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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 that stimulate
         altered microcoagulation and thrombus formation.
    •    Mechanical ventilation adds 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 ALI/ARDS. Mechanical injury during ventilation contributes to
poorer outcomes. Future therapeutic targets 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 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 alveolar
                                                                1
infiltrates, without evidence of elevated left atrial pressure.

Common End Point: Failure of the ACM [Figure 1]
Edema in the alveolus results from failure of alveolar structures to retain plasma within the capillaries, reducing lung compliance and gas exchange.
Changes include endothelial swelling, endothelial structural and functional changes due to cytokines, thrombin, and other substances, deregulation
of endothelial activation, and deranged vasomotor responses.

Pathophysiologic Mechanisms [Figure 2]
    •   Two mechanisms of lung injury: direct (e.g. aspiration) and indirect (e.g. extrathoracic trauma).
                                                                                      2
    •   Overall mortality of direct and indirect injuries do not differ substantially
                                                                         3,4
    •   Age, sex, and race may influence risk of developing ALI/ARDS

Leukocytes and Soluble Mediators [Figure 1] [Figure 2].
    •    Neutrophils are likely key participants in endothelial injury. Resolution of neutropenia in neutropenic patients is associated with
         worsening of ALI/ARDS.
    •                            IL 
         Cytokines: TNF and-1 cause release of secondary mediators, e.g. CXC cytokins and CC cytokines
             •    Inflammation in ALI/ARDS results from the net balance of both pro-and anti-inflammatory mediators.
             •    Genetic variation involving cytokines may affect the risk of ALI/ARDS after injury.

Coagulation and Platelets
                                                                                                                          5
    •    Intra-alveolar hyaline membranes and microvascular thrombi are histologic hallmarks of acute ALI/ARDS [Figure 1] .
    •    Anticoagulant therapies for ALI/ARDS have had mixed results, but there has been recent success with activated protein C in treatment of
                                                                         6
         sepsis, which may also may have a treatment role in ALI/ARDS .
    •    Variations in clinical outcomes in patients with sepsis and ALI/ARDS have been related to genetic polymorphisms of coagulation proteins.

Surfactant
                                                                                                       7
     •   Surfactant is altered early in ALI/ARDS, both in composition and in surface tension properties .
     •   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 and may have increased mortality in those with indirect lung
                8
         injury.

Ventilator-Induced Lung Injury
    •    Mechanical ventilation may increase lung injury through over distension of the patent alveoli, shear injury in areas of cyclic atelectasis,
         stretching and activation of lung macrophages and type II penumoctyes with release of cytokines.
      •    Cytokine release is attenuated by use of lower tidal volumes (<6 mL/kg).
                                                                                                           9
      •    Lower tidal volumes (6 mL/kg) have been shown to reduce ALI/ARDS mortality from 40% to 31%.

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 ALI/ARDS, is predictive of mortality.
     •   The “fibroproliferative phase” of ALI/ARDS develops about 5-7 days into the course, with the formation of granulation tissue and
         physiologic compromise. Blockage of the migration of fibroblasts into the alveolus may represent a future therapeutic approach.
     •   Higher levels of lung vascular endothelial growth factor (VEGF), are associated with recovery from ALI/ARDS (50) and polymorphisms of
                                                                                                       10
         VEGF resulting decreased VEGF production are associated with elevated risk from ALI/ARDS.
References


1. Bernard GR, Artigas A, Brigham KL, et al. TheAmerican-European Consensus Conference on
ARDS. Definitions, mechanisms, relevant outcomes,and clinical trial coordination.AmJ Respir Crit Care
Med 1994;149(3 Pt 1):818–24.

2. Callister ME, Evans TW. Pulmonary versus extrapulmonary acute respiratory distress syndrome: different diseases or just a useful concept? Curr
Opin Crit Care 2002;8(1):21–5.

3. Zilberberg MD, Epstein SK. Acute lung injury in the medical ICU: comorbid conditions, age, etiology, and hospital outcome. Am J Respir Crit Care
Med 1998;157(4 Pt 1):1159–64.

4. Moss M, ManninoDM. Race and gender differences in acute respiratory distress syndrome deaths in the United States: an analysis of multiple-
cause mortality data (1979-1996). Crit Care Med 2002;30(8): 1679–85.

5. Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults. Lancet 1967;2(7511): 319–23.

6. Nick JA, Coldren CD, Geraci MW, et al. Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via
inhibition of neutrophil chemotaxis. Blood 2004; 104(13):3878–85.

7. Gregory TJ, Longmore WJ, Moxley MA, et al. Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome. J
Clin Invest 1991;88(6):1976–81.

8. Spragg RG, Lewis JF, Walmrath HD, et al. Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome.
N Engl J Med 2004;351(9):884–92.

9. ARDS Clinical Trials Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute
respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342(18):1301–8.

10. Medford AR, Thickett DR, Keen L, et al. Frequency of vascular endothelial growthfactor (VEGF) 936C/T polymorphism in patients with or at risk
of adult respiratory distress syndrome (ARDS). Am J Respir Crit Care Med 2002;165(8):A474.

				
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