盐酸戊乙奎醚对急性肺损伤患者Toll样受体4表达的影响

目的 观察急性肺损伤(ALI)患者早期应用盐酸戊乙奎醚治疗效果;早期应用盐酸戊乙奎醚治疗ALI患者外周血单核细胞Toll样受体4(TLR4)表达及其下游炎症因子和血清中抗炎因子的表达变化;探讨TLR4在ALI过程中的参与机制.方法 2007/年9月至2008年8月,南京军区南京总医院急救医学科重症监护病房收治的45例ALI患者.全部患者符合国内外普遍应用的ALI诊断标准.45例ALI患者随机分成盐酸戊乙奎醚治疗组(实验组,n=21)和常规治疗组(对照组,n=24).两组均给予常规综合治疗,实验组在常规综合治疗基础上加用盐酸戊乙奎醚治疗,1 mg,肌注,1次/12h.观察两组48 h临床疗效、动脉血气、细胞因子等的变化,流式细胞仪即时检测血液中TLR4的表达变化.两组间均数比较用成组t检验,组内各时间点与0 h的比较采用配对t检验.两组率的比较采用Fisher精确概率法.结果 治疗后心率、呼吸频率48 h两组均较0 h有改善,组间无统计学差异(P>0.05),两组PaO_2和PaO_2/FiO_2均逐渐升高,6 h,24 h,48 h实验组改善优于对照组(P<0.05);加用盐酸戊乙奎醚治疗可明显缩短患者在ICU监护治疗的时间(P<0.01);流式细胞仪TLR4检测显示,0 h两组患者TLR4表达水平明显高于正常健康体检者(P<0.01);治疗后24 h、48 h两组患者TLR4均较0 h下降(P<0.05),实验组下降幅度大于对照组24 h(P<0.05),48 h(P<0.01),且两组TLR4水平0 h就明显升高的患者预后不良,大部分发展为ARDS;24 h ARDS发生率实验组为23.8%,对照组为29.17%,至48 h对照组又有2例进展为ARDS,实验组无再发患者;细胞因子检测:0～48 h IL-1、IL-广8和TNF-α浓度两组均进行性下降,其中24 h IL-8和TNF-α实验组较对照组下降明显(P<0.05),48 h三者实验组均较对照组下降明显(P<0.05);IL-13在0～24 h进行性升高,48 h较24 h略有下降,与0 h相比组内有统计学差异(P<0.05),组间无统计学差异.结论 盐酸戊乙奎醚能够早期改善氧合、抑制TLE4的表达,使其传导通路下游炎症因子表达下降,这种对炎症因子的抑制作用并非是通过早期上调抗炎介质而是通过下调TLR4来实现的,盐酸戊乙奎醚可能成为急性肺损伤治疗的重要药物.TLR4在急性肺损伤发生、发展的病理过程中有重要作用,并可以考虑作为判断ALI预后的参考标志.

Effect of penehyclidine hydrochloride on the expression of Toll-like receptor 4 during acute lung injury

Objective To observe the effects of penehydidine hydrochloride (PHC) on t acute lung injury ( ALI) . To investigate into the expression of TLR4 on peripheral monocytes, kinetics of inflammatory and anti- inflammatory mediators. To explore the mechanism of TLR4 in ALI. Method A total of 45 patients with ALI were randomly divided into PHC treatment group(experimental group, n =21) and routine treatment group (control group, n = 24) . Patients of both groups were given with the routine treatment,and patients in experimental group were given with PHC in addition (1 mg,im,ql2h) . Therapeutic effects, average length of hospital stay, ICU stay,PaO_2 and PaO_2/FiO_2 > as well as the expression of TLR4 and some cytokines were observed for 48 hours. Results Patients of both groups got better gradually after treatment. The PaO_2 and PaO_2/FiO_2 of patients of both groups progressively increased. At 6 hours, 12 hours, 24 hours and 48 hours after treatment, the PaO_2 and PaO_2/FiO_2significantly increased than 0 hour ( P < 0.05). The improvement in experimental group was obviously better than that in control group at 6 hours, 24 hours and 48 hours after treatment (P < 0.05). There were no differences in average length of hospital stay between the two groups. The ICU stay was significantly shorter in the experimental group ( P < 0.01) . The expressions of TLR4 were higher in patients of both groups than in healthy ones (P <0.01) . TLR4 decreased significantly at 24 hours and 48 hours, while it was lower in experimental group than that in the control group (P < 0.05). The higher level of TLR4in the early stage implied worse prognosis. Most of them deteriorated to ARDS stage. At 24 hours, the incidence of ARDS in experimental group was 23.8 % , and 29.17% in control group. Two patients in control group didn' t become ARDS till 48 hours. Serum IL-1, IL-8 and TNF-α level reduced atr 24 hours in both groups. The reduction of IL-8 and TNF-α in experimental group was more obvious than in control group ( P < 0.05). IL-13 increased gradually from 0 hour to 24 hours, then descended a little at 48 hours. There was no difference in IL-13 some difference between the two groups ( P > 0.05) . Conclusions PHC can improve the arterial oxygen pressure, down-regulate TLR4, restrain inflammatory factors in its signal transduction downstream. This inhibitory action is not accomplished by increase in anti-inflammatory factors,but by down-regulating TLR4. PHC can prevent the development of ALI, and can be considered to act as an effective medicine for the treatment of ALI. TLR4 plays an important role in ALT process, and it is suggested that TLR4 can be used as a prognostic factor.