血气的影响ECMO支持前(T1)、支持后24小时(T2)及48小时(T3)三个时间点的平均动脉压、心率及血气相关指标进行方差分析,结果提示动脉平均压、pH值、BE与Lac水平在各个时间点有显著差异(p<0.05)。动脉平均压、pH值、BE和Lac进一步做多重比较可看出：平均压在T1与T2和T3时间点之间比较均有显著差异(p<0.05),而在T2和T3时间点之间比较无显著差异(p=0.75)。pH值在T1与T2和T3时间点之间比较均有显著差异(p<0.05),而T2与T3之间比较无显著差异(p=0.99)。BE在T1与T2和T3时间点之间比较均有显著差异(p<0.05),而T2与T3之间比较无显著差异(p=0.99)。Lac在T1与T2之间比较无显著差异(p=0.54),T1与T3时间点之间比较有显著差异(p<0.05),而T2与T3之间比较无显著差异(p=0.36)。与术前相比,接受ECMO支持后动脉平均压明显升高,血气分析提示pH也较术前升高、BE值趋于正常,乳酸水平也持续下降。ECMO能很好地改善机体灌注,内环境酸中毒得到改善。5.ECMO支持过程中并发症及处置ECMO支持过程中的并发症主要分为两大类：机械并发症及机体并发症机械并发症及处置：5例在支持期间出现膜肺血浆渗漏,发生率41.7%,出现膜肺血浆渗漏只能更换膜肺；1例出现插管堵塞,该事故与插管位置不合适导致插管打折有关,发生率8.3%。机体并发症与处置：1例(病例10)出现右下肢脚趾缺血坏死,发生率8.3%；5例出现手术切口渗血,发生率41.7%,输注血小板及新鲜冰冻血浆,维持ACT在140-160秒之间,均能控制住手术切口渗血；1例出现颅内出血,发生率8.3%,给予脑室引流；共有5例出现尿量少、肌酐尿素氮增高等急性肾功损伤症状。发生率41.7%,给予CRRT治疗。6.ECMO的撤离与终止所有患儿在ECMO撤离前,均床旁胸片以及心脏超声检查,评估肺部及心功能恢复情况。本组资料中共有7例患儿成功撤离ECMO,撤机成功率为58.3%,5例撤离ECMO失败,其中3例是心肺功能无法恢复,经家长同意,ECMO小组讨论决定后主动终止ECMO。7.ECMO撤离成功组与失败组的比较本组资料中,7例成功撤离ECMO,撤机成功率58.3%；5例撤离ECMO失败。4例呼吸支持的患儿,2例成功撤离ECMO,但术前OI值>100的2例患儿均未能存活下来,唯一例存活患儿术前OI值为33。OI过高可能预示预后不良。与ECMO撤离失败组比较,成功撤离组在ECMO支持后24小时乳酸水平明显下降,与撤离ECMO失败的患儿比较差异显著(p<0.05),AKI的发生率也较低,与撤离ECMO失败的患儿比较差异显著(p<0.05)。乳酸水平的变化趋势与AKI的发生率可能是与撤离ECMO的相关因素,这两点仍需要更多的病例临床实践证明。8.ECPR技术在心肺骤停患儿救治中的应用5例接受ECPR的患儿中,3例成功撤离ECMO,其中1例(病例5)撤离ECMO后1月后因手术切口感染,肺动脉出血死亡；存活2例(病例6、病例8),死亡2例(病例7、病例11),其中1例因出现NEC后终止ECMO,另1例在ECMO支持第26小时,家属决定终止治疗,撤离ECMO后死亡。主动终止ECMO程序如下：首先是经ECMO小组讨论,确定心肺功能无法恢复,由副高职称以上医师决定终止ECMO支持,其次充分将病情告知家属,取得家属同意或要求终止ECMO支持。9.ECMO支持过程中出现AKI的肾替代治疗本组资料中,12例患儿共有5例出现AKI,发生率约为41.7%,这5例患儿中共死亡4例；而未发生AKI的7例患儿中共死亡3例。选择CRRT系统直接与ECMO管路系统并联方式进行血液滤过治疗,CRRT系统取血端连接于泵后膜肺前,回血段连接于泵前,经本单位实践证明,该连接方法能够保证CRRT系统正常运转时,各个压力监测点都能保证在正常范围内。本组资料的CRRT治疗方式能够有效地维持机体液体平衡,有效清除肌酐和尿素氮等代谢产物。结论：1.ECMO技术能为心肺功能衰竭的患儿提供有效的呼吸循环支持。目前临床上呼吸支持手段多样化,使部分呼吸衰竭患儿避免ECMO支持,同时也延误了部分确实需要ECMO支持的患儿的治疗时机。如何从呼吸衰竭的患儿中甄别出真正需要ECMO支持的患儿,是下一步的儿童重症医学临床工作者的研究方向。2. ECPR技术是抢救对常规CPR技术反应不良的心肺骤停患者的有效手段,能为治疗导致心肺骤停的原发病争取了时间窗口,在儿科心肺骤停患儿的救治中有非常重要意义。在临床上组建一个ECPR小组,建立一套ECPR’决速反应机制,在及时有效心肺复苏,在准确充分评估心、肺及神经系统功能情况下,进行ECPR,能够提高心肺骤停患儿的救治成功率,与ECPR前的血清乳酸水平相比,在建立有效循环支持后乳酸水平的动态变化可能是提示预后的指标。3.ECMO相关并发症是影响病人预后的最大因素。机械并发症包括膜肺血浆渗漏和管道堵塞,一般都只能够通过更换ECMO系统解决。出血是最常见的机体并发症,调整肝素用量,维持较短的ACT时间,输注血小板和新鲜冰冻血浆,绝大部分出血都能得到有效控制。AKI是儿科ECMO期间的最严重的并发症,采用将CRRT系统直接并联入ECMO系统的方法,能够保证CRRT期间血流和超滤速度的可控,有效维持内环境稳定和液体平衡,达到完全肾替代治疗的效果,精确控制肾代替治疗的血流速度及超滤速度,维持患儿容量和循环稳定,对于低龄低体重患儿意义尤其重大。在ECMO循环管路上并联CRRT系统进行肾替代治疗方法目前国内外文献中未见报道。第二部分ECMO对外周血单个核细胞.Annexin Al蛋白表达的影响目的：ECMO支持期间,机体并发症的发生与ECMO相关全身炎症反应综合征有密切的关系。临床上可以观察到在开始ECMO支持的数小时内,全身炎症反应综合征开始出现并逐渐强烈,临床表现为低血压、尿量减少、肺顺应性下降、毛细血管渗漏全身水肿以及肝功能损伤,由全身炎症反应综合征导致的这些症状会持续数天,而且还会影响原发病的恢复。本研究的目的：(1)研究ECMO血液转流前后对外周血单个核细胞中蛋白质表达谱的差异。(2)明确ECMO血液转流对外周血单个核细胞Annexin Al蛋白表达水平的影响。方法：(1)本单位12例因出现心肺功能衰竭接受ECMO支持患儿,其中男9例,女3例；年龄生后1天～7岁；体重8±6.1kg；作为研究对象。(2)于ECMO支持前(T1)和开始ECMO支持后24小时(T2)两个个时点抽取动脉血3-5ml,分离外周血单个核细胞(PBMC),裂解、离心,取上清液。随后将收集到的各组蛋白采用2D-QUANT方法进行蛋白定量。(3)利用UMAX PowerLook1100投射扫描仪获取图像,用PDQuest7.1.0软件包进行图像分析,选取表达量差异1.5倍以上的点作为后续质谱分析的候选蛋白质点,利用质谱鉴定差异表达蛋白,对差异蛋白进行Western Blot验证。(4)计量资料以均数±标准差(x±s)表示,所有统计分析均采用SPSS19.0软件进行处理。P<0.05表示差异有统计学意义。结果：1.12例ECMO辅助患儿平均支持时间为81.2±46.5h,其中成功撤离ECMO7例,撤机率58.3%,近期存活5例,存活率41.7%,死亡7例,死亡率为58.3%。2.在开始ECMO支持前(T1)、和ECMO支持24小时(T2)两个时点外周血中单个核细胞蛋白进行了双向电泳分离,一共得到了12个差异蛋白。与T1相比,5种蛋白质在T2点明显增加,包括C3前体,前列环素合成酶,谷胱甘肽过氧化酶1,补体成分1Q子结合蛋白,Annexin Al;其余7种蛋白质在T2时间点明显下降,分别是蛋白质S100-A9,肌动蛋白1,ATP合酶α亚基,线粒体前体,血红蛋白α亚基,载脂蛋白Cl, EF1-beta.3.鉴于Annexin Al是一种一个重要的炎症调控蛋白,在炎性代谢产物产生、中性粒细胞／单核细胞与内皮细胞黏附的过程中起重要作用,本研究选择了Annexin Al作为了其中一个深入验证研究的对象。对其进行Western blot验证,结果显示Annexin Al表达量在开始ECMO转流后表达量开始增加,支持24小时的时间点表达量增加明显(P<0.05)。提示ECMO的体外转流能促进单个核细胞中Annexin Al的表达。结论：1.认为ECMO支持过程中,机体的全身炎症反应发生主要和ECMO支持前患者就已存在的机体炎症反应以及其ECMO管道表面与血液的接触促发的炎症反应有关。2. ECMO体外转流时激发机体复杂的炎症反应是ECMO支持期间一系列并发症发生的病理基础。ECMO支持期间所出现的后所出现的机体并发症均直接或间接源于炎性级联反应,血液循环中的单个核细胞既是重要的效应细胞,又是炎症反应的调节细胞,在ECMO相关炎症反应中所扮演的重要角色。3.初步揭示了ECMO过程中单核细胞参与炎症反应的分子机制。但对于包括Annexin Al在内的这些差异蛋白质,在ECMO所诱导的全身炎症反应综合症中,如何被激活,并如何通过不同炎症信号转导通路发挥各自的作用机制还需要进一步的深入研究。更多还原

【Abstract】 PART I Application of ECMO in Pediatric Critical Care MedicineObjective:Extracorporeal membrane oxygenation (ECMO) is an extracorporeal life support technique that can replace of the cardiac and pulmonary function for a long time, and maintain the body’s oxygen supply of every organs for the patients of heart and lung failure in severe situation. ECMO is the key technique of extracorporeal life support system of Pediatric Critical Care Medicine(PCCM) and backward in Chinese PCCM. The data of the critical children underwent ECMO in our hospital recent years was reviewed in this study, the ECMO indication, prognosis, ECMO aid cardiopulmonary resuscitation(ECPR), complications of ECMO and CRRT during ECMO were analyzed. Hope to provide some clinical references for development of ECMO in PCCM field in China.Methods:Research personnel retrospectively analyzed clinical data collected by a standardized data collection sheet through medical record review. The study group consisted of our Hospital, between2010and2013. The admitted children were the patients who were diagnosised with heart or lung function failure and accepted ECMO support.SPSS (SPSS for Windows, version20.0, IBM-SPSS, Chicago, IL, USA) was used for statistical analysis. Continuous variables were presented as means and SD and compared with the rate of occurrence or the composition ratio of the chi square. Values of P<0.05were considered to be significant.Results:1.Clinical Situation and Prognosis12cases of children with ECMO assisted support time was81.2±46.5h, the shortest time was12h and the longest time was173h, ICU stay time was10.9±6.4d. There were7cases that successful weaned off ECMO, the probability was58.3%,5cases survived at last, the survival rate was41.6%.5cases can not wean off ECMO and7cases death at last.2. ECMO support application indications and contraindicationsRespiratory support indication:This group of children according to the oxygenation index(OI) and pH value to evaluate whether has the respiratory support indication.4cases of respiratory support, OI was117,40,100and33,3cases were under NO inhalation; pH value of all cases was less than7.25, the body’s oxygen supply and consumption was imbalance caused by hypoxia, resulting in internal environment disturbance of acid-base balance of body.Circulatory support indications:8cases were circulatory support,5cases of these children, ECMO was established to support cardiopulmonary resuscitation. And2cases, ECMO support was put on for weaned off CPB failure after cardiac surgery.1cases are replaced cardiopulmonary bypass during surgery. Contraindications:The irreversible injury of cardiopulmonary function is the contraindications of ECMO application. The pulmonary function evaluation was according to the chest X ray, lung CT scan and ventilator parameters before the ECMO support. The assessment of cardiac function was based on cardiac arrest duration and heart malformation correction. Evaluation of nerve function was based on bedside cranial ultrasound examination, whether intracranial, hydrocephalus etc. Finally, if children were found necrotizing enterocolitis, which would be the absolute contraindications of ECMO support.3. The mode and establishment of ECMOAll children were treated with V-A model ECMO both respiratory and circulatory support. On6cases, with right atrial and ascending aortic cannulation to establish ECMO, accounting for50%. On4cases, with right internal jugular vein and right common carotid artery cannulation to establish ECMO, accounted for33.3%. on2cases, right femoral artery and femoral vein cannulation was procedured to establish ECMO, accounted for16.7%.4. Effect of ECMO on the vital signs and blood gas analysisBefore the ECMO support (T1), after24hours (T2) and48hours (T3), on these three time points, mean arterial pressure(MAP), heart rate and blood gas analysis result were recorded and analyzed by one way ANOVA, results suggest that the MAP, pH value, BE and Lac levels at different time points were significantly different (p<0.05).MAP, pH value, BE and Lac further multiple comparisons can be find:MAP was significantly difference between T1and T2, T3(p<0.05), but no significantly difference between T2and T3(p=0.75). pH was significantly difference between Tl and T2, T3(p<0.05), but no significantly difference between T2and T3(p=0.99). BE was significantly difference between T1and T2, T3(p<0.05), but no significantly difference between T2and T3(p=0.99). Between T1a nd T2, T2and T3, Lac was no significantly difference(p=0.54, p=0.36), but there was significantly difference between T1and T3.(p<0.05).Compared with pre-ECMO support, MAP was obviously increased and blood gas analysis revealed that pH is also higher, BE values tended to be normal, the lactate level is declining. ECMO can well improve the perfusion, internal environment acidosis improved after ECMO support.5. The complication and treatment during ECMOThe complications during ECMO supports can be divided into two categories: mechanical complications and systemic complicationsMechanical complication and treatment:Plasma leakage of the oxygenator were found in5cases during ECMO support period, the incidence was41.7%. When plasma leakage of oxygentor was appeared, only thing we can do was to replace oxygenator. The venous cannula in1cases was blockage, Maybe the cannulation position is not appropriate to discount, the incidence was8.3%.Systemic complication and treatment:In1cases (case10), Rright lower limb ischemic necrosis of toes was appeared, the incidence was8.3%. in5cases, bleeding of operation incision oozing was appeared, the incidence was41.7%, after transfusion of platelets and fresh frozen plasma, ACT was maintained at between140to160seconds, can control the operation incision hemorrhage.1cases had intracranial hemorrhage, incidence was8.3%, the ventricle drainage was given, there were5cases appeared with oliguria, creatinine and urea nitrogen increased, acute renal injury(AKI) were diagnosised, The incidence of AKI was41.7%, all the AKI children were treated with CRRT.6. Wean off and termination of ECMO Before wean off ECMO, bedside chest X ray and cardiac ultrasound were done for evaluation cardiac function recovery in all the children.7cases were successfully weaned off ECMO, the success rate of weaning was58.3%.5cases were failed to wean off ECMO, including3cases were cardiopulmonary function can not be restored, and with the parents consent, ECMO team decided to terminated ECMO.7. Comparision between the successful and failed wean off ECMO groups7cases were successfully weaned off ECMO, weaning rate was58.3%.5cases were failed to wean off ECMO.4cases with respiratory support,2cases were successful weaned off ECMO, but2cases of these children with01>100before ECMO were failed to survive, the only survivors in respiratory support group OI is33pre-ECMO. High values of01may be a risk factor for poor prognosis.Compared with children who were failed to wean off ECMO, successfully weaned off group after24hours ECMO support, the lactic acid level decreased significantly(p<0.05). And the significantly lower incidence of AKI in successful group, compared with the failed ECMO group. Change trend of lactate and AKI incidence could be the related factors of ECMO weaned of,but still needed more clinical data to prove these two points.8. Application of ECPR on cardiopulmonary arrest childrenAmong5cases with ECPR,3cases were successfully weaned off ECMO,1cases (case5) was for the operation incision infection and pulmonary hemorrhage after withdrawal of ECMO for1months.2cases survived (6cases6, cases8).2cases died (cases7, cases11),1case was diagnosis of NEC and terminated of ECMO, another case was weaned off ECMO under the patients’termination decision after26hours on ECMO. Active termination of ECMO program is as follows:firstly, a discussion of the ECMO team, determine whether the cardiopulmonary function can be restored or not, decision to terminate the ECMO support were made after a unified opinion got by the ECMO team, and with the families consent, that the ECMO support will be terminated for ECPR case.9. Treatment of AKI during ECMO support periodAmong12cases, there were5cases diagnosis with AKI during ECMO support period, the incidence of AKI approximately41.7%, and4cases were died of these5patients. And there were3cases died in7cases without AKI during ECMO support period. CRRT system of hemofiltration was selected for the treatment of AKI during ECMO, and the CRRT system was parallel connected with ECMO circuit. The blood inlet of CRRT system is connected to circuit between the pump and the oxygenator, blood returning was connected to the circuit before pump. This way of CRRT on ECMO patients works wll on our clinical practice, the connecting method can guarantee the normal operation of CRRT system, the pressure monitoring points can be guaranteed in the normal range. CRRT treatment in this way can effectively maintain the body fluid balance, effective removal of creatinine and urea nitrogen and other metabolites.Conclusions:1.ECMO can provide effective respiratory and circulatory support for heart failure patients. Today, many other respiratory treatment in respiratory failure children can help to avoid ECMO support, but also delay the those who do need ECMO support. How to distinguish the patients who really need ECMO support from children with respiratory failure is the research direction of clinical workers in PCCM.2.ECPR is the effective means to rescue patients with cardiopulmonary arrest who can not rescue by conventional CPR, it can win the window time for cure the primary disease that lead to cardiac arrest, and have a very important significance in the treatment of pediatric cardiac arrest in children. A practical team of ECPR and a set of ECPR rapid response mechanism, with timely and effective cardiopulmonary resuscitation and accurate assessment of the patients’heart, lungs and nervous system function, can improve the prognosis of cardiac arrest patients. Compared with the pre ECPR serum lactic acid level, dynamic changes in the effective circulatory support after the lactic acid level may be prognostic index for mortality.3.On the critical children with ECMO support, ECMO related complications is the mainly factor affecting the prognosis of the patients. Mechanical complications include plasma leakage of oxygenator and ECMO circuit blockage, generally can only be solved by replacing the ECMO system. Hemorrhage is the most common complications of the system. adjust the amount of heparin, maintain a short ACT time, transfusion of platelets and fresh frozen plasma, most bleeding can be effectively controlled. AKI is the most serious complication of pediatric ECMO support period, Connecting CRRT system with ECMO system in parallel, can guarantee the controllable blood flow and ultrafiltration velocity during CRRT, it can effective maintain volume and fluid balance. To achieve control the flow velocity and ultrafiltration speed accurately was especially significant for low body weight infants on ECMO. This method has not been reported in literature in China and abroad. PART II Effect of ECMO on Annexin A1expression in Peripheral blood mononuclear cellsObjective:ECMO associated systemic inflammatory response syndrome has a close relationship with the body complications. With the beginning hours of the ECMO, systemic inflammatory response syndrome becomes stronger. The clinical manifestations,caused by systemic inflammatory response syndrome, are hypotension, decreased urine output, decreased lung compliance, capillary leakage of systemic edema and damage of liver function which will last for several days and impact the prognosis of the original disease. The aims of the study are as follows.(1)To investigate the involved proteomic profiling of PBMC in the ECMO inflammatory reaction.(2)To examine the effect of ECMO on Annexin Al expression in peripheral blood mononuclear cells (PBMCs) before and after ECMO.Methods:In this study12patients(9males,3females;age:1days to7years old; weight8±6. lkg received ECMO support. PBMCs of peripheral blood(3-5ml) was collected by density gradient centrifugation before and24h after ECMO. The lysis protein extraction was qualificated by2D-QUANT.The images were acquired by UMAX PowerLook1100and then analyzed by PDQuest7.1.0. Mass spectrometry was followed to identify candidate proteins with1.5folds difference after ECMO which were validated by western blot. The data are expressed as x+-s, analyzed by one-way ANOVO test with SPSS13.0software.P<0.05indicates significant difference.Results:l.The average support time of ECMO in12cases was81.2±46.5h.7cases (58.3%) were successfully weaned off ECMO,41.7%(5cases) survived,7cases died, the mortality rate was58.3%.2.Peripheral blood collected at two time points were subjected to two-dimensional electrophoresis and a total of12differentially expressed proteins had been identified. Compared to before ECMO(T1),5proteins (Complement C3precursor, Prostacyclin synthase, Glutathione peroxidase1, Complement component1Q subcomponent-binding protein, Annexin A1) increased after ECMO (T2). However, the remaining7proteins (Protein S100-A9, Actin cytoplasmic1, ATP synthase subunit alpha, mitochondrial precursor, Hemoglobin subunit alpha, Apolipoprotein C-III precursor, Elongation factor1-beta) decreased.3.Considering Annexin A1is an important inflammation regulatory protein, playing a critical role in the production of inflammation, in this study we choose Annexin Al as the subject. Western blot assay shows that Annexin Al expression began to increase after ECMO, and increased significantly24h after CPB (P=0.000). This indicates ECMO can induce the expression of ECMO.Conclusions:1.ECMO support process, the systemic inflammatory reactions mainly originate from existed inflammation before ECMO and contact proinflammatory reactions between the ECMO pipeline and blood.2.The complicated inflammation responses resulted in a series of outcomes. Mononuclear cells are both effective cells of inflammation and regulatory cells, playing an important role in the associated inflammation of ECMO.3. We initially shows the molecular mechanism of mononuclear cell in the inflammation response. However, the activated mechanism of these proteins including Annexin Al and signaling pathways involved are still unclear, and more studies are required.更多还原