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					Title: Mechanisms of Acute Lung Injury/Acute Respiratory Distress Syndrome
Authors: Suratt BT, Parsons PE
Clin Chest Med 2006; 27:579-89

Key Points
    •    The primary physiologic abnormality in ALI/ARDS is failure of the alveolar capillary membrane (ACM).
    •    Alterations in endothelial and epithelial structure and function cause changes in immune and inflammatory processes underlying the
         development of ALI/ARDS
    •    Altered microcoagulation and thrombus formation is stimulated by the inflammatory and immune response
    •    Mechanical ventilation contributes to lung injury.
    •    Derangements in repair mechanisms and processes also contribute to outcomes from ALI/ARDS

Clinical Conclusions
     •     Inflammation, immune mediation and coagulation derangements all contribute to lung injury. Mechanical injury during ventilation
           further contributes to poorer outcomes. Future targets for therapy to prevent or treat ALI/ARDS will likely focus on altering immune
           modulators, blocking recruitment of certain types of inflammatory and bone marrow cells in the injured lung, and other means of
           modifying the molecular and cellular mediators of lung injury.

Sections Highlights
The American-European Consensus Conference (AECC) defined ARDS as arterial hypoxemia (with PaO2/FiO2 ratio ≤ 200) plus bilateral alveo lar
infiltrates, without evidence of elevated left atrial pressure. [Bernard GR et al, 1994]

Common End Point: Failure of the ACM
   •   ACM is formed by the capillary endothelium and the alveolar epithelium. Both are affected in ALI/ARDS [Figure 1]. Type I epithelial cells
       of the alveolus appear more critical than the endothelial surface of the ACM. [WienerpKronish JP et al, 1991]
   •   Endothelial swelling occurs with widening of the intercellular junctions [Bachofen M and Weibel ER, 1982] and capillary leak [Raijmakers
       PG et al 1996]. . Proteinaceous fluid floods the alveoli, impeding gas exchange and reducing lung compliance.
   •   Endothelial structure and function may be altered independently by cytokines, thrombin, lipopolysaccharide, and other microbial
       products. Endothelial activation becomes uncontrolled.[Zimmerman GA et al, 1999]
   •   Type II epithelial cells provide resorption of air-space fluid [Matthay MA et al, 2002]; loss of this function contributes to ALI/ARDS. [Ware
       LB and Matthay MA, 2001].

Pathophysiologic Mechanisms[Figure 2]

    •    Two mechanisms of injury occur in ALI/ARDS: direct (e.g. aspiration) and indirect. (e.g. extrathoracic trauma).
    •    Overall mortality of direct and indirect mechanisms of injury do not differ substantially [Callister ME et al, 2002][Eisner MD et al, 2001]
    •    Age, sex, and race may influence risk of developing ALI/ARDS and subsequent mortality. [Zilberberg MD et al, 1998] [Barnes KC, 2005].

Leukocytes and Soluble Mediators [Figure 1] [Figure 2].
    •    Neutrophils
             o Neutrophils are a likely key participant in endothelial injury [Ashbaugh DG et al, 1967][Bachofen M, 1982].
             o In neutropenic patients, ALI/ARDS worsen dramatically when neutropenia resolves. [Azoulay E et al, 2002].
    •    Cytokines
         o Tumor necrosis factor alpha (TNF) and interleukin 1beta (IL ) cause release of secondary cytokines, such as CXC cytokines and CC
                                                                           -1
             cytokines, and other mediators that amplify inflammation,.
         o Inflammation in ALI/ARDS results from the net balance of both pro-and anti-inflammatory mediators. [Park WY et al, 2001].
         o Cytokines also activate the vascular endothelium.[Zimmerman GA et al, 1999]
         o Genetic variation involving cytokines may affect the risk of ALI/ARDS after injury. Polymorphism for TNF has been shown to
             increase susceptibility to ALI/ARDS [Gong MN et al, 2005]. Polymorphism in multiple other pro- and anti-inflammatory mediators
             influence clinical manifestations of sepsis and possibly ALI/ARDS [Barnes KC, 2005].

Coagulation and Platelets

    •    Intra-alveolar hyaline membranes and microvascular thrombi are histologic hallmarks of acute ALI/ARDS [Figure 1][Ashbaugh DG et al,
         1967]
    •     Expression of procoagulant molecules by injured endothelial and epithelial components of the ACM and increase in inhibitors of
         fibrinolysis leads to unopposed procoagulant activity. [Gunther A et al, 2000]
    •    Microthrombi in the airspaces interfere with gas exchange.
    •    Anticoagulant therapies for ALI/ARDS have had mixed results [Laterre PF et al, 2003], but there has been recent success with activated
         protein C in treatment of sepsis, and such therapies may have a role in ALI/ARDS [Nick JA et al, 2004].
    •    Variations in clinical outcomes in patients with sepsis and ALI/ARDS have been related to genetic polymorphisms of coagulation proteins.
         [Menges T et al, 2001][Maloney J et al, 2002].

Surfactant
     •    Surfactant decreases surface tension at the air/liquid interface of the alveolus and participates in host defense. [Wright JR, 2005].
     •    Surfactant is altered early in ALI/ARDS, both in composition and in surface tension properties [Gregory TJ et al, 1991]. Subsequent
          alveolar collapse decreases lung compliance and hypoxemia and draw additional fluid into the alveolus, causing a vicious cycle.[Figure 2].
     •    Trials of recombinant surfactant in ALI/ARDS have been disappointing. It may have increased mortality in those with indirect lung
          injury.[Spragg RG et al, 2004].

Ventilator-Induced Lung Injury

     •    During cyclic tidal volume delivery, 3 areas exist in the lung: [Frank JA and Matthay MA, 2003]: fluid-filled collapsed areas, patent areas in
          which shunting of gas may cause alveoli over distention, and atelectatic areas that open and close with the respiratory cycle.
     •    Mechanical ventilation may increase lung injury through over distension of the patent alveoli and shear injury in areas of cyclic atelectasis
          and activation of lung. macrophages and type II pneumocytes promotes with release of cytokines [Dunn I and Pugin J, 1999][Pugin J et al,
          1998]
      •    Cytokine release is attenuated by use of lower tidal volumes (<6 mL/kg). [Ranieri VM et al, 1999][ARDS Network, 2000][Parsons PE et al,
           2005].
      •    Lower tidal volumes (6 mL/kg) have been shown to reduce ALI/ARDS mortality from 40% to 31%. [ARDS Network, 2000].

Late-Phase Pathophysiology: Dysregulated and Maladaptive Repair

     •    Resolution of ALI/ARDS involves termination of the inflammatory response, clearance of fluid and debris from the alveoli, and repair of
          the ACM [Figure 1].
          Failure of fluid resorption, even measured early in ALIL/ARDS, is predictive of mortality [Ware LB et al, 2001]. Regeneration of alveolar
          structure and function and removal of cellular debris are crucial steps in resolution. [Huynh ML et al, 2002]
     •    The “fibroproliferative phase” of ALI/ARDS develops about 5-7 days into the course, leading to formation of granulation tissue with
          physiologic compromise.[Bitterman PB, 1992]. Blockage of the migration of fibroblasts into the alveolus may represent a future
          therapeutic approach.
     •    Higher levels of lung vascular endothelial growth factor (VEGF), a chemoattractant for endothelial precursors, are associated with
          recovery from ALI/ARDS [Thickett DR et al, 2002]. Polymorphisms of VEGF associated with decreased VEGF production are associated
          with elevated risk from ALI/ARDS.[Medford AR et al, 2002].

Summary

Pathophysiology of ALI/ARDS is complex, with recent appreciation of the role of immunology and inflammation, and genetic variation, in the
evolution of the disease.

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