Erythropoetin as a novel agent with pleiotropic effects against acute lung injury

Current pharmacotherapy for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is not optimal, and the biological and physiological complexity of these severe lung injury syndromes requires consideration of combined-agent treatments or agents with pleiotropic action. In this regard, exogenous erythropoietin (EPO) represents a possible candidate since a number of preclinical studies have revealed beneficial effects of EPO administration in various experimental models of ALI. Taken together, this treatment strategy is not a single mediator approach, but it rather provides protection by modulating multiple levels of early signaling pathways involved in apoptosis, inflammation, and peroxidation, potentially restoring overall homeostasis. Furthermore, EPO appears to confer vascular protection by promoting angiogenesis. However, only preliminary studies exist and more experimental and clinical studies are necessary to clarify the efficacy and potentially cytoprotective mechanisms of EPO action. In addition to the attempts to optimize the dose and timing of EPO administration, it would be of great value to minimize any potential toxicity, which is essential for EPO to fulfill its role as a potential candidate for the treatment of ALI in routine clinical practice. The present article reviews recent advances that have elucidated biological and biochemical activities of EPO that may be potentially applicable for ALI/ARDS management.     

Preventive effect of tranilast on oleic acid-induced lung injury in guinea pigs

Acute respiratory distress syndrome or acute lung injury (ARDS)/(ALI) involve the severe lung injury with pulmonary vascular hyper-permeability and hypoxemia induced by inflammatory reactions. Since ARDS/ALI carries high mortality, the development of new drugs against ARDS/ALI is required. We examined the effect of tranilast, an anti-allergic drug, on vascular hyper-permeability in the lungs and airways, and on hypoxemia, in oleic acid (OA)-induced acute lung injury, an animal model of ARDS/ALI. The increase in pulmonary and airway vascular permeability and the decrease in partial oxygen pressure of arterial blood induced by an intravenous injection of OA were drastically ameliorated by the oral administration of tranilast in a dose-dependent manner. This is the first report to prove that tranilast prevents pulmonary and airway vascular permeability and hypoxemia induced by OA. These results suggest that tranilast may be a candidate drug for the treatment of ARDS/ALI.     

化学吸入性急性肺损伤/急性呼吸窘迫综合征患者的药学监护实践

摘 要 目的： 探讨临床药师对化学吸入性急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）患者的药学监护模式,保障患者用药安全、合理和有效。方法: 根据化学吸入性ALI/ARDS患者的药物治疗特点,对患者进行药学监护,有针对性提出用药建议。结果: 通过药学监护,可提高化学吸入性ALI/ARDS患者用药的安全性、合理性及有效性,减少药品不良反应的发生。结论:临床药师积极开展药学服务,协同临床医师优化给药方案,有利于患者用药安全、有效。     

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 beta2-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.     

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.     

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.     

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.     

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.     

Procoagulant signalling mechanisms in lung inflammation and fibrosis: novel opportunities for pharmacological intervention?

There is compelling evidence that uncontrolled activation of the coagulation cascade following lung injury contributes to the development of lung inflammation and fibrosis in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and fibrotic lung disease. This article reviews our current understanding of the mechanisms leading to the activation of the coagulation cascade in response to lung injury and the evidence that excessive procoagulant activity is of pathophysiological significance in these disease settings. Current evidence suggests that the tissue factor-dependent extrinsic pathway is the predominant mechanism by which the coagulation cascade is locally activated in the lungs of patients with ALI/ARDS and pulmonary fibrosis. Whilst, fibrin deposition might contribute to the pathophysiology of ALI/ARDS following systemic insult; current evidence suggests that the cellular effects mediated via activation of proteinase-activated receptors (PARs) may be of particular importance in influencing inflammatory and fibroproliferative responses in experimental models involving direct injury to the lung. In this regard, studies in PAR(1) knockout mice have shown that this receptor plays a major role in orchestrating the interplay between coagulation, inflammation and lung fibrosis. This review will focus on our current understanding of excessive procoagulant signalling in acute and chronic lung injury and will highlight the novel opportunities that this may present for therapeutic intervention.     

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.     

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.     

Pharmacological therapies for pediatric and neonatal ALI/ARDS: an evidence-based review

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threating conditions still lacking a definite therapy and carrying a high mortality and morbidity, especially in children and infants. Albeit respiratory assistance and supportive therapies are crucial for ALI/ARDS, many drugs have been proposed to treat such syndromes through various mechanisms of action. On the whole the pharmacological therapy might play an important role in such a complex clinical situation but few evidence based data are available in pediatric and neonatal critical care. This review will focus on drugs directly available on the bedside, that is, medicines already administered in the practice or investigated in at least one clinical study. We will value the differences due to patient's age and the various causes of the syndrome, that may affect the response to the pharmacological therapy. A special attention will be given to the drugs directly deliverable into the lungs, as this strategy allows a total availability to the lung tissue. The experimental background behind each drug will be discussed and then clinical data in neonates and infants will be presented, if available. Data coming from adult critical care and thought to be somehow pertinent for the pediatric setting will otherwise be reviewed. Quality and evidence for or against each therapy will be evaluated according to the Scottish Intercollegiate Guidelines Network statement and practical reminders for clinicians will accordingly be provided.     

Protective effect of zerumbone reduces lipopolysaccharide-induced acute lung injury via antioxidative enzymes and Nrf2/HO-1 pathway

Acute lung injury (ALI) is a serious disease with high morbidity and mortality rate. Although there are effective strategies for treatment of ALI; a widely accepted specific pharmacotherapy has not yet established. Zerumbone, the major active phytochemical compound from Zingiber zerumbet Smith, exhibits various beneficial biological and pharmacological activities, such as antioxidation, anti-inflammation, immunomodulation, and anti-cancer. We aimed to study the potential protective effects and mechanisms of zerumbone in mouse model of lipopolysaccharide (LPS)-induced ALI. Pretreatment with zerumbone inhibited the histopatholgical changes such as neutrophils infiltration, increased in alveolar barrier thickness, hemorrhage, and hyaline membrane formation occurred in lungs in LPS-induced ALI. In addition, not only LPS-induced activation of myeloperoxidase (MPO) and metallopeptidase-9 (MMP-9) was suppressed by zerumbone, but also lipid peroxidation in lungs was inhibited as well. Moreover, pretreatment with zerumbone reversed the antioxidative enzymes activities, including superoxide dismutase, catalase, and glutathione peroxidase, decreased by LPS and enhanced the expression of nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase (HO-1) induced by LPS. These results from present study suggested that the protective mechanisms of zerumbone on LPS-induced ALI were via up-regulation of antioxidative enzymes and Nrf2/HO-1 pathway.     

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.     

脓毒症相关性急性肺损伤发病机制研究进展

急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）是临床上常见的危重病之一,病因多、影响因素复杂、救治困难,病死率高。脓毒症是危重病最主要的死亡原因,也是引起ALI/ARDS的最常见的病因,尽管对脓毒症致ALI/ARDS的机制研究较多,其确切机制尚不完全清楚。本文就脓毒症致急性肺损伤的发病机制进行综述。     

Emerging role of anticoagulants and fibrinolytics in the treatment of acute respiratory distress syndrome

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high mortality rates despite therapeutic advances. The pathogenesis of ALI and ARDS is similar to that of sepsis, as these disease states involve uncontrolled host defense responses that lead to inflammation, endothelial damage, enhanced coagulation, diminished fibrinolysis, and fibroproliferation. Recent studies of anticoagulants have shown positive outcomes in patients with severe sepsis. In addition, emerging evidence suggests that the use of anticoagulants, such as tissue factor pathway inhibitor, antithrombin, thrombomodulin, heparin, activated protein C, and fibrinolytics (plasminogen activators and particularly tissue plasminogen activator), may be useful in the treatment of ALI and ARDS. Data from experimental models of sepsis, ALI, and ARDS indicate that some of these agents improve lung function and oxygenation. Although clinical data are less convincing than these findings, results from clinical trials may influence the design of future studies.     

通腑泻肺法对ALI/ARDS大鼠血清炎症因子表达的影响

目的观察通腑泻肺法对ALI/ARDS大鼠血清炎症因子的影响,探讨ALI/ARDS肺肠同治的生物学基础。方法将100只健康Wistar大鼠随机分为5组:空白对照组、模型组、治肺组、治肠组和肺肠同治组,采用尾静脉注射油酸加内毒素方法造成大鼠ALI/ARDS模型,观察大鼠血清TNF-α、IL-1β、IL-6、IL-10含量。结果通腑泻肺法可以有效降低大鼠全身炎性因子TNF-α、IL-1β、IL-6、IL-10表达水平。结论 (1)通腑泻肺法能够明显减轻ALI/ARDS大鼠免疫炎症损伤,其保护作用较单纯用泻肺法或通腑法效果更有优势;(2)泻肺法、通腑法和通腑泻肺法对ALI/ARDS大鼠血清炎性因子作用靶点不同。     

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.