Bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome

Summary. Enhanced intrapulmonary fibrin deposition as a result of abnormal broncho‐alveolar fibrin turnover is a hallmark of acute respiratory distress syndrome (ARDS), pneumonia and ventilator‐induced lung injury (VILI), and is important to the pathogenesis of these conditions. The mechanisms that contribute to alveolar coagulopathy are localized tissue factor‐mediated thrombin generation, impaired activity of natural coagulation inhibitors and depression of bronchoalveolar urokinase plasminogen activator‐mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. There is an intense and bidirectional interaction between coagulation and inflammatory pathways in the bronchoalveolar compartment. Systemic or local administration of anticoagulant agents (including activated protein C, antithrombin and heparin) and profibrinolytic agents (such as plasminogen activators) attenuate pulmonary coagulopathy. Several preclinical studies show additional anti‐inflammatory effects of these therapies in ARDS and pneumonia.     

急性肺损伤/急性呼吸窘迫综合征血凝状态异常及抗凝治疗进展

ALI/ARDS是由局部或全身的多种疾病引起的一种常见的危重病,目前尚缺乏新的特异性强的治疗手段。近年来许多研究者开始关注ALI/ARDS发生时凝血和纤维蛋白溶解系统的异常并通过改变这些异常来研究治疗ALI/ARDS的方法。本文综述了近年来报道的ALI/ARDS发生时凝血系统及纤维蛋白溶解系统的变化特点,特别是组织因子通路、蛋白C通路及由纤溶酶原活化物抑制因子(PAI-1)调节的纤维蛋白溶解系统,这些可能成为ALI/ARDS新的治疗靶点和研究的方向。     

Acute lung injury and the coagulation pathway: potential role of gene polymorphisms in the protein C and fibrinolytic pathways

There is evidence that dysregulation of coagulation and fibrinolysis may participate in the pathogenesis of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Altered concentrations of several proteins of the coagulation and fibrinolytic pathways in plasma and pulmonary edema fluid from patients with acute lung injury have been related to the severity of lung injury and clinical outcomes. Polymorphisms in the genes encoding for proteins of the protein C and fibrinolysis pathways are known to regulate the production of the respective proteins. It is plausible that these polymorphisms may be associated with the susceptibility to and severity of illness in ALI and ARDS. Well-designed studies that examine the association of these polymorphisms with susceptibility and severity of ALI and ARDS are needed to test the influence of both genetic and environmental factors on the clinical outcomes in patients with ALI and ARDS. There are several important considerations in the design of these genetic association studies, including selection of candidate genes with the most biological plausibility, definition of the phenotype, selection of appropriate controls, determination of the appropriate sample size and assessment of Hardy–Weinberg equilibrium among controls as a measure of internal validity.     

Surfactant therapy for acute lung injury and acute respiratory distress syndrome

This article examines exogenous lung surfactant replacement therapy and its usefulness in mitigating clinical acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Surfactant therapy is beneficial in term infants with pneumonia and meconium aspiration lung injury, and in children up to age 21 years with direct pulmonary forms of ALI/ARDS. However, extension of exogenous surfactant therapy to adults with respiratory failure and clinical ALI/ARDS remains a challenge. This article reviews clinical studies of surfactant therapy in pediatric and adult patients with ALI/ARDS, focusing on its potential advantages in patients with direct pulmonary forms of these syndromes.     

Clinical Review: Gene-based therapies for ALI/ARDS: where are we now?

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) confer substantial morbidity and mortality, and have no specific therapy. The accessibility of the distal lung epithelium via the airway route, and the relatively transient nature of ALI/ARDS, suggest that the disease may be amenable to gene-based therapies. Ongoing advances in our understanding of the pathophysiology of ALI/ARDS have revealed multiple therapeutic targets for gene-based approaches. Strategies to enhance or restore lung epithelial and/or endothelial cell function, to strengthen lung defense mechanisms against injury, to speed clearance of infection and to enhance the repair process following ALI/ARDS have all demonstrated promise in preclinical models. Despite three decades of gene therapy research, however, the clinical potential for gene-based approaches to lung diseases including ALI/ARDS remains to be realized. Multiple barriers to effective pulmonary gene therapy exist, including the pulmonary architecture, pulmonary defense mechanisms against inhaled particles, the immunogenicity of viral vectors and the poor transfection efficiency of nonviral delivery methods. Deficits remain in our knowledge regarding the optimal molecular targets for gene-based approaches. Encouragingly, recent progress in overcoming these barriers offers hope for the successful translation of gene-based approaches for ALI/ARDS to the clinical setting.     

The impact of clinical risk factors in the conversion from acute lung injury to acute respiratory distress syndrome in severe multiple trauma patients

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are different stages of the same disease, the aggravated stage of ALI leading to ARDS. Patients with ARDS have higher hospital mortality rates and reduced long-term pulmonary function and quality of life. It is, therefore, important to prevent ALI converting to ARDS. This study evaluated 17 risk factors potentially associated with the conversion from ALI to ARDS in severe multiple trauma. The results indicate that the impact of pulmonary contusion, APACHE II score, gastrointestinal haemorrhage and disseminated intravascular coagulation may help to predict conversion from ALI to ARDS in the early phase after multiple-trauma injury. Trauma duration, in particular, strongly impacted the short- and long-term development of ALI. Being elderly (aged > or = 65 years) and undergoing multiple blood transfusions in the early phase were independent risk factors correlated with secondary sepsis, deterioration of pulmonary function and transfusion-related acute lung injury due to early multiple fluid resuscitation.     

High-frequency oscillatory ventilation in ALI/ARDS

In the last 2 decades, our goals for mechanical ventilatory support in patients with acute respiratory distress syndrome (ARDS) or acute lung injury (ALI) have changed dramatically. Several randomized controlled trials have built on a substantial body of preclinical work to demonstrate that the way in which we employ mechanical ventilation has an impact on important patient outcomes. Avoiding ventilator-induced lung injury (VILI) is now a major focus when clinicians are considering which ventilatory strategy to employ in patients with ALI/ARDS. Physicians are searching for methods that may further limit VILI, while still achieving adequate gas exchange.     

Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations

ABSTRACT: BACKGROUND: Data from interventional trials of systemic anticoagulation for sepsis inconsistently suggest beneficial effects in case of acute lung injury (ALI). Severe systemic bleeding due to anticoagulation may have offset the possible positive effects. Nebulization of anticoagulants may allow for improved local biological availability and as such may improve efficacy in the lungs and lower the risk of systemic bleeding complications. METHOD: We performed a systematic review of preclinical studies and clinical trials investigating the efficacy and safety of nebulized anticoagulants in the setting of lung injury in animals and ALI in humans. RESULTS: The efficacy of nebulized activated protein C, antithrombin, heparin and danaparoid has been tested in diverse animal models of direct (for example, pneumonia-, intra-pulmonary lipopolysaccharide (LPS)-, and smoke inhalation-induced lung injury) and indirect lung injury (for example, intravenous LPS- and trauma-induced lung injury). Nebulized anticoagulants were found to have the potential to attenuate pulmonary coagulopathy and frequently also inflammation. Notably, nebulized danaparoid and heparin but not activated protein C and antithrombin, were found to have an effect on systemic coagulation. Clinical trials of nebulized anticoagulants are very limited. Nebulized heparin was found to improve survival of patients with smoke inhalation-induced ALI. In a trial of critically ill patients who needed mechanical ventilation for longer than two days, nebulized heparin was associated with a higher number of ventilator-free days. In line with results from preclinical studies, nebulization of heparin was found to have an effect on systemic coagulation, but without causing systemic bleedings. CONCLUSION: Local anticoagulant therapy through nebulization of anticoagulants attenuates pulmonary coagulopathy and frequently also inflammation in preclinical studies of lung injury. Recent human trials suggest nebulized heparin for ALI to be beneficial and safe, but data are very limited.     

Activation of the contact system of plasma proteolysis in the adult respiratory distress syndrome

Adult respiratory distress syndrome (ARDS) is a complex pulmonary clinicopathologic condition associated with pulmonary endothelial injury and blood coagulation activation. In patients with ARDS from all causes, factor VII levels were significantly reduced. Patients with ARDS caused by sepsis had more evidence of intravascular coagulation and fibrinolysis than did patients with trauma-related ARDS by having significantly (p less than or equal to 0.05) increased prothrombin times, activated partial thromboplastin times, and fibrin degradation products, and decreased antithrombin III concentration. We sought to determine whether the proteins of the contact system of plasma proteolysis (factor XII, prekallikrein, high molecular weight kininogen, and C1 inhibitor) were also activated after acute lung injury. Patients with ARDS caused by either trauma or sepsis had significantly (p less than or equal to 0.01) reduced factor XII levels, high molecular weight kininogen functional activity, prekallikrein activity, and prekallikrein antigen levels compared with controls. In both the sepsis-related and trauma-related ARDS groups, C1 inhibitor activity was significantly reduced but C1 inhibitor antigen levels were significantly elevated from control. These findings showed that the proteins of the contact system were more extensively activated in ARDS than were the proteins that contribute to later reactions in intravascular coagulation and fibrinolysis. Activation of the contact system proteins could be the result of endothelial injury occurring as part of ARDS. Intravascular coagulation and fibrinolysis in patients with ARDS also arise from components independent from contact system activation.     

Nebulized anticoagulants limit coagulopathy but not inflammation in pseudomonas aeruginosa-induced pneumonia in rats

Disturbed alveolar fibrin turnover is a characteristic feature of pneumonia. Inhibitors of coagulation could exert lung-protective effects via anticoagulant (inhibiting fibrin deposition) and possibly anti-inflammatory pathways, but could also affect host defense. In this randomized controlled in vivo laboratory study, rats were challenged intratracheally with Pseudomonas aeruginosa, inducing pneumonia, and randomized to local treatment with normal saline (placebo), recombinant human activated protein C (rh-APC), plasma-derived antithrombin (AT), heparin, or danaparoid. Induction of P. aeruginosa pneumonia resulted in activation of pulmonary coagulation and inhibition of pulmonary fibrinolysis, as reflected by increased pulmonary levels of thrombin-AT complexes and fibrin degradation products and decreased pulmonary levels plasminogen activator activity. Pseudomonas aeruginosa pneumonia was accompanied by systemic coagulopathy, since systemic levels of thrombin-AT complexes increased, and systemic levels of plasminogen activator activity decreased. Although rh-APC and plasma-derived AT potently limited pulmonary coagulopathy, neither heparin nor danaparoid affected net pulmonary fibrin turnover. Recombinant human APC also displayed systemic anticoagulant effects. Neither bacterial clearance nor pulmonary inflammation was affected by anticoagulant therapy. Nebulization of rh-APC or plasma-derived AT attenuated pulmonary coagulopathy, but not bacterial clearance or inflammation, in a rat model of P. aeruginosa pneumonia.     

The future of exogenous surfactant therapy

Since the identification of surfactant deficiency as the putative cause of the infant respiratory distress syndrome (RDS) by Avery and Mead in 1959, our understanding of the role of pulmonary surfactant in respiratory physiology and the pathophysiology of acute lung injury (ALI) has advanced substantially. Surfactant replacement has become routine for the prevention and treatment of infant RDS and other causes of neonatal lung injury. The role of surfactant in lung injury beyond the neonatal period, however, has proven more complex. Relative surfactant deficiency, dysfunction, and inhibition all contribute to the disturbed physiology seen in ALI and acute respiratory distress syndrome (ARDS). Consequently, exogenous surfactant, while a plausible therapy, has proven to be less effective in ALI/ARDS than in RDS, where simple deficiency is causative. This failure may relate to a number of factors, among them inadequacy of pharmaceutical surfactants, insufficient dosing or drug delivery, poor drug distribution, or simply an inability of the drug to substantially impact the underlying pathophysiology of ALI/ARDS. Both animal and human studies suggest that direct types of ALI (eg, aspiration, pneumonia) may be more responsive to surfactant therapy than indirect lung injury (eg, sepsis, pancreatitis). Animal studies are needed, however, to further clarify aspects of drug composition, timing, delivery, and dosing before additional human trials are pursued, as the results of human trials to date have been inconsistent and largely disappointing. Further study and perhaps the development of more robust pharmaceutical surfactants offer promise that exogenous surfactant will find a place in our armamentarium of treatment of ALI/ARDS in the future.     

Science review: Mechanisms of beta-receptor stimulation-induced improvement of acute lung injury and pulmonary edema

Acute lung injury (ALI) and the acute respiratory distress syndrome are complex syndromes because both inflammatory and coagulation cascades cause lung injury. Transport of salt and water, repair and remodeling of the lung, apoptosis, and necrosis are additional important mechanisms of injury. Alveolar edema is cleared by active transport of salt and water from the alveoli into the lung interstitium by complex cellular mechanisms. Beta-2 agonists act on the cellular mechanisms of pulmonary edema clearance as well as other pathways relevant to repair in ALI. Numerous studies suggest that the beneficial effects of beta-2 agonists in ALI include at least enhanced fluid clearance from the alveolar space, anti-inflammatory actions, and bronchodilation. The purposes of the present review are to consider the effects of beta agonists on three mechanisms of improvement of lung injury: edema clearance, anti-inflammatory effects, and bronchodilation. This update reviews specifically the evidence on the effects of beta-2 agonists in human ALI and in models of ALI. The available evidence suggests that beta-2 agonists may be efficacious therapy in ALI. Further randomized controlled trials of beta agonists in pulmonary edema and in acute lung injury are necessary.     

急性肺损伤治疗措施的研究进展

急性肺损伤(acute lung injury,ALI)及其严重形式急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)是临床常见的急危重症,此类患者住院时间长、病死率高,其标志性病理特征为肺部炎症和肺组织结构破坏,主要临床表现为低氧合和低肺顺应性。ALI的发病机制并不是很明确,目前已知氧化应激及炎症反应失控是其发生发展的重要机制。临床上ALI常用治疗手段包括药物和机械通气等综合疗法,但其病死率仍居高不下。新兴的治疗方式如干细胞、分子靶向疗法等已取得一定研究成果,有望成为ALI潜在的可靠治疗方法。     

Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome.

To determine the possible mechanism(s) promoting alveolar fibrin deposition in the adult respiratory distress syndrome (ARDS), we investigated the initiation and regulation of both fibrinolysis and coagulation from patients with ARDS (n = 14), at risk for ARDS (n = 5), and with interstitial lung diseases (ILD) (n = 8), and normal healthy individuals (n = 13). Bronchoalveolar lavage (BAL) extrinsic pathway inhibitor activity was increased in ARDS BAL compared with patients at risk for ARDS (P = 0.0146) or normal controls (P = 0.0013) but tissue factor-factor VII procoagulant activity was significantly increased in ARDS BAL compared with all other groups (P less than 0.001). Fibrinolytic activity was not detectable in BAL of 10 of the 14 patients with ARDS and low levels of activity were found in BAL of the other four ARDS patients. Depressed fibrinolysis in ARDS BAL was not due to local insufficiency of plasminogen; rather, there was inhibition of both plasmin and plasminogen activator. Plasminogen activator inhibitor 1 was variably detected and low levels of plasminogen activator inhibitor 2 were found in two ARDS BAL samples, but plasminogen activator inhibitor 2 was otherwise undetectable. ARDS BAL antiplasmin activity was, in part, due to alpha 2-antiplasmin. We conclude that abnormalities that result in enhanced coagulation and depressed fibrinolysis, thereby predisposing to alveolar fibrin deposition, occur in the alveolar lining fluids from patients with ARDS.     

Gene therapy for ALI/ARDS

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by acute respiratory failure and are associated with diverse disorders. Gene therapy is a potentially powerful approach to treat diseases related to ALI/ARDS, and numerous viral and nonviral methods for gene delivery to the lung have been developed. Discussed are recent advances in the development of more efficient viral and nonviral gene transfer systems, and the current status of gene therapy applied to ALI/ARDS-associated pulmonary diseases is reviewed. With the development of more efficient gene therapy vectors, gene therapy is a promising strategy for clinical application.     

Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID‐19

The global pandemic of coronavirus disease 2019 (COVID‐19) is associated with the development of acute respiratory distress syndrome (ARDS), which requires ventilation in critically ill patients. The pathophysiology of ARDS results from acute inflammation within the alveolar space and prevention of normal gas exchange. The increase in proinflammatory cytokines within the lung leads to recruitment of leukocytes, further propagating the local inflammatory response. A consistent finding in ARDS is the deposition of fibrin in the air spaces and lung parenchyma. COVID‐19 patients show elevated D‐dimers and fibrinogen. Fibrin deposits are found in the lungs of patients due to the dysregulation of the coagulation and fibrinolytic systems. Tissue factor (TF) is exposed on damaged alveolar endothelial cells and on the surface of leukocytes promoting fibrin deposition, while significantly elevated levels of plasminogen activator inhibitor 1 (PAI‐1) from lung epithelium and endothelial cells create a hypofibrinolytic state. Prophylaxis treatment of COVID‐19 patients with low molecular weight heparin (LMWH) is important to limit coagulopathy. However, to degrade pre‐existing fibrin in the lung it is essential to promote local fibrinolysis. In this review, we discuss the repurposing of fibrinolytic drugs, namely tissue‐type plasminogen activator (tPA), to treat COVID‐19 associated ARDS. tPA is an approved intravenous thrombolytic treatment, and the nebulizer form has been shown to be effective in plastic bronchitis and is currently in Phase II clinical trial. Nebulizer plasminogen activators may provide a targeted approach in COVID‐19 patients to degrade fibrin and improving oxygenation in critically ill patients.     

A phase 1 trial of nebulised heparin in acute lung injury

Introduction  

Animal studies of acute lung injury (ALI) suggest nebulised heparin may limit damage from fibrin deposition in the alveolar space and microcirculation. No human studies have been undertaken to date. We assessed the feasibility, safety and potential anticoagulant effects of administration of nebulised heparin to patients with ALI.     

Airway pressure release ventilation in acute respiratory distress syndrome

Airway pressure release ventilation (APRV) is an alternative mode of ventilation that is increasingly used in patients with acute respiratory failure, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Animal and clinical studies have demonstrated that, compared with conventional ventilation, APRV has beneficial effects on lung recruitment, oxygenation, end-organ blood flow, pulmonary vasoconstriction, and sedation requirements. Further studies, however, are required to directly compare APRV to ARDSnet protocol ventilation, specifically in patients with ALI/ARDS, and to determine whether managing ALI/ARDS with APRV will also achieve mortality reduction.     

Nebulised heparin: a new approach to the treatment of acute lung injury?

The administration of heparin by nebulisation has been proposed for the 'local' treatment of pulmonary coagulation disturbances in acute lung injury (ALI). Alveolar and lung micro-vascular fibrin accumulation and breakdown inhibition indeed play a central role in the development and clinical course of this disease. Preclinical studies provide some evidence of the beneficial effects of heparin inhalation in several animal models of ALI. Clinical investigations are sparse, and trials such as the one presented by Dixon and colleagues in a recent issue of Critical Care are welcome as they provide insight into the possible clinical use of nebulised heparin in this situation. This phase 1 trial involved 16 patients with early ALI, and showed the feasibility of the approach. In addition, non-significant changes in respiratory functions and systemic anticoagulant effects were documented with the four doses tested. The study of Dixon and colleagues adds to data that helps pave the way towards a possible clinical use of heparin by nebulisation in ALI. It remains to be clarified in which clinical situations, at what time points and with which dosages the best chances exist for a beneficial effect on the prognosis of these patients.     

纤溶酶原激活物抑制物-1与急性脑梗死并发急性肺损伤/急性呼吸窘迫综合征的相关性研究

目的探讨急性脑梗死并发急性肺损伤/急性呼吸窘迫综合征患者血清纤溶酶原激活物抑制物-1(PAI-1)水平变化及临床意义。方法采用前瞻性研究方法,收集急性脑梗死并发ALI/ARDS患者28例,单纯ALI/ARDS患者26例,健康对照组20例。根据脑梗死部位不同,A组被进一步分为前循环区组(5例)、后循环区组(15例)、分水岭区组(8例)。所有研究对象均已行头颅CT/MRI检查。A、B组行APACHEⅡ评分。检测所有患者血清PAI-1水平,比较各组PAI-1水平变化及其与A-PACHEⅡ评分相关性。结果脑梗死并发ALI/ARDS组、单纯ALI/ARDS组PAI-1水平高于对照组(P<0.01),脑梗死并发ALI/ARDS组高于单纯ALI/ARDS组(P<0.05)。后循环梗死患者ALI/ARDS发生率最高(53.57%)。血清PAI-1水平与A-PACHEⅡ评分呈正相关(P<0.01)。结论 ALI/ARDS存在凝血纤溶功能障碍,脑梗死(尤其后循环区梗死)更易致ALI/ARDS的发生,PA-I1水平可预示疾病的严重程度。