TNFα是一種作用很強的細胞因子,除對腫瘤細胞有特異的殺傷作用外,還有抗病毒、激活T細胞、促進細胞因子分泌和誘發(fā)炎癥反應等重要生物功能。本組實驗觀察到,TNFα刺激16HBE引起ICAM1mRNA表達增高,與以往的報道類似〔7〕,TNFα可誘導一系列與炎癥有關的細胞因子〔如IL1、IL6、IL8、粒細胞巨噬細胞集落刺激因子(GMCSF)〕、黏附分子〔如ICAM1、血管細胞間黏附因子1(VCAM1)〕的生成,通過誘導這些因子的產(chǎn)生和釋放,造成機體炎癥損傷,同時,通過再激活炎癥效應細胞,釋放更多的炎性因子,使炎癥信號進一步放大和加強。本實驗還顯示,不同濃度EM作用于16HBE 24 h或48 h后,再用TNFα刺激16 h,與僅用TNFα刺激組比較,16HBE ICAM1mRNA表達均降低,提示有濃度和時間依賴性。本實驗從分子水平上說明EM能抑制ICAM1mRNA表達,且與其作用濃度和時間相關,這一機制可能是EM抗炎作用機制之一。在國外,Suzuki等〔8〕研究發(fā)現(xiàn),EM抑制病毒感染人氣管上皮細胞導致的ICAM1分泌從而調(diào)節(jié)氣道炎癥。Sanz等〔9〕報告在老鼠體內(nèi)實驗中,EM抑制白細胞在肺內(nèi)的聚集,其機制是通過下調(diào)ICAM1mRNA和VCAM1 mRNA表達。Li等〔10,11〕研究結果顯示大環(huán)內(nèi)酯類抗生素能抑制博來霉素誘導大鼠的急性肺損傷和肺纖維,其作用機制主要是通過抑制ICAM1mRNA和VCAM1mRNA表達從而抑制白細胞特別是中性粒細胞向氣道內(nèi)遷移。有臨床實驗證明,長期小劑量EM治療COPD患者,可顯著減少患者感冒發(fā)生率,對阻止COPD患者病情惡化有良好的效果,這種效果是EM的抗炎而非抗菌機制所致,可能與EM能抑制16HBE表達和釋放IL6、IL8和ICAM1有關〔12〕。
【參考文獻】
1 Koyama H,Geddes DM.Erythromycin and diffuse panbronchiolitis〔J〕. Thorax,1997;52(10):9158.
2 Gotfried MH.Macrolides for the treatment of chronic sinusitis,asthma,and COPD〔J〕.Chest,2004;125(2):S5260醫(yī).學.全.在.線m.52667788.cn.
3 Rubin BK,Henke MO.Immunomodulatory activity and effectiveness of macrolides in chronic airway disease〔J〕.Chest,2004;125(2):708.
4 Seemungal TA,Wilkinson TM,Hurst JR,et al.Longterm erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations〔J〕.Am J Respir Crit Care Med,2008;178(11):113947.
5 Takizawa H,Desaki M,Ohtoshi T,et al.Erythromycin modulates IL8 expression in normal and inflamed human bronchial epithelial cells〔J〕.Am J Respir Crit Care Med,1997;156(1):26671.
6 Takizawa H,Desaki M,Ohtoshi T,et al.Erythromycin suppresses interleukin 6 expression by human bronchial epithelial cells:a potential mechanism of its antiinflammatory action〔J〕.Biochem Biophys Res Commun,1995;210(3):7816.
7 薛玉文,李 玉,王 玲,等.紅霉素抗哮喘氣道炎癥機理的研究〔J〕.免疫學雜志,1998;14(3):1845.
8 Suzuki T,Yamaya M,Sekizawa K,et al.Erythromycin inhibits rhinovirus infection in cultured human tracheal epithelial cells〔J〕.Am J Respir Crit Care Med,2002;165(8):11138.
9 Sanz MJ,Nabah YN,CerdaNicolas M,et al.Erythromycin exerts in vivo antiinflammatory activity downregulating cell adhesion molecule expression〔J〕.Br J Pharmacol,2005;144(2):190201.
10 Li Y,Azuma A,Takahashi S,et al.Fourteenmembered ring macrolides inhibit vascular cell adhesion molecule 1 messenger RNA induction and leukocyte migration:role in preventing lung injury and fibrosis in bleomycinchallenged mice〔J〕.Chest,2002;122(6):213745.
11 Li Y,Azuma A,Usuki J,et al.Attenuated mRNA induction of molecules associated with neutrophil migration by 14membered ring macrolides inhibits bleomycin induced acute lung injury in mice〔J〕.J Nippon Med Sch,2002;69(3):25261.
12 Suzuki T,Yanai M,Yamaya M,et al.Erythromycin and common cold in COPD〔J〕.Chest,2001;120(3):7303.