参麦对内毒素型急性肺损伤家兔血清TNF-α、IL-6变化的研究

目的探讨参麦注射液对内毒素型急性肺损伤（ALI）家兔血清TNF-α、IL-6的变化,评价参麦对ALI的保护作用。方法24只家兔随机分为3组：正常对照组、单纯急性肺损伤（ALI）组和参麦治疗组（内毒素型ALI＋参麦治疗）,采用内毒素（LPS）制备成急性肺损伤（ALI）家兔模型后即进行参麦治疗,观察不同时段的血清TNF-α、IL-6的变化及左肺叶组织湿质量/干质量（W/D）值。结果参麦注射液可明显缓解内毒素所致肺损伤,与对照组比较血清TNF-α、IL-6活性、血氧分压有明显改善,经参麦治疗后,W/D值明显下降,渗出减轻。结论TNF-α、IL-6在家兔内毒素型急性肺损伤（ALI）炎症过程中可能起重要作用,参麦注射液可能通过抑制TNF-α、IL-6过量分泌,减轻肺损伤,具有防治ALI作用。     

Tanshinone IIA suppresses lung injury and apoptosis, and modulates protein kinase B and extracellular signal-regulated protein kinase pathways in rats challenged with seawater exposure

1. Tanshinone IIA (TIIA) is one of the main active components of the Chinese herb, Danshen. In the present study, we investigated the role of apoptosis in seawater exposure-induced acute lung injury (ALI), and explored the effects of TIIA on lung injury, apoptosis, and protein kinase B (Akt) and extracellular signal-regulated protein kinase (ERK) pathways in seawater-challenged rats. The rats were randomly divided into four groups: (i) naive group, no drug was given; (ii) TIIA control group, TIIA (50 mg/kg) was given intraperitoneally; (iii) seawater (SW) group, seawater (4 mL/kg) was given; and (iv) TIIA/SW group, TIIA (50 mg/kg) was injected intraperitoneally 10 min after seawater instillation. 2. The results showed that TIIA treatment significantly improved seawater exposure-induced lung histopathological changes, alleviated the decrease in PaO(2) , and reduced lung oedema, vascular leakage and cell infiltration. As shown by terminal deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) assay, seawater exposure induced apoptosis in lung tissue cells. Furthermore, seawater exposure also changed apoptosis-related factors Bcl-2 and caspase-3, and caused a reduction in the activation of Akt and ERK1/2 pathways. Furthermore, TIIA treatment decreased the number of apoptotic cells, reversed changes in Bcl-2 and caspase-3, and upregulated the activation of Akt and ERK1/2 in seawater-challenged rats. 3. In conclusion, the data suggest that apoptosis might play an important role in seawater exposure-induced lung injury and that TIIA could significantly attenuate the severity of ALI and apoptosis in seawater-challenged rats, which is possibly through modulation of Akt and ERK1/2 pathways.     

地塞米松对重症胎粪吸入新生兔环氧化酶水平的影响

目的 观察地塞米松对重症胎粪吸入新生兔环氧化酶水平的影响.方法 将24只新生兔完全随机分为空白组、生理盐水组、地塞米松组,每组8只.空白组气管插管后不灌胎粪;后2组气管插管后注入胎粪混合物,地塞米松组在胎粪灌入后1和3 h静脉注射地塞米松,生理盐水组在同时间静脉注射等量生理盐水.3组均比例辅助通气模式机械通气,以维持正常潮气量、正常血氧饱和度及正常血气值,8 h后处死,取肺泡灌洗液,制备肺组织匀浆,用酶联免疫吸附法检测环氧化酶的含量.结果 3组间肺泡灌洗液和肺组织匀浆中环氧化酶I含量比较,差异均无统计学意义(均P＞0.05).空白组、生理盐水组、地塞米松组动物,肺泡灌洗液中环氧化酶2含量分别为(1.07±0.84)、(3.98±0.54)、(2.58±0.43)μg/L,肺组织匀浆中分别为(1.22±0.77)、(6.14±0.18)、(5.33±0.57)μg/L,3组间两两比较,差异亦均有统计学意义(均P＜0.05).结论 地塞米松可抑制环氧化酶2的表达,减轻胎粪吸入导致的肺部炎症反应.

Abstract：

Objective To observe the effect of dexamethasone on Cyclooxygenase in newborn rabbits with severe meconium aspiration syndrome. Methods Twenty four newborn rabbits were divided randomly into control group, saline group and dexamethasone group. Meconium solutions were injected into the endotracheal tube by 4 ml/kg in the two groups. Dexamethasone group intravenous injection of dexamethasone 0. 5 mg/kg at two doses 1h and 3h after meconium solutions instilled, Saline group received an equal volume of saline at the same points of time. All rabbits of three groups used proportional assist ventilation in order to maintain normal range of tidal volume (4-10mi/kg) and normal oxygen saturation (85% or more), The rabbits were killed at 8h after meconium instillation,lungs and trachea were excised. The Cyclooxygenase was tested by enzyme-link immunosorbent assay(ELISA) which in bronchoalveolar lavage fluid(BALF) and lung homogenate, and compared among three groups. Results Among the three groups, there was no statistically significant difference in bronchoalveolar lavage fluid and lung homogenate ( P ＞ 0. 05 ) levels of cyclooxygenase-1. Compared the levels of cyclooxygenase-2 in control group, saline group and dexamethasone group, in bronchoalveolar lavage fluid[( 1.07 ±0. 84) μg/L, (3.98 +0.54) μg/L, (2.58 +0.43)μg/L] the differences were significant ( P ＜ 0.05 ), in lung homogenate [( 1.22 ± 0. 77) μg/L, (6. 14 + 0. 18) μg/L,(5.33 + 0. 57) μg/L], the differences were significant ( P ＜ 0.05 ). Conclusion Dexamethasone inhibites the expression of COX-2, alleviates the lungs inflammation which is caused by meconium aspiration.     

Zileuton对局灶性脑缺血/再灌注致急性肺损伤的保护作用

目的探讨选择性5-脂氧合酶(5-LO)抑制剂zileu-ton对局灶性脑缺血/再灌注损伤(CIRI)引发急性肺损伤(ALI)的保护作用及其机制。方法线栓法制作大鼠大脑中动脉闭塞/再灌注(MCAO/R)模型,缺血2h,再灌注24h。于缺血前2h,再灌注0、5、10h,分别4次灌胃给予zileuton 10、50mg·kg-1。HE染色观察肺组织形态学改变;湿干重比(W/D)检测肺组织含水量;RT-PCR法检测肺组织白三烯受体1 mRNA(CysLTR1 mRNA);酶联免疫吸附法(ELISA)检测血清白三烯B4(LTB4)浓度;免疫组化法检测肺组织肿瘤坏死因子-α(TNF-α)蛋白;生化法检测肺组织髓过氧化物酶(MPO)、总抗氧化能力(T-AOC)和Na+,K+-ATPase活性。结果Zileuton10、50mg·kg-1均可改善肺组织病理变化,减少肺组织W/D比值(P<0.01),并下调肺组织CysL-TR1mRNA和TNF-α蛋白表达(P<0.05,P<0.01),降低血清LTB4浓度(P<0.01),缓解肺组织MPO升高和Na+,K+-ATPase活性下降(P<0.05,P<0.01),提高肺组织T-AOC(P<0.05,P<0.01)。结论Zileuton可有效抑制CIRI所致的ALI,其机制与抑制5-LO通路活性,减轻肺组织炎症反应、氧化损伤和离子转运障碍有关。     

Protective effect of U74500A on phorbol myristate acetate-induced acute lung injury

1. The present study was designed to determine whether U74500A could ameliorate acute lung injury (ALI) induced by phorbol myristate acetate (PMA) in our rat isolated lung model compared with any amelioration induced by dimethylthiourea (DMTU), superoxide dismutase (SOD) and catalase. 2. Acute lung injury was induced successfully by PMA during 60 min of observation. At 2 microg/kg, PMA elicited a significant increase in microvascular permeability (measured using the capillary filtration coefficient Kfc), lung weight gain, the lung weight/bodyweight ratio, pulmonary arterial pressure and protein concentration of the bronchoalveolar lavage fluid. 3. Pretreatment with 1.5 mg/kg U74500A significantly attenuated ALI; there was no significant increase in any parameters measured, except for pulmonary arterial pressure. The protective effect of U74500A was approximately the same as that of 600 mg/kg DMTU. However, 6000 U/kg SOD, 50,000 U/kg catalase and 6000 U/kg SOD + 50,000 U/kg catalase had no protective effect. 4. These experimental data suggest that U74500A significantly ameliorates ALI induced by PMA in rats.     

胸段硬膜外阻滞对油酸致猪急性肺损伤时呼吸力学的影响

目的观察胸段硬膜外阻滞对油酸致猪急性肺损伤（ALI）时呼吸力学的影响。方法选健康家猪14只,肌内注射氯胺酮20mg／kg、阿托品0．05mg／kg,动物入睡后,建立耳缘静脉液路,静脉注射2．5％硫贲妥钠10mg／kg,经口气管插管,机械控制呼吸,维持正常的PaCO2。将油酸0．1ml／kg用0．9％氯化钠溶液稀释至20ml,经颈内静脉以40ml／h的速率持续静脉输注造模。造模成功后,将动物随机分S组（n=7）：向硬膜外腔注入0．9％氯化钠溶液5ml;R组（n=7）：向硬膜外腔注入0．25％罗哌卡因5ml。随后2组均持续泵入0．9％氯化钠溶液或0．25％罗哌卡因,观察4h。通过麻醉机气道压监测系统连续监测吸气峰压（PIP）、平均气道压（MPaw）、内源性呼吸末正压（PEEPi）作为基础值,并分别于ALI成功时（T0）及给罗哌卡因或0．9％氯化钠溶液1h（T1）、2h（T2）、3h（T3）、4h（T4）测定上述值。实验结束后,取肺组织,在光镜下观察肺组织病理变化。结果与基础值比较,ALI模型建立时2组PIP、Mpaw、PEEPi均升高（P〈0．05）,DLC降低（P〈0．05）。2组基础及ALI模型建立时PIP、Mpaw、PEEPi和DLC差异无统计学意义（P〉0．05）,给药后各时间点R组PIP、Mpaw、PEEPi低于S组,DLC高于S组（P〈0．05或〈0．01）。光镜观察,R组肺组织病理学较S组明显减轻。结论胸段硬膜外阻滞可降低肺气道阻力,增加肺动态顺应性,改善肺组织的通气功能,对肺损伤有一定的保护作用。     

泮托拉唑对急性肺损伤模型大鼠和人肺微血管内皮细胞损伤的作用及作用机制

目的 探讨泮托拉唑对急性肺损伤(ALI)模型大鼠和人肺微血管内皮细胞(HPMECs)损伤的作用及作用机制.方法 将48只SD大鼠随机分为正常对照组,脂多糖组,阳性对照组,泮托拉唑低、高剂量组和泮托拉唑高剂量+氯喹组,各8只.除正常对照组外,其余各组大鼠均腹腔注射5 mg/kg脂多糖复制ALI模型;阳性对照组大鼠腹腔注射...     

Inhibition of poly(ADP-ribose) polymerase attenuates lung tissue damage after hind limb ischemia-reperfusion in rats.

The objective of this study was to investigate the effects of 3-aminobenzamide (3-AB) on tissue damage in lung after hind limb ischemia-reperfusion (I/R), by assessing blood biochemical assay and histopathological analysis. Thirty-five adult Wistar rats were divided into five groups. After application of anaesthesia both hind limbs were occluded with tourniquets. Following ischemia period for 60 min, the tourniquets were removed allowing reperfusion for 120 min. The IR group received 0.5 ml of saline while the IR+AB group received 3-AB (10 mgkg(-1) intraperitoneally). The IR+DMSO group was given 0.5 ml 10% DMSO 30 min before the removal of the tourniquets. The control group received 0.5 ml saline and the AB group received 0.5 ml 3-AB (10 mgkg(-1)) intraperitoneally. At the end of the reperfusion period, mid-line sternotomy was performed. Blood samples were taken with cardiac puncture. Bronchoalveolar lavage (BAL) of the left lung was performed with saline. Right lung was preserved for histopathological evaluation and biochemical examination. Lung tissue malondialdehyde (MDA) and 3-nitrotyrosine levels, myeloperoxidase and Na+/K+ ATP-ase activities, wet to dry weight ratios, and plasma and BAL fluid MDA levels were determined. Histopathological evaluation was performed, too. Hind limb IR caused significant increase in the lung tissue 3-NT to total tyrosine ratio (p = 0.014), wet to dry weight ratio (p = 0.000), MPO activity (p = 0.000), and MDA levels (p = 0.000). The animals treated with 3-AB showed a statistically significant decrease in these values (p < 0.05). Na+/K+ ATP-ase activity which was found to be decreased significantly with IR, returned to near normal levels with 3-AB treatment. Additionally, lung tissue injury in IR group characterized with moderate interstitial congestion and neutrophil infiltration, showed remarkable amelioration following 3-AB treatment. Our results strongly support the view that poly(ADP-ribose) polymerase (PARP) plays an important role in the inflammatory process in hind limb I/R-induced lung injury and as a PARP inhibitor, 3-AB seems to have a potential to treat this inflammatory injury.     

血必净对内毒素致急性肺损伤大鼠炎症反应的影响

目的探讨血必净在内毒素(LPS)诱导的大鼠急性肺损伤(ALI)发病中的影响。方法健康雄性Wistar大鼠40只随机分成4组。正常对照组(NC):经尾静脉注射4ml/kg的生理盐水(5min内);假手术组(SO):沿腹中线做一条长1.5cm的切口,取出盲肠,2min后将盲肠还纳腹腔,逐层缝合腹壁切口,并生理盐水4ml/kg尾静脉注射(5min内);盲肠结扎穿孔组(CLP):采用盲肠结扎手术复制脓毒症模型,并生理盐水4ml/kg尾静脉注射(5min内);CLP+血必净组:手术方法同CLP组,术后血必净4ml/kg尾静脉注射(5min内)。于制模后15h采集动脉血测量血气,然后分离血清,采用酶联免疫吸附试验(ELISA)检测血清中肿瘤坏死因子α(TNF-α)、白细胞介素(IL)-6和IL-8含量的变化,并与NC组进行比较。观察大鼠肺组织苏木素-伊红(HE)染色结果。结果CLP组大鼠血清中TNF-α、IL-6及IL-8的含量明显升高,CLP组大鼠动脉血氧分压(PaO2)的含量显著降低。肺组织HE染色观察CLP组大鼠肺泡间隔增宽,肺间质见多量炎性细胞浸润,肺泡腔变窄、出血、中性粒细胞渗出及炎症渗出物。CLP+血必净组中性粒细胞渗出及炎症渗出物明显减轻。结论血必净能减轻内毒素血症所致的肺脏炎症反应,对内毒素致ALI时肺脏具有保护作用。     

ODN2088减轻线粒体DNA致脓毒症大鼠急性肺损伤

目的:探讨血浆线粒体DNA(mtDNA)含量与脓毒症大鼠急性肺损伤(ALI)程度的关系及选择性TLR9受体抑制剂ODN2088对脓毒症大鼠ALI的保护作用.方法:按随机数表法将80只大鼠分为假手术(sham)组、脓毒症(sepsis)组、脓毒症大鼠腹腔注射mtDNA 1.4 mg/kg(sepsis+mtDNA)组、脓...     

Treatment with N-methyl-D-aspartate receptor antagonist (MK-801) protects against oxidative stress in lipopolysaccharide-induced acute lung injury in the rat

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are common syndromes that affect both clinical and surgical patients. This study describes the effects of a potent and specific N-methyl-d-aspartate receptor antagonist (MK-801) against oxidative stress in acute lung injury induced by intratracheal lipopolysaccharide (LPS) injection. This study was performed using male Wistar rats weighing 200-250g. Rats were randomly divided into four groups: control with isotonic saline instillation (n=6); LPS (100μg/100g of body weight) treated with saline (n=6); LPS treated with MK-801 (0.3mg/kg, intraperitoneally; n=6); LPS treated with MK-801 (0.3mg/kg, intratracheally; n=6). Twelve hours after the LPS instillation, rats were anesthetized and a bronchoalveolar lavage (BAL) was performed in order to determine the alveolar-capillary membrane alterations and the inflammatory infiltrate level. Blood and lung samples were isolated and assayed for oxidative stress variables and histopathologic analysis. The use of MK-801 decreased bronchoalveolar lavage fluid protein, LDH activity and inflammatory cells. Indeed, the treatment with MK-801 significantly attenuated lung oxidative damage and histopathologic alterations after LPS instillation. Our data provide the first experimental demonstration that MK-801 decreases oxidative stress and limits inflammatory response and alveolar disarray in lipopolysaccharide-induced acute lung injury.     

脂多糖诱导大鼠急性肺损伤中钠氢交换体的表达

目的:建立脂多糖诱导大鼠急性肺损伤实验模型,观察实验模型中大鼠肺组织上钠氢交换体1mRNA和蛋白的表达水平变化情况。方法:40只(250~350g)雄性清洁级SD大鼠随机均分成空白对照组(C组)、脂多糖2h组(L-2h组)、脂多糖4h组(L-4h组)和脂多糖6h组(L-6h组)。监测各组大鼠基本生命体征;光学显微镜下观察大鼠肺组织病理改变;计算急性肺损伤评分和肺组织湿/干重比值;检测支气管肺泡灌洗液中总蛋白、肿瘤坏死因子-α和巨噬细胞炎性蛋白的浓度;测定肺组织髓过氧化物酶活性;免疫组化、RT-PCR和Western Blot检测肺组织钠氢交换体1mRNA和蛋白的表达水平。结果:空白对照组大鼠肺组织肺泡结构正常,肺泡腔无渗出物;脂多糖各组大鼠肺组织病理改变明显,肺泡间隔增厚,肺泡腔内可见较多的炎性细胞,肺泡腔内有血性渗出液。和空白对照组比较,脂多糖各组大鼠支气管肺泡灌洗液中总蛋白、肿瘤坏死因子-α和巨噬细胞炎性蛋白的浓度均依次明显增高(FTP=31.67、FTNF-α=275.33、FMIP-2=239.26,均P<0.05);肺组织急性损伤评分、湿/干重比、髓过氧化物酶活性、钠氢交换体1的免疫组化表达水平、钠...     

氨溴索对急性肺损伤兔E-选择素和细胞间黏附分子-1的影响

目的观察氨溴索对油酸诱导的兔急性肺损伤E－选择素和ICAM－1的影响,探讨氨溴索抗急性肺损伤作用及其机制。方法健康日本大耳白兔24只,随机分为3组：生理盐水组（NS组）,油酸组（OA组）。氨溴索治疗组（AMB组）。采用耳缘静脉注射复制兔油酸型急性肺损伤模型。检测各组动脉氧分压、肺组织湿干比（W／D）,光镜观察肺组织病理改变;检测在静注氨澳索（AMB）或生理盐水6h后BALF和肺组织匀浆白细胞介素－1β（IL-1β）、肿瘤坏死因子－α（TNF-α）、E-选择素、细胞间黏附分子－1（ICAM－1）含量。结果AMB组肺W／D显著低于OA组（P〈0．01）,但显著高于NS组（P〈0．05）,肺组织病理损伤明显减轻;用药前AMB组和OA组PaO2显著低于NS组;用药后6小时,AMB组PaO2显著高于OA组（P〈0．01）,但显著低于NS组（P〈0．01）。AMB组BALF和肺组织匀浆中IL-10、TNF-α、E-选择素及ICAM－1含量含量均显著低于OA组（P〈0．01）,但均高于NS组（P〈0．01）。BALF和肺组织匀浆中E-选择素、ICAM－1含量与相应标本的IL－1β、TNF-α含量有高度的正相关关系（P〈0．001）。结论氮溴索有较好的抗急性肺损伤的作用。氨溴索能抑制促炎细胞因子等的释放及肺组织细胞黏附分子的合成,部分阻止多形核白细胞（PMN）与内皮细胞的粘附。进而阻止PMN的跨膜运动和其在肺内的聚集．从而发挥抗急性肺损伤的作用。     

CXCR4高表达骨髓间充质干细胞对百草枯中毒肺损伤大鼠的治疗作用

目的 观察CXC趋化因子受体4(CXC chemokine receptor 4,CXCR4)高表达的骨髓间充质干细胞(bone marrow mesenchymal stem cell,BMSC)对百草枯中毒致急性肺损伤大鼠的治疗作用.方法 建立BMSC-CXCR4细胞株.制备并鉴定百草枯中毒致急性肺损伤大鼠模型.将成年雄性SD大鼠随机分为4组:生理盐水组、BMSC治疗组(BMSC组)、BMSC-CXCR4治疗组(BMSC-CXCR4组)和5％O2低氧培养的BMSC-CXCR4治疗组(BMSC-CXCR4+ 5％O2组),于4组大鼠尾静脉给予不同处理后,比较各组血清中白介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-oα)和超氧化物歧化酶(SOD)活性变化,并观察肺组织病理变化.结果 成功构建稳定转染BMSC-CXCR4细胞株.急性肺损伤大鼠肺组织可见肺泡大片融合,肺泡结构明显破坏;与对照组比较,实验组随着时间延长动脉血氧分压持续下降,肺湿干比持续升高,血清IL-1β、TNF-α水平持续升高,SOD活性持续下降(P＜0.05,P＜0.01).百草枯中毒致急性肺损伤12h时,BMSC治疗组、BMSC-CXCR4组和BMSC-CXCR4 +5％O2组大鼠血清IL-1β和TNF-α水平均低于生理盐水组,SOD活性高于生理盐水组,且BMSC-CXCR4 +5％O2组优于BMSC组和BMSC-CXCR4组(P＜0.01).急性肺损伤12 h时,与生理盐水组比较,各治疗组大鼠肺泡形态大致完整,肺泡壁比较光滑;其中BMSC-CXCR4+ 5％O2组最接近于正常肺组织.结论 低氧培养的BMSC-CXCR4对百草枯中毒致急性肺损伤具有良好的治疗作用.     

Cicletanine and reperfusion injury: is there any correlation between arrhythmias, 6-keto-PGF1 alpha, thromboxane B2, and myocardial ion shifts (Na+, K+, Ca2+, and Mg2+) induced by ischemia/reperfusion in isolated rat heart.

We studied the effects of cicletanine, an anti-hypertensive drug, on reperfusion arrhythmias in relation to 6-keto-PGF1 alpha, thromboxane B2 (TXB2), and ion shifts (Na+, K+, Ca2+, and Mg2+) induced by ischemia and reperfusion in hearts isolated from spontaneously hypertensive rats. Hearts were subjected to 30-min global ischemia followed by 10-min reperfusion. 6-keto-PGF1 alpha and TXB2 concentrations were determined by radioimmunoassay (RIA) from coronary effluents, and myocardial Na+, K+, Ca2+, and Mg2+ contents were measured by atomic absorption spectrophotometry from myocardial tissue. Two basic protocols were used: (a) acute administration when 3, 10, 30, or 100 mg/L cicletanine was included in the perfusion buffer; and (b) chronic application, in which rats received cicletanine 3, 10, 30, or 100 mg/kg/day orally for 14 days. Acute administration of the drug in low concentrations (3 or 10 mg/L), significantly increased endogenous 6-keto-PGF1 alpha production before ischemia and during reperfusion, whereas higher doses of cicletanine (30 or 100 mg/L) as well as chronic application of the drug failed to increase production of 6-keto-PGF1 alpha in the myocardium. TXB2 production was not influenced by either acute or chronic treatment with the drug. Neither treatment changed myocardial ion contents in comparison with control values (Na+ = 45 +/- 4, K+ = 252 +/- 7, Ca2+ = 1.4 +/- 0.1, and Mg2+ = 12.5 +/- 0.3 mmol/kg dry weight) in nonischemic hearts. Thirty-minute ischemia resulted in a two- and fourfold accumulation of myocardial Na+ and Ca2+ and a 50% decrease in both K+ and Mg2+.(ABSTRACT TRUNCATED AT 250 WORDS)     

甘草酸单铵对脂多糖致小鼠急性肺损伤的保护作用

采用脂多糖(lipopolysaccharide，LPS)气道滴入诱导小鼠急性肺损伤(acute lung injury，ALI)模型，研究甘草酸单铵(monoammonium glycyrrhizinate，MAG)对ALI的防治作用及其机制。雄性ICR小鼠随机分为生理盐水(NS)对照组、MAG 3、10 及30 mg·kg^-1组、LPS组、地塞米松(dexamethasone，DXM) 5 mg·kg^-1组。MAG各组气道滴入LPS前1 h及滴入后3 h各给药1次，DXM组气道滴入LPS前1 h给药1次。LPS气道滴入后6 h处死动物，测定各组的肺湿重/干重比、肺通透性、肺组织中性粒细胞髓过氧化物酶(myeloperoxidase，MPO)含量、ELISA法检测肺组织匀浆TNF-α、IL-10含量，常规细胞形态学检测中性粒细胞在支气管肺泡灌洗液(bronchoalveolar lavage fluid，BALF)中的比例和肺组织病理改变。结果表明，MAG剂量依赖性减轻气道内滴入LPS诱导的小鼠ALI程度，降低肺湿重/干重比及肺组织伊文斯蓝的渗出，降低BALF中白细胞总数和中性粒细胞数比例，抑制组织MPO的释放，降低肺组织匀浆TNF-α的含量，增加肺组织IL-10的释放。以上结果提示，MAG可能通过调节TNF-α/IL-10的平衡而有效保护脂多糖诱导的急性肺损伤。     

Prophylaxis against lipopolysaccharide-induced lung injuries by liposome-entrapped dexamethasone in rats

Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, stimulates phagocytes to generate metabolites that play an important role in the pathogenesis of acute lung injury. In this study, the prophylactic effect of liposome-entrapped dexamethasone (L-DEX) was evaluated in an animal acute lung injury model. Rats were pretreated intratracheally with L-DEX or dexamethasone phosphate (DEX) at a dose of 800 microg dexamethasone/kg body weight; 1 hr later, pretreated animals were challenged i.v. with LPS (Escherichia coli 0111:B4, 1 mg/kg body weight) and killed 24 hr later. Challenge of saline-pretreated animals with LPS resulted in lung injury, as evidenced by increases in wet lung weight and decreases in lung angiotensin-converting enzyme and alkaline phosphatase activities, injury markers of pulmonary capillary endothelial and alveolar type II epithelial cells, respectively. Also, LPS injection resulted in significant increases in plasma phospholipase A(2), thromboxane B(2), and leukotriene B(4) concentrations. The LPS challenge also increased pulmonary myeloperoxidase and elastase activities as well as chloramine concentrations, suggestive of neutrophil infiltration and activation of the inflammatory response. Pretreatment of animals with L-DEX was significantly more effective than pretreatment with the free drug in reducing lung inflammation and other lung injuries, as indicated by the appropriate injury markers used in this study. Our results suggested that the pulmonary delivery of liposome-entrapped anti-inflammatory drugs such as dexamethasone improves prophylactic efficacy in counteracting LPS-induced lung injury.     

Budesonide-Loaded Bilosomes as a Targeted Delivery Therapeutic Approach Against Acute Lung Injury in Rats

Budesonide (BUD), a glucocorticoids drug, inhibits all steps in the inflammatory response. It can reduce and treat inflammation and other symptoms associated with acute lung injury such as COVID-19. Loading BUD into bilosomes could boost its therapeutic activity, and lessen its frequent administration and side effects. Different bilosomal formulations were prepared where the independent variables were lipid type (Cholesterol, Phospholipon 80H, L-alpha phosphatidylcholine, and Lipoid S45), bile salt type (Na cholate and Na deoxycholate), and drug concentration (10, 20 mg). The measured responses were: vesicle size, entrapment efficiency, and release efficiency. One optimum formulation (composed of cholesterol, Na cholate, and 10 mg of BUD) was selected and investigated for its anti-inflammatory efficacy in vivo using Wistar albino male rats. Randomly allocated rats were distributed into four groups: The first: normal control group and received intranasal saline, the second one acted as the acute lung injury model received intranasal single dose of 2 mg/kg potassium dichromate (PD). Whereas the third and fourth groups received the market product (Pulmicort® nebulising suspension 0.5 mg/ml) and the optimized formulation (0.5 mg/kg; intranasal) for 7 days after PD instillation, respectively. Results showed that the optimized formulation decreased the pro-inflammatory cytokines TNF-α, and TGF-β contents as well as reduced PKC content in lung. These findings suggest the potentiality of BUD-loaded bilosomes for the treatment of acute lung injury with the ability of inhibiting the pro-inflammatory cytokines induced COVID-19.     

肝肾功能损害状态下蝙蝠葛碱的药动学

以HgCl_2所致家兔急性中毒性肾功衰(ARF)和CCl_4所致急性中毒性肝损害(ALI)为模型,研究蝙蝠葛碱(Dau)在肝肾功能损害状态下的药代动力学。结果表明:ARF组的药代动力学参数与正常对照组无显著性差异。ALI组α,t1/2α,V_d,V_c与正常对照组无显著差异,其β,K_(10),Cl值均显著低于正常对照组,其t1/2β值显著高于正常对照组。     

Polyethyleneimine and DNA nanoparticles-based gene therapy for acute lung injury

Acute lung injury (ALI) is a devastating clinical syndrome causing a substantial mortality, but to date without any effective pharmacological management in clinic. Here, we tested whether nanoparticles based on polyethylenimine (PEI) and DNA could be a potential treatment. In mouse model of ALI induced by lipopolysaccharide (LPS) (10 mg/kg), intravenous injection of PEI/DNA mediated a rapid (in 6 h) and short-lived transgene expression in lung, with alveolar epithelial cells as major targets. When β2-Adrenergic Receptor (β2AR) was applied as therapeutic gene, PEI/β2AR treatment significantly attenuated the severity of ALI, including alveolar fluid clearance, lung water content, histopathology, bronchioalveolar lavage cellularity, protein concentration, and inflammatory cytokines in mice with pre-existing ALI. In high-dose LPS (40 mg/kg)-induced ALI, post-injury treatment of PEI/β2AR significantly improved the 5-day survival of mice from 28% to 64%. These data suggest that PEI/DNA nanoparticles could be an effective agent in future clinical application for ALI treatment.From the Clinical EditorIn this novel study, PEI/DNA nanoparticles are presented as an effective agent for the treatment of the devastating and currently untreatable syndrome of acute lung injury, using a rodent model system.