Pharmacotherapy of acute lung injury and acute respiratory distress syndrome

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by rapid-onset respiratory failure following a variety of direct and indirect insults to the parenchyma or vasculature of the lungs. Mortality from ALI/ARDS is substantial, and current therapy primarily emphasizes mechanical ventilation and judicial fluid management plus standard treatment of the initiating insult and any known underlying disease. Current pharmacotherapy for ALI/ARDS is not optimal, and there is a significant need for more effective medicinal chemical agents for use in these severe and lethal lung injury syndromes. To facilitate future chemical-based drug discovery research on new agent development, this paper reviews present pharmacotherapy for ALI/ARDS in the context of biological and biochemical drug activities. The complex lung injury pathophysiology of ALI/ARDS offers an array of possible targets for drug therapy, including inflammation, cell and tissue injury, vascular dysfunction, surfactant dysfunction, and oxidant injury. Added targets for pharmacotherapy outside the lungs may also be present, since multiorgan or systemic pathology is common in ALI/ARDS. The biological and physiological complexity of ALI/ARDS requires the consideration of combined-agent treatments in addition to single-agent therapies. A number of pharmacologic agents have been studied individually in ALI/ARDS, with limited or minimal success in improving survival. However, many of these agents have complementary biological/biochemical activities with the potential for synergy or additivity in combination therapy as discussed in this article.     

Emerging therapies for treatment of acute lung injury and acute respiratory distress syndrome

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a life-threatening form of respiratory failure that affects a heterogeneous population of critically ill patients. Although overall mortality appears to be decreasing in recent years due to improvements in supportive care, there are presently no proven, effective pharmacological therapies to treat ARDS and prevent its associated complications. The most common cause of death in ARDS is not hypoxemia or pulmonary failure, but rather multiple organ dysfunction syndrome (MODS), suggesting that improving survival in patients with ARDS may be linked to decreasing the incidence or severity of MODS. The key to developing novel treatments depends, in part, on identifying and understanding the mechanisms by which ARDS leads to MODS, although the heterogeneity and complexity of this disorder certainly poses a challenge to investigators. Novel therapies in development for treatment of ALI/ARDS include exogenous surfactant, therapies aimed at modulating neutrophil activity, such as prostaglandin and complement inhibitors, and treatments targeting earlier resolution of ARDS, such as beta-agonists and granulocyte macrophage colony-stimulating factor. From a clinical perspective, identifying subpopulations of patients most likely to benefit from a particular therapy and recognising the appropriate stage of illness in which to initiate treatment could potentially lead to better outcomes in the short term.     

Emerging therapies for treatment of acute lung injury and acute respiratory distress syndrome

In 2007, Bosma et. al provided a comprehensive review of emerging therapies for the acute respiratory distress syndrome (ARDS), a condition which continues to carry a mortality rate of greater than 30%. Over the past several years, the development of novel and effective therapeutic agents for ARDS remains disappointing, and unfortunately, no recent therapeutic interventions have demonstrated a clear benefit. Herein, the results of several of these early and late phase clinical trials are reviewed, the majority of which address known maladaptive processes that have been deemed critical in ARDS pathophysiology. Based on the ongoing futility of current therapeutic models to yield effective therapies, it is speculated whether or not novel treatment paradigms, which address distinctly different aspects of this disease paradigm, may be warranted.     

Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome

The use of small interfering RNAs (siRNAs) has been under investigation for the treatment of several unmet medical needs, including acute lung injury/acute respiratory distress syndrome (ALI/ARDS) wherein siRNA may be implemented to modify the expression of pro-inflammatory cytokines and chemokines at the mRNA level. The properties such as clear anatomy, accessibility, and relatively low enzyme activity make the lung a good target for local siRNA therapy. However, the translation of siRNA is restricted by the inefficient delivery of siRNA therapeutics to the target cells due to the properties of naked siRNA. Thus, this review will focus on the various delivery systems that can be used and the different barriers that need to be surmounted for the development of stable inhalable siRNA formulations for human use before siRNA therapeutics for ALI/ARDS become available in the clinic.     

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.     

Therapeutic modulation of coagulation and fibrinolysis in acute lung injury and the acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are characterized by excessive intraalveolar fibrin deposition, driven, at least in part by inflammation. The imbalance between activation of coagulation and inhibition of fibrinolysis in patients with ALI/ARDS favors fibrin formation and appears to occur both systemically and in the lung and airspace. Tissue factor (TF), a key mediator of the activation of coagulation in the lung, has been implicated in the pathogenesis of ALI/ARDS. As such, there have been numerous investigations modulating TF activity in a variety of experimental systems in order to develop new therapeutic strategies for ALI/ARDS. This review will summarize current understanding of the role of TF and other proteins of the coagulation cascade as well the fibrinolysis pathway in the development of ALI/ARDS with an emphasis on the pathways that are potential therapeutic targets. These include the TF inhibitor pathway, the protein C pathway, antithrombin, heparin, and modulation of fibrinolysis through plasminogen activator- 1 (PAI-1) or plasminogen activators (PA). Although experimental studies show promising results, clinical trials to date have proven unsuccessful in improving patient outcomes. Modulation of coagulation and fibrinolysis has complex effects on both hemostasis and inflammatory pathways and further studies are needed to develop new treatment strategies for patients with ALI/ARDS.     

静脉注射人免疫球蛋白治疗新生儿急性肺损伤/呼吸窘迫综合征的效果

目的 探讨静注人免疫球蛋白（IVIG）在新生儿急性肺损伤/呼吸窘迫综合征（ALI/ARDS）临床治疗中的应用效果。方法 选取2014年1月至2016年12月在东南大学附属盐城医院新生儿科住院的60例新生儿ALI/ARDS患者,按随机数字表法分为对照组和治疗组,每组30例。对照组予机械通气+肺表面活性物质、抗感染、营养等对症支持治疗,治疗组在对照组的基础上加用IVIG治疗。比较两组患儿治疗前、治疗后24、48及72小时血清白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、IL-10水平及机械通气时间、住院时间、病死率。结果 治疗组患儿血清IL-6、TNF-α、血清IL-6、TNF-α较对照组降低（F_{时间/组间/交互}=210.851/50.921/6.258,P_{时间/组间/交互}<0.01,F_{时间/组间/交互}=220.613/133.583/11.083,P_{时间/组间/交互}<0.01）,而IL-10较对照组升高（F_{时间/组间/交互}=154.547/300.944/43.851,P_{时间/组间/交互}<0.01）,差异均有统计学意义（P均<0.05）;治疗组机械通气时间、住院时间少于对照组,差异有统计学意义（P<0.05）;治疗组病死率低于对照组,差异有统计学意义（P<0.05）。结论 IVIG治疗新生儿ALI/ARDS可以减轻全身炎症反应,缩短机械通气时间、住院时间,降低病死率,安全可靠。     

Stress-dose corticosteroid therapy for sepsis and acute lung injury or acute respiratory distress syndrome in critically ill adults

Sepsis and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) are associated with high mortality rates despite recent therapeutic advances. Both disease states involve uncontrolled host defense responses that lead to inflammation, endothelial damage, enhanced coagulation, diminished fibrinolysis and fibroproliferation to produce microthrombi, and relative adrenal insufficiency. Corticosteroids inhibit the host defense response and may offer an inexpensive therapeutic option. Results of several randomized, double-blind studies demonstrated no survival benefit and higher secondary infection rates when supraphysiologic doses of corticosteroids were administered for less than 24 hours. Recently, the emphasis of research for corticosteroid therapy has involved adrenocortical replacement dosage regimens administered for several days to weeks, with doses corresponding to the stress level of the disease. Stress-dose therapy with hydrocortisone in patients with septic shock who require vasopressor support, especially if adrenal insufficiency is present, accelerates hemodynamic stability and reduces mortality. The frequency of gastrointestinal hemorrhage was higher with corticosteroid therapy than with placebo, but the occurrence of secondary infections was similar to that of placebo. The only randomized, double-blind study that evaluated stress-dose methylprednisolone therapy for ARDS was terminated early after only 24 patients were enrolled because therapy with methylprednisolone was associated with enhanced survival despite higher secondary infection rates. A multicenter study investigating stress-dose methylprednisolone for ARDS is under way and should provide valuable information. Sufficient data support stress-dose hydrocortisone therapy for vasopressor-dependent septic shock. Stress-dose methylprednisolone therapy for ALI-ARDS requires further study but may be warranted in cases of refractory infection-induced ARDS when impending mortality is likely.     

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.     

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.     

Treatment of acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is characterized by significant intrapulmonary mismatch of ventilation and perfusion with increased right-to-left shunting, decreased lung compliance, and acute pulmonary hypertension. Pulmonary artery hypertension induces an increase in pulmonary microvascular filtration     

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.     

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.     

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。     

重症胸外伤所致急性呼吸窘迫征的临床治疗分析

目的探讨重症胸外伤并发呼吸窘迫综合征的诊疗方法。方法对43例重症胸外伤合并急性呼吸窘迫综合征患者进行回顾性分析。结果所有患者除2例死于多脏器功能衰竭外,其余均治愈出院。结论呼吸窘迫综合征一经确诊,应积极进行早期有效治疗,同时改善低氧血症是治疗呼吸窘迫综合征成功的关键。     

Targeting MALAT1 and miRNA-181a-5p for the intervention of acute lung injury/acute respiratory distress syndrome

探讨大补肺汤通过调控HIF-1α/NLRP3信号通路及相关分子的表达,从而对高原低氧大鼠急性肺损伤的干预作用。

SPF级SD大鼠60只随机分为空白组,模型组,阳性药物组,大补肺汤高、中、低剂量组,每组10只。适应性饲养3 d后给药,空白组和模型组大鼠灌胃给予等量生理盐水;大补肺汤高、中、低剂量组分别连续灌胃大补肺汤14 d;阳性药物组给予地塞米松,腹腔注射,进舱前连续给药3 d。除空白组外,第15天起各组大鼠于实验动物低压模拟舱中进行低氧暴露,连续3 d。最后,检测大鼠肺组织湿干重比(wet to dry ratio,W/D);HE染色法观察大鼠肺组织形态;ELISA法检测血清中IL-1β、IL-18的水平;Western blotting与RT-qPCR法分别检测大鼠肺组织中HIF-1α、NLRP3、GSDMD、caspase-1蛋白和mRNA表达。

W/D值结果表明,与空白组相比,模型组大鼠W/D显著升高(P<0.01);与模型组相比,阳性药物组及大补肺汤高、中、低剂量组大鼠W/D显著降低(P<0.01或P<0.05)。HE结果显示,与空白组相比,模型组大鼠肺组织可见肺泡间隔增厚,肺间质充血、水肿,炎性细胞浸润,肺泡腔内可见少量渗出;与模型组相比,阳性药组及大补肺汤高、中、低剂量组肺泡壁增厚减轻,肺间质充血、水肿及炎性细胞浸润明显减轻。ELISA结果显示大鼠血清中IL-1β、IL-18水平在模型组中均显著高于空白组(P<0.01);与模型组相比,阳性药组及大补肺汤高、中、低剂量组血清中IL-1β、IL-18水平均显著下降(P<0.05或P<0.01)。此外,Western blotting与RT-qPCR结果显示,与空白组相比,模型组大鼠肺组织HIF-1α、NLRP3、GSDMD和caspase-1蛋白及mRNA相对表达显著升高(P<0.01);与模型组相比,阳性药组及大补肺汤高剂量肺组织HIF-1α、NLRP3、caspase-1、GSDMD蛋白及mRNA表达显著降低(P<0.05或P<0.01),大补肺汤中剂量肺组织HIF-1α、NLRP3、caspase-1、GSDMD蛋白表达显著降低且HIF-1α、caspase-1 mRNA表达降低(P<0.05),大补肺汤低剂量肺组织HIF-1α、GSDMD蛋白表达降低(P<0.05)。阳性药物组及大补肺汤高剂量组作用效果更显著。

大补肺汤可调控HIF-1α/NLRP3信号通路,抑制细胞焦亡、减轻炎症反应,对高原低氧大鼠急性肺损伤具有一定的保护作用。

     

低分子肝素雾化吸入治疗ALI/ARDS的临床疗效观察

目的探讨雾化吸入低分子肝素治疗急性肺损伤的临床疗效及可能的作用机制。方法选择42例急性肺损伤/急性呼吸窘迫综合征(ALI/ARDS)的患者,随机分为对照组、皮下组和雾化组,对照组使用常规治疗,皮下组和雾化组则分别在常规治疗基础上采用皮下注射及气道雾化吸入低分子肝素钠。观察和比较三组患者治疗7 d后氧合指数、急性生理学与慢性健康状况Ⅱ(APACHEⅡ)评分I、L-6以及PLT、APTT变化、7 d死亡率。结果各组治疗7 d后各项指标较前有好转,抗凝组(皮下组和雾化组)较对照组氧合指数明显升高I,L-6、APACHEⅡ评分下降更显著。其中,雾化组氧合指数优于皮下组,而IL-6、A-PACHEⅡ评分较皮下组高(P<0.05)。抗凝组治疗后PLT、APTT与对照组比较无差异。皮下组、雾化组、对照组死亡率分别为6.7%,11.1%4,4.4%,组间比较有差异,抗凝组优于对照组。结论雾化吸入低分子肝素治疗ALI/ARDS,能够改善氧合;可能通过抑制IL-6等炎症介质的释放,降低全身炎症反应,从而降低患者的死亡率。     

Beta-blockers in intensive care medicine: potential benefit in acute brain injury and acute respiratory distress syndrome

Sympathetic activation is a well-known phenomenon after acute brain injury and in critical illness. In this review we describe pathophysiological considerations that may help in elucidating the potential role of beta (β)-adrenergic antagonists to block some of the adverse sympathetic effects in acute brain injury (subarachnoid hemorrhage and traumatic brain injury) and the acute respiratory distress syndrome. In acute brain injury cardiac dysfunction has been studied most extensively but its pathophysiology is only partly elucidated in man. Further, several adverse consequences of sympathetic activation on the brain itself may occur. Clinical and preclinical studies are described in this review that lend support to the idea that β blockers may have beneficial effects on both cardiac, cerebral and other adverse consequences of sympathetic overactivation after acute brain injury. Second, the acute respiratory distress syndrome (ARDS) may also respond to β blocker therapy, albeit through a different mechanism than in acute brain injury. Some studies reported on beneficial effects of these drugs on ARDS through the mitigation of pulmonary blood flow, without a decrease in systemic hemodynamics. However, in both acute brain injury and ARDS further studies are needed to distinguish those patients who are most likely to benefit from β blockers from those more likely to be harmed by them. Furthermore, recent patents of β blockers relevant to the content of this paper are referenced.