可溶性髓樣細胞觸發受體1在感染性疾病中的研究應用進展

李健球(綜述),熊旭明(審校)

(1.廣州醫學院附屬深圳沙井醫院重癥醫學科，廣東 深圳 518104； 2.廣州醫學院第二附屬醫院重癥醫學科，廣州 510260)

髓樣細胞觸發受體1(triggering receptors expressed on myeloid cells,TREM-1)是Bouchon等[1]在2000年首次發現的細胞膜受體,屬免疫球蛋白超家族成員，其選擇性地表達于中性粒細胞、成熟單核-巨噬細胞等髓樣細胞表面，金屬蛋白酶可以使膜上TREM-1的胞外功能區脫落成剪切變異體，為分泌亞型，是可溶性髓樣細胞觸發受體1(soluble triggering receptor expressed on myeloid cells-1,sTREM-1),在感染或炎性反應時可以特異性地分泌到血液及體液中[2-3]。在血漿、腦脊液、胸腔積液及支氣管肺泡灌洗液中均可以檢測到sTREM-1水平升高[4]。現就sTREM-1在感染性疾病中的應用進展綜述如下。

1 sTREM-1在炎性反應的作用

大量研究提示TREM-1在炎性反應中發揮重要作用，其通過特殊的細胞信號轉導途徑導致其下游的促炎介質的產生(包括腫瘤壞死因子α、白細胞介素2、白細胞介素6和白細胞介素8)，導致髓過氧化物酶的產生，中性粒細胞脫粒，呼吸爆發及吞噬反應[5]。研究提示，TREM-1的活化需要其天然配體與Toll樣受體(Toll like receptor，TLR)家族配體的協調作用來實現[6-7]。其中TLR4的效應因子腫瘤壞死因子α和白細胞介素1β能明顯上調TREM-1的表達，同時阻斷TREM-1和TLR4的信號則能夠完全消除促炎反應[8]。信號轉導分子DAP12(DNA-X-associated protein of 12 kd)是表達于單核細胞、巨噬細胞、自然殺傷細胞及樹突細胞表面的跨膜銜接蛋白，在DAP12的幫助下，TREM-1能夠激活下游的瀑鏈式炎性反應信號，用TREM-1拮抗劑可以阻止TREM-1誘導的DAP12發出信號[9-10]。研究證實，核因子κB也可以高效誘導多種細胞因子，包括腫瘤壞死因子α、白細胞介素1β、白細胞介素6、白細胞介素8、黏附分子和催化因子，參與炎性反應的放大與延續，同時對多種酶的活性也有調控作用；而干擾TREM-1信號轉導可以下調核因子κB的活性而抑制腫瘤壞死因子α、白細胞介素1β、白細胞介素6及白細胞介素8等炎性介質的基因轉錄[11]。

Bouchon等[6]研究提示，用TREM-1胞外區和人的IgG1 Fc段蛋白(mTREM-1/IgG1)腹腔注射，可以有效降低血中的腫瘤壞死因子α及白細胞介素8的水平，對脂多糖、盲腸結扎或穿刺所造成的內毒素休克的動物模型有顯著的保護作用，從而引發對這種sTREM-1的廣泛研究。研究發現，sTREM-1是通過競爭與TREM-1的未知配體結合，從而阻斷髓樣細胞膜上的TREM-1介導的信息傳導，下調炎性反應[6，12]。事實上，sTREM-1所發揮的作用可以認為是機體在炎性反應中的自我保護調節機制。

2 sTREM-1與膿毒癥

Gibot等[13]對76例可疑膿毒癥患者的回顧性研究顯示，sTREM-1診斷膿毒癥的靈敏度為96%，特異度89%，分別優于降鈣素原的84%、70%,C反應蛋白的76%、67%。最近研究顯示，創傷后的患者，在無并發感染時血清sTREM-1顯著升高，但并發感染后sTREM-1水平會進一步顯著升高，提示血清sTREM-1與創傷患者是否并發膿毒癥密切相關，可以用于創傷患者非感染因素所致的全身炎癥反應綜合征與膿毒癥的鑒別診斷[14-17]。另一項對151例社區獲得性肺炎的研究發現，血清TREM-1對診斷細菌性肺炎的靈敏度是84%，特異度為40%，低于血清降鈣素原和C反應蛋白[18]。一項關于63例機械通氣急性呼吸窘迫綜合征患者的前瞻性研究發現，血清sTREM-1對膿毒性急性呼吸窘迫綜合征和非膿毒性急性呼吸窘迫綜合征無鑒別價值[19]。Latour-Pérez等[20]研究認為，在并發全身炎癥反應綜合征的重癥患者中，sTREM-1對感染患者的鑒別診斷沒有明顯意義。Bopp等[21]對65例外科重癥監護治療病房患者(全身炎癥反應綜合征11例、嚴重膿毒癥39例、膿毒性休克15例)研究發現，全身炎癥反應綜合征、嚴重膿毒癥和膿毒性休克患者診斷后3 d內血漿sTREM-1水平與健康對照組無顯著差異，死亡組和存活組血漿sTREM-1水平也無顯著差異，因此建議應用sTREM-1作為膿毒癥診斷和判斷預后的指標需要謹慎。新生兒遲發型敗血癥的研究發現，sTREM-1的診斷價值不如白細胞介素6[22]。可見，血清sTREM-1對膿毒癥診斷價值的存在比較大的差異，考慮可能與標本的檢測方法不同有關。另外，不同部位的感染對血液sTREM-1也可能產生影響。研究顯示血清sTREM-1對泌尿道感染的靈敏度只有18%[4]。

Latour-Pére等[23]和王紅霞[24]等研究顯示，膿毒癥患者的早期血sTREM-1水平顯著高于非膿毒癥和正常對照組，死亡組顯著高于存活組，提示早期sTREM-1水平與預后不良有關。Gibot等[25]研究發現，存活組入院當日的血sTREM-1水平顯著高于死亡組，存活組的sTREM-1水平逐漸下降，而死亡組的sTREM-1水平不斷上升，從而對sTREM-1的作用產生疑惑，早期的水平升高是否有保護作用，后期不斷升高是提示膿毒癥不能緩解，預示預后不良，將有待深入研究。

3 sTREM-1與肺炎

Gibot等[30]研究發現，肺炎患者支氣管肺泡灌洗液比非肺炎患者顯著升高，如果以5 ng/L為閾值，sTREM-1對細菌性和真菌性肺炎診斷的特異度是90%，靈敏度是98%。Huh等[31]對肺炎的研究有相似的結果，細菌性和真菌肺炎患者的支氣管肺泡灌洗液的sTREM-1的水平顯著高于病毒性肺炎、非典型肺炎、肺結核以及非感染性患者，如果以支氣管肺泡灌洗液中sTREM-1≥184 ng/L為診斷標準，其診斷細菌或真菌感染的靈敏度為86%，特異度為90%。Wu等[32]最近一項關于呼吸機相關性肺炎患者的研究結果發現，支氣管肺泡灌洗液中細菌培養陽性患者灌洗液sTREM-1水平顯著高于灌洗液培養陰性患者，若以起病后7～9 d下降10 ng/L為標準，灌洗液sTREM-1濃度預測死亡率的靈敏度為90%，特異度是88%。上述研究結果提示，支氣管肺泡灌洗液sTREM-1水平可作為臨床上細菌和真菌感染性肺炎的診斷、鑒別診斷以及判斷預后有較好的價值。也有研究質疑支氣管肺泡灌洗液sTREM-1對VAP的診斷價值。一項對VAP研究發現，雖然確診呼吸機相關性肺炎患者支氣管肺泡灌洗液(bronchial alveolar lavage fluid，BALF)中sTREM-1濃度較未確診患者顯著升高，但受試者工作特征曲線下面積僅為0.58(95%CI0.50～0.65;P=0.04)，提示BALF中sTREM-1水平不能有效診斷呼吸機相關性肺炎[33]。Anand等[34]研究也得出相似的結果，研究者通過免疫測定法檢測105例機械通氣患者BALF中sTREM-1，發現VAP患者較非VAP患者BALF中sTREM-1水平增高，以sTREM-1水平>200 ng/L為標準,其診斷VAP的靈敏度為42.1%，特異度為72.6%。

此外，還有學者提出可應用呼吸機管道呼出氣冷凝液(exhaled breath condensate，EBC)中sTREM-1診斷VAP。Horonenko等[35]比較了灌洗液和冷凝液中sTREM-1對VAP的診斷價值，通過免疫酶聯吸附測定檢測23例懷疑VAP患者的BALF和EBC中sTREM-1，發現9例VAP患者和14例無肺部感染患者BALF中sTREM-1水平無顯著差異，然而9例VAP患者EBC中sTREM-1水平較14例無肺部感染患者顯著升高，提示EBC中sTREM-1水平可作為診斷VAP的可靠指標，而BALF中sTREM-1的檢測對于診斷VAP沒有幫助。

支氣管肺泡灌洗液的sTREM-1對肺部感染性疾病的診斷價值和預后判斷存在比較大的差異，考慮可能與標本獲取和檢測方法不同有關。

4 sTREM-1與慢性阻塞性肺疾病

Phua等[36]研究發現，肺炎和Anthonisen標準Ⅰ型急性加重慢性阻塞性肺疾病患者組的血sTREM-1水平顯著高于Anthonisen標準Ⅱ、Ⅲ型急性加重組、健康對照組和支氣管哮喘組，血sTREM-1水平可能對慢性阻塞性肺疾病的病情判斷和抗生素的應用有一定指導意義。Radsak等[37]研究發現，慢性阻塞性肺疾病患者組的血sTREM-1水平顯著高于健康對照組，血sTREM-1水平與肺功能呈負相關，sTREM-1同時可能是慢性阻塞性肺疾病潛在的炎性因子。

5 sTREM-1與胸腔積液

胸腔積液無特異性的鑒別指標，臨床上難以鑒別積液的性質。Huang等[38]通過免疫酶聯吸附測定檢測109例胸腔積液患者的胸腔積液sTREM-1水平，分別是35例惡性胸腔積液、3l例結核性胸腔積液、2l例炎性胸腔積液和22例漏出液，結果顯示，炎性胸腔積液較其他三類胸腔積液sTREM-1水平顯著升高，以768.1 ng/L為閾值，其診斷炎性胸腔積液靈敏度為86%，特異度為93%。最近有一項薈萃分析顯示，胸腔sTREM-1對細菌性胸腔積液診斷靈敏度為78%，特異度為84%，可以作為細菌性胸腔積液的診斷指標[39]。Chan等[40]通過用免疫酶聯吸附測定檢測67例胸腔積液患者胸腔積液sTREM-1水平，結果顯示，炎性胸水較結核性胸腔積液sTREM-1水平顯著升高，結核性感染較非細菌感染導致的胸腔積液sTREM-1顯著升高；以114 ng/L為閾值，其鑒別結核性與非細菌感染導致的胸水靈敏度為87.5%，特異度為89.7%；以374 ng/L為閾值，鑒別炎性和結核性胸水的靈敏度為93.8%，特異度為90.8%。

6 sTREM-1與細菌性腦膜炎

腦膜炎的性質難以鑒別，細菌性腦膜炎腦脊液細菌培養陽性率也不高。Bishara等[41]研究21例懷疑腦膜炎或腦炎患者，發現腦脊液sTREM-1對診斷細菌性腦膜炎的靈敏度為77.8%，特異度為100%，陽性預測值為100%，陰性預測值為85.7%。Determann等[42]分別收集了92例社區獲得性細菌性腦膜炎患者、8例病毒性腦膜炎患者以及9例正常人腦脊液標本，檢測分析腦脊液中sTREM-1對診斷細菌性腦膜炎的準確性，結果顯示，細菌性腦膜炎患者腦脊液的sTREM-1水平顯著高于病毒性腦膜炎患者和正常人；用sTREM-1鑒別細菌性腦膜炎和非細菌性腦膜炎的診斷準確度為82%，以20 ng/L為臨界值診斷細菌性腦膜炎的靈敏度為73%，特異度為77%，陽性預測值為94%，陰性預測值為34%。上述研究表明，腦脊液sTREM-1水平對細菌性腦膜炎的診斷及鑒別診斷有比較大價值。

7 展 望

sTREM-1是近年來天然免疫和炎性反應研究的熱點，雖然sTREM-1在感染性疾病中的應用研究取得了很大的進步，但還存在許多爭議，究其原因可能與基礎研究還不夠成熟有關，如sTREM-1通過何種獨特的路徑在炎性反應中發揮負反饋作用，起著抗炎反應作用；其次是sTREM-1的天然配體仍然未明確，研究提示其可能是一種表達于血小板表面的蛋白，但是分子結構仍然不清楚。sTREM-1和TLR-4均在炎性反應中起著非常關鍵的作用，兩者的關系有待研究。隨著越來越多的學者對sTREM-1的關注，研究方法和手段的不斷進步，檢測方法不斷提高和完善，這些問題最終都可以解決，sTREM-1有望為炎性反應的調控和治療帶來突破，為臨床上感染性疾病的診斷和預后的判斷帶來幫助。

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