Reperfusion injury pathophysiology: Difference between revisions

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* '''Cardiovascular system'''
* '''Cardiovascular system'''
** In the [[cardiovascular system]], the most common complications studied are [[arrhythmias]], and [[myocardial stunning]] and myocardial cells death also. According to various studies done so far, Impaired [[microvascular function]] is the main reason behind the [[Stunned myocardium|myocardial stunning]].
** In the [[cardiovascular system]], the most common complications studied are [[arrhythmias]], and [[myocardial stunning]] and myocardial cells death also. According to various studies done so far, Impaired [[microvascular function]] is the main reason behind the [[Stunned myocardium|myocardial stunning]].


==References==
==References==

Latest revision as of 21:56, 21 August 2020

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4] Associate Editor(s)-in-Chief: Anjan K. Chakrabarti, M.D. [5] Shivam Singla, M.D.[6] Kashish Goel,M.D.,

Overview

The component playing a major role in the pathophysiology of Ischemia-reperfusion injury is Reactive oxygen species (ROS) causing damage to cellular and biological membranes. Neutrophils also play an important role in initiating and propagating much of the damage involved in the process of Ischemia-reperfusion injury. Ischemia is the phase that precedes the restoration of blood flow to that organ or tissue, resulting in the built-up of xanthine oxidase and hypoxanthine that upon the restoration of blood flow leads to the formation of ROS. Neutrophils also potentiate the effect of Ischemia-reperfusion injury through microvascular injury by releasing various proteolytic enzymes and ROS. Most of the experimental studies carried out in helping understand the mechanism of Ischemia reperfusion injury are mainly on the cat, dog, and horses.

Pathophysiology

Mainly divided into 2 phases

1) Ischemic phase

2) Reperfusion Phase

Ischemic Phase

Reperfusion Injury (Ischemic Phase). Various steps and intermediates involved in the process of reperfusion injury. [1]

Reperfusion injury ( Ischemic Phase) During this phase mainly the dysregulation of metabolic pathways occurs and in the reperfusion phase there will be a 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[5]. Reperfusion Injury

Reperfusion injury ( Reperfusion phase). Various steps and intermediates formed and involved in the pathogenesis of the Reperfusion phase of Ischemia-reperfusion injury. [2]

During the Ischemia-reperfusion injury ROS also activate endothelial cells, which further produces numerous adhesion molecules.[6]

  • 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 the 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[11]

In the first 15 minutes of ischemia NO level rises due to transient ENOS activation. As said this elevation is transient so ultimately after a few minutes there will be a general decline in endothelial function resulting in the fall of NO production. The reduction in ENOS levels during ischemia reperfusion injury are also predisposed to vasoconstriction, the response mainly seen in IRI[12].

Neutrophils, attachment, rolling and extravasation. Explained the role of neutrophils and the various steps involved in their extravasation so as to contribute to Ischemia-reperfusion injury. [3]

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[13].

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[18]. Activated neutrophils secrete proteases, metalloproteinase, that results in the degradation of basement membrane and contributes to tissue damage. Selectins[19] are expressed on the surface of leucocytes, endothelial cells and platelets. Selectins[20] 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[21]. The C5b-9[22] also gets deposited into the endothelial cell after ischemia leading to osmotic lysis.

Main organs affected in reperfusion injury

  • Central Nervous System
    • Reperfusion injury is a major pathophysiological mechanism involved in ischemia related injury to the central nervous system consequently resulting in the patients landing up with complications of a stroke, TIA, and other neurological problems. A lot of studies regarding this are still under the pipeline.


References

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  2. Paoni NF, Peale F, Wang F, Errett-Baroncini C, Steinmetz H, Toy K, Bai W, Williams PM, Bunting S, Gerritsen ME, Powell-Braxton L (December 2002). "Time course of skeletal muscle repair and gene expression following acute hind limb ischemia in mice". Physiol. Genomics. 11 (3): 263–72. doi:10.1152/physiolgenomics.00110.2002. PMID 12399448.
  3. Safronova O, Morita I (May 2010). "Transcriptome remodeling in hypoxic inflammation". J. Dent. Res. 89 (5): 430–44. doi:10.1177/0022034510366813. PMID 20348484.
  4. Hierholzer C, Harbrecht BG, Billiar TR, Tweardy DJ (2001). "Hypoxia-inducible factor-1 activation and cyclo-oxygenase-2 induction are early reperfusion-independent inflammatory events in hemorrhagic shock". Arch Orthop Trauma Surg. 121 (4): 219–22. doi:10.1007/s004020000211. PMID 11317684.
  5. Yokoyama K, Kimura M, Nakamura K, Nakamura K, Itoman M (April 1999). "Time course of post-ischemic superoxide generation in venous effluent from reperfused rabbit hindlimbs". J Reconstr Microsurg. 15 (3): 215–21. doi:10.1055/s-2007-1000094. PMID 10226957.
  6. Pacher P, Nivorozhkin A, Szabó C (March 2006). "Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol". Pharmacol. Rev. 58 (1): 87–114. doi:10.1124/pr.58.1.6. PMC 2233605. PMID 16507884.
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  9. Rowlands TE, Gough MJ, Homer-Vanniasinkam S (November 1999). "Do prostaglandins have a salutary role in skeletal muscle ischaemia-reperfusion injury?". Eur J Vasc Endovasc Surg. 18 (5): 439–44. doi:10.1053/ejvs.1999.0929. PMID 10610833.
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  14. Lutz J, Thürmel K, Heemann U (May 2010). "Anti-inflammatory treatment strategies for ischemia/reperfusion injury in transplantation". J Inflamm (Lond). 7: 27. doi:10.1186/1476-9255-7-27. PMC 2894818. PMID 20509932.
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