Lung Reperfusion Injury After Transplantation

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Lung Reperfusion Injury After Transplantation

• Intern ???

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References

• Ischemia-Reperfusion-induced Lung Injury
  
  
  
  Am J Respir Crit Care Med,2003
• Reduced Neutrophil Infiltration Protects Against
  Lung Reperfusion Injury After Transplantation
  Ann Thorac Surg 1999

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Contents

• Introduction
• Donor lung assessment
• Effect of cold ischemic storage
• Oxidative stress
• Sodium pump inactivation
• Intracellular calcium overload
• Iron release
• Cell death
• Consequences of ischemia reperfusion
• Upregulation of molecules on cell surface
  membrane
• Release of proinflammatory mediators
• Leukocyte activation
• Strategies to prevent lung dysfunction
• Method of lung preservation and reperfusion
• Clinical evidence in prevention and treatment of
  lung reperfusion injury
• Future Strategies
• Take home message

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Introduction

• Non-specific alveolar damage, lung edema, and
  hypoxemia occurring within 72 hours after lung
  transplantation
• Remains a significant cause of morbidity and
  mortality after lung transplantation

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Donor Lung Assessment

• Parameters donor hx, ABG, CXR, bronchoscopy
  findings, PE of the lung
• Strict contraindicationsbil. infiltrates on CXR,
  persistent pus at bronchoscopy, signs of
  bronchaspiration
• Brain stem death upregulated IL-8 significantly
  correlate w/ primary graft failure after
  reperfusion

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Donor Lung Assessment
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Donor Lung Assessment
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Effect of Cold Ischemic Storage

• Oxidative stress
• Sodium pump inactivation
• Intracellular calcium overload
• Iron release
• Cell death

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Oxidative Stress

• Formation of ROS superoxide anion?hydrogen
  peroxide?hydroxyl radical
• Cell injury produced by lipid peroxidation
• Ischemia-reperfusion?anoxia-reoxygenation in most
  organ transplantation
• Lung to be considered differently
• Endothelium one of the predominant sources of
  oxidants during nonhypoxic lung ischemia

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Oxidative Stress
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Sodium Pump Inactivation

• Sodium (Na/K-ATPase) pump important to preserve
  proper intracellular electrolyte conc. and to
  maintain adequate clearance of alveolar fluid
• Hypothermic storage results in loss of function,
  then cell swelling
• Preservation at 10? superior than at 4?
• Resume better if preserved w/ extracellular-type
  preservation solution (low K, high Na)

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Intracellular Calcium Overload

• Hypothermic storage alters calcium metabolism by
  release of calcium from intracellular depots and
  by pathologic influx through the plasma membrane
• Elevated cytosolic Ca enhance the conversion of
  xanthine dehydrogenase to xanthine oxidase,
  potentiate the damaging effect of free radicals
  on mitochondria
• Protective effect of verapamil, nifedipine and
  diltiazem

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Iron Release

• Essential element, highly toxic under
  pathophysiologic or stress conditions
• Fenton reaction reactive hydroxyl radical
• Increased injury observed in iron-supplemented
  tissue
• Protection by iron chelator, deferoxamine

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Iron Release
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Consequences of Ischemia Reperfusion

• Upregulation of molecules on cell surface
  membrane
• Release of proinflammatory mediators
• Leukocyte activation

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Upregulation of Molecules on Cell Surface
Membrane

• Adhesion molecules
• Selectins?Ig superfamily?integrins
• Upregulated during ischemia, blockade of adhesion
  molecules while reperfusion can reduce
  reperfusion injury
• Prothrombotic antifibinolytic factors
• Hypoxia develop procoagulant properties,
  contribute to microvascular thrombosis?impede
  return of blood flow after reperfusion

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Release of Proinflammatory Mediators

• Cytokines
• IL-8 rapidly increased after reperfusion
  negatively correlated w/ lung function
• IL-10 age of donor inversely correlated w/
  anti-inflammatory cytokine lungs from older
  donor might be more susceptible to
  ischemia-reperfusion injury
• Lipids
• Phospholipase A2, induces the production of
  platelet-activating factor, an potent mediator of
  inflammation, which activates leukocytes,
  stimulates platelet aggregation, induces the
  release of cytokines and expression of cell
  adhesion molecules

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Release of Proinflammatory Mediators

• Complement
• Activation may lead to cellular injury
• Smooth m. contraction, increased vascular
  permeability, degranulation of phagocytic cells,
  mast cells, and basophils
• Complement receptor-1 natural complement
  antagonist inhibiting C3 C5 convertases,
  preventing the activation of both classic
  alternative pathways
• Endothelin
• Powerful vasoconstrictor 3 isoforms
• Endothelin-1 ?the production of cytokines,
  retention of neutrophils in the lung
• Endothelin-1 receptor antagonist lung function
  improved

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Leukocyte Activation

• Biphasic pattern
• Early phase depends primarily on donor
  characteristics
• Delayed phase occurs over the ensuing 24 hrs,
  depends primarily on recipient factors

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Strategies to Prevent Lung Dysfunction

• Method of lung preservation and reperfusion
• Clinical evidence in prevention and treatment of
  lung reperfusion injury
• Future Strategies

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Method of Lung Preservation and Reperfusion

• Lung preservation solution
• Intracellular- type Euro-Collins?University of
  Winsconsin
• Extracellular- type LPD?Celsior
• LPD the only specifically developed for lung
  preservation
• LPD-glucose the preservation solution of choice
  for lung transplantation currently

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Composition of Preservation Solutions
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Method of Lung Preservation and Reperfusion

• Volume, pressure, and temperature of flush
  solutions
• High perfusate vol. given at high flow rate (60
  ml/kg given in 4 min) better cooling of lungs
  better lung function after reperfusion
• Flushing pressure of 10 to 15 mmHg associated w/
  complete flushing of the pulmonary vascular beds,
  and better lung function after reperfusion
• Hypothermic recommended

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Method of Lung Preservation and Reperfusion

• Inflation, oxygenation, and storage temperature
• Preservation improved when inflated w/ O2
• Expansion w/ O2 during ischemic period
• Maintain some aerobic metabolism
• Preserves integrity of surfactant
• Preserves epithelial fluid transport
• Inflation during storage should be limited to 50
  of total lung capacity to avoid barotrauma

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Clinical Evidence in Prevention and Treatment of
Lung Reperfusion Injury

• Nitric Oxide
• Decreased after ischemia and reperfusion
• Inhaled NO clinically useful to treat
  ischemia-reperfusion injury
• The role in preventing ischemia-reperfusion
  injury remains controversial
• Prostaglandins
• PGE1 vasodilator properties, better distribution
  of preservation solution

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Clinical Evidence in Prevention and Treatment of
Lung Reperfusion Injury

• Complement inhibition
• Soluble complement receptor-1 14/29 v.s 6/30
• Antagonist of platelet-activating factor
• Better alveolar-arterial O2 gradient and CXR
• Encourage larger multi-center trials

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Clinical Evidence in Prevention and Treatment of
Lung Reperfusion Injury

• Surfactant therapy
• Surfactant dysfunction occurs during
  ischemia-reperfusion injury
• Exogenous surfactant therapy improve lung
  function, enhance immediate recovery

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Future Strategies

• Heme oxygenase pathway
• Preconditioning
• Gene therapy

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Heme Oxygenase Pathway

• Heme oxygenase catalyze the conversion of heme
  into biliverdin, CO, and free iron
• Heme oxygenase-1 provide potent cytoprotective
  effects
• Heme oxygenase-1 deficient mice and humans
  exhibit increased susceptibility to oxidative
  stress
• Future studies required

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Preconditioning

• Tissues exposed to one insult can develop
  tolerance to a subsequent injury
• Biological adaptation
• Short periods of ischemia (ischemic
  preconditioning)?increased temperature
  (hyperthermic preconditioning)?administration of
  pharmacologic agents (chemical preconditioning)
• Mechanism not well understood
• Ischemic preconditioning effective clinically in
  hepatic resection?CABG remains unproven in
  clinical lung transplantation

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Gene Therapy

• Transfection of the donor lung through
  transtracheal route using a 2nd-generation
  adenoviral vector
• Transfection of the gene coding for
  anti-inflammatory cytokine, human IL-10, reduced
  ischemia-reperfusion injury, improves lung
  function in a rat single lung transplant model
• Human lung protection by gene therapy may soon be
  possible

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Take Home Message

• Donor lung assessment
• Effect of cold ischemic storage
• Oxidative stress
• Sodium pump inactivation
• Intracellular calcium overload
• Iron release
• Cell death
• Consequences of ischemia reperfusion
• Up-regulation of molecules on cell surface
  membrane
• Release of pro-inflammatory mediators
• Leukocyte activation
• Strategies to prevent lung dysfunction
• Method of lung preservation and reperfusion
• Clinical evidence in prevention and treatment of
  lung reperfusion injury
• Future Strategies
• One of the major challenges will be to improve
  the number of donor lungs available for
  transplantation

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