The role of bronchoalveolar hemostasis in the pathogenesis of acute lung injury

Disturbed alveolar fibrin turnover is intrinsic to acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and pneumonia and is important to its pathogenesis. Recent studies also suggest disturbed alveolar fibrin turnover to be a feature of ventilator-induced lung injury (VILI). 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. Administration of anticoagulant agents (including activated protein C, antithrombin, tissue factor-factor VIIa pathway inhibitors, and heparin) and profibrinolytic agents (including plasminogen activators) attenuate pulmonary coagulopathy. Several preclinical studies show additional anti-inflammatory effects of these therapies in ALI/ARDS and pneumonia. In this article, we review the involvement of coagulation and fibrinolysis in the pathogenesis of ALI/ARDS pneumonia and VILI and the potential of anticoagulant and profibrinolytic strategies to reverse pulmonary coagulopathy and pulmonary inflammatory responses.     

Future research directions in acute lung injury: summary of a National Heart,Lung, and Blood Institute working group

Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are syndromes of acute respiratory failure that result from acute pulmonary edema and inflammation. The development of ALI/ARDS is associated with several clinical disorders including direct pulmonary injury from pneumonia and aspiration as well as indirect pulmonary injury from trauma, sepsis, and other disorders such as acute pancreatitis and drug overdose. Although mortality from ALI/ARDS has decreased in the last decade, it remains high. Despite two major advances in treatment, low VT ventilation for ALI/ARDS and activated protein C for severe sepsis (the leading cause of ALI/ARDS), additional research is needed to develop specific treatments and improve understanding of the pathogenesis of these syndromes. The NHLBI convened a working group to develop specific recommendations for future ALI/ARDS research. Improved understanding of disease heterogeneity through use of evolving biologic, genomic, and genetic approaches should provide major new insights into pathogenesis of ALI. Cellular and molecular methods combined with animal and clinical studies should lead to further progress in the detection and treatment of this complex disease.     

Adult Respiratory Distress Syndrome

The adult respiratory distress syndrome (ARDS) is a form of acute lung injury that is characterized by florid extravascular fibrin deposition. Thrombosis in the pulmonary vasculature and disseminated intravascular coagulation have also been observed in association with ARDS. Fibrin deposition does not occur in the normal lung but is virtually universal in acute lung injury induced by disparate insults. A large body of basic and preclinical evidence further implicates abnormalities of pathways of fibrin turnover in the pathogenesis of acute inflammation and fibrotic repair. Coagulation is locally upregulated in the injured lung, while fibrinolytic activity is depressed. These abnormalities occur concurrently and favor alveolar fibrin deposition. The systemic derangements of fibrin turnover in sepsis are similar to those that occur in the injured lung.Recent clinical trials demonstrate that interventions using selective anticoagulation can provide a mortality advantage and that selective anticoagulants differ in their ability to provide clinical benefit. Preclinical trials in primates with sepsis-induced ARDS now indicate that anticoagulant interventions that block the extrinsic coagulation pathway can protect against the development of pulmonary fibrin deposition as well as lung dysfunction and acute inflammation. These observations provide proof of principle that key steps in the coagulation cascade are appropriate therapeutic targets to prevent the development of acute lung injury in ARDS. Ongoing studies and prior publications also support the hypothesis that reversal of the fibrinolytic defect in ARDS could protect against the development of acute lung injury. In all, these studies suggest that fibrin deposition in the injured lung as well as abnormalities of coagulation and fibrinolysis are integral to the pathogenesis of ARDS. The ability of selective anticoagulants to effectively and safely alter clinical outcome in ARDS remains to be determined.     

Adult respiratory distress syndrome: do selective anticoagulants help?

The adult respiratory distress syndrome (ARDS) is a form of acute lung injury that is characterized by florid extravascular fibrin deposition. Thrombosis in the pulmonary vasculature and disseminated intravascular coagulation have also been observed in association with ARDS. Fibrin deposition does not occur in the normal lung but is virtually universal in acute lung injury induced by disparate insults. A large body of basic and preclinical evidence further implicates abnormalities of pathways of fibrin turnover in the pathogenesis of acute inflammation and fibrotic repair. Coagulation is locally upregulated in the injured lung, while fibrinolytic activity is depressed. These abnormalities occur concurrently and favor alveolar fibrin deposition. The systemic derangements of fibrin turnover in sepsis are similar to those that occur in the injured lung. Recent clinical trials demonstrate that interventions using selective anticoagulation can provide a mortality advantage and that selective anticoagulants differ in their ability to provide clinical benefit. Preclinical trials in primates with sepsis-induced ARDS now indicate that anticoagulant interventions that block the extrinsic coagulation pathway can protect against the development of pulmonary fibrin deposition as well as lung dysfunction and acute inflammation. These observations provide proof of principle that key steps in the coagulation cascade are appropriate therapeutic targets to prevent the development of acute lung injury in ARDS. Ongoing studies and prior publications also support the hypothesis that reversal of the fibrinolytic defect in ARDS could protect against the development of acute lung injury. In all, these studies suggest that fibrin deposition in the injured lung as well as abnormalities of coagulation and fibrinolysis are integral to the pathogenesis of ARDS. The ability of selective anticoagulants to effectively and safely alter clinical outcome in ARDS remains to be determined.     

Pharmacology of acute lung injury

The acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a clinical syndrome that affects both medical and surgical patients. To date, despite improved understanding of the pathogenesis of ALI/ARDS, pharmacological modalities have been unsuccessful in decreasing mortality. However, several pharmacological agents for ARDS are in development and have shown great promise. In addition to the anti-inflammatory category including late corticosteroids, inhaled nitric oxide, alveolar surfactant, and vasodilators are being evaluated. Replacements of anticoagulation mediators have also suggested beneficial effects on the patient outcome. This article provides an overview of pharmacological treatments of ALI/ARDS.     

Pathophysiology of acute lung injury

The acute respiratory distress syndrome (ARDS) is a life-threatening syndrome that may occur in any patient without any predisposition and that is mostly triggered by underlying processes such as sepsis, pneumonia, trauma, multiple transfusions, and pancreatitis. ARDS is defined by (1) acute onset, (2) bilateral infiltrates in chest x-rays, (3) absence of left ventricular failure, and (4) severe arterial hypoxemia with a PaO2/FiO2 ratio less than 200 mmHg. Still, ARDS is feared (mortality 30-40%) and relatively frequent (incidence between 13.5 per 100,000 to 75 per 100,000). Acute lung injury (ALI) describes a similar, but less severe, clinical condition, with PaO2/FiO2 values between 200 and 300 mmHg. Despite ongoing and intensive scientific research in this area, the mechanisms underlying ALI/ARDS are still not completely understood, and until recently, there were no studies demonstrating any beneficial effect of a single treatment modality in ARDS. The recent report that a specific approach to ventilatory support can significantly reduce mortality in ARDS underscores the need for better understanding of the pathophysiological events occurring in this syndrome. This review therefore summarizes the current pathophysiological concepts underlying the evolution of acute hypoxemic respiratory failure and focuses on: (1) possible reasons for the development of ALI/ARDS; (2) cellular and humoral mediator responses leading to a sustained and self-perpetuating inflammation of the lung; (3) consequences with regard to fluid balance, pulmonary perfusion, ventilation, and efficiency of gas exchange; and (4) mechanisms underlying the aggravating complications commonly seen in ARDS, especially ventilator-associated lung injury, ventilator-associated pneumonia, and lung fibrosis.     

蛋白组学在急性肺损伤/急性呼吸窘迫综合征发病机制研究中的应用进展

近年来,随着分子生物学和生物信息学技术的发展,蛋白组学已被应用于急性肺损伤/急性呼吸窘迫综合征(ALI/ARDS)发病机制的研究.蛋白组学能够捕获一个有机体内一套完整表达的蛋白,包括蛋白异构体和转录后修饰.与基因组学研究比较,蛋白组学研究具有许多优点.尽管蛋白组学技术应用于ALI/ARDS发病机制的研究刚刚起步,但其在加深理解ALI/ARDS时的蛋白表达模式、发现新的损伤介质、开发新的治疗药物等方面的巨大潜力已经显现.     

microRNA在ALI/ARDS发病机制中调节作用的研究进展

急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)是一种肺内外多种因素导致的急性进展性呼吸衰竭。目前,ALI/ARDS发病机制尚未完全明了,缺乏特异性治疗,其病死率居高不下。microRNA是一种高度保守的小非编码RNA,受其他非编码RNA调控,并特异结合炎症反应、免疫应答相关mRNA的3′-UTR,最终影响ALI/ARDS发展进程。深入研究microRNA在ALI/ARDS发生和发展中的作用,不仅可以进一步了解ALI/ARDS的发生机制,并有助于为其药物治疗寻找新的靶点。     

Newly recognized causes of acute lung injury: transfusion of blood products, severe acute respiratory syndrome, and avian influenza

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a clinical syndrome that has an ever-growing list of potential causes. The transfusion of blood products is often a life-saving therapy, but it can be associated with the development of ALI/ARDS. Transfusion-related ALI is now the leading cause of transfusion-associated fatalities in the United States. Two infectious causes of ALI/ARDS, severe acute respiratory syndrome and H5N1 influenza, have recently emerged and have the potential for pandemic spread. This article discusses the clinical importance, pathogenesis, diagnosis, management, and prevention of these newly recognized causes of respiratory failure.     

The role of cytokines during the pathogenesis of ventilator-associated and ventilator-induced lung injury

Mortality rates from acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) range from 30 to 65%. Although mechanical ventilation (MV) may delay mortality in critically ill patients with ALI/ARDS, it may also cause a lung injury that further promotes and perpetuates ALI/ARDS and multiorgan dysfunction syndrome (MODS). Recent studies have demonstrated that lung protective strategies of MV, as compared with the injurious strategy of conventional MV (CMV) can reduce absolute mortality rates during ALI/ARDS. The protective strategies limit tidal volumes and peak/plateau pressures while maximizing positive end-expiratory pressure. The injury to the lung by CMV is characterized histologically by edema, leukocyte extravasation, and endothelial and epithelial damage. Both human and animal studies suggest that alveolar cell deformation from CMV leads to the release of cytokines/chemokines which orchestrate the extravasation, activation, and recruitment of leukocytes, causing ventilator-associated lung injury (VALI) and ventilator-induced lung injury (VILI). Moreover, VALI/VILI can perpetuate the chronic inflammatory response during ALI/ARDS and MODS. This article explores the role of cytokines/chemokines during the pathogenesis of VALI/VILI.     

Incidence and short-term outcome of acute lung injury in mechanically ventilated children.

The aim of this study was to determine the incidence and short-term outcome of mechanically ventilated children suffering from acute lung injury (ALI) on a paediatric intensive care unit (PICU). Between January 1 1998 and January 1 2000, all mechanically ventilated children were evaluated using the criteria of an American-European Consensus Conference. Of the 443 children eligible for analysis, 44 (9.9%) were diagnosed as suffering from ALI. Of these, 79.5% developed the acute respiratory distress syndrome (ARDS); 54.5% (24 of 44) fulfilled the ARDS criteria at inclusion and 25% (11 of 44) later. PICU mortality for ALI was 27.3% (12 of 44) and within the ARDS subgroup 31.4% (11 of 35). Of the 12 children who died, 11 had ARDS; the main cause of death was cerebral damage (seven of 12). Acute lung injury and acute respiratory distress syndrome are rare diseases on a paediatric intensive care unit with a high mortality. Most of the children with acute lung injury develop acute respiratory distress syndrome. In the acute respiratory distress syndrome subgroup, mortality is higher than in the acute lung injury nonacute respiratory distress syndrome subgroup. Further investigations should confirm prognostic factors (e.g. respiratory parameters) for prediction of outcome.     

Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three Australian States

To determine the incidence and 28-d mortality rate for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) using the 1994 American-European Consensus Conference definitions, we prospectively screened every admission to all 21 adult intensive care units in the States of South Australia, Western Australia, and Tasmania (total population older than 15 yr of age estimated as 2,941,137), between October 1 and November 30, 1999. A total of 1,977 admissions were screened of which 168 developed ALI and 148 developed ARDS, which represents a first incidence of 34 and 28 cases per 100,000 per annum, respectively. The respective 28-d mortality rates were 32% and 34%. The most common predisposing factors for ALI were nonpulmonary sepsis (31%) and pneumonia (28%). Although the incidences of ALI and ARDS are higher and the mortality rates are lower than those reported from studies in other countries, multicenter international studies are required to exclude methodological differences as the cause for this finding.     

Prospective observational study of antiphospholipid antibodies in acute lung injury and acute respiratory distress syndrome: comparison with catastrophic antiphospholipid syndrome

Detection of antiphospholipid (aPL) antibodies in bronchoalveolar lavage fluid (BALF) of patient with acute respiratory distress syndrome (ARDS) suggests involvement of autoimmune mechanisms in the pathogenesis of ARDS. We investigated whether aPL antibodies could be detected in the serum as well as BALF of patients with acute lung injury (ALI) and ARDS. IgG anticardiolipin, IgG anti-beta2-glycoprotein I, IgG antiphosphatidic acid and IgG antiphosphatidylserine antibodies were detected by ELISA in low titers within the normal range in the BALF and serum of nine patients with ALI and 17 patients with ARDS. However, one out of 27 patients investigated had high levels of aPL antibodies in both BALF and serum. This patient suffered from severe ARDS due to sepsis. The high aPL antibody levels in serum possibly triggered by sepsis were associated with high aPL antibody levels in BALF, which can be explained by high capillary-alveolar permeability. Computed tomography scan revealed widespread infarctions in brain, spleen and kidneys, and pulmonary thromboembolism, suggesting the diagnosis of catastrophic antiphospholipid syndrome.     

Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome.

In patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), a recent ARDS Network randomized controlled trial demonstrated that a low tidal volume (VT) mechanical ventilation strategy (6 ml/kg) reduced mortality by 22% compared with traditional mechanical ventilation (12 ml/kg). In this study, we examined the relative efficacy of low VT mechanical ventilation among 902 patients with different clinical risk factors for ALI/ARDS who participated in ARDS Network randomized controlled trials. The clinical risk factor for ALI/ARDS was associated with substantial variation in mortality. The risk of death (before discharge home with unassisted breathing) was highest in patients with sepsis (43%); intermediate in subjects with pneumonia (36%), aspiration (37%), and other risk factors (35%); and lowest in those with trauma (11%) (p < 0.0001). Despite these differences in mortality, there was no evidence that the efficacy of the low VT strategy varied by clinical risk factor (p = 0.76, for interaction between ventilator group and risk factor). There was also no evidence of differential efficacy of low VT ventilation in the other study outcomes: proportion of patients achieving unassisted breathing (p = 0.59), ventilator-free days (p = 0.58), or development of nonpulmonary organ failure (p = 0.44). Controlling for demographic and clinical covariates did not appreciably affect these results. After reclassifying the clinical risk factors as pulmonary versus nonpulmonary predisposing conditions and infection-related versus non-infection-related conditions, there was still no evidence that the efficacy of low VT ventilation differed among clinical risk factor subgroups. In conclusion, we found no evidence that the efficacy of the low VT ventilation strategy differed among clinical risk factor subgroups for ALI/ARDS.     

New modalities of mechanical ventilation: high-frequency oscillatory ventilation and airway pressure release ventilation

Management of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) is largely supportive, with the use of mechanical ventilation being a central feature. Recent advances in the understanding of ALI/ARDS and mechanical ventilation have revealed that lung-protective ventilation strategies may attenuate ventilator-associated lung injury and improve patient morbidity/mortality. High-frequency oscillatory ventilation and airway pressure release ventilation are two novel alternative modes of ventilation that theoretically fulfill the principles of lung protection and may offer an advantage over conventional ventilation for ALI/ARDS.     

磷酸二酯酶及其抑制剂在急性肺损伤/急性呼吸窘迫综合征中的研究进展

磷酸二酯酶（PDE）在急性肺损伤／急性呼吸窘迫综合征（ALI／ARDS）的发病机制中起重要作用，PDE抑制剂能调节ALI／ARDS诸个环节，这方面的资料主要来自动物实验及体外细胞培养。本文就PDE及其抑制剂在ALI／ARDS中的研究进展做一综述。     

Acute lung injury and ARDS in acute pancreatitis: Mechanisms and potential intervention

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in acute pancreatitis still represents a substantial problem,with a mortality rate in the range of 30%-40%.The present review evaluates underlying pathophysiological mechanisms in both ALI and ARDS and potential clinical implications.Several mediators and pathophysiological pathways are involved during the different phases of ALI and ARDS.The initial exudative phase is characterized by diffuse alveolar damage,microvascular injury and inf...     

Administration of a specific inhibitor of neutrophil elastase attenuates pulmonary fibrosis after acute lung injury in mice

Excess production of neutrophil elastase contributes to the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, the role of neutrophil elastase in the repair process following ALI/ARDS is not well understood. The objective of this study was to evaluate the effect of neutrophil elastase on the process of tissue repair after acute lung injury in mice. C57BL/6 mice were exposed to sublethal irradiation followed by intranasal instillation of lipopolysaccharide (LPS) to generate a model of impaired lung repair. The authors assessed the histopathology, lung mechanics, and total lung collagen content 7 days after irradiation and/or LPS-induced injury with daily administration of a neutrophil elastase inhibitor. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) was also evaluated. In addition, the concentration of activated transforming growth factor (TGF)-β1 in the BALF and the expression of phospho-SMAD2/3 were investigated. Irradiated and LPS-treated mice developed pulmonary fibrosis after injury. The neutrophil elastase inhibitor significantly decreased the collagen deposition in lung parenchyma and improved the static lung compliance of injured lungs. Administration of the neutrophil elastase inhibitor also decreased the accumulation of neutrophils in the BALF, TGF-β1 activation, and expression of phospho-SMAD2/3. The authors conclude that inhibiting neutrophil elastase protects against the development of lung fibrosis after acute injury. In addition, these data suggest that this neutrophil elastase inhibitor has therapeutic potential for the fibroproliferative phase of ALI/ARDS.     

ACE2/Ang1-7/Mas在ALI/ARDS中作用机制研究

肾素-血管紧张素系统在 ALI/ARDS的病理过程中有重要作用。大约60% ARDS患者进展成肺纤维化且其病死率明显增加。目前研究显示 ACE/AngⅡ/AT1 R 与 ALI/ARDS 发病机制有关,而ACE2/Ang1-7/Mas起负向调节作用———ACE2和Ang1-7对ALI/ARDS有保护作用。因此,本文就 ACE2/Ang1-7/Mas在 ALI/ARDS中的保护作用和相关信号传导通路等方面最新研究进展作一阐述。