急性肺损伤/急性呼吸窘迫综合征发病机制的研究进展

急性肺损伤(ALI)是全身炎症反应综合征在肺部的表现,可进一步发展为急性呼吸窘迫综合征(ARDS),其发病机制复杂,病死率高达35%～40%。在其复杂的发病机制中,失控的炎症反应中的炎症细胞、细胞因子和炎症介质所构成的"细胞网络"和"细胞因子网络"发挥重要作用,此外还有凝血/纤溶的失衡、氧化还原不平衡、细胞凋亡、水通道蛋白及个体差异、遗传因素的影响等参与这一过程。本文就近年来的研究做一阐述。     

重症急性胰腺炎致肺损伤发病机制研究进展

重症急性胰腺炎(SAP)常在早期出现肺损伤(ALI),甚至是急性呼吸窘迫综合征(ARDS),这是SAP早期死亡的主要原因.其发生机制复杂,中性粒细胞的活化、胰酶、补体系统和激肽的激活、炎症介质及细胞因子、核因子-kB、P物质等种因素在其发病机制中发挥一定的作用,现就重症急性胰腺炎肺损伤的机制作一综述.     

Caveolin-1在急性肺损伤／急性呼吸窘迫综合征发病机制中的作用进展

1953年Palade在电镜下发现血管内皮细胞表面有一些细颈瓶状的内陷结构,2年后Yamada在膀胱上皮细胞表面发现同类结构,并将其命名为胞膜窖（caveolae,Cle）。胞膜窖直径约50-100nm,主要由窖蛋白（caveolin,Cln）、胆固醇、鞘磷脂、糖基鞘磷脂及脂蛋白组成,     

急性肺损伤/急性呼吸窘迫综合征治疗药物的研究进展

急性肺损伤/急性呼吸窘迫综合征的高病死率一直以来都是呼吸系统疾病的棘手问题。除了病因治疗外,积极对症处理有可能减少病死率。近年来研究证明:循环内皮祖细胞在修复肺损伤中起着重要的作用,是一个潜在的治疗急性肺损伤/急性呼吸窘迫综合征的细胞。PDE-4选择性抑制剂可望用于治疗急性肺损伤/急性呼吸窘迫综合征。早期应用小剂量糖皮质激素有助于改善炎症和肺纤维病变。肺表面活性物质对新生儿呼吸窘迫征有确切疗效。其他正在进行临床研究的药物包括:乙酰半胱氨酸、一氧化氮、前列环素和β2受体激动剂等。     

糖皮质激素治疗急性肺损伤/急性呼吸窘迫综合征的抗炎机制研究进展

目的:为糖皮质激素(GC)治疗急性肺损伤/急性呼吸窘迫综合征(ALI/ARDS)提供实践和理论依据。方法:查阅近5年来国内外相关文献,对GC治疗ALI/ARDS的基础研究、临床应用、抗炎机制等方面的进展进行归纳和总结。结果:共查阅到相关文献129篇,其中有效文献84篇。GC抗炎机制众多,药理作用广泛,对于治疗ALI/ARDS的效果褒贬不一,剂量-时间-效应关系尚不明确。结论:GC治疗ALI/ARDS的抗炎效果理论上是可行的,临床疗效可能更依赖的是医师针对患者的个体化治疗。     

重新评价吸入一氧化氮在急性肺损伤中的作用

Inhaled nitric oxide (iNO) has now been used clinically since 1991, or twelve years. The acute aims of therapy have mainly been improvement of oxygenation and reduction of lung vasoconstriction. This is true also for the use in ALl (acute lung injury) of various degrees of severity including ARDS (acute respiratorydistress syndrome).     

山莨菪碱对急性肺损伤作用机制研究进展

急性肺损伤（Acute lung injury，ALI）系由化学因素（吸入烟雾、毒气、胃内容物等）、物理因素（创伤、化学损伤、放射损伤等）、生物因素（病原微生物）、某些治疗措施（血液透析、体外循环等）以及全身病理过程（休克、大面积烧伤等）等多种因素所致的急性弥漫性肺损伤，严重者可形成肺不张，甚至可发展为呼吸窘迫综合征（ARDS），且ARDS的死亡率可达50％。因此，人们研究具有预防和减轻肺损伤作用的药物有重要的临床意义。近年来，国内许多学者采用油酸、创伤、脂多糖（LPS）等复制的实验性ALI模型，研究了山莨菪碱（Anisodamine，ADM，合成品为654-2）对ALI的治疗作用，并对其机制进行较深入的探讨。     

氯胺酮治疗急性肺损伤研究进展

目前临床已经逐渐认识到,急性肺损伤(ALI)实质是全身炎症反应综合征(SIRS)所致的肺部过度炎症反应,其临床治疗尚未取得明显进展。氯胺酮具有抗炎作用,其在治疗ALI中的作用及其机制尚未完全阐明。该文就氯胺酮治疗ALI的效应及其可能的各种生物学抗炎途径,以及降低肺动脉压,提高肺顺应性机制研究等进展进行综述。     

内毒素所致急性肺损伤发病机制的研究进展

急性肺损伤是临床常见的危重症。内毒素是导致急性肺损伤最常见的原因。近年来关于内毒素所致的急性肺损伤发病机制的研究发现:核转录因子κB、IL-8和中性粒细胞在促炎/抗炎反应的失衡中发挥重要作用,组织因子和肺泡上皮细胞在调节促凝/抗凝反应的失衡中发挥重要作用,而氧化应激和炎症反应之间可以相互促进。而且肺泡上皮细胞和PMN凋亡功能的紊乱、肺泡上皮细胞上Na+通道的下调、PMN释放的中性粒细胞弹性蛋白酶等在LPS导致的ALI发展过程中都发挥重要作用。     

N-acetylcysteine abrogates acute lung injury induced by endotoxin

1. Acute lung injury (ALI) or acute respiratory distress syndrome is a serious clinical problem with high mortality. N-Acetylcysteine (NAC) is an anti-oxidant and a free radical scavenger. It has been reported recently that NAC ameliorates organ damage induced by endotoxin (lipopolysaccharide; LPS) in conscious rats. The present study was designed to evaluate the effects of NAC on LPS-induced ALI and other changes in anaesthetized rats. 2. Sprague-Dawley rats were anaesthetized with pentobarbital (40 mg/kg, i.p.). Endotracheal intubation was performed to provide artificial ventilation. Arterial pressure and heart rate were monitored. The extent of ALI was evaluated with the lung weight (LW)/bodyweight ratio, LW gain, exhaled nitric oxide (NO) and protein concentration in bronchoalveolar lavage (PCBAL). Haematocrit, white blood cells, plasma nitrate/nitrite, methyl guanidine (MG), tumour necrosis factor (TNF)-alpha and interleukin (IL)-1b were measured. Pathological changes in the lung were examined and evaluated. 3. Endotoxaemia was produced by injection of 10 mg/kg, i.v., LPS (Escherichia coli). Animals were randomly divided into three groups. In the vehicle group, rats received an i.v. drip of physiological saline solution (PSS) at a rate of 0.3 mL/h. The LPS group received an i.v. drip of PSS for 1 h, followed by LPS (10 mg/kg by slow blous injection, i.v., over 1-2 min). Rats in the LPS + NAC group received NAC by i.v. drip at a rate of 150 mg/kg per h (0.3 mL/h) for 60 min starting 10 min before LPS administration (10 mg/kg by slow blous injection, i.v., over 1-2 min). Each group was observed for a period of 6 h. 4. N-Acetylcysteine treatment improved the LPS-induced hypotension and leukocytopenia. It also reduced the extent of ALI, as evidenced by reductions in LW changes, exhaled NO, PCBAL and lung pathology. In addition, NAC diminished the LPS-induced increases in nitrate/nitrite, MG, TNF-a and IL-1b. 5. In another series of experiments, LPS increased the mortality rate compared with the vehicle group (i.v. drip of PSS at a rate of 0.3 mL/h) during a 6 h observation period. N-Acetylcysteine, given 10 min prior to LPS, significantly increased the survival rate. 6. The results of the present study suggest that NAC exerts a protective effect on the LPS-induced ALI. The mechanisms of action may be mediated through the reduction of the production of NO, free radicals and pro-inflammatory cytokines.     

炎调方对脓毒症急性肺损伤大鼠肺组织髓过氧化物酶和丙二醛水平的影响

目的 观察炎调方对脓毒症急性肺损伤(ALI)大鼠肺组织髓过氧化物酶(MPO)、丙二醛(MDA)水平的影响。方法 清洁级健康雄性SD大鼠随机分为对照组、假手术组、模型组、炎调方组、地塞米松组,炎调方组ig 9.9 g/kg炎调方,地塞米松组ig 0.45 mg/kg地塞米松,每天给药1次,连续给药3 d。末次ig 2 h后采用盲肠结扎穿孔术(CLP)制备脓毒症ALI模型,分别于造模后24 h处死动物,进行肺组织HE染色,测定各组大鼠湿/干重比(W/D),肺组织MPO、MDA水平。结果 模型组大鼠肺组织损伤程度、MPO及MDA水平较对照组及假手术组显著增高(P<0.01),炎调方组、地塞米松组肺组织损伤程度、MPO及MDA水平较模型组显著降低(P<0.05、0.01)。结论 炎调方可有效减轻脓毒症ALI大鼠的炎症及氧化应激反应。     

The angiopoietin-Tie2 system as a therapeutic target in sepsis and acute lung injury

Background: Sepsis and acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are life-threatening syndromes characterised by inflammation and increased vascular permeability. Amongst other factors, the angiopoietin–tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (Tie2) system is involved. Objective: To explore whether the angiopoietin–Tie2 system provides suitable targets for the treatment of sepsis and ALI/ARDS. Methods: Original experimental and patient studies on angiopoietins and sepsis/endotoxemia, inflammation, lung injury, hyperpermeability, apoptosis, organ functions and vital outcomes were reviewed. Results/conclusion: The angiopoietin–Tie2 system controls the responsiveness of the endothelium to inflammatory, hyperpermeability, apoptosis and vasoreactive stimuli. Angiopoietin-2 provokes inflammation and vascular hyperpermeability, while angiopoietin-1 has a protective effect. Targeted angiopoietin-2 inhibition with RNA aptamers or blocking antibodies is a potential anti-inflammatory and anti-vascular hyperpermeability strategy in the treatment of sepsis and ALI/ARDS.     

Endothelial pathomechanisms in acute lung injury

Acute lung injury (ALI) and its most severe extreme the acute respiratory distress syndrome (ARDS) refer to increased-permeability pulmonary edema caused by a variety of pulmonary or systemic insults. ALI and in particular ARDS, are usually accompanied by refractory hypoxemia and the need for mechanical ventilation. In most cases, an exaggerated inflammatory and pro-thrombotic reaction to an initial stimulus, such as systemic infection, elicits disruption of the alveolo-capillary membrane and vascular fluid leak. The pulmonary endothelium is a major metabolic organ promoting adequate pulmonary and systemic vascular homeostasis, and a main target of circulating cells and humoral mediators under injury; pulmonary endothelium is therefore critically involved in the pathogenesis of ALI. In this review we will discuss mechanisms of pulmonary endothelial dysfunction and edema generation in the lung with special emphasis on the interplay between the endothelium, the immune and hemostatic systems, and highlight how these principles apply in the context of defined disorders and specific insults implicated in ALI pathogenesis.     

乌司他丁治疗新型冠状病毒肺炎可行性的研究进展

新型冠状病毒肺炎（COVID-19）仍在全球范围内传播,尚无特效药应用于临床。乌司他丁（ulinastatin）在抗炎方面发挥重要作用,临床上主要应用于急性胰腺炎、休克和弥散性血管内凝血等,其还具有抗氧化应激、抗凝、免疫调节作用,可能对于降低COVID-19的严重程度和死亡率有重要意义。主要结合乌司他丁的药理作用及其在治疗急性呼吸窘迫综合征、脓毒症肺损伤等COVID-19并发症中的临床应用,论述其应用于COVID-19的可行性,以期为该病的临床治疗及新药研发提供帮助。     

microRNA-125b在脓毒症急性肺损伤中的表达及其与炎症因子水平相关性

摘要：目的探讨microRNA-125b（miR-125b）在脓毒症急性肺损伤中的表达及其与炎症因子的相关性。方法 腹腔注射脂多糖（LPS）诱导急性肺损伤大鼠模型,对照组注射等量的生理盐水（n=20）;各模型组（n=20）大鼠注射LPS 4、8、12及24 h后取其肺组织,HE染色观察病理学变化;PCR检测各组各时点肺组织中miR-125b、肿瘤坏死因子-α（TNF-α）与白细胞介素-6（IL-6）变化。Pearson相关性分析实验组肺组织中miR-125b的表达与TNF-α、IL-6水平的相关性。NR8383细胞培养后分组,对照组不进行LPS刺激,实验组加入LPS刺激4 h、8 h、12 h及24 h时收集细胞,检测各组miR-125b、TNF-α与IL-6的含量变化。另NR8383细胞设3组,阴性对照组只转染空表达质粒,miR-125b mimic组转染miR-125b mimic表达质粒,miR-125b inhibitor组转染miR-125b inhibitor质粒。PCR测各组细胞中miR-125b 表达情况,Western blot测Notch1的表达情况。结果LPS各处理组大鼠模型肺组织严重出血、水肿及大量炎症细胞浸润。与对照组比较,在注射LPS 4、8、12以24 h后,实验组大鼠肺组织中miR-125b显著降低;而肺组织中TNF-α与IL-6水平则升高,其中在LPS注射4 h后,TNF-α与IL-6的表达水平达到峰值（P＜0.05）。实验组肺组织中miR-125b的表达与TNF-α及IL-6呈负相关（r 分别为-0.599、-0.580;P＜0.05）。在LPS诱导的第4、8、12、24 h,实验组NR8383细胞系miR-125b表达水平均低于对照组,而TNF-α、IL-6的表达水平均高于对照组（P＜0.05）。与阴性对照组比较,miR-125b mimic组miR-125b 相对表达量升高、Notch1蛋白相对表达量则降低（P＜0.05）,miR-125binhibitor组miR-125b 相对表达量降低、Notch1蛋白相对表达量升高（P＜0.05）;与miR-125b mimic组比较,miR-125binhibitor组miR-125b 相对表达量降低、Notch1蛋白相对表达量升高（P＜0.05）。结论在脓毒症急性肺损伤中,microRNA-125b可能通过调控Notch1蛋白的表达,影响炎症因子TNF-α与IL-6的表达,参与其免疫炎症调控过程。     

Evolution of treatments for patients with acute lung injury

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are acute life-threatening forms of hypoxemic respiratory failure. ALI/ARDS patients require intensive care with prolonged mechanical ventilation. Despite advances in our understanding of the pathophysiology of ALI/ARDS, mortality rates remain > 30% and survivors suffer significant decrements in their quality of life. The evolving understanding of ALI/ARDS and the complex interactions involved in ALI/ARDS open the door for many potential targets for treatment. The condition is characterised by an acute inflammatory state that leads to increased capillary permeability and accumulation of proteinaceous pulmonary oedema. The changes that occur as a result of this inflammation clinically manifest themselves as hypoxemia, infiltrates on chest radiograph and reduced lung compliance. Many years have been dedicated to analysing the complexities involved in ALI/ARDS in order to improve current and future possibilities for treatment, with the aim of improving patient outcomes. Although some therapies have demonstrated benefits of improved oxygenation, such as surfactant and nitric oxide, these benefits have not translated into reductions in the duration of mechanical ventilation or mortality. Inflammatory mediator-targeted therapies were promising early on; however, larger trials have found therapies such as cytokine modulation, platelet-activating factor inhibition and neutrophil elastase inhibitors to be ineffective in the treatment of ALI/ARDS. Preclinical studies with β2-agonists and granulocyte macrophage colony-stimulating factor have shown promise for restoring alveolar capillary barrier integrity or reducing pulmonary oedema, and further studies are being conducted to test for true clinical benefit. Despite previous therapeutic failures, newer surfactant formulations have shown promise, particularly in patients with direct forms of lung injury, and are currently in Phase III trials. Anticoagulant therapy with activated protein C has been shown to improve survival in sepsis, the most common risk factor for the development of ALI/ARDS, and is now being studied in ALI/ARDS. Until new data emerge, the focus must remain on supportive care, including optimised mechanical ventilation, nutritional support, manipulation of fluid balance and prevention of intervening medical complications.     

王不留行黄酮苷对脓毒症小鼠急性肺损伤保护作用及机制研究

目的 基于网络药理学和动物实验探究王不留行黄酮苷（VAC）对脓毒症小鼠急性肺损伤的保护作用机制。方法 通过 Swiss Target Prediction数据库收集 VAC的潜在作用靶点;利用 GeneCards数据库检索肺脓毒症相关的疾病靶点;运用Draw Venn Diagram 软件构建 VAC 和疾病的共同靶点;利用 STRING 11.5数据库和 Cytoscape 3.10.0软件构建共同靶点蛋白质-蛋白质相互作用（PPI）网络;利用 Metascape 数据库进行基因本体（GO）富集分析和京都基因与基因组百科全书（KEGG）通路分析。采用 ip 给予脂多糖（LPS）构建脓毒症模型,造模同时给予 VAC（1、5 mg·kg^-1）或地塞米松干预,取各组小鼠肺组织及血清,苏木精-伊红（HE）、Masson 及 TUNEL 染色观察肺组织形态变化、纤维化及细胞凋亡情况,ELISA 法和实时荧光定量 PCR（qRT-PCR）法分别检测血清和肺组织中炎症因子水平,免疫组织化学法和 Western blotting法检测肺组织炎症通路相关蛋白表达。结果 VAC和肺脓毒症共同靶点有44个;GO富集分析涉及生物过程（BP）823个条目、细胞组分（CC）52个条目和分子功能（MF）49个条目;KEGG分析筛选出癌症通路、PI3K-Akt、JAK-STAT信号通路等 20 条信号通路。验证实验结果显示,与对照组相比,模型组小鼠肺组织损伤且纤维化严重,肺脏指数显著增加（P＜0.05）,血清及肺组织中相关炎症因子表达升高（P＜0.01、0.001）。与模型组相比,VAC及地塞米松组肺组织病理形态得到改善,纤维化程度减轻,肺脏指数显著降低（P＜0.05）,血清中肿瘤坏死因子（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素6（IL-6）水平、肺组织炎症蛋白表达量及细胞凋亡数量降低,PI3K、Akt蛋白表达升高（P＜0.05、0.01、0.001）。动物实验结果与网络药理学结果一致。结论 VAC 对脓毒症小鼠急性肺损伤具有一定的保护作用,其机制可能与调控 PI3K-Akt、NLRP3/TNF-α等通路抑制炎症的发展有关,为VAC抗炎作用机制的深入研究提供了依据。     

Potential clinical application of KGF-2 (FGF-10) for acute lung injury/acute respiratory distress syndrome

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an acute life-threatening form of hypoxemic respiratory failure with a high mortality rate, and there is still a great need for more effective therapies for such a severe and lethal disease. Dysfunction of endothelial and epithelial barriers is one of the most important mechanisms in hypoxia-associated ALI/ARDS. The acceleration of the epithelial repair process in the injured lung may provide an effective therapeutic target. KGF-2, a potent alveolar epithelial cell mitogen, plays an important role in organ morphogenesis and epithelial differentiation, and modulates a variety of mechanisms recognized to be important in alveolar repair and resolution in ALI/ARDS. Preclinical and clinical studies have suggested that KGF-2 may be the candidate of novel therapies for alveolar epithelial damage during ALI/ARDS.     

内毒素诱导犬急性肺损伤模型的建立

目的建立犬内毒素性急性肺损伤模型。方法选择健康杂种犬8条,静脉注入LPS650μg/kg,当PaO2/FiO2<300时,可认为ALI模型复制成功;同时监测呼吸力学,采用放免法测定血TNF-α、IL-6和IL-10含量,电镜下观察肺组织病理改变。结果所有动物在16h左右出现急性肺损伤,表现为肺动态顺应性(Cdyn)、总顺应性(Ctot)下降,呼吸功(WOBvent)、吸气峰压(PIP)、吸气阻力(Rawi)上升,PaO2和PaO2/FiO2下降。血中TNF-α、IL-6和IL-10的浓度有明显上升,电镜下肺间质及肺泡炎性水肿出血、中性粒细胞浸润、Ⅱ型肺泡上皮细胞损伤。结论内毒素输注后16h左右达到ALI标准,且该模型稳定,重复性好。