Prophylaxis against lipopolysaccharide-induced liver injuries by lipoic acid in rats

Lipopolysaccharide (LPS) is a major cell wall molecule of Gram-negative bacteria known to stimulate the synthesis and secretion of several metabolites, such as reactive oxygen species, from phagocytes that play an important role in the pathogenesis of tissue injuries. In this study, the prophylactic effect of the antioxidant lipoic acid was evaluated in an animal acute organ injury model. Animals were pre-treated intraperitoneally with lipoic acid (50 mg kg(-1) body weight) or saline; 3 h later, pretreated animals were challenged intravenously with LPS (Escherichia coli 0111:B4, 1.0 mg kg(-1) body weight) or saline and killed 21 h later. Saline-pretreated animals challenged with LPS were extensively damaged in the liver, as evidenced by an increase in plasma alanine and aspartate aminotransferase activities. Also, LPS injection to saline-pretreated animals resulted in significant increases in plasma tumour necrosis factor-alpha (TNFalpha) and nitric oxide (NO) concentrations, suggestive of activation of the proinflammatory response. The LPS challenge to saline-pretreated animals also increased hepatic myeloperoxidase activity as well as protease and chloramine levels, suggestive of neutrophil infiltration and activation of the inflammatory response. In addition, the involvement of oxidative stress was evident, because a significant increase in lipid peroxidation was observed in the livers of saline-pretreated animals challenged with LPS. The administration of lipoic acid prior to LPS challenge resulted in a significant alleviation of liver injuries, evidenced by a general reversal of the altered biochemical indices toward normal among treated animals. These results indicate that lipoic acid may serve as a potentially effective prophylactic pharmacological agent in alleviating LPS-induced tissue injuries.     

Riboflavin attenuates lipopolysaccharide-induced lung injury in rats

Abstract

Riboflavin (vitamin B2) is an easily absorbed micronutrient with a key role in maintaining health in humans and animals. It is the central component of the cofactors flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) and is therefore required by all flavoproteins. Riboflavin also works as an antioxidant by scavenging free radicals. The present study was designed to evaluate the effects of riboflavin against acute lungs injury induced by the administration of a single intranasal dose (20?μg/rat) of lipopolysaccharides (LPS) in experimental rats. Administration of LPS resulted in marked increase in malondialdehyde (MDA) level (p?<?0.01) and MPO activity (p?<?0.001), whereas marked decrease in glutathione (GSH) content (p?<?0.001), glutathione reductase (GR) (p?<?0.001) and glutathione peroxidase (p?<?0.01) activity. These changes were significantly (p?<?0.001) improved by treatment with riboflavin in a dose-dependent manner (30 and 100?mg/kg, respectively). Riboflavin (100?mg/kg, p.o.) showed similar protective effects as dexamethasone (1?mg/kg, p.o.). Administration of LPS showed marked cellular changes including interstitial edema, hemorrhage, infiltration of PMNs, etc., which were reversed by riboflavin administration. Histopathological examinations showed normal morphological structures of lungs tissue in the control group. These biochemical and histopathological examination were appended with iNOS and CAT gene expression. The iNOS mRNA expression was increased significantly (p?<?0.001) and levels of CAT mRNA expression was decreased significantly (p?<?0.001) in the animals exposed to LPS, while treatment with riboflavin significantly (p?<?0.01) improved expression of both gene. In conclusion, the present study clearly demonstrated that riboflavin caused a protective effect against LPS-induced ALI. These results suggest that riboflavin may be used to protect against toxic effect of LPS in lungs.     

Nilotinib ameliorates lipopolysaccharide-induced acute lung injury in rats

The present study aimed to investigate the effect of the new tyrosine kinase inhibitor, nilotinib on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats and explore its possible mechanisms. Male Sprague-Dawley rats were given nilotinib (10 mg/kg) by oral gavage twice daily for 1 week prior to exposure to aerosolized LPS. At 24 h after LPS exposure, bronchoalveolar lavage fluid (BALF) samples and lung tissue were collected. The lung wet/dry weight (W/D) ratio, protein level and the number of inflammatory cells in the BALF were determined. Optical microscopy was performed to examine the pathological changes in lungs. Malondialdehyde (MDA) content, superoxidase dismutase (SOD) and reduced glutathione (GSH) activities as well as nitrite/nitrate (NO₂⁻/NO₃⁻) levels were measured in lung tissues. The expression of inflammatory cytokines, tumor necrosis factor-α (TNF-α), transforming growth factor-β₁ (TGF-β₁) and inducible nitric oxide synthase (iNOS) were determined in lung tissues. Treatment with nilotinib prior to LPS exposure significantly attenuated the LPS-induced pulmonary edema, as it significantly decreased lung W/D ratio, protein concentration and the accumulation of the inflammatory cells in the BALF. This was supported by the histopathological examination which revealed marked attenuation of LPS-induced ALI in nilotinib treated rats. In addition, nilotinib significantly increased SOD and GSH activities with significant decrease in MDA content in the lung. Nilotinib also reduced LPS mediated overproduction of pulmonary NO₂⁻/NO₃⁻ levels. Importantly, nilotinib caused down-regulation of the inflammatory cytokines TNF-α, TGF-β₁ and iNOS levels in the lung. Taken together, these results demonstrate the protective effects of nilotinib against the LPS-induced ALI. This effect can be attributed to nilotinib ability to counteract the inflammatory cells infiltration and hence ROS generation and regulate cytokine effects.     

Lactoferrin protects against lipopolysaccharide-induced acute lung injury in mice

Lactoferrin (LF) plays various anti-inflammatory roles in inflammation experimentally induced by lipopolysaccharides (LPS). But the protective effects of LF on LPS-induced acute lung injury (ALI) have not been elucidated. In this study, we aimed to study the effects of LF on ALI caused by LPS in mice. At 1h before or after LPS injection, an intraperitoneal injection of LF (5mg/body) was administered. Lung specimens and the bronchoalveolar lavage fluid (BALF) were isolated for histopathological examinations and biochemical analyses 12h after LPS exposure. We found that both prophylactic and therapeutic administration of LF significantly decreased the W/D ratio of the lung and protein concentration in the BALF. LF significantly reduced the pulmonary myeloperoxidase activity and the number of total cells in the BALF 12h after LPS challenge. LF treatment markedly attenuated lung edema, alveolar hemorrhage and inflammatory cells infiltration. Moreover, LF also decreased the production of TNF-α and increased interleukin-10 in the BALF. These results firstly indicate that LF may protect against LPS-induced ALI in mice.     

隐孔菌多糖对小鼠内毒素性肺损伤的保护作用

目的研究隐孔菌多糖(cryptoporus polysaccharide,CP)对脂多糖(LPS)诱导小鼠急性肺损伤(ALI)的影响。方法LPS气管内滴入诱导小鼠ALI模型,设立对照组、模型组、隐孔菌多糖(1、10、30mg·kg-1)组和地塞米松(0·5mg·kg-1)组,检测支气管肺泡灌洗液(BALF)和肺组织中中性粒细胞的浸润情况、比色法测定伊文氏兰渗出量及BALF中的中性粒细胞髓过氧化物酶(MPO)、超氧根阴离子自由基(O2·)含量,观察肺组织病理及肺湿重/干重比值改变,ELISA法检测肺组织中TNF-α和IL-10含量。结果隐孔菌多糖(1、10、30mg·kg-1)尾静脉给药能够抑制BALF MPO活性,改善ALI小鼠BALF及肺组织中的炎症细胞的聚集和肺水肿程度,降低肺组织中TNF-α水平及升高IL-10/TNF-α比值。结论隐孔菌多糖通过抑制中性粒细胞黏附、趋化、减轻肺水肿等改善LPS诱导的小鼠ALI。     

Protective effects of Isofraxidin against lipopolysaccharide-induced acute lung injury in mice

Acute lung injury (ALI) is a life-threatening disease characterized by serious lung inflammation and increased capillary permeability, which presents a high mortality worldwide. Isofraxidin (IF), a Coumarin compound isolated from the natural medicinal plants such as Sarcandra glabra and Acanthopanax senticosus, has been reported to have definite anti-bacterial, anti-oxidant, and anti-inflammatory activities. However, the effects of IF against lipopolysaccharide-induced ALI have not been clarified. The aim of the present study is to explore the protective effects and potential mechanism of IF against LPS-induced ALI in mice. In this study, We found that pretreatment with IF significantly lowered LPS-induced mortality and lung wet-to-dry weight (W/D) ratio and reduced the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and prostaglandin E₂ (PGE₂) in serum and bronchoalveolar lavage fluid (BALF). We also found that total cells, neutrophils and macrophages in BALF, MPO activity in lung tissues were markedly decreased. Besides, IF obviously inhibited lung histopathological changes and cyclooxygenase-2 (COX-2) protein expression. These results suggest that IF has a protective effect against LPS-induced ALI, and the protective effect of IF seems to result from the inhibition of COX-2 protein expression in the lung, which regulates the production of PGE₂.     

胆红素对内毒素肺损伤大鼠中性粒细胞肺浸润的抑制作用

目的:探讨胆红素对急性肺损伤(ALI)的保护作用及其对中性粒细胞肺浸润的抑制作用。方法:用雄性wistar大鼠30只,随机分为正常对照组、ALI模型组、胆红素干预组。检测肺组织肺系数(LI)、支气管肺泡灌洗液(BALF)中白细胞(WBC)计数、中性粒细胞(PMN)百分比。采用免疫组织化学染色测定肺血管内皮细胞NF-κB蛋白的表达。结果:ALI模型组LI,BALF中WBC计数、PMN百分比和肺血管内皮细胞NF-κB核染色阳性细胞百分比均显著高于正常对照组(P<0.01,P<0.001)。胆红素干预组LI,BALF中WBC计数、PMN百分比和NF-κB核染色阳性细胞百分比均显著低于ALI模型组(P<0.01,P<0.05,P<0.001)。结论:胆红素对内毒素导致肺损伤的PMN肺浸润有一定的抑制作用,可能与抑制肺血管内皮细胞NF-κB的表达有关。     

依布硒啉对大鼠脂多糖诱导的急性肺损伤的保护作用

目的探讨依布硒啉对内毒素性急性肺损伤大鼠肺功能的保护作用及对肺组织中相关细胞因子表达的影响。方法健康雄性SD大鼠随机分成6组：正常对照组,模型组,地塞米松对照组,依布硒啉30、15和7.5 mg/kg治疗组。通过大鼠尾静脉注射脂多糖（5 mg/kg）建立急性肺损伤模型,治疗大鼠组于造模前30 min腹腔注射给药,对照组和模型组分别注入等量溶剂。造模后6 h,麻醉抽取动脉血并放血处死动物,检测动脉血氧分压（PaO2）和二氧化碳分压（PaCO2）,取肺组织,测定肺湿/干质量比,收集支气管肺泡灌洗液,检测其中总蛋白水平。分别检测肺组织中丙二醛（MDA）、TNF-α含量及核因子E2相关因子（Nrf2）蛋白表达。结果与模型组相比,依布硒啉15和30 mg/kg剂量组大鼠动脉血中PaO2明显增高、PaCO2明显降低,肺湿/干质量比降低,肺组织MDA和TNF-α含量显著减少,而Nrf2表达明显增高。结论依布硒啉对内毒素性急性肺损伤有一定保护作用,其机制可能与诱导Nrf2表达有关。     

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。     

丹酚酸B拮抗大鼠缺血再灌注引起的脑损伤(英文)

目的:研究丹酚酸B对缺血再灌注脑损伤的拮抗作用。方法:采用大鼠局灶性脑缺血再灌注模型。以行为学实验评价中枢神经系统的损伤。采用比色法检测脑匀浆液中超氧化物歧化酶(SOD)的活性,以及还原型谷胱苷肽(GSH)、丙二醛(MDA)、三磷酸腺苷(ATP)和乳酸(LA)的含量。结果:局灶性脑缺血再灌注可造成行为学异常,丹酚酸B 10 mg·kg~(-1)可减轻此种异常。同时,丹酚酸B 10mg·kg~(-1)可以改善由于脑缺血再灌注所造成的SOD、GSH、和ATP含量降低以及MDA和LA含量增加。结论:丹酚酸B对脑缺血再灌注脑损伤具有保护作用,其作用机制与减轻脂质过氧化、促进自由基的清除以及改善能量代谢有关。     

地塞米松对脓毒症大鼠急性肺损伤影响的实验研究

目的 观察急性肺损伤(ALI)肺组织核因子(NF)-κB的活性变化及地塞米松(Dex)的干预作用。方法 采用LPS诱导的急性肺损伤动物模型,将30只SD大鼠随机分为实验组(AU Dex,10只)、模型组(ALI NS,10只)和对照组(NS,10只)三组,实验组在建模成功后腹腔注射地塞米松,模型组在建模成功后腹腔注射相同剂量的生理盐水,对照组仅腹腔注射相同剂量的生理盐水。注药6小时后留取肺组织,用免疫组织化学法结合图像分析仪检测其NF-κBP65、IκB-α蛋白的相对含量,并进行病理学光镜检查。结果ALI大鼠肺组织可见大量出血和炎性细胞浸润,NF-κBP65的蛋白表达明显升高,IκB-α表达显著降低。Dex能明显下调NF-κBP65的蛋白表达,上调IκB-α表达,并能减轻肺组织的损伤程度。结论 NF-κBP65活化在ALI的发生、发展过程中起着重要作用。Dex具有明显的抗炎作用,减少了肺组织损害。     

Effectiveness of liposomal-N-acetylcysteine against LPS-induced lung injuries in rodents

Acute lung injury (ALI) and its most severe form, the acute respiratory distress syndrome (ARDS) are frequent complications in critically ill patients and are responsible for significant morbidity and mortality. So far, experimental evidence supports the role of oxidants and oxidative injury in the pathogenesis of ALI/ARDS. In this study, the antioxidant effects of conventional N-acetylcysteine (NAC) and liposomally entrapped N-acetylcysteine (L-NAC) were evaluated in experimental animals challenged with lipopolysaccharide (LPS). Rats were pretreated with empty liposomes, NAC, or L-NAC (25mg/kg body weight, iv); 4h later were challenged with LPS (E. coli, LPS 0111:B4) and sacrificed 20h later. Challenge of saline (SAL)-pretreated animals with LPS resulted in lung injury as evidenced by increases in wet lung weight (edema), increases in lipid peroxidation (marker of oxidative stress), decreases of lung angiotensin-converting enzyme (ACE) (injury marker for pulmonary endothelial cells) and increases in the pro-inflammatory eicosanoids, thromboxane B(2) and leukotriene B(4). The LPS challenge also increased pulmonary myeloperoxidase activity and chloramine concentrations indicative of neutrophil infiltration and activation of the inflammatory response. Pretreatment of animals with L-NAC resulted in significant increases in the levels of non-protein thiols and NAC levels in lung homogenates (p<0.05) and bronchoalveolar lavage fluids (p<0.001), respectively. L-NAC was significantly (p<0.05) more effective than NAC or empty liposomes in attenuating the LPS-induced lung injuries as indicated by the aforementioned injury markers. Our results suggested that the delivery of NAC as a liposomal formulation improved its prophylactic effectiveness against LPS-induced lung injuries.     

丙泊酚对内毒素诱导大鼠急性肺损伤及细胞凋亡的影响

目的 探讨丙泊酚对内毒素诱导的肺损伤及细胞凋亡的影响.方法 将18只SD雄性大鼠随即分为对照组、盐水组、丙泊酚组各6只,一次性雾化吸入内毒素（1 mg/kg）诱导急性肺损伤后,丙泊酚组大鼠立即给予负荷剂量丙泊酚5 mg/kg,继以丙泊酚10mg （kg·h）维持6 h,对照组及盐水组予以等量生理盐水代替.分别以HE染色观察病理变化、湿干重比（W/D）检测肺水肿程度、TUNEL染色检测细胞凋亡、western blot检测Bax及Bcl-2表达变化、荧光法检测caspase-3活性.结果 与对照组相比,盐水组病理可见问质水肿,大量中性粒细胞浸润等炎症改变,W/D增加（P＜ 0.01）,凋亡细胞数及caspase-3活性明显增高（P＜0.01）,Bax表达增高及Bcl-2表达降低;与盐水组相比,丙泊酚组HE染色仅少量中性粒细胞浸润,W/D降低（P＜0.05）,凋亡细胞数及caspase-3活性明显降低（P＜0.01）,Bax表达下降及Bcl-2表达增加.结论 丙泊酚可以通过抑制细胞凋亡的发生从而保护LPS诱导的ALI.     

丙泊酚对内毒素性大鼠急性肺损伤的保护作用

目的探讨丙泊酚对内毒素(LPS)性大鼠急性肺损伤(ALI)的影响。方法 60只SD大鼠随机均分5组:A组为ALI模型;B1、B2、B3组静脉注射LPS5mg/kg后,再分别输注丙泊酚5、10、15mg.kg-1.h-1;C组为假手术对照。放血处死大鼠,右肺HE染色,左肺测定湿干重比;分离外周血中性粒细胞(PMN),流式细胞仪检测PMN凋亡。结果与C组比较,A组肺部损伤严重,肺泡损伤比值(IQA)显著增加、PMN的凋亡率显著降低(P<0.05);与A组比较,丙泊酚处理组肺损伤程度减轻,IQA降低,凋亡显著增加,且呈剂量依赖性(P<0.05)。结论丙泊酚减轻LPS诱导的大鼠ALI,这可能与促进PMN的凋亡有关。     

Protective effect of erdosteine against hypochlorous acid-induced acute lung injury and lipopolysaccharide-induced neutrophilic lung inflammation in mice

The effect of erdosteine, a mucoactive drug, on hypochlorous acid (HOCl)-induced lung injury, and the lipopolysaccharide (LPS)-induced increase in tumour necrosis factor-alpha (TNF-alpha) production and neutrophil recruitment into the airway, was investigated. Male BALB/c mice were orally administered erdosteine (3-100 mgkg(-1)), ambroxol hydrochloride (ambroxol) (3-30 mgkg(-1)), S-carboxymethyl-L-cysteine (S-CMC) (100-600 mgkg(-1)) or prednisolone (10 mgkg(-1)), 1 h before intratracheal injection of HOCl or LPS. In the HOCl-injected mice, erdosteine markedly suppressed increases in the ratios of lung wet weight to bodyweight and lung dry weight to bodyweight, whereas the other mucoactive drugs ambroxol and S-CMC had little effect. Erdosteine also inhibited the LPS-induced neutrophil influx, although it did not affect the increased level of TNF-alpha in the bronchoalveolar lavage fluid. The results suggest that attenuation of reactive oxygen species and neutrophil recruitment is involved in the clinical efficacy of erdosteine in the treatment of chronic bronchitis.     

Ethyl ferulate protects against lipopolysaccharide-induced acute lung injury by activating AMPK/Nrf2 signaling pathway

Ethyl ferulate (EF) is abundant in Rhizoma Chuanxiong and grains (e.g.,rice and maize) and possesses antioxidative,antiapoptotic,antirheumatic,and anti-inflamma...     

Protective effect of magnolol-loaded polyketal microparticles on lipopolysaccharide-induced acute lung injury in rats

Magnolol has shown inhibitory effects on NO production and TNF-alpha production in lipopolysaccharide (LPS)-activated macrophages and LPS-induced acute lung injury; however, the poor solubility of magnolol has hindered its clinical success. In this study, magnolol-loaded microparticles were prepared via single emulsion method from a polyketal polymer, termed PK3. The particle sizes of magnolol-loaded PK3 microparticle is 3.73?±?0.41?μm, and was suitable for phagocytosis by macrophages and pulmonary drug delivery. PK3 microparticles exhibited excellent biocompatibility both in vitro and in vivo. More importantly, intratracheal delivery of these magnolol-loaded microparticles significantly reduced the lung inflammatory responses at low dosage of magnolol (0.5?mg/kg), and have great clinical potential in treating acute lung injury.     

Autotransplantation of circulating endothelial progenitor cells protects against lipopolysaccharide-induced acute lung injury in rabbit

Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are leading causes of morbidity and mortality in critically ill patients. Recent studies suggest that endothelial progenitor cells (EPCs) transplantation could become a novel cell-based therapeutic strategy for ALI/ARDS, but the exact therapeutic effect and possible mechanisms still need to be elucidated. In the present study, autologous circulating EPCs were obtained from rabbits using Ficoll centrifugation and cultured in vitro for 7 days. ALI was induced in rabbits by lipopolysaccharide (LPS), and EPCs were administered systemically. Fluorescence microscopy showed that CM-DiI labelled EPCs could migrate to the injured lung tissues. Reduced pulmonary edema level, inflammation, hemorrhage and hyaline membrane formation were present in rabbit treated with EPCs. EPCs autotransplantation significantly decreased the expression of adhesion molecules of sICAM-1 and P-selectin. Furthermore, EPCs administration mediated a down-regulation of proinflammatory responses (reducing IL-1β and TNF-α) while increasing the anti-inflammatory cytokine IL-10. Apoptosis of endothelial and epithelial cells was substantially reduced in EPCs-treated rabbit. Those findings suggest that autotransplantation of circulating EPCs can reduce the severity of LPS-induced ALI. Possible mechanisms include EPCs engraftment and reendothelization, down-regulation of adhesion molecules, alleviation of inflammatory response and apoptosis prevention.