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.     

The role of the coagulation cascade in the continuum of sepsis and acute lung injury and acute respiratory distress syndrome

Sepsis is a common and life-threatening condition with a high mortality rate. Severe sepsis includes multiorgan dysfunction syndrome. The organ most often affected is the lung, with development of acute lung injury (ALI), which, in its most severe form, is referred to as acute respiratory distress syndrome (ARDS). Our understanding of inflammation in the pathogenesis of sepsis and ALI is continually growing. However, therapies aimed at the inflammatory cascade in sepsis have been unsuccessful. These failures have led investigators to consider other pathways that may be important in the development of sepsis and ALI, including the coagulation and fibrinolytic cascades. In fact, the first therapy to reduce mortality in sepsis modulates the coagulation cascade. With this clinical success, administration of drotecogin alfa (recombinant activated protein C), the importance of coagulation in the pathogenesis of human sepsis is becoming clearer. This review summarizes the current understanding of the role of coagulation and fibrinolytic abnormalities in sepsis and the development of ALI and ARDS. Both in vitro and in vivo studies of the role of the coagulation cascade in sepsis and lung injury will be discussed, including initiation of coagulation through modulation of tissue factor and tissue factor pathway inhibitor, propagation of coagulation via protein C and thrombomodulin, inhibition of thrombin generation and resolution through thrombolysis by plasminogen activator, and plasminogen activator inhibitor-1.     

Local abnormalities of coagulation and fibrinolysis and alveolar fibrin deposition in sheep with oleic acid-induced lung injury

Extravascular, primarily intra-alveolar, fibrin deposition is a histologic hallmark of acute lung injury in humans and experimental animals, but the mechanisms leading to this finding are poorly understood. To determine whether local abnormalities in the fibrinolytic-procoagulant balance contribute to alveolar fibrin deposition in acute lung injury, we studied bronchoalveolar lavage (BAL) fluids of anesthetized sheep that received intravenous oleic acid. Prominent alveolar fibrin deposition was observed within 2 h after oleic acid-induced lung injury. Procoagulant and fibrinolytic activities were determined in BAL samples of anesthetized, mechanically ventilated sheep before and 2 h after intravenous oleic acid or saline. BAL procoagulant activity was found to be due mainly to tissue factor associated with Factor VII. In baseline BAL samples, we found relatively low levels of procoagulant activity and relatively high levels of fibrinolytic activity. After induction of oleic acid-induced lung injury, the procoagulant activity of BAL was markedly increased, whereas fibrinolytic activity was either depressed or undetectable. Antiplasmin activity was detectable in BAL of sheep after oleic acid-induced lung injury, which contributed at least in part to the depressed fibrinolytic activity observed. These perturbations occurred with the appearance of extensive alveolar fibrin deposition. In control sheep, BAL fibrinolytic activity was decreased, and antiplasmin activity increased modestly after 2 h of mechanical ventilation, but procoagulant activity was unchanged and alveolar fibrin was not observed. Procoagulant activity in lung lymph and plasma after lung injury did not differ from baseline values, and fibrinolytic activity was undetectable in lymph or plasma samples. These data indicate that increased procoagulant activity and concurrent disruption of the balance of coagulation and fibrinolysis establish local conditions that promote acute fibrin deposition in the alveoli of mechanically ventilated, oleic acid-injured sheep.     

急性肺损伤/急性呼吸窘迫综合征中凝血与纤溶研究进展

纤维蛋白沉积有其利与弊。凝血级联活化、纤溶抑制和生理性抗凝物质下调均参与急性肺损伤／急性呼吸窘迫综合征（ALI／ARDS）中纤维蛋白的沉积。三系统功能异常与其基因多态性有关联,微肺不张、死腔增加和炎性因子的表达上调是纤维蛋白沉积的主要致病机制。活化的蛋白C具有抗凝和抗炎的作用，可能有效抑制ALI／ARDS中肺损伤和加速肺纤维化。     

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.     

Cytoprotection of heme oxygenase-1/carbon monoxide in lung injury

Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) have been the major cause of morbidity and mortality in intensive care units (ICU) over the past decades despite advances in therapeutic modalities. This syndrome is characterized by noncardiogenic pulmonary edema, and pulmonary and systemic inflammation resulting in respiratory failure (1, 2). Both exudative and proliferative organizing phases of ARDS/ALI have been described pathologically (3, 4). The exudative phase is often called diffuse alveolar damage (DAD) characterized by inflammation and hyaline membrane composed of fibrin and cellular debris (3--5). Pulmonary alveolar cell death is the major pathologic change during the exudative phase in DAD. Repair and remodeling of injured lung cells occur during the proliferative phase, characterized by hyperplasia of alveolar type II cells and fibroblast proliferation (3-5). A variety of cellular insults can cause ALI/ARDS including but not limited to sepsis, trauma, drugs, high concentration of oxygen therapy, and mechanical ventilation (1, 2, 5). The broad spectrum of insults that potentially cause ARDS highlights the complexity of pathogenesis of this syndrome.     

Tissue fibrin deposition during acute lung injury in rabbits and its relationship to local expression of procoagulant and fibrinolytic activities

Parenchymal fibrin deposition is well recognized in many forms of acute lung injury. Proteins derived from the actions of the coagulation and fibrinolytic systems may potentiate these inflammatory reactions as well as influence the subsequent repair process. However, the factors regulating fibrin formation and dissolution in acute pneumonitis have not been defined. In this study, we characterized the procoagulant (PC) and fibrinolytic activities simultaneously present in the alveolar space during the course of acute lung injury induced in rabbits by an intravenous injection of phorbol myristate acetate (PMA). Within 6 h of PMA injection, this injury was characterized histologically by extensive intra-alveolar fibrin formation and marked accumulation in pulmonary parenchyma of intravenously administered 125I-fibrinogen. Clearance of fibrin ensued over the remainder of the 72-h study period. Normal BAL fluid contained high levels of procoagulant activity which did not vary after the onset of inflammation. The procoagulant activity was attributed to particle-bound tissue thromboplastin as well as other factors of the extrinsic coagulation pathway. There were low levels of plasminogen activator (PA) activity in normal BAL fluid, but the mean activity increased 9.3-fold over control values by 12 h after PMA injection (p less than 0.01). When plasminogen activator activity in BAL fluid was referenced to the concomitant procoagulant activity, this ratio (PA/PC) increased 17.8-fold over controls, peaking 24 h after PMA injection (p less than 0.01). The levels of both procoagulant and plasminogen activator activities associated with alveolar macrophages were stable during the study period. Compared to alveolar macrophages, granulocytes expressed similar levels of plasminogen activator but negligible procoagulant activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

A review of pulmonary coagulopathy in acute lung injury,acute respiratory distress syndrome and pneumonia

Enhanced bronchoalveolar coagulation is a hallmark of many acute inflammatory lung diseases such as acute lung injury, acute respiratory distress syndrome and pneumonia. Intervention with natural anticoagulants in these diseases has therefore become a topic of interest. Recently, new data on the role of pulmonary coagulation and inflammation has become available. The aim of this review is to summarize these findings. Furthermore, the results of anticoagulant therapeutic interventions in these disorders are discussed.     

ALI/ARDS的治疗进展

关于ALI和ARDS发病机制的研究和探讨众多.主要集中在炎症反应、氧化应激损伤、凝血纤溶系统失衡、细胞损伤及凋亡、肺泡液体清除异常、医疗操作损伤等层面.针对这些因素所带来的机体损伤,人们进行了大量的实验室及临床的研究与治疗,虽然表现出一定的治疗效果,但是单独应用的适用范围仍有限.     

Treatment of ARDS

Improved understanding of the pathogenesis of acute lung injury (ALI)/ARDS has led to important advances in the treatment of ALI/ARDS, particularly in the area of ventilator-associated lung injury. Standard supportive care for ALI/ARDS should now include a protective ventilatory strategy with low tidal volume ventilation by the protocol developed by the National Institutes of Health ARDS Network. Further refinements of the protocol for mechanical ventilation will occur as current and future clinical trials are completed. In addition, novel modes of mechanical ventilation are being studied and may augment standard therapy in the future. Although results of anti-inflammatory strategies have been disappointing in clinical trials, further trials are underway to test the efficacy of late corticosteroids and other approaches to modulation of inflammation in ALI/ARDS.     

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.     

Effects of inhaled plasminogen activator on the balance between coagulation and fibrinolysis in traumatized pigs.

A profibrinolytic state is normal in the alveoli, but this may change as a result of trauma, possibly leading to fibrin deposition, a characteristic of acute lung injury/acute respiratory distress syndrome. Therefore, the present study investigated in a double-blind, placebo-controlled manner the effect of severe trauma on the alveolar fibrinolytic/coagulation balance, and the effect here-upon of inhalation of single-chain urokinase plasminogen activator (scu-PA) in pigs. The study shows an increased concentration of scu-PA in the bronchoalveolar lavage fluid of the treated animals in association with an increased plasmin-dependent fibrinolytic activity without increased systemic fibrinolytic activity, the transient increase in the concentration of scu-PA in the plasma being minimal. In conclusion, the study shows that activatable scu-PA can be nebulized to the lower respiratory tract and can increase the alveolar fibrinolysis without any significant systemic effects.     

Blockade of tissue factor: treatment for organ injury in established sepsis

Blockade of tissue factor before lethal sepsis prevents acute lung injury and renal failure in baboons, indicating that activation of coagulation by tissue factor is an early event in the pathogenesis of acute lung injury and organ dysfunction. We hypothesized that blockade of tissue factor would also attenuate these injuries in established sepsis by prevention of further fibrin deposition and inflammation. Twelve male baboons received heat-killed Escherichia coli intravenously followed 12 hours later by live E. coli infusion. Six animals were treated 2 hours after the live bacteria with site-inactivated Factor VIIa, a competitive tissue factor inhibitor, and six animals were vehicle-treated sepsis control subjects. Animals were ventilated and monitored for 48 hours. Physiologic and hematologic parameters were measured every 6 hours, and pathologic evaluation was performed after 48 hours. Animals treated with site inactivated Factor VIIa had less severe lung injury, with preserved gas exchange, better lung compliance and histology scores, and decreased lung wet/dry weight. In treated animals, urine output was higher, metabolic acidosis was attenuated, and renal tubular architecture was protected. Coagulopathy was attenuated, and plasma interleukin-6, interleukin-8, and soluble tumor necrosis factor receptor-1 levels were significantly lower in the treated animals. These results show that blockade of coagulation attenuates acute lung and renal injury in established Gram-negative sepsis accompanied by antiinflammatory effects of therapy.     

Occurrence of the adult respiratory distress syndrome in neutropenic patients

Neutrophils are believed to play an essential role in the pathogenesis of the adult respiratory distress syndrome (ARDS). This concept is largely based on the observation that neutrophil depletion protects against altered pulmonary vascular permeability in several models of acute lung injury produced in laboratory animals. Four patients who developed ARDS during periods of profound neutropenia are presented. These patients met commonly accepted clinical and roentgenographic criteria for the syndrome, and each had the characteristic findings of diffuse alveolar damage by lung histologic examination. The failure of this degree of neutropenia to protect against ARDS in humans raises questions about whether neutrophils or neutrophil products are essential in the pathogenesis of the syndrome.     

Fibrinolysis in critically ill patients

Impaired fibrinolysis may contribute to development of adult respiratory distress syndrome (ARDS). Pathologic increases in endogenous plasminogen activator inhibitor (PAI-1) may blunt normal fibrinolysis and unmask alternate fibrinolytic mechanisms, such as elastase-induced fibrin degradation. We measured PAI-1 and elastase-induced fibrin(ogen) degradation products in 69 critically ill patients in our medical intensive care unit (MICU) and in nine healthy volunteers. Factor VIII-related antigen protein (VIII:Ag), a reported marker of acute lung injury, and alpha-1-protease inhibitor (alpha-1-PI), an acute phase reactant, were also measured. MICU patients included 24 control patients with no known risk of ARDS, 35 patients with risk factors for ARDS including sepsis, pneumonia, aspiration, and shock, and 12 patients with ARDS including two patients from at-risk groups who developed ARDS. Plasma PAI-1 was determined by chromogenic assay, elastase-induced peptides by a new radioimmunoassay, VIII:Ag by immunoelectrophoresis, and alpha-1-PI by immunodiffusion. When compared to normal volunteers, MICU control patients had elevated PAI-1, VIII:Ag, elastase-induced peptides, and alpha-1-PI. Patients with ARDS had significantly higher PAI-1 and VIII:Ag than did MICU control patients; elastase-induced peptides and alpha-1-PI were not higher. However, at-risk patients who did not develop ARDS also had high PAI-1 or VIII:Ag. Although these data cannot refute the possible role of these compounds in the pathogenesis of ARDS, they demonstrate that PAI-1 and VIII:Ag may be elevated in many critically ill patients but may not be useful markers for the subsequent development of ARDS.     

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.     

Respiratory failure

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common causes of hypoxemic respiratory failure. Multiple etiologies lead to direct and indirect pulmonary injury that progresses through an acute exudative phase, fibroproliferative phase, and recovery phase. Inflammatory mechanisms are thought to play a predominant role in the pathophysiology of ALI/ARDS. Mechanical ventilation with a lower tidal volume and an inspiratory plateau pressure of < or = 30 cm H2O is one intervention that has demonstrated a reduction in mortality. A clinical trial to determine the role of restrictive versus liberal fluid management is underway. Inhaled nitric oxide has been used to improve oxygenation but has not resulted in any outcome benefit. Glucocorticoids may be beneficial in the fibroproliferative phase of lung injury by suppressing chronic inflammation. Rigorous clinical trials of new and established interventions are required to determine optimum therapy and reduce mortality in ALI/ARDS.     

Bronchoalveolar lavage procoagulant activity in bleomycin-induced lung injury in marmosets. Characterization and relationship to fibrin deposition and fibrosis

Although pulmonary fibrin deposition and coagulation abnormalities have been observed in acute lung injury in humans, their role in the pathogenesis of pulmonary disorders is unclear. In order to gain further insights into the role of the coagulation in lung injury, we examined the relationship between procoagulant activity in bronchoalveolar lavage (BAL) fluids and the evolution of bleomycin-induced lung injury in marmosets. The BAL procoagulant activity was increased at 1, 2, and 4 wk after bleomycin challenge compared with that in control subjects, and it was capable of shortening the recalcification times of plasmas deficient in factor VII and factor VIII but not in factor X. This profile suggested the presence in BAL of an activator of factor X. Activation of purified human factor X by BAL was demonstrated by measuring the amidolytic activity of the generated factor Xa on its N-benzoyl-L-isoleucyl L-glutamyl-glycyl-L-argenine-p-nitroanilide substrate. Factor X activating activity was increased in BAL at 2 wk after bleomycin challenge. Cleavage of 125I-labeled human factor X by BAL from bleomycin-challenged marmosets yielded a 55,500 Mr product that comigrated with factor Xa, the appearance of which correlated strongly with amidolytic evidence of factor Xa activity. Electron microscopy of the lungs of animals from all groups revealed pulmonary fibrin deposition at 2 wk after bleomycin challenge, at the time of increased BAL procoagulant and factor X activating activity. The BAL procoagulant activity was completely sedimentable by ultracentrifugation and was inhibited by concanavalin A and phospholipase C. Activation of purified factor X by BAL was inhibited by monospecific polyclonal goat and rabbit antibodies to human factor VII as well as antibody to bovine tissue factor, demonstrating that factor X activating activity in BAL was attributable to tissue factor associated with material similar to factors VII or VIIa. We conclude that procoagulant activity in BAL increases after bleomycin challenge in marmosets and is attributable to activation of factor X by tissue factor associated with factors VII or VIIa-like material. Increased BAL procoagulant activity is temporally associated with pulmonary fibrin deposition and pulmonary fibrosis during bleomycin-induced pulmonary injury in the marmoset.     

Pharmacological inhibition of tissue factor

Tissue factor plays an essential role in the initiation of coagulation in vivo. In severe conditions, including sepsis and acute lung injury, increased expression of tissue factor may induce disseminated intravascular coagulation and fibrin deposition in organs, which are believed to have a determining impact on patient outcome. Tissue factor also acts as a signaling receptor and is involved in the systemic inflammatory response, as in cancer progression and atherosclerosis. Interventions aiming at limiting tissue factor activities have been evaluated in multiple experimental studies and the observed results have supported the potential benefits for coagulation disorders, inflammation, and survival. The effects of the main physiological inhibitor of tissue factor, tissue factor pathway inhibitor, have been evaluated in two large clinical trials in sepsis. Even though they are not associated with an improved outcome, the observed data support further clinical studies.     

Pathophysiology of acute lung injury and the acute respiratory distress syndrome

Since the adult respiratory distress syndrome was first described substantial progress has been made in understanding the pathogenesis of this complex syndrome. This review summarizes our current understanding of the pathophysiology of what is now termed the acute respiratory distress syndrome (ARDS) and its less severe form acute lung injury (ALI), with an emphasis on cellular and molecular mechanisms of injury that may represent potential therapeutic targets. Although it is difficult to synthesize all of these abnormalities into a single, unified, pathogenetic pathway, a theme that emerges repeatedly is that of imbalance, be it between pro- and anti-inflammatory cytokines, oxidants and antioxidants, procoagulants and anticoagulants, neutrophil recruitment and activation and mechanisms of neutrophil clearance, or proteases and protease inhibitors. Future therapies aimed at restoring the overall balance of cytokines, oxidants, coagulants, and proteases may ultimately be successful where therapies that target individual cytokines or other mediators have not.