Reperfusion injury pathophysiology

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Editors-In-Chief: Anjan K. Chakrabarti, M.D. [1]; C. Michael Gibson, M.S., M.D. [2]; Dr. Shivam Singla M.D [1], Kashish Goel,M.D.,

Pathophysiology

Mainly divided into 2 phases

1) Ischemic phase

2) Reperfusion Phase


Reperfusion Injury (Ischemic phase)

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Ischemic Phase ===

Reperfusion injury ( Ischemic Phase) During this phase mainly the dysregulation of metabolic pathways occurs and in the reperfusion phase there will be generation of free radicals.


Reperfusion Phase

Reactive oxygen species

The ROS play major role in the tissue damage related to ischemia reperfusion injury. Once the ischemic tissue is reperfused the molecular oxygen catalyzes the conversion of hypoxanthine to uric acid and liberating the superoxide anion (O2-). This superoxide gets further converted to (H2O2) and the hydroxyl radical (OH). This OH ion causes the peroxidation lipids in the cell membranes resulting in the production and release of proinflammatory eicosanoids and ultimately cell death. Reperfusion Injury

Reperfusion injury ( Reperfusion phase)

During the Ischemia reperfusion injury ROS also activate endothelial cells, which further produces numerous adhesion molecules.

  • E-selectin
  • VCAM-1 (vascular cell adhesion molecule-1)
  • ICAM-1 (intercellular adhesion molecule-1)
  • EMLMl Am -1 ( endothelial-leukocyte adhesion molecule)
  • PAi-1 (plasminogen activator inhibitor-1 ), and
  • Interleukin-8 (il-8)

Eicosanoids

ROS causes lipid peroxidation of cell membranes resulting in release of

Nitric oxide

L-arginine is the substrate for the synthesis of Nitric oxide with the help of nitric oxide synthase enzyme. The nitric oxide synthase enzyme is usually of 3 types

In the first 15 minutes of ischemia NO level rises due to transient ENOS activation. As said this elevation is transient so ultimately after few minutes there will be general decline in endothelial function resulting in fall of NO production. The reduction in ENOS levels during ischemia reperfusion injury are also predispose to vasoconstriction , the response mainly seen in IRI.

Neutrophils, attachment, rolling and extravasation

Endothelin

These are peptide vasoconstrictors mainly produced from the endothelium. They mainly mediate vasoconstriction through Ca2+-mediated vasoconstriction. Endothelin -1 levels increase during ischemia reperfusion injury in both the phases of ischemia as well as reperfusion, that mainly help in capillary vasoconstriction. Endothelin - 1 inhibitors are studied widespread regarding their role in inhibiting vasoconstriction and increasing vascular permeability.

Cytokines

Ischemia and reperfusion phase of ischemia reperfusion injury induces expression of numerous cytokines mainly:

These cytokines mainly generate systemic inflammatory response ultimately leads to multi organ failure.

Neutrophils and endothelial interactions

Neutrophils plays Important role in the tissue damage. Activated neutrophils secrete proteases, metalloproteinase, that results in the degradation of basement membrane and contributes to tissue damage. Selectins are expressed on the surface of leucocytes, endothelial cells and platelets. Selectins play important role in the initiation of neutrophil–endothelial cell interactions (rolling) which is essential for their subsequent adhesion and extravasation. L-selectin are present on surface of neutrophils and help in the reversible attachment of neutrophils to endothelial cells. Antibody-mediated blocking of L-selectin studied widely and is one of the important treatment option under consideration.

Complement activation

Contributes in the pathogenesis of IRI. Reperfusion is usually associated with depletion of complement proteins, factor B that will indicates the turning on of alternate complement pathway. The C5b-9 also gets deposited into the endothelial cell after ischemia leading to osmotic lysis.

Specific organs affected by reperfusion injury

CNS

Reperfusion injury plays a part in the brain's ischemic cascade, which is involved in stroke and brain trauma. Repeated bouts of ischemia and reperfusion injury also are thought to be a factor leading to the formation and failure to heal of chronic wounds such as pressure sores and diabetic foot ulcers. Continuous pressure limits blood supply and causes ischemia, and the inflammation occurs during reperfusion. As this process is repeated, it eventually damages tissue enough to cause a wound

CVS ( Myocardium)

Restoration of epicardial patency can be associated with reperfusion injury in the myocardium. This can manifest clinically as arrhythmia, microvascular dysfunction, myocardial stunning, and myocyte death.

Microvascular dysfunction, or "no reflow," as well as myocardial stunning, are the possible consequences of reperfusion injury. Myocardial stunning, may to some extent be mediated by impaired microvascular function.

References