拟人参皂苷-F11对脂多糖所致急性肺损伤小鼠的保护作用

目的拟人参皂苷F11(PF11)是从西洋参茎、叶中提取分离的一种三萜皂苷。课题组前期研究表明,PF11具有抑制神经炎症、抗氧化应激的神经保护作用。但是,PF11是否对脂多糖(LPS)所致急性肺损伤(ALI)小鼠具有保护作用仍未报导。方法气管滴注脂多糖(3 mg·kg~(-1))构建小鼠ALI模型,在造模前连续3 d尾静脉注射PF11(3,10和30 mg·kg~(-1))。通过测定肺组织病理学变化、肺湿/干重比值、支气管肺泡灌洗液(BALF)中细胞数目及蛋白浓度来评价PF11对ALI小鼠的保护作用,随后采用酶联免疫吸附、免疫组织化学和流式细胞术等实验方法,对炎症反应、中性粒细胞募集、中性粒细胞凋亡以及凋亡后吞噬等方面进行研究。结果 PF11显著减轻LPS所致ALI小鼠肺组织病理损伤,逆转肺湿/干重比值及BALF中的细胞数目和蛋白浓度的增加。此外,PF11显著抑制LPS所致ALI小鼠BALF中炎症因子及趋化因子(IL-6,TNF-α,IL-1β,MIP-2)蛋白水平的升高、逆转肺组织中髓过氧化物酶活性和中性粒细胞浸润的增加,同时还能显著促进BALF内中性粒细胞的凋亡和巨噬细胞对凋亡中性粒细胞的吞噬。结论 PF11通过抑制中性粒细胞浸润和加速中性粒细胞清除发挥对LPS所致ALI小鼠的保护作用,有可能成为防治ALI的潜在药物。     

白花前胡有效成分Pd-Ia对急性肺损伤的作用及机制研究

目的探讨白花前胡甲素(dl-praeruptorin,Pd-Ia)对脂多糖(lipopolysaccharide,LPS)诱导急性肺损伤的作用及其机制。方法气管滴注LPS建立小鼠急性肺损伤模型,PdIa腹腔注射进行干预治疗,应用组织细胞染色及定量PCR、ELISA等方法评估Pd-Ia对急性肺损伤的作用。结果病理形态学显示,Pd-Ia治疗组炎性细胞浸润明显减轻,细胞染色也显示BALF中炎性细胞数量明显减少,定量PCR及ELISA结果显示,Pd-Ia治疗组抑制了肺组织中细胞因子IL-6、TNF-α、IL-1β、趋化因子MIP-1α、MIP-2的表达。结论 Pd-Ia治疗可以明显减轻肺部的炎症反应,从而改善肺损伤。     

可溶性晚期糖基化终末产物受体对脂多糖肺损伤小鼠肺内细胞因子的干预作用

目的探讨应用重组可溶性晚期糖基化终末产物受体(sRAGE)对脂多糖(LPS)介导的急性肺损伤(ALI)小鼠肺内细胞因子水平的影响。方法健康雄性BALB/C小鼠随机分为磷酸盐缓冲液(PBS)组、LPS组和sRAGE组。LPS组和sRAGE组通过气管内滴注LPS(3mg/kg体质量)建立ALI模型,造模后1hsRAGE组腹腔注射100μg重组小鼠sRAGE,各组于24h留取标本,采用Bio-Plex悬浮芯片技术检测支气管肺泡灌洗液(BALF)中8种细胞因子含量,并计数炎症细胞数量和蛋白(TP)含量,对肺组织进行病理学评估。观察sRAGE干预对造模后4h肺组织核因子(NF)-κB P65DNA结合活性的影响。结果 LPS滴注24h后,BALF中8种细胞因子含量均显著升高,白细胞(WBC)总数和中性粒细胞(NEU)数量显著增加,TP含量升高,肺组织出现典型的ALI病理损害。sRAGE干预显著降低了BALF中肿瘤坏死因子(TNF)-α、巨噬细胞炎症蛋白(MIP)-1β和MIP-1α水平,减少了BALF中WBC、NEU数量及TP含量,减轻了LPS引起的肺组织病理改变,并对造模后4hLPS介导的肺内NF-κB活化有抑制作用。结论应用重组sRAGE阻止RAGE信号能调控LPS介导的肺内细胞因子的表达,这构成了sRAGE抑制肺内炎症的重要机制之一。     

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。     

西地那非对脂多糖诱导的小鼠急性肺损伤的作用

目的明确西地那非对急性肺损伤(ALI)的治疗作用及可能机制。方法采用脂多糖(LPS,4 mg·kg~(-1))气道滴入诱导的小鼠ALI模型。随机分为生理盐水组、LPS模型组、西地那非3,10及30 mg·kg~(-1)组、地塞米松5 mg·kg~(-1)组。测定肺干/湿重比值,常规细胞形态学检测支气管肺泡灌洗液(BALF)中白细胞,肺组织切片观察病理改变;测定肺组织匀浆髓过氧化酶(MPO)活性、NO含量、NOS活性及TNF-α含量。结果LPS诱导的ALI小鼠肺干/湿重比值明显下降;BALF中白细胞总数及中性粒细胞比例明显增加;肺毛细血管通透性明显增加;肺组织间隙大量中性粒细胞浸润和红细胞渗出;肺组织匀浆TNF-α含量和MPO活性明显增加,NO含量、总NOS活性及iNOS活性明显增加。同时腹腔注射西地那非可剂量依赖性地降低ALI小鼠肺干/湿重比值;减少BALF中的白细胞总数及中性粒细胞的比例;降低肺毛细血管通透性;改善肺组织病理变化;抑制肺组织匀浆TNF-α含量、MPO活性及NO含量、总NOS活性及iNOS活性的增加。结论西地那非对LPS诱导的ALI有保护作用,提示NO- cGMP途径可能在ALI中起重要作用。     

sRAGE对脂多糖介导的小鼠急性肺损伤的保护作用

目的探讨可溶性晚期糖基化终末产物受体(sRAGE)对脂多糖(LPS)介导的小鼠急性肺损伤(ALI)的保护作用。方法向小鼠气管内滴注LPS建立ALI模型,造模后1h sRAGE组腹腔注射100μg sRAGE,于24 h留取标本,检测各组动物支气管肺泡灌洗液(BALF)中白细胞及中性粒细胞数量、蛋白浓度和肿瘤坏死因子(TNF)α-水平,并对肺组织进行病理学观察。结果LPS滴注24 h后,BALF中白细胞总数和中性粒细胞数量显著增加,蛋白含量升高,TNFα-释放增多,肺组织出现典型的ALI病理损害,sRAGE干预显著降低了BALF中白细胞及中性粒细胞数量、蛋白含量和TNFα-水平,减轻了LPS引起的肺组织病理改变。结论应用sRAGE阻止RAGE信号通过抑制LPS引起的肺内中性粒细胞聚集、肺毛细血管渗出、炎症因子TNFα-释放,对ALI发挥保护作用。     

桉柠蒎肠溶软胶囊对脂多糖诱导小鼠急性肺损伤的改善作用

目的:研究桉柠蒎肠溶软胶囊对脂多糖(LPS)诱导小鼠急性肺损伤(ALI)的改善作用。方法:将60只小鼠随机分为空白对照组、模型对照组和桉柠蒎肠溶软胶囊低、中、高剂量组(100、300、900 mg/kg),每组12只。给药组小鼠ig相应药物,空白对照组和模型对照组小鼠ig等体积生理盐水(0.1 m L/10 g)。给药2 h后,除空白对照组外,其余各组小鼠均采用LPS雾化吸入的方法诱导ALI模型。造模6 h后,处死小鼠取肺泡灌洗液(BALF)和肺组织,镜下观察肺组织形态学变化;血细胞计数板计算BALF中总细胞数和瑞氏-吉姆萨染色后计算BALF中中性粒细胞数;二喹啉甲酸法检测BALF上清液中总蛋白浓度;酶联免疫吸附法检测BALF上清液中肿瘤坏死因子α(TNF-α)、白细胞介素6(IL-6)含量。结果:与空白对照组比较,模型对照组小鼠肺组织发生明显病理学损伤,肺水肿严重;BALF中总细胞数、中性粒细胞数和BALF上清液中总蛋白浓度以及TNF-α、IL-6含量均显著增加(P<0.01)。与模型对照组比较,桉柠蒎肠溶软胶囊高剂量组小鼠肺组织病理损伤明显改善,BALF中总细胞数、中性粒细胞数和BALF上清液中总蛋白浓度以及TNF-α、IL-6含量均显著减少(P<0.05);其余各组差异无统计学意义(P>0.05)。结论:高剂量桉柠蒎肠溶软胶囊能明显改善LPS诱导的小鼠ALI。     

蛞蝓提取物对LPS致小鼠气道及肺部急性炎症的影响

目的 探讨蛞蝓提取物对脂多糖（lipopolysaccharide，LPS）致小鼠气道及肺部急性炎症的影响。方法 将48只C57BL/6雄性小鼠随机分为正常对照组（Ctl）、正常对照+蛞蝓干预组（Ctl+Limax）、模型组（LPS）、模型+蛞蝓干预组（LPS+Limax），每组12只。各蛞蝓干预组于造模前1 d起给予4.36 g·kg^-1蛞蝓提取物灌胃，每日1次，直至造模结束。经鼻滴入LPS对小鼠进行急性气道炎症造模，非造模组经鼻滴入同体积生理盐水。观测各组小鼠肺病理、肺的髓过氧化物酶表达；肺泡灌洗液中白细胞及IL-6、CXCL1、TNF-α、IFN-γ的分泌；采用LC-MS对蛞蝓提取物进行主成分分析，计算机模拟分子对接推测可能的活性成分。结果 蛞蝓提取物可明显缓解LPS致小鼠急性气道炎症的肺组织病理，减少肺部的白细胞浸润，抑制肺部髓过氧化物酶表达，降低肺泡灌洗液中IL-6、CXCL1、TNF-α、IFN-γ含量，其中活性成分可能是黄酮Ononin，且与Siglecs受体有潜在结合可能。结论 蛞蝓提取物具有明显的抑制急性气道炎症的作用，其中活性成分黄酮Ononin通过Siglecs受体抑制中性粒细胞浸润可能是其改善急性肺损伤病理的作用机制之一。     

地昔帕明对小鼠内毒素急性肺损伤的影响

目的探讨地昔帕明(DP)对脂多糖(LPS)引起的急性肺损伤的作用并初步探讨其作用机制。方法昆明种小鼠随机分为生理盐水对照组(NS组)、地昔帕明对照组(DP组)、模型组(LPS组)及地昔帕明处理组(DP+LPS组)。腹腔注射LPS建立小鼠急性肺损伤模型。造模6h后测定肺湿/干重比值(W/D)、肺泡灌洗液(BALF)中白细胞数和蛋白含量、肺组织匀浆中髓过氧化物酶(MPO)活性和丙二醛(MDA)水平,同时用ELISA法检测肺匀浆中肿瘤坏死因子-α(TNF-α)含量。结果LPS可提高小鼠肺W/D、BALF中白细胞数和蛋白含量、肺匀浆MPO活性、MDA和TNF-α含量(P<0.01),DP处理组可有效减轻LPS所引起的上述变化(P<0.05)。结论DP对LPS导致的小鼠急性肺损伤有保护作用,其保护机制可能与抑制肺TNF-α的产生,进而减轻中性粒细胞的肺部扣押和肺组织脂质过氧化损伤的程度有关。     

丹参酮IIA磺酸钠对脂多糖致小鼠急性肺损伤的预防与治疗作用及其机制

目的观察丹参酮IIA磺酸钠(STS)对脂多糖(LPS)引起的小鼠急性肺损伤(ALI)的预防与治疗作用,并初步探讨其作用机制。方法昆明种小鼠随机分为生理盐水(NS)对照组、STS对照组、LPS组、STS+LPS组及LPS+STS组,腹腔注射LPS建立小鼠急性肺损伤模型。造模6h后观察肺组织形态学改变,测定左肺湿/干重比值(W/D)、肺/体重比值(L/B)、肺泡灌洗液(BALF)中蛋白含量及肺组织匀浆中髓过氧化物酶(MPO)活力,同时微量滴定法检测肺组织匀浆与BALF中磷脂酶A2(PLA2)的活性。结果形态学观察表明LPS组肺组织明显充血、水肿,并有大量炎性细胞浸润,而在STS+LPS组及LPS+STS组内毒素所致肺损伤明显减轻;W/D、L/B、BALF中蛋白含量与肺匀浆MPO活力LPS组较对照组明显升高(P<0·05),但STS+LPS组及LPS+STS组较LPS组明显减低(P<0·05)。LPS组小鼠肺匀浆与BALF中PLA2活性为[(49·2±4·3)U与(40·8±6·5)U],均高于正常对照组[(23·8±4·8)U与(27·2±6·9)U],而在STS+LPS组及LPS+STS组分别降为[(29·0±5·8)U,(30·0±5·8)U]与[(31·4±4·9)U,(31·0±3·8)U],与LPS组相比差异有统计学意义。结论STS能够对LPS导致的小鼠急性肺损伤起预防与治疗作用,这种保护作用可能与其通过抑制肺中PLA2活力作用有关。     

Effects of inhaled nanoparticles on acute lung injury induced by lipopolysaccharide in mice

We have previously shown that intratracheal instillation of carbon nanoparticles exacerbates lung inflammation related to bacterial endotoxin (lipopolysaccharide, LPS) and subsequent systemic inflammation with coagulatory disturbance in mice [Inoue, K., Takano, H., Yanagisawa, R., Hirano, S., Sakurai, M., Shimada, A., Yoshikawa, T., 2006b. Effects of airway exposure to nanoparticles on lung inflammation induced by bacterial endotoxin in mice. Environ. Health Perspect. 114, 1325-1330]. The present study was performed to determine whether inhalation of diesel engine-derived nanoparticles also exacerbates the model. ICR mice were exposed for 5h to clean air or diesel engine-derived nanoparticles at a concentration of 15, 36, or 169 microg/m(3) after intratracheal challenge with 125 microg/kg of LPS or vehicle, and were sacrificed for evaluation 24h after the intratracheal challenge. Nanoparticles alone did not induce lung inflammation. Nanoparticle inhalation increased LPS-elicited inflammatory cell recruitment into the bronchoalveolar lavage fluid and lung parenchyma as compared with clean air inhalation in a concentration-dependent manner. Lung homogenates derived from the nanoparticle+LPS groups tended to have increased tumor necrosis factor-alpha level and chemotaxis activity for polymorphonuclear leukocytes as compared to those from the LPS group or the corresponding nanoparticle groups. Nanoparticle inhalation did not significantly increase lung expression of proinflammatory cytokines or facilitate systemic inflammation and coagulatory disturbance. Isolated alveolar macrophages (AMs) from nanoparticle-exposed mice showed greater production of interleukin-1beta and keratinocyte chemoattractant stimulated with ex vivo LPS challenge than those from clean air-exposed mice, although the differences did not reach statistical significance. These results suggest that acute exposure to diesel nanoparticles exacerbates lung inflammation induced by LPS.     

Size effects of nanomaterials on lung inflammation and coagulatory disturbance

Effects of nano-sized materials (nanomaterials) on subjects with predisposing inflammatory disorders have not been well elucidated. This study examined the effects of pulmonary exposure to TiO2 nanomaterials on lung inflammation induced by lipopolysaccharide (LPS) and consequent systemic inflammation with coagulatory disturbance in mice, in particular regarding their size-dependency. Also, gene expression pattern in the lung was compared among the experimental groups using cDNA microarray analysis. ICR male mice were divided into 8 experimental groups that intratracheally received vehicle, three sizes (15, 50, 100 nm) of TiO2 nanomaterials (8 mg/kg), LPS (2.5 mg/kg), or LPS plus nanomaterials. Twenty four h after the treatment, these nanomaterials exacerbated the lung inflammation and vascular permeability elicited by LPS, with an overall trend of amplified lung expressions of cytokines such as interleukin (IL)-1beta, macrophage chemoattractant protein (MCP)-1, and keratinocyte chemoattractant (KC). LPS plus nanomaterials, especially of a size less than 50 nm, elevated circulatory levels of fibrinogen, IL-1beta, MCP-1, and KC, and von Willebrand factor as compared with LPS alone. The enhancement tended overall to be greater with the smaller nanomaterials than with the larger ones. cDNA microarray analyses revealed that there was no difference in gene expression pattern between the LPS group and the LPS + nanomaterial. These results suggest that nanomaterials exacerbate lung inflammation related to LPS with systemic inflammation and coagulatory disturbance, and that the exacerbation is more prominent with smaller nanomaterials than with larger ones.     

Size effects of latex nanomaterials on lung inflammation in mice

Effects of nano-sized materials (nanomaterials) on sensitive population have not been well elucidated. This study examined the effects of pulmonary exposure to (latex) nanomaterials on lung inflammation related to lipopolysaccharide (LPS) or allergen in mice, especially in terms of their size-dependency. In protocol 1, ICR male mice were divided into 8 experimental groups that intratracheally received a single exposure to vehicle, latex nanomaterials (250 μg/animal) with three sizes (25, 50, and 100 nm), LPS (75 μg/animal), or LPS plus latex nanomaterials. In protocol 2, ICR male mice were divided into 8 experimental groups that intratracheally received repeated exposure to vehicle, latex nanomaterials (100 μg/animal), allergen (ovalbumin: OVA; 1 μg/animal), or allergen plus latex nanomaterials. In protocol 1, latex nanomaterials with all sizes exacerbated lung inflammation elicited by LPS, showing an overall trend of amplified lung expressions of proinflammatory cytokines. Furthermore, LPS plus nanomaterials, especially with size less than 50 nm, significantly elevated circulatory levels of fibrinogen, macrophage chemoattractant protein-1, and keratinocyte-derived chemoattractant, and von Willebrand factor as compared with LPS alone. The enhancement tended overall to be greater with the smaller nanomaterials than with the larger ones. In protocol 2, latex nanomaterials with all sizes did not significantly enhance the pathophysiology of allergic asthma, characterized by eosinophilic lung inflammation and Igs production, although latex nanomaterials with less than 50 nm significantly induced/enhanced neutrophilic lung inflammation. These results suggest that latex nanomaterials differentially affect two types of (innate and adaptive immunity-dominant) lung inflammation.     

Effects of organic chemicals derived from ambient particulate matter on lung inflammation related to lipopolysaccharide

The effects of components of ambient particulate matter (PM) on individuals with predisposing respiratory disorders are not well defined. We have previously demonstrated that airway exposure to diesel exhaust particles (DEP) or organic chemicals (OC) extracted from DEP (DEP–OC) enhances lung inflammation related to bacterial endotoxin (lipopolysaccharide, LPS). The present study aimed to examine the effects of airway exposure to OC extracted from urban PM (PM–OC) on lung inflammation related to LPS. ICR mice were divided into four experimental groups that intratracheally received vehicle, LPS (2.5 mg/kg), PM–OC (4 mg/kg), or PM–OC + LPS. Lung inflammation, lung water content, and lung expression of cytokines were evaluated 24 h after intratracheal administration. LPS challenge elicited lung inflammation evidenced by cellular profiles of bronchoalveolar lavage fluid and lung histology, which was further aggravated by the combined challenge with PM–OC. The combination with PM–OC and LPS did not significantly exaggerate LPS-elicited pulmonary edema. LPS instillation induced elevated lung expression of interleukin-1β, macrophage inflammatory protein-1α, macrophage chemoattractant protein-1, and keratinocyte chemoattractant, whereas the combined challenge with PM–OC did not influence these levels. All the results were consistent with our previous reports on DEP–OC. These results suggest that the extracted organic chemicals from PM exacerbate infectious lung inflammation. The mechanisms underlying the enhancing effects are not mediated via the enhanced local expression of proinflammatory cytokines.     

Low-level laser therapy decreases levels of lung neutrophils anti-apoptotic factors by a NF-kappaB dependent mechanism

BACKGROUND AND OBJECTIVE: Low-level laser therapy (LLLT) is a known modulator of inflammatory process. Herein we studied the effect of 660 nm diode laser on mRNA levels of neutrophils anti-apoptotic factors in lipopolysaccharide (LPS)-induced lung inflammation. STUDY DESIGN/METHODOLOGY: Mice were divided into 8 groups (n=7 for each group) and irradiated with energy dosage of 7.5 J/cm(2). The Bcl-xL and A1 mRNA levels in neutrophils were evaluated by Real Time-PCR (RT-PCR). The animals were irradiated after exposure time of LPS. RESULTS: LLLT and an inhibitor of NF-kappaB nuclear translocation (BMS 205820) attenuated the mRNA levels of Bcl-xL and A1 mRNA in lung neutrophils obtained from mice subjected to LPS-induced inflammation. CONCLUSION: LLLT reduced the levels of anti-apoptotic factors in LPS inflamed mice lung neutrophils by an action mechanism in which the NF-kappaB seems to be involved.     

Endotoxin induces late increase in the production of pulmonary proinflammatory cytokines in murine lupus-like pristane-primed modelp

Lupus-like syndrome is characterized by multiple organ injuries including lungs and kidneys. Endotoxin induces a transiently intent systemic inflammatory response and indirectly transient acute lung injury in normal condition. However, whether endotoxin may trigger the persistent development of lung injury in chronic, inflammatory lupus-like syndrome compared with normal condition remains unclear. We examined the pulmonary vascular permeability and production of proinflammatory cytokines, such as TNF-alpha, IL-6, IL-10 and IFN-gamma, which play prominent roles in the pathogenesis of lupus-like tissue injury, 6 h and 72 h after i.p. lipopolysaccharide (LPS; endotoxin) injection in pristane-primed chronic inflammation ICR mice characterized by a lupus-like syndrome. These results demonstrated that levels of serum IL-6, IL-10 and IFN-gamma and bronchoalveolar lavage (BAL) IL-6 and IFN-gamma were remarkably increased 6 h in LPS-exposed pristane-primed mice compared with pristane-primed controls, while pulmonary vascular permeability and levels of serum and BAL TNF-alpha were not. And levels of BAL TNF-alpha, IL-6 and IL-10 were significantly enhanced 72 h in LPS-exposed pristane-primed mice compared with pristane-primed controls. Also, LPS significantly induced the increased in vitro production of TNF-alpha, IL-6 and IL-10 by lung cells obtained from LPS-exposed pristane-primed mice compared with LPS-exposed normal mice. Our findings indicate that LPS may trigger persistent progression of lung injury through late overproduction of BAL TNF-alpha, IL-6, and IL-10 in lupus-like chronic inflammation syndrome compared with normal condition.     

Progress in allergy signal research on mast cells: regulation of allergic airway inflammation through toll-like receptor 4-mediated modification of mast cell function

In a mouse experimental asthma model, the administration of bacterial lipopolysaccharide (LPS), particularly at low doses, enhances the levels of ovalbumin (OVA)-induced eosinophilic airway inflammation. In an effort to clarify the cellular and molecular basis for the LPS effect, we demonstrate that the OVA-induced eosinophilic inflammation in the lung is dramatically increased by administration of LPS at the priming phase in wild-type mice, whereas such an increase was not observed in mast cell deficient mice. Adoptive transfer of bone marrow-derived mast cells (BMMC) from wild type but not from Toll-like receptor 4 (TLR4)-deficient mice restored the increased eosinophilic inflammation in mast cell-deficient mice. Moreover, in vitro analysis revealed that treatment of BMMC with LPS resulted in sustained up-regulation of GATA1 expression and increased production of Th2 cytokines (IL-4, IL-5, and IL-13) upon restimulation. Thus, mast cells appear to control allergic airway inflammation after their activation and modulation through TLR4-mediated induction of GATA1 proteins and subsequent increase in Th2 cytokine production.     

Lipopolysaccharide-induced lung inflammation is inhibited by neutralization of GM-CSF

Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the pathogenesis of acute and chronic lung disease as a major regulator governing the functions of granulocyte and macrophage lineage populations. Chronic obstructive pulmonary disease (COPD) is a disease characterized by lung inflammation with accumulation of neutrophils and increased levels of pro-inflammatory cytokines including GM-CSF in the patient's lungs. We used intranasal administration of lipopolysaccharide (LPS) to mice to induce a disease that resembles COPD with pulmonary inflammation, neutrophil recruitment and release of pro-inflammatory mediators in the bronchoalveolar lavage fluid of the diseased mice. 2 h prior to LPS administration, mice were systemically treated with the murine GM-CSF neutralizing antibody mAb 22E9 per intraperitoneal injection. Intranasal challenge with LPS-induced an increase of total cell number and of neutrophils in the bronchoalveolar lavage fluid. Elevated levels of tumor necrosis factor alpha (TNF-alpha), keratinocyte cytokine and macrophage inflammatory protein-2 (MIP-2) were also observed at this time point. GM-CSF was no longer detectable in bronchoalveolar lavage fluid at 24 h due to its early expression with a peak reached 6 h after LPS challenge. Pretreatment of mice with GM-CSF neutralizing antibody dose-dependently inhibited the accumulation of neutrophils and reduced TNF-alpha and MIP-2 protein levels in bronchoalveolar lavage fluid. These data suggest that neutralization of GM-CSF may represent a novel treatment modality for lung inflammation and in particular for COPD.     

Fibroblast Growth Factor 21 dependent TLR4/MYD88/NF-κB signaling activation is involved in lipopolysaccharide-induced acute lung injury

Fibroblast Growth Factor 21 (FGF21) has been reported to reduce inflammation and apoptosis. Inflammation and apoptosis are both the essential mechanisms during development of acute lung injury. This study evaluated whether pre-treatment of FGF21 could alleviate acute lung injury. Mice were pre-treated with FGF21 prior to lipopolysaccharide (LPS) treatment. 24 h later, the lung tissues and BALF were obtained to detect H&E pathology, W/D ratio, pro-inflammatory factors (TNF-α, IL-1β and IL-6) and apoptosis. In vitro, Human BEAS-2B and THP-1 cells were overexpressed with TLR4 or MYD88 or NF-κB plasmid to detect the inflammation or apoptosis. Data showed that FGF21 was proved to be beneficial for inhibiting inflammation and apoptosis in the LPS- induced Balb/c mice or LPS induced BEAS-2B or THP-1 cells. Furthermore, the data showed that FGF21 suppressed inflammation and apoptosis via inhibition of TLR4/MYD88/NF-κB signaling pathway. Therefore, FGF21 provides a possibility for the treatment of LPS induced acute lung injury.     

远志酊对脂多糖致炎小鼠抗炎活性的实验研究

目的：研究远志酊对LPS致炎症小鼠的抗炎活性，探讨远志酊在细胞因子水平的抗炎机制。方法：将40只ICR小鼠随机分为正常对照组、脂多糖（LPS）组、远志酊高、中和低剂量组（40，20，10 μL·g^-1）。实验进行6 d后，检测各组小鼠脾脏指数；ELISA测定小鼠外周血TNF-α和IL-6的表达；RT-PCR方法检测小鼠肾脏TNF-α和IL-6的表达；HE染色观察各组小鼠肺脏组织的炎症变化。结果：远志酊组小鼠的脾脏指数明显降低，外周血及肾脏组织中TNF-α和IL-6的表达均显著下降，并且小鼠肺脏组织的炎症明显减轻，并呈现一定的剂量依赖性。结论：远志酊对LPS致炎症小鼠具有很好的抗炎活性，可一定程度上降低炎性细胞因子的表达。