Reperfusion injury pathophysiology: Difference between revisions

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'''Editors-In-Chief:''' {{AC}}; [[C. Michael Gibson]], M.S., M.D. [mailto:Mgibson@perfuse.org]; [[User:Shivam Singla|Dr. Shivam Singla M.D [1]]],  [[User:Kashish Goel|Kashish Goel,M.D.,]]  
'''Editors-In-Chief:''' [[C. Michael Gibson]], M.S., M.D. [mailto:Mgibson@perfuse.org] {{AE}} {{AC}} {{Shivam Singla}} [[User:Kashish Goel|Kashish Goel,M.D.,]]  
 
==Pathophysiology ==
==Pathophysiology ==



Revision as of 17:18, 17 August 2020


Editors-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Anjan K. Chakrabarti, M.D. [2] Shivam Singla, M.D.[3] Kashish Goel,M.D.,

Pathophysiology

Mainly divided into 2 phases

1) Ischemic phase

2) Reperfusion Phase

Ischemic Phase

Reperfusion Injury (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[5] (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.[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 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.[11] 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.[12] 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.[14] 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.[15]

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

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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.
  7. Neumann UP, Kaisers U, Langrehr JM, Glanemann M, Müller AR, Lang M, Jörres A, Settmacher U, Bechstein WO, Neuhaus P (February 2000). "Administration of prostacyclin after liver transplantation: a placebo controlled randomized trial". Clin Transplant. 14 (1): 70–4. doi:10.1034/j.1399-0012.2000.140113.x. PMID 10693639.
  8. 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.
  9. Słupski M, Szadujkis-Szadurska K, Szadujkis-Szadurski R, Szadujkis-Szadurski L, Włodarczyk Z, Andruszkiewicz J, Sinjab AT (2006). "Nitric oxide and thromboxane A2 modulate pulmonary pressure after ischemia and intestinal reperfusion". Transplant. Proc. 38 (1): 334–7. doi:10.1016/j.transproceed.2005.12.085. PMID 16504740.
  10. Mangino MJ, Murphy MK, Anderson CB (April 1994). "Effects of the arachidonate 5-lipoxygenase synthesis inhibitor A-64077 in intestinal ischemia-reperfusion injury". J. Pharmacol. Exp. Ther. 269 (1): 75–81. PMID 8169854.
  11. Khanna A, Cowled PA, Fitridge RA (September 2005). "Nitric oxide and skeletal muscle reperfusion injury: current controversies (research review)". J. Surg. Res. 128 (1): 98–107. doi:10.1016/j.jss.2005.04.020. PMID 15961106.
  12. Kiriş I, Narin C, Gülmen S, Yilmaz N, Sütçü R, Kapucuoğlu N (2009). "Endothelin receptor antagonism by tezosentan attenuates lung injury induced by aortic ischemia-reperfusion". Ann Vasc Surg. 23 (3): 382–91. doi:10.1016/j.avsg.2008.10.003. PMID 19135850.
  13. 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.
  14. Roach DM, Fitridge RA, Laws PE, Millard SH, Varelias A, Cowled PA (March 2002). "Up-regulation of MMP-2 and MMP-9 leads to degradation of type IV collagen during skeletal muscle reperfusion injury; protection by the MMP inhibitor, doxycycline". Eur J Vasc Endovasc Surg. 23 (3): 260–9. doi:10.1053/ejvs.2002.1598. PMID 11914015.
  15. Kyriakides C, Austen W, Wang Y, Favuzza J, Kobzik L, Moore FD, Hechtman HB (December 1999). "Skeletal muscle reperfusion injury is mediated by neutrophils and the complement membrane attack complex". Am. J. Physiol. 277 (6): C1263–8. doi:10.1152/ajpcell.1999.277.6.C1263. PMID 10600778.