Emerging drugs for treating the acute respiratory distress syndrome

Introduction: The acute respiratory distress syndrome (ARDS) is a common and catastrophic condition, with a high mortality rate and economic burden on society. Despite 50 years of study, there is no specific pharmacological therapy for ARDS.

Areas covered: This review outlines the definitions, epidemiology, risk factors and pathophysiology of ARDS. The priority of developing a clinically-relevant model for ARDS to test pre-clinical candidates is discussed, together with the limitations of current models. The scientific rationale of emerging therapeutic candidates is outlined in the setting of the biological mechanisms implicated in the complex pathogenesis of ARDS. Emerging therapies, currently in clinical trials, are discussed, including the pre-clinical basis for their use and the expected timeline to trial completion.

Expert opinion: We highlight the necessity of improving pre-clinical models of ARDS and the design of clinical trials for the development of novel pharmacological therapies. We reflect on the most promising emerging strategies and their potential role in ARDS management.     

Characterization of a double‐hit murine model of acute respiratory distress syndrome

The aim of the present study was to characterize a murine model of acute respiratory distress syndrome (ARDS) abiding by the Berlin definition of human ARDS and guidelines for animal models of ARDS. To this end, C57BL/6NCrl mice were challenged with lipopolysaccharide (LPS; 15 mg/kg, i.p.) followed 18 h later by injection of oleic acid (OA; 0.12 mL/kg, i.v.). Controls received saline injection at both time points. Haemodynamics were monitored continuously. Arterial blood gas analyses were performed just before and every 30 min after OA challenge. Ninety minutes after OA challenge, the chest of mice was scanned using micro‐computed tomography (CT). Cytokine concentrations were measured in plasma samples. Lungs were harvested 90 min after OA challenge for histology, immunohistochemistry, lung weight measurements and tissue cytokine detection. A histological lung injury score was determined. Eighteen hours after LPS challenge, mice exhibited a severe systemic inflammatory response syndrome. Oxygenation declined significantly after OA injections (P_ao ₂/F_io ₂ 283 ± 73 and 256 ± 71 mmHg at 60 and 90 min, respectively; P < 0.001). Bilateral patchy infiltrates were present on the micro‐CT scans. Histology revealed parenchymal damage with accumulation of polymorphonuclear neutrophils, intra‐alveolar proteinacous debris and few hyaline membranes. The lung wet : dry ratio indicated damage to the alveolar capillary membrane. Cytokine patterns evidenced a severe local and systemic inflammatory state in plasma and lung tissue. In conclusion, the described two‐hit model of ARDS shows a pathological picture of ARDS closely mimicking human ARDS according to the Berlin definition and may facilitate interpretation of prospective experimental results.     

Pharmacotherapy of acute respiratory distress syndrome

To date, the only therapeutic option that has convincingly been shown to decrease mortality in acute respiratory distress syndrome (ARDS) has been to use a lung-protective strategy that minimises the iatrogenic consequences of providing adequate life support through the use of mechanical ventilation. In terms of the pharmacological options for ARDS, no single drug or treatment has been shown to be the magic bullet in this disease. The search for novel therapies and pharmacological agents is active and relentless. Important pathophysiological areas of focus are preventative therapy, supportive care and treatment of the underlying inflammatory process. In this paper we will review current and experimental approaches to the management of ARDS. In addition, the pathophysiological basis for their putative modes of action, the current state of the literature and the potential for future clinical development will be discussed.     

东莨菪碱在急性呼吸窘迫综合征治疗中的价值

目的探讨东莨菪碱在各种原因引起的急性呼吸窘迫综合征（ARDS）治疗中的价值。方法把入住我院重症监护室的58例诊断为ARDS患者随机分为对照组和治疗组,两组接受同样治疗,但治疗组加用东莨菪碱,观察对照组和治疗组的氧合变化、胸片渗出吸收时间、上机时间、生存率等的变化情况。结果两组治疗前后比较：氧分压、氧合指数两组均有明显改善;前3天两组比较,治疗组的氧分压、氧合指数改善、胸片渗出吸收时间均优于对照组,第7天两组相仿;上机时间对照组稍长于治疗组,但无统计学意义（P〉0．05）;生存率两组相仿（P〉0．05）。结论东莨菪碱对ARDS患者l早期氧合改善及促进肺部渗出吸收有明显作用,但对患者上机时间及预后无明显改善作用。     

First case of acute respiratory distress syndrome and alimentary tract hemorrhage following mass ingestion of methylisothiazolinone

The frequency of methylisothiazolinone (MIT)-related health concerns regarding allergic contact dermatitis with a spongiotic reaction pattern and restrictive lung function indicating peripheral airway dysfunction caused by the use of humidifier disinfectant is increasingly rising. There is a limited number of evidences supporting the environmentally acute and mass exposure to MIT resulting in acute respiratory distress syndrome (ARDS). Here, we report the first case of ARDS and alimentary tract hemorrhage following mass ingestion of methylisothiazolinone.     

机械通气治疗急重症颅脑损伤合并ARDS 47例分析

目的探讨机械通气治疗急重症颅脑损伤合并急性呼吸窘迫综合征（ARDS）的有效性和可行性。方法回顾性分析47例急重症颅脑损伤合并ARDS患者的治疗过程。结果本组患者均给予人工开放气道及呼吸机辅助呼吸,13例死亡,死亡率为27.66%。结论早期诊断并尽早呼吸机治疗可有效降低本病的死亡率。     

Inhibition of CD8+ T cells and elimination of myeloid cells by CD4+ Foxp3− T regulatory type 1 cells in acute respiratory distress syndrome

Acute lung injury and acute respiratory distress syndrome (ARDS) are caused by rapid‐onset bilateral pulmonary inflammation. We therefore investigated the potential role of interleukin (IL)‐10⁺CD4⁺ Tr1 cells, a regulatory T cell subset with previously identified immunosuppressive functions, in ARDS patients. We first showed that circulating Tr1 cells were upregulated in active and resolved ARDS patients compared to healthy controls and pneumonia patient controls. A significant fraction of these Tr1 cells expressed granzyme B and perforin, while most Tr1 cells did not express interferon gamma (IFN‐γ), IL‐4, IL‐17 or FOXP3, suggesting that the effector functions of these Tr1 cells were primarily mediated by IL‐10, granzyme B, and perforin. Indeed, Tr1 cells effectively suppressed CD8⁺ T cell IFN‐γ production and induced lysis of monocytes and dendritic cells in vitro. The elimination of myeloid antigen‐presenting cells depended on granzyme B production. We also discovered that Tr1 cells could be identified in the bronchoalveolar lavage fluid collected from ARDS patients. All these results suggested that Tr1 cells possessed the capacity to downregulate inflammation in ARDS. In support of this, we found that ARDS patients who resolved the inflammation and survived the syndrome contained significantly higher levels of Tr1 cells than ARDS patients who succumbed to the syndrome. Overall, this report added a novel piece of evidence that ARDS could be intervened by regulatory T cell‐mediated suppressive mechanisms.     

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.     

乌司他丁联合甲基泼尼松龙治疗急性呼吸窘迫综合征的效果分析

目的探讨乌司他丁联合小剂量甲基泼尼松龙治疗急性呼吸窘迫综合征的临床效果。方法选取本院收治的62例急性呼吸窘迫综合征患者,随机均分为对照组（甲基泼尼松龙）和观察组（乌司他丁联合小剂量甲基泼尼松龙）,比较两组治疗前后的肺泡灌洗液TNF-α和IL-10、机械通气时间、ICU住院时间、急性肺损伤评分和APACHEⅡ评分。结果治疗后,观察组的肺泡灌洗液TNF-α和IL-10改善情况显著优于对照组,机械通气时间、ICU住院时间短于对照组,APACHEⅡ评分低于对照组（P〈0.05）;两组的急性肺损伤评分比较差异无统计学意义（P〉0.05）。结论乌司他丁联合小剂量甲基泼尼松龙治疗急性呼吸窘迫综合征能取得更好的效果。     

Protective mechanisms of activated protein C in severe inflammatory disorders

The protein C system is an important natural anticoagulant mechanism mediated by activated protein C (APC) that regulates the activity of factors VIIIa and Va. Besides well-defined anticoagulant properties, APC also demonstrates anti-inflammatory, anti-apoptotic and endothelial barrier-stabilizing effects that are collectively referred to as the cytoprotective effects of APC. Many of these beneficial effects are mediated through its co-receptor endothelial protein C receptor, and the protease-activated receptor 1, although exact mechanisms remain unclear and are likely pleiotropic in nature. Increased insight into the structure–function relationships of APC facilitated design of APC variants that conserve cytoprotective effects and reduce anticoagulant features, thereby attenuating the risk of severe bleeding with APC therapy. Impairment of the protein C system plays an important role in acute lung injury/acute respiratory distress syndrome and severe sepsis. The pathophysiology of both diseases states involves uncontrolled inflammation, enhanced coagulation and compromised fibrinolysis. This leads to microvascular thrombosis and organ injury. Administration of recombinant human APC to correct the dysregulated protein C system reduced mortality in severe sepsis patients (PROWESS trial), which stimulated further research into its mechanisms of action. Several other clinical trials evaluating recombinant human APC have been completed, including studies in children and less severely ill adults with sepsis as well as a study in acute lung injury. On the whole, these studies have not supported the use of APC in these populations and challenge the field of APC research to search for additional answers.This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009     

Pharmacological modulation of C‐X‐C motif chemokine receptor 4 influences development of acute respiratory distress syndrome after lung ischaemia–reperfusion injury

Activation of C‐X‐C motif chemokine receptor 4 (CXCR4) has been reported to result in lung protective effects in various experimental models. The effects of pharmacological CXCR4 modulation on the development of acute respiratory distress syndrome (ARDS) after lung injury, however, are unknown. Thus, we studied whether blockade and activation of CXCR4 influences development of ARDS in a unilateral lung ischaemia–reperfusion injury rat model. Anaesthetized, mechanically ventilated animals underwent right lung ischaemia (series 1, 30 minutes; series 2, 60 minutes) followed by reperfusion for 300 minutes. In series 1, animals were treated with vehicle or 0.7 μmol/kg of AMD3100 (CXCR4 antagonist) and in series 2 with vehicle, 0.7 or 3.5 μmol/kg ubiquitin (non‐cognate CXCR4 agonist) within 5 minutes of reperfusion. AMD3100 significantly reduced PaO₂/FiO₂ ratios, converted mild ARDS with vehicle treatment into moderate ARDS (PaO₂/FiO₂ ratio<200) and increased histological lung injury. Ubiquitin dose‐dependently increased PaO₂/FiO₂ ratios, converted moderate‐to‐severe into mild‐to‐moderate ARDS and reduced protein content of bronchoalveolar lavage fluid (BALF). Measurements of cytokine levels (TNFα, IL‐6, IL‐10) in lung homogenates and BALF showed that AMD3100 reduced IL‐10 levels in homogenates from post‐ischaemic lungs, whereas ubiquitin dose‐dependently increased IL‐10 levels in BALF from post‐ischaemic lungs. Our findings establish a cause‐effect relationship for the effects of pharmacological CXCR4 modulation on the development of ARDS after lung ischaemia–reperfusion injury. These data further suggest CXCR4 as a new drug target to reduce the incidence and attenuate the severity of ARDS after lung injury.     

盐酸氨溴索对急性呼吸窘迫综合征大鼠肺纤维化的影响

目的研究盐酸氨溴索对急性呼吸窘迫综合征(ARDS)大鼠肺纤维化的影响及作用机制。方法将60只雄性Wistar大鼠随机分为对照组(n=20)、模型组(n=20)及实验组(n=20)。模型组及实验组大鼠均用气管滴注3 mg·kg^-1脂多糖(LPS)100μL,构建ARDS大鼠模型。造模成功后,实验组大鼠腹腔注射盐酸氨溴索注射液40.0 mg·kg^-1·d^-1,对照组与模型组则注射等量生理盐水,连续干预21 d。用酶联免疫吸附法检测肺组织肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)水平及羟脯氨酸(HYP)、丙二醛(MDA)、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物(GSH-Px)含量,用蛋白质印迹法检测大鼠肺组织中核因子-κB(NF-κB)P65蛋白表达水平。结果对照组、模型组及实验组大鼠肺组织炎性因子TNF-α分别为(10.87±1.22),(36.93±3.14),(17.86±2.38)pg·g^-1,IL-6分别为(14.73±1.56),(37.12±4.61),(20.96±2.03)pg·g^-1,HYP分别为(319.55±46.37),(743.22±91.31),(415.38±57.88)μg·g^-1;MDA分别为(12.78±1.96),(33.45±5.16),(18.02±3.34)μmol·g^-1;SOD分别为(69.76±10.32),(28.63±2.89),(56.12±5.33)kU·g^-1,GSH-Px分别为(46.23±4.81),(15.04±2.39),(37.73±3.68)kU·g^-1,大鼠肺组织中NF-κB P65蛋白相对表达量分别为0.09±0.04,0.81±0.15,0.34±0.11。模型组和实验组与对照组比,以上各指标差异均有统计学意义(均P<0.05);实验组与模型组比较,差异均有统计学意义(均P<0.05)。结论盐酸氨溴索可降低炎症因子水平、减少氧自由基生成,抑制肺组织NF-κB P65蛋白表达,进而减轻ARDS大鼠肺损伤及肺纤维化。     

Activated protein C in the treatment of acute lung injury and acute respiratory distress syndrome

Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) frequently necessitate mechanical ventilation in the intensive care unit. The syndromes have a high mortality rate and there is at present no treatment specifically directed at the underlying pathogenesis. Central in the pathophysiology of ALI/ARDS is alveolocapillary inflammation leading to permeability edema. As a result of the crosstalk between inflammation and coagulation, activation of proinflammatory and procoagulant/antifibrinolytic pathways contributes to disruption of the endothelial barrier. Protein C (PC) plays a central role in maintaining the equilibrium between coagulation and inflammation. Additionally, natural anticoagulants, such as PC, are depleted, both in blood as well as in the lung. Therefore, the PC system is of interest as a therapeutic target in patients with ALI/ARDS. Method: This review is based on a Medline search of relevant basic and clinical studies. Objective: It discusses the potential role of activated PC in modulating the proinflammatory/procoagulant state for enhancing endothelial barrier function in animal models and human ALI/ARDS.     

羟乙基淀粉130/0.4治疗外伤后致急性呼吸窘迫综合征的临床研究

目的 研究羟乙基淀粉130/0.4对外伤后致急性呼吸窘迫综合征的临床疗效。方法 50例外伤后致呼吸窘迫综合证的患者随机分为治疗组（25例）和对照组（25例）,两组患者入院明确诊断后,分别行血常规、血生化、肝肾功能及血气检查,均给予机械通气,呼气末正压≥5 cm H2O（1 cm H2O=97.72 Pa）时,行APACHEⅡ评分,记录患者体征及氧合指数,且给予支气管肺泡灌洗,送支气管灌洗液（BALF）检查IL-6及白蛋白;对照组给予林格氏液1 000 mL,静脉滴注,1 次/d;治疗组患者给予羟乙基淀粉130/0.4 1 000 mL,静脉滴注,1 次/d,两组均治疗3 d。治疗结束后1 h复查血常规、血生化、肝肾功能及血气分析,记录氧合指数,再次行支气管肺泡灌洗,检测BALF中IL-6和白蛋白浓度。结果 治疗后,治疗组症状改善优于对照组;对照组氧合指数及支气管肺泡灌洗液中白蛋白、IL-6前后变化无统计学差异,治疗组这3项指标治疗前后变化有明显统计学差异（P＜0.05）。结论 羟乙基淀粉130/0.4可减轻肺部炎症,有毛细血管堵漏作用,对急性呼吸窘迫综合征有保护作用。     

早期应用呼吸机对ICU急性呼吸窘迫综合征患者的临床分析

目的分析早期应用呼吸机对ICU急性呼吸窘迫综合征（ARDS）患者的治疗效果。方法选取本院ICU收治的64例ARDS患者,均行早期应用呼吸机进行辅助通气,并行常规抗炎、补液与对症治疗,分析治疗7d后患者的病死率、脱机率。结果治疗7d后,患者脱机率为79．69％,平均带机时间为（7．5±3．1）d,脱机后未出现缺氧症状且均能正常自主呼吸;病死率为20．31％,平均带机时间为（10．9±5．4）d。结论在ARDS患者治疗中,早期应用呼吸机可使患者脱机率提高,病死率降低,具有确切的治疗效果,值得在临床中推广。     

血管紧张素转换酶2在SARS病理途径中的作用

人类严重急性呼吸综合征(SARS)相关冠状病毒(SARS-CoV)感染导致的严重急性呼吸系统病变,其临床肺部病理损害特征与急性肺损伤和急性呼吸窘迫病变相似。SARS-CoV可以结合人血管紧张素转换酶(ACE)2,二者结合效率与病毒感染复制能力相关。ACE2与ACE1共同调控肾素-血管紧张素系统,二者的功能平衡维持肺的正常功能。SARS-CoV感染时,其棘突蛋白与ACE2结合,下调人体ACE2水平,肺内ACE2和ACE1功能失衡,血管紧张素Ⅱ过度激活AT1受体,导致肺部毛细血管通透性增加,随之出现肺水肿和急性肺损伤。ACE2是SARS病理途径中的关键因子,在SARS临床治疗和SARS药物研制中有重要意义。     

无创高频振荡通气在足月儿轻度急性呼吸窘迫综合征救治过程中的应用价值

目的:研究对足月儿轻度急性呼吸窘迫综合征（acute respiratory distress syndrome,ARDS）应用无创高频振荡通气治疗的价值。方法:选取佛山市高明区人民医院2021年2月至12月收治的60例轻度ARDS足月儿,通过随机数字表法分组,分成双水平组、高频组各30例。双水平组男∶女为18∶12,...     

漆黄素激活SIRT1/Nrf2信号通路改善急性呼吸窘迫综合征大鼠铁死亡的研究

目的 探究漆黄素通过激活沉默信息调节因子1（SIRT1）/核因子E2相关因子2（Nrf2）信号通路对急性呼吸窘迫综合征大鼠铁死亡的影响。方法 将SD大鼠随机分为对照组、模型组以及漆黄素1、2、4 mg/kg组和漆黄素（4 mg/kg）＋SIRT1抑制剂（10 mg/kg EX-527）组,每组各14只。漆黄素、SIRT1抑制剂于造模前30 min ip给药,对照组、模型组ip给予等量生理盐水。除对照组外,其余各组大鼠均采用气管内滴注脂多糖法建立急性呼吸窘迫综合征模型。检测支气管肺泡灌洗液（BALF）中炎性因子白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）水平;测定肺组织湿/干质量比（W/D）;HE染色观察肺组织病理改变;检测肺组织中铁死亡相关指标活性氧（ROS）、铁、谷胱甘肽（GSH）、丙二醛（MDA）水平;免疫印迹法检测肺组织中SIRT1/Nrf2信号通路相关蛋白表达。结果 与模型组比较,漆黄素各剂量组BALF中IL-6、TNF-α水平降低,肺组织W/D比值降低,肺组织中ROS、铁、MDA水平降低,GSH水平升高,肺组织中SIRT1、核Nrf2蛋白水平升高（P<0.05）,且4 mg/kg漆黄素干预的改善效果更显著;在4 mg/kg漆黄素干预的基础上增加SIRT1抑制剂后,漆黄素的改善作用被削弱。结论 漆黄素对脂多糖诱导的急性呼吸窘迫综合征有保护作用,能够改善铁死亡,可能是通过激活SIRT1/Nrf2信号通路实现的。     

The complex lipid,SPPCT-800, reduces lung damage,improves pulmonary function and decreases pro-inflammatory cytokines in the murine LPS-induced acute respiratory distress syndrome (ARDS) model

ContextAcute respiratory distress syndrome (ARDS) is a highly fatal, inflammatory condition of lungs with multiple causes. There is no adequate treatment.ObjectiveUsing the murine LPS-induced ARDS model, we investigate SPPCT-800 (a complex lipid) as treatment for ARDS.Materials and methodsC57B16/N mice received 50 μg of Escherichia coli O111:B4 lipopolysaccharide (LPS). SPPCT-800 was given as either: (1) 20 or 200 mg/kg dose 3 h after LPS; (2) 200 mg/kg (prophylactically) 30 min before LPS; or (3) eight 200 mg/kg treatments over 72 h. Controls received saline installations.ResultsAt 48 and 72 h, SpO₂ was 94% and 90% in controls compared to 97% and 94% in treated animals. Expiration times, at 24 and 48 h, were 160 and 137 msec for controls, but 139 and 107 msec with SPPCT-800. In BALF (24 h), cell counts were 4.7 × 10⁶ (controls) and 2.9 × 10⁶ (treated); protein levels were 1.5 mg (controls) and 0.4 mg (treated); and IL-6 was 942 ± 194 pg/mL (controls) versus 850 ± 212 pg/mL (treated) [at 72 h, 4664 ± 2591 pg/mL (controls) versus 276 ± 151 pg/mL (treated)]. Weight losses, at 48 and 72 h, were 20% and 18% (controls), but 14% and 8% (treated). Lung injury scores, at 24 and 72 h, were 1.4 and 3.0 (controls) and 0.3 and 2.2 (treated).Discussion and conclusionsSPPCT-800 was effective in reducing manifestations of ARDS. SPPCT-800 should be further investigated as therapy for ARDS, especially in longer duration or higher cumulative dose studies.     

有创机械通气在急性呼吸窘迫综合征治疗中的应用分析

目的：探讨有创机械通气在急性呼吸窘迫综合征(ARDS)治疗中的应用。方法回顾性分析2012年3月~2013年12月在本院行机械通气治疗的37例ARDS患者的临床资料。结果治愈28例,死亡9例,治愈率为75.7豫。无机械通气并发症发生。9例患者主要死于原发病并多器官功能衰竭。结论有创机械通气是ARDS最重要的治疗手段。临床机械通气过程中实行肺保护性通气策略、早期定时肺复张、选择最佳PEEP、毫不犹豫早上机早撤离,可最大限度发挥机械通气的功效并减少并发症,大大提高ARDS的救治成功率。