急性低氧应激反应在高原肺水肿发生中的作用.pdf

；20242024年JOURNALOFCHINESEALTITUDEMEDICINEANDBIOLOGYVol.45No.1之第1期第45卷中国高原医杂志与生物急性低氧应激反应在高原肺水肿发生中的作用*郝承潇，张景宣，张长欢，山婷，谢发龙，张伟1.2（1.青海大学医学部，西宁8 10 0 0 1;2.高原医学教育部重点实验室，西宁810001)摘要目的明确急性低氧应激反应与高原肺水肿发生的关系。方法将SD雄性大鼠随机分为对照组和美替拉酮药物组，对照组于腹腔注射生理盐水（0.0 5mL/100g），药物组于腹腔注射美替拉酮（50 mg/kg0.05mL/100g）；将两组大鼠再次分为常氧组（西宁，大气压为582mmHg，PO，为12 1.6 mmHg）和急性低氧不同时间（6 h、12 h、2 4h）处理组（模拟海拔7 0 0 0 m，大气压为30 8 mmHg，PO，为6 4.3mmHg）。应用DSI-BUXCO无创呼吸功能检测系统检测大鼠肺功能；应用EvansBlue含量测定法检测大鼠肺微血管通透性；应用HE染色法观察肺组织形态学改变；应用WesternBlot法检测大鼠肺组织内皮素-1（ET-1）相对表达量；应用ELISA法检测大鼠血清促肾上腺皮质激素释放激素（CRH）和皮质酮（CORT）含量。结果较对照常氧组，对照低氧组的潮气量（TV）每分通气量（MV）和呼吸中期流速（EF50）显著降低（P0.05），气道阻力（RaW）显著上升（P0.05）。较对照低氧组，药物低氧组的呼吸频率（FR）有下降趋势较对照常氧组，对照低氧组肺微血管通透性显著增加（P0.05）较药物常氧组，药物低氧组肺微血管通透性显著增加（P0.05）。急性低氧各组肺泡腔内有液体和红细胞渗出，药物低氧2 4h组肺泡腔和间质中的渗出最明显。较对照组，对照低氧2 4h组血清CRH含量显著上升（P0.05）。药物组血清CRH含量显著高于对照组（P0.05）。较对照常氧组，对照低氧各组血清CORT含量均显著增加（P0.05）。药物低氧组血清CORT含量显著低于对照低氧组（P 0.0 5）。较对照常氧组，对照低氧各组ET-1相对表达量明显增加（P0.05）。较对照组，药物组ET-1相对表达量显著升高（P0.05）。ET-1多肽表达量与肺组织EvansBlue、血清CORT含量呈正相关。结论在急性低氧引发的应激反应中，CRH、C O R T 的增加起着重要的代偿作用：通过抑制肺组织释放ET-1，防止缺氧性肺血管过度收缩，从而保护肺微血管免受损害并抑制肺水肿发生关键词低氧应激；肺功能；肺微血管通透性；内皮素-1；促肾上腺皮质激素释放激素；皮质酮中图分类号R363文献标志码马AD0110.13452/ki.jqmc.2024.01.001Role of acute hypoxic stress response in the occurrence of highaltitude pulmonary edemaHAO Chengxiao,ZHANG Jingxuan,ZHANG Huan,SHAN Ting,XIE Falong,ZHANG Weijl-*(1.Medical Department of Qinghai University,Xining 810001,China;2.Key Laboratory of Plateau Medicine,Min-istryofEducation,Xining810001,China)收稿日期：2 0 2 3-12-17修回日期：2 0 2 4-0 2-2 4：国家自然科学基金项目（No.81560301），青海省科技厅项目（2 0 2 2-ZJ-905），青海省“昆仑英才高端创新创业人才”计划杰出人才项目*：通信作者，教授，博士生导师，郝承（1997 一），男，藏族，甘肃籍，在读硕士研究生Abstract Objective To clarify the relationship between acute hypoxic stress response and the occurrence ofhigh altitude pulmonary edema.Methods Male SD rats were randomly divided into control group and metyraponetreatment group.The control group was intraperitonelly injecied with normal saline(0.05 ml/100 g),and the drugtreatment group was intraperitoneally injected with metyrapone(50 mg/kg,0.05 mL/100 g).The two groups werefurther divided into normoxia group(Xining,atmospheric pressure 582 mmHg,PO,121.6 mmHg)and acute hy-poxia treatment groups for dfferent time(6h,12h and 24 h)(simulated altitude of7000 m,atmospheric pressure308 mmHg,PO,64.3 mmHg).The lung function of rats was detected by DSI-BUXCO non-invasive respiratoryfunction detection system.Evans Blue content determination method was adopted to measure the pulmonary micro-vascular permeability.HE staining was used to observe the morphological variations of lung tissue.The expressionof endothelin-1(ET-1)in lung tissue was detected by Western Blot.The serum levels of corticotropin-releasinghormone(CRH)and corticosterone(CORT)were detected by enzyme-linked immunosorbent assay(ELISA).Re-sults Compared with the control normoxia group,the tidal volume(TV),minute ventilation(MV)and mid-expi-ratory flow rate(EF50)of the control hypoxia group were significantly reduced(P0.05),while airway resistance(Raw)was significantly increased(P0.05).Compared with the control hypoxia group,the respiratory rate(FR)ofthe drug hypoxia group showed a downward trend.Compared with the control normoxia group,the pulmonary mi-crovascular permeability of the control hypoxia group was significantly increased(P0.05).Compared with thedrug normoxia group,the pulmonary microvascular permeability of the drug hypoxia group was significantly in-creased(P0.05).There was exudation of fluid and red blood cells in the alveolar space of the acute hypoxiagroup.The exudation of alveolar space and interstitial space was the most obvious in the drug hypoxic 24 h group.Compared with the control group,the level of serum CRH in the control hypoxia 24 h group was significantly in-creased(P0.05).The level of serum CRH in the drug group was significantly higher than that in the control group(P0.05).Compared with the control normoxia group,the levels of serum CORT in the control hypoxia groupswere significantly increased(P0.05).The level of serum CORT in the drug hypoxia group was significantly lowerthan that in the control hypoxia group(P0.05).Compared with the control normoxia group,the expression ofET-1 in the control hypoxia group was significantly increased(P0.05).Compared with the control group,the rela-tive expression of ET-1 in the drug group was significantly increased(P0.05).The expression of ET-1 poly-peptide is positively correlated with the content of Evans Blue in lung tissue and serum CORT.Conclusions Theincrease of CRH and CORT plays a crucial compensatory role in the stress response induced by acute hypoxia,which might be achieved by inhibiting the release of ET-1 from lung tissue,preventing excessive contraction of hy-poxic pulmonary vessels,thereby protecting the lung microvessels from damage and suppressing the occurrence ofpulmonaryedema.Keywords hypoxia stress;lung function;pulmonary microvascular permeability;endothelin-l;corticotro-pin-releasing hormone(CRH);corticosterone(CORT)目前认为高原肺水肿（HAPE）的发生机制主要为低氧性肺动脉压力过度增高、肺血管通透性增高、肺水清除障碍、液体贮留及体液转运失调,其中低氧性肺动脉压力过度增高和肺血管通透性增高是其发生的主要原因。急性低氧应激反应是以急性低氧为应激源刺激机体做出的非特异性适应反应2 ，在反应中，下丘脑一垂体-肾上腺皮质(HPA)系统被激活，皮质醇（CORT)的释放增加。CORT作用于肺血管平滑肌的糖皮质激素受体（C R），通过抑制炎症反应、调节水电解质平衡、调控血管张力影响肺动脉压力和肺血管通透性。本研究在急性低氧应激动物模型上应用肾CORT抑制剂美替拉酮,明确急性低氧应激反应与高原肺水肿发生的关系。1材料与方法1.1材料1.1.1实验动物SD雄性大鼠，8 周龄，2 50 g20g，购于广东维通利华实验动物技术有限公司许可证号：SCXK（粤）2 0 2 2-0 0 6 3。动物使用和实验程序按照中华人民共和国国家标准一实验动物质量控制要求(GB/T3491-2017)执行1.1.2实验仪器与试剂实验动物低压模拟舱购于西安富康空气净化设备工程有限公司（HCP-D 8 0 0），D SI-BU XC O 无创呼吸功能检测仪购于美国DSI公司；美替拉酮粉剂购于美国sigma公司。1.2方法1.2.1实验动物分组大鼠饲养在大鼠层流架中（温度为2 2 2，相对湿度为50%10%，光照周期为12 h，自由进食、饮水）。实验前适应性饲养1w，于第2 w开始实验。将大鼠随机分为对照组和美替拉酮药物组，对照组于腹腔注射生理盐水（0.0 5mL/100g）,药物组于腹腔注射美替拉酮（50 mg/kg，0.0 5mL/10 0 g）;将两组大鼠再次分为常氧组(西宁,大气压为58 2 mmHg，PO,为12 1.6 mmHg)和急性低氧不同时间（6 h、12 h、24h)处理组（模拟海拔7 0 0 0 m，大气压为30 8 mmHg，PO,为 6 4.3 mmHg)。1.2.2肺功能评估应用无创呼吸功能检测仪检测大鼠肺呼吸功能。采集参数包括呼吸频率（FR）、潮气量（TV）、每分钟通气量（MV）、呼吸中期流速（EF50）、气道阻力(Raw)。1.2.3肺微血管通透性评估应用Evans Blue含量测定法评估大鼠肺微血管通透性。经股静脉注射EvansBlue（2 5mg/k g），注射30 min后立即开胸，剪开左心耳连接输液装置，将注射针头插入肺动脉圆锥，灌注生理盐水至左心耳处无血性液体流出为止。取全肺，吸干表面水分及血渍，测定湿重。将肺组织剪成小块，加人PBS缓冲液（10 0 mL/100g），用组织研磨匀浆机振荡6 0 s后加人甲酰胺溶液（1mL/100mg）水浴（6 0，2 4h），离心（30 0 0 r/min，2 0 mi n）后取上清液，测定上清液及标准品在6 2 0 nm处的吸光度（OD)值。用标准品制作标准曲线，通过计算每克肺组织中EvansBlue含量反映肺毛细血管通透性。1.2.4肺组织形态观察用4%多聚甲醛固定肺组织，以常规方法制片，通过显微镜进行形态学观察1.2.5ET-1多肽相对表达量比较取大鼠适量肺组织，用RIPA裂解液裂解，提取蛋白，用BCA蛋白浓度试剂盒测定蛋白浓度后进行SDS-PAGE电泳，经蛋白转移、显色，加一抗、二抗，在化学发光仪上曝光，之后再利用Image-J软件分析蛋白灰度值。1.2.6血清CRH、C O R T 检测麻醉(用2 0%乌拉坦于腹腔注射)大鼠后,采用促凝管经腹主动脉收集大鼠全血，静置1h离心（30 0 0 r/m i n，10 m i n），用移液器吸取血清至EP管中，置-6 0 冰箱保存，用于CRH、C O R T 含量测定。自然解冻待测血清，将梯度稀释的标准品和待测血清加人由一抗包被的96 孔板。为每个样品设置2个复孔，按ELISA试剂盒说明书操作，最后测定450 nm处的OD值。根据试剂盒自带已知浓度的标准品OD值绘制标准曲线，计算待测样品CRH、C O R T含量。1.2.7统计学处理采用SPSS27.0软件进行统计学分析。实验数据以xs表示，组间比较采用单因素方差法分析，变量间相关性采用Pearson相关法分析。视P0.05），但呈增加趋势，TV、M V、EF50呈下降趋势；对照低氧6 h组的TV、M V显著降低（P0.05），对照低氧12 h组的TV、M V、EF50 显著降低（P0.05），对照低氧2 4h组的EF50明显下降（P0.05）对照低氧各组Raw呈上升趋势，对照低氧2 4h组的Raw明显上升（P 0.0 5）,但呈降低趋势；药物低氧各组TV、M V呈下降趋势；药物低氧6 h组和药物低氧12 h组的TV、M V显著降低（P0.05）。与对照低氧2 4h组比较,药物低氧2 4h组的FR明显下降(P0.05）。与药物低氧6 h组比较，药物低氧2 4h组的EF50明显上升（P0.05）。具体数据见表1。2.2对肺微血管通透性的评估与对照常氧组比较，对照低氧各组肺微血管通透性呈增加趋势，对照低氧12 h组、2 4h组的肺微血管通透性均明显增加（P0.05）。与对照低氧6 h组比较，对照低氧2 4h组的肺微血管通透性明显增加(P0.05）。与药物常氧组比较,药物低氧各组肺微血管通透性呈增加趋势，药物低氧12 h组和2 4h组肺微血管通透性显著增加(P0.05)。与药物低氧6 h组比较,药物低氧12 h组和2 4h组肺微血管通透性显著增加（P0.05）。具体数据见表2。表1各组大鼠肺通气功能检测结果（x士s）Table1Pulmonary function test results of rats in each group(x+s)groupsFR(BPM)TV(mL)MV(mL/min)Raw(cmH,OxS/mL)EF50(mL/s)Control(n=6)Normoxia134.2011.072.970.41392.8063.01.250.4217.282.86Hypoxia 6h154.6017.321.480.55a222.7076.36a3.301.6210.494.28Hypoxia 12h152.1021.311.480.21a220.8035.82a3.261.419.661.874Hypoxia 24h161.8011.411.950.67303.40115.24.001.36a9.633.93aDrug(n=6)Normoxia153.0020.032.490.85373.80129.41.360.5914.934.97Hypoxia 6h141.7014.811.280.65176.9093.31e2.981.498.191.92Hypoxia 12h152.309.601.280.37190.6050.84c3.141.6310.183.91Hypoxia 24h133.1017.95d2.250.97299.60135.72.520.9715.445.9fF2.6726.1194.8843.7234.641P0.0220.0010.0010.0030.001a：与对照常氧组比较，P0.05;d：与对照低氧2 4h组比较，P0.05;e:与药物常氧组比较，P0.05;f:与药物低氧6 h组比较，P0.05表2各组大鼠肺组织EvansBlue含量（mg/g，x s）Table 2Evans Blue content in lung tissue of rats in each group(mg/g,xs)groupsEvans Blue(mg/g)Control(n=3)Normoxia0.110.05Hypoxia 6h0.150.03Hypoxia 12h0.230.04aHypoxia 24h0.270.09abDrug(n=3)Normoxia0.100.04Hypoxia 6h0.190.06Hypoxia 12h0.300.07dHypoxia 24h0.300.08dF5.200P0.030a：与对照常氧组比较,P0.05;b：与对照低氧6 h组比较，P0.05;c:与药物常氧组比较,P0.05;d:与药物低氧6 h组比较，P0.052.3对各组大鼠血清CRH、C O R T 含量的比较与对照常氧组比较，对照低氧各组血清CRH含量呈增加趋势，对照低氧2 4h组血清CRH含量显著增加(P0.05）,对照低氧12 h组血清CRH含量显著增加(P0.05），但呈增加趋势。与对照组比较,药物组血清CRH含量呈增加趋势，药物常氧组血清CRH含量显著高于对照常氧组（P0.05）,药物低氧6 h组血清CRH含量高于对照低氧6 h组（P0.05）。相较于对照常氧组，对照低氧各组血清CORT含量均显著增加(P0.05)。对照低氧2 4h组血清CORT含量显著高于对照组(P0.05)。与药物常氧组比较,药物低氧各组血清CORT含量呈增加趋势，药物低氧12 h组和2 4h组血清CORT含量显著增加(P0.05)。与对照组比较，药物组血清CORT含量呈下降趋势，药物低氧6 h组血清CORT含量显著低于对照低氧6 h组(P0.05）。药物低氧12 h组血清CORT含量显著低于对照低氧12 h组（P0.05）。药物低氧2 4h组血清CORT含量显著低于对照低氧2 4h组（P0.05）。具体数据见表3。表3各组大鼠血清CRH和CORT含量（s）Table3Content of serum CRH and CORT of rats in each group(x+s)groupsCRH(ng/mL)CORT(ng/mL)Control(n=3)Normoxia9.752.4126.843.44Hypoxia 6h18.065.3336.292.31aHypoxia 12h19.676.80a37.905.25aHypoxia 24h40.14 11.65 abc45.391.24abcDrug(n=3)Normoxia25.334.04a22.482.15Hypoxia 6h32.823.63b26.034.35bHypoxia 12h28.981.1730.974.87ceHypoxia 24h31.871.9235.182.50defF8.98713.512P0.0010.001a:与对照常氧组比较，P0.05;b：与对照低氧6 h组比较，P0.05;c：与对照低氧12 h组比较，P0.05;d:与对照低氧2 4h组比较，P0.05;e:与药物常氧组比较,P0.05;f:与药物低氧6 h组比较，P0.052.4对各组大鼠肺组织ET-1多肽表达水平的比较与对照常氧组比较,对照低氧各组ET-1相对表达量明显增加（P0.05）。对照低氧2 4h组ET-1相对表达量显著高于对照组(P0.05）。药物常氧组ET-1相对表达量显著高于对照常氧组(P0.05)。药物低氧12 h组ET-1相对表达量显著高于对照低氧12h组、药物常氧组和药物低氧6 h组（P0.05）。药物低氧2 4h组ET-1相对表达量显著高于药物常氧组和药物低氧6 h组（P0.05)。具体数据见表4、图1。表4各组大鼠肺组织ET-1多肽表达水平（s）Table 4Expression of ET-1 polypeptide in lung tissue of rats in each group(x+s)groupsET-1Control(n=3)Normoxia0.580.02Hypoxia 6h0.880.05aHypoxia 12h0.930.034Hypoxia 24h1.160.01abcDrug(n=3)Normoxia0.810.07aHypoxia 6h0.860.12Hypoxia12h1.130.05cdeHypoxia 24h1.160.04deF35.936P0.001a:与对照常氧组比较，P0.05;b：与对照低氧6 h组比较,P0.05;c:与对照低氧12 h组比较,P0.05;d：与药物常氧组比较,P0.05;e:与药物低氧6 h组比较,P0.056-actin45KDET-135KDNH6hH12hH24hNH6hH12hH24hControlDrug图1各组大鼠肺组织ET-1多肽表达图Figure1Expression levels of ET-1 polypeptide in lung tissue of rats in each group2.5对肺组织ET-1多肽表达水平与肺EvansBlue含量、血清CORT含量相关性的分析肺组织ET-1多肽表达水平与肺EvansBlue含量、血清CORT含量相关性分析结果显示，ET-1多肽表达量与肺组织EvansBlue含量、血清CORT含量呈正相关（r=0.7078,P0.001;r=0.6157,P0.01)，具体数据见图2、图3。0.47r=0.7078P0.0010.3-0.20.10.00.51.01.5ET-1T-1:肺内皮素-1;EB:肺Evans Blue图2 肺组织ET-1多肽表达水平与EvansBlue含量相关性分析图Figure 2 Correlation analysis between the expression level of ET-1 polypeptide and Evans Blue content in lung tissue1.57r=0.6157P0.011.0-0.50.020304050CORTET-1:肺内皮素-1;CORT:血清皮质酮图3肺组织ET-1多肽表达水平与血清CORT含量相关性分析图Figure3Correlation analysis between the expression level of ET-1 polypeptide in lung tissue and serum CORT content2.6对各组大鼠肺组织病理结构的观察在40 倍镜下观察肺组织，各常氧组肺泡壁轮廓清晰、结构完整，肺泡腔内无渗出，肺间质无渗出，无炎性细胞浸润；低氧各组表现出不同程度的肺组织结构损伤，肺泡结构完整性受损，肺间质中有水肿液渗出，部分肺泡中有红细胞浸润，药物低氧2 4h组肺泡腔内液体渗出，红细胞渗出更明显具体情形见图4。Control groupNormoxiaHypoxia 6hHypoxia 12hHypoxia 24hDrug groupNormoxiaHypoxia 6hHypoxia 12hHypoxia 24h：渗出物图4各组大鼠肺组织HE染色切片图（HE染色，40）Figure4HE stained sections of lung tissue in each group(HE staining,4Ox)3讨论对新进人30 0 0 m及以上海拔的人群，会出现应激反应3。低氧应激反应会引起下丘脑-垂体-肾上腺皮质（HPA)和交感-肾上腺髓质系统（SAM)激活4。HPA作为神经内分泌免疫网络的枢纽，在机体内环境平衡中起着十分重要的作用。神经内分泌的调控主要是CRH与其受体结合，导致糖皮质激素（CC)分泌调动机体各系统参与应激反应5.6 GC在人体内表现为皮质醇,在大鼠体内表现为皮质酮7 。研究发现,GC能够通过降低白细胞介素-1(IL-1）、白细胞介素-6(IL-6)和肿瘤坏死因子-（T NF-）进而降低ET-1的生物合成和释放(8.9。ET-1的合成和释放可以被低氧诱导10.1。在低氧条件下，ET-1可以通过激活电压门控钙离子通道增加细胞内钙离子浓度，从而引起肺动脉平滑肌细胞的收缩12 ,也可以通过抑制ATP敏感的钾离子通道的活性，导致肺动脉平滑肌细胞的去极化，进而促使细胞内钙离子浓度升高，使肺动脉平滑肌收缩13,发生低氧性肺血管收缩(HPV)14,将血液从通气不良的肺血管区域分流到氧气丰富的地方，优化肺换气。但HPV的持续存在会导致血管重构，致使肺动脉高压进行性发展，当血管压力超过了肺泡毛细血管屏障维持正常液体平衡的结构能力时因肺泡毛细血管通透性增加而导致的液体渗出增加，从而促进HAPE发生。在本研究中，对照低氧组大鼠肺组织ET-1多肽表达量和肺微血管通透性明显增加；在阻断GC生成后,ET-1多肽的表达量和肺微血管的通透性增加更为明显；在阻断GC生成后的低氧2 4h组，观察到肺泡液体渗出较其他各组明显增加，这些进一步印证了GC对HAPE发生的抑制作用。在肺功能检测结果中,对照低氧组的TV、M V明显下降,EF50显著降低，Raw明显升高,提示大鼠在急性低氧2 4h内，在一定程度上出现了气道的狭窄和肺功能的下降。在急性低氧初期，,SAM激活，肾上腺素和去甲肾上腺素使呼吸中枢兴奋，致呼吸运动加深加快，当呼吸加深加快时气流速度也随之加快，气流速度和气道阻力之间成正比关系，当气流通过呼吸道形成流时气道阻力进一步增大15。有研究指出16 ,在急进高原者的鼻细胞学检查发现中心粒细胞比例升高,鼻腔黏液纤毛转运率降低；鼻功能检测发现Raw明显增加，EF50明显下降。在海拔上升过程中，长期的高通气量和高呼吸频率使呼吸肌的耐力随着低氧时间的推移而下降17 ，从而使肺通气指标和流速指标明显降低。皮质类激素在预防和治疗HAPE方面的效果已经得到了证实18.19,其机制除了上述提及的抑制ET-1生成之外,GC可通过增加肺血管内皮一氧化氮合酶(eNOS)的表达和一氧化氮(NO)的产生来降低肺血管阻力2 0.2 1,还可能通过减少肺血管交感神经张力来降低肺动脉压力18 。此外，还可以增加肺表面活性物质的分泌，从而降低肺泡-毛细血管跨膜压力差，减少血管通透性，从而降低肺血管阻力2 1综上所述，在急性低氧引发的应激反应中，CRH、C O R T 的增加起着重要的代偿作用，它们可能通过抑制肺组织ET-1的释放，防止缺氧性肺血管收缩过度，从而保护肺微血管免受损害并抑制肺水肿发生。8（责任编辑：陈芃）参考文献1高文祥,吴刚,徐立聪，等.高原肺水肿发生机制与临床转化的现状与展望J.生物医学转化,2 0 2 1,2(2)：1-7+7 1.2纪巧荣，张伟.交感-肾上腺素系统与低氧应激J.青海医学院学报，2 0 16，37（4）：2 7 7-2 8 0+2 8 5.3 Nelson ML,Cons JM.Pituitary hormones and growth re-tardation in rats raised at simulated high altitude(3800m)J.Environ Physiol Biochem,1975,5(5):273-282.4 Knezevic E,Nenic K,Milanovic V,et al.The Role ofCortisol in Chronic Stress,Neurodegenerative Diseases,andPsychological DisordersJ.Cells,2023,12(23):2726.5 Dautzenberg FM,Hauger RL.The CRF peptide familyand their receptors:yet more partners discovered J.TrendsPharmacol Sci,2002,23(2):71-77.6 Bu G,Fan J,Yang M,et al.Identification of a NovelFunctional Corticotropin-Releasing Hormone(CRH2)in Chick-ens and Its Roles in Stimulating Pituitary TSH Expressionand ACTH Secretion J.Front Endocrinol(Lausanne),2019(10):595.7刘志元.不同运动应激状态下丘脑-垂体-肾上腺轴应激反应机制研究D.苏州：苏州大学,2 0 10.8孙玉景，吴建华，任建国，等.糖皮质激素在脓毒症治疗中研究进展J.中国老年学杂志，2 0 2 2,42(17)：436 5-436 9.9 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