Reperfusion injury pathophysiology: Difference between revisions

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* [[Ischemia]] when the [[blood]] supply to the [[Tissue (biology)|tissues]] decreases with respect to the demand required to function properly. This results in [[deficiency]] in [[oxygen]], [[glucose]] and various other substrates required for [[cellular metabolism]]. As previously dais the derangement or dysregulation of metabolic function begins in this phase. Due to less [[oxygen]] supply [[cellular metabolism]] shifts to [[anaerobic]] [[glycolysis]] causing the [[glycogen]] to breakdown resulting in the production of 2 ATP and a [[lactic acid]]. This decrease in tissue PH starts further inhibits the [[Adenosine triphosphate|ATP generation]] by negative feed back mechanism. [[Adenosine triphosphate|ATP]] gets broken down into [[Adenosine diphosphate|ADP]], [[Adenosine monophosphate|AMP]] and [[Inosine monophosphate|IMP]]. This finally gets converted to [[adenosine]], [[inosine]], [[hypoxanthine]] and [[xanthine]].
* [[Ischemia]] when the [[blood]] supply to the [[Tissue (biology)|tissues]] decreases with respect to the demand required to function properly. This results in [[deficiency]] in [[oxygen]], [[glucose]] and various other substrates required for [[cellular metabolism]]. As previously dais the derangement or dysregulation of metabolic function begins in this phase. Due to less [[oxygen]] supply [[cellular metabolism]] shifts to [[anaerobic]] [[glycolysis]] causing the [[glycogen]] to breakdown resulting in the production of 2 ATP and a [[lactic acid]]. This decrease in tissue PH starts further inhibits the [[Adenosine triphosphate|ATP generation]] by negative feed back mechanism. [[Adenosine triphosphate|ATP]] gets broken down into [[Adenosine diphosphate|ADP]], [[Adenosine monophosphate|AMP]] and [[Inosine monophosphate|IMP]]. This finally gets converted to [[adenosine]], [[inosine]], [[hypoxanthine]] and [[xanthine]].


* Lack of [[Adenosine triphosphate|ATP]] at the cellular level causes impairment in the function of ionic pumps - [[Na+/K+-ATPase|Na+/K+]] and Ca<sup>2</sup>+ pumps. As a result [[cytosolic]] sodium rises which in turn withdraws water to maintain the [[Osmosis|osmotic]] [[equilibrium]] consequently resulting in the [[cellular]] [[Swelling (medical)|swelling]]<ref name="pmid10972541">{{cite journal |vauthors=Allen DG, Xiao XH |title=Activity of the Na+/H+ exchanger contributes to cardiac damage following ischaemia and reperfusion |journal=Clin. Exp. Pharmacol. Physiol. |volume=27 |issue=9 |pages=727–33 |date=September 2000 |pmid=10972541 |doi=10.1046/j.1440-1681.2000.03329.x |url=}}</ref>. To maintain ionic balance [[Potassium ion channels|potassium ion]] escape from the cell. [[Calcium]] is released from the [[Mitochondrion|mitochondria]] to the [[cytoplasm]] and into extracellular spaces resulting in the activation of Mitochondrial calcium- dependent [[Proteases|cytosolic proteases]]. These converts the enzyme [[xanthine dehydrogenase]] to [[xanthine oxidase]]. Phospholipases activated during [[ischemia]] promotes membrane degradation and increases level of [[Fatty acid|free fatty acids]]
* Lack of [[Adenosine triphosphate|ATP]] at the cellular level causes impairment in the function of ionic pumps - [[Na+/K+-ATPase|Na+/K+]] and Ca<sup>2</sup>+ pumps. As a result [[cytosolic]] sodium rises which in turn withdraws water to maintain the [[Osmosis|osmotic]] [[equilibrium]] consequently resulting in the [[cellular]] [[Swelling (medical)|swelling]]. To maintain ionic balance [[Potassium ion channels|potassium ion]] escape from the cell. [[Calcium]] is released from the [[Mitochondrion|mitochondria]] to the [[cytoplasm]] and into extracellular spaces resulting in the activation of Mitochondrial calcium- dependent [[Proteases|cytosolic proteases]]. These converts the enzyme [[xanthine dehydrogenase]] to [[xanthine oxidase]]. Phospholipases activated during [[ischemia]] promotes membrane degradation and increases level of [[Fatty acid|free fatty acids]]


* [[Ischemia]] also induces expression of a large number of [[genes]] and [[Transcription factor|transcription factors]], which play a major role in the damage to the tissues.<ref name="pmid12399448">{{cite journal |vauthors=Paoni NF, Peale F, Wang F, Errett-Baroncini C, Steinmetz H, Toy K, Bai W, Williams PM, Bunting S, Gerritsen ME, Powell-Braxton L |title=Time course of skeletal muscle repair and gene expression following acute hind limb ischemia in mice |journal=Physiol. Genomics |volume=11 |issue=3 |pages=263–72 |date=December 2002 |pmid=12399448 |doi=10.1152/physiolgenomics.00110.2002 |url=}}</ref><ref name="pmid20348484">{{cite journal |vauthors=Safronova O, Morita I |title=Transcriptome remodeling in hypoxic inflammation |journal=J. Dent. Res. |volume=89 |issue=5 |pages=430–44 |date=May 2010 |pmid=20348484 |doi=10.1177/0022034510366813 |url=}}</ref>
* [[Ischemia]] also induces expression of a large number of [[genes]] and [[Transcription factor|transcription factors]], which play a major role in the damage to the tissues.
** Transcription factors
** Transcription factors
*** Activating protein-1 ([[AP-1 (transcription factor)|AP-1]])
*** Activating protein-1 ([[AP-1 (transcription factor)|AP-1]])
*** Hypoxia-inducible factor-1 (HIF-1) which in turn activates transcription of VEGF, [[Erythropoietin]] and [[Glucose transporter|Glucose transporter-1]]
*** Hypoxia-inducible factor-1 (HIF-1) which in turn activates transcription of VEGF, [[Erythropoietin]] and [[Glucose transporter|Glucose transporter-1]]
*** Nuclear factor-kappa b ([[NF-kB|NF-kb]])<ref name="pmid11317684">{{cite journal |vauthors=Hierholzer C, Harbrecht BG, Billiar TR, Tweardy DJ |title=Hypoxia-inducible factor-1 activation and cyclo-oxygenase-2 induction are early reperfusion-independent inflammatory events in hemorrhagic shock |journal=Arch Orthop Trauma Surg |volume=121 |issue=4 |pages=219–22 |date=2001 |pmid=11317684 |doi=10.1007/s004020000211 |url=}}</ref>
*** Nuclear factor-kappa b ([[NF-kB|NF-kb]])
*** Activation of NF-kb occurs during both the [[Ischemia|ischemic]] and [[reperfusion]] phases
*** Activation of NF-kb occurs during both the [[Ischemia|ischemic]] and [[reperfusion]] phases


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==== Reactive oxygen species ====
==== 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|superoxide anion]]<ref name="pmid10226957">{{cite journal |vauthors=Yokoyama K, Kimura M, Nakamura K, Nakamura K, Itoman M |title=Time course of post-ischemic superoxide generation in venous effluent from reperfused rabbit hindlimbs |journal=J Reconstr Microsurg |volume=15 |issue=3 |pages=215–21 |date=April 1999 |pmid=10226957 |doi=10.1055/s-2007-1000094 |url=}}</ref> (O<sub>2</sub><sup>-</sup>). This superoxide gets further converted to (H<sub>2</sub>O<sub>2</sub>) and the [[hydroxyl radical]] ([[Hydroxyl radical|OH<sup>•</sup>)]]. This OH ion causes the  peroxidation [[Lipid|lipids]] in the [[Cell membrane|cell membranes]] resulting in the production and release of proinflammatory [[Eicosanoid|eicosanoids]] and ultimately [[cell death]].
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|superoxide anion]] (O<sub>2</sub><sup>-</sup>). This superoxide gets further converted to (H<sub>2</sub>O<sub>2</sub>) and the [[hydroxyl radical]] ([[Hydroxyl radical|OH<sup>•</sup>)]]. This OH ion causes the  peroxidation [[Lipid|lipids]] in the [[Cell membrane|cell membranes]] resulting in the production and release of proinflammatory [[Eicosanoid|eicosanoids]] and ultimately [[cell death]].
Reperfusion Injury
Reperfusion Injury
[[File:Reperfusion Injury Mech.jpg|thumb|Reperfusion injury ( Reperfusion phase)]]
[[File:Reperfusion Injury Mech.jpg|thumb|Reperfusion injury ( Reperfusion phase)]]
During the Ischemia reperfusion injury ROS also activate [[Endothelium|endothelial cells]], which further produces numerous [[Cell adhesion molecule|adhesion molecules.]]<ref name="pmid16507884">{{cite journal |vauthors=Pacher P, Nivorozhkin A, Szabó C |title=Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol |journal=Pharmacol. Rev. |volume=58 |issue=1 |pages=87–114 |date=March 2006 |pmid=16507884 |pmc=2233605 |doi=10.1124/pr.58.1.6 |url=}}</ref>
During the Ischemia reperfusion injury ROS also activate [[Endothelium|endothelial cells]], which further produces numerous [[Cell adhesion molecule|adhesion molecules.]]  


* [[E-selectin]]
* [[E-selectin]]
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* ''[[Arachidonic acid]] (substrate for [[Prostaglandin|prostaglandins]])''
* ''[[Arachidonic acid]] (substrate for [[Prostaglandin|prostaglandins]])''
** Prostaglandins usually have a [[Vasodilatory|vasodilatory effect]] hat provides protective effect during [[Ischemia]] [[reperfusion injury]]. But they have short life so their fast depletion leads to [[vasoconstriction]] ultimately leading to reduced blood flow and exacerbation of [[ischemia]]<ref name="pmid10693639">{{cite journal |vauthors=Neumann UP, Kaisers U, Langrehr JM, Glanemann M, Müller AR, Lang M, Jörres A, Settmacher U, Bechstein WO, Neuhaus P |title=Administration of prostacyclin after liver transplantation: a placebo controlled randomized trial |journal=Clin Transplant |volume=14 |issue=1 |pages=70–4 |date=February 2000 |pmid=10693639 |doi=10.1034/j.1399-0012.2000.140113.x |url=}}</ref>.<ref name="pmid10610833">{{cite journal |vauthors=Rowlands TE, Gough MJ, Homer-Vanniasinkam S |title=Do prostaglandins have a salutary role in skeletal muscle ischaemia-reperfusion injury? |journal=Eur J Vasc Endovasc Surg |volume=18 |issue=5 |pages=439–44 |date=November 1999 |pmid=10610833 |doi=10.1053/ejvs.1999.0929 |url=}}</ref>
** Prostaglandins usually have a [[Vasodilatory|vasodilatory effect]] hat provides protective effect during [[Ischemia]] [[reperfusion injury]]. But they have short life so their fast depletion leads to [[vasoconstriction]] ultimately leading to reduced blood flow and exacerbation of [[ischemia]].
* ''[[Thromboxane]]''
* ''[[Thromboxane]]''
**[[Thromboxane A2|Plasma thromboxane A<sub>2</sub>]]  level rises within minutes after [[reperfusion]], resulting in [[vasoconstriction]] and [[platelet aggregation]]. This usually coincide with rapid rise in [[Pulmonary artery hypertension|pulmonary artery pressure]] and a subsequent increase in [[Lung|pulmonary]] [[Microvascular bed|microvascular]] permeability.<ref name="pmid16504740">{{cite journal |vauthors=Słupski M, Szadujkis-Szadurska K, Szadujkis-Szadurski R, Szadujkis-Szadurski L, Włodarczyk Z, Andruszkiewicz J, Sinjab AT |title=Nitric oxide and thromboxane A2 modulate pulmonary pressure after ischemia and intestinal reperfusion |journal=Transplant. Proc. |volume=38 |issue=1 |pages=334–7 |date=2006 |pmid=16504740 |doi=10.1016/j.transproceed.2005.12.085 |url=}}</ref>
**[[Thromboxane A2|Plasma thromboxane A<sub>2</sub>]]  level rises within minutes after [[reperfusion]], resulting in [[vasoconstriction]] and [[platelet aggregation]]. This usually coincide with rapid rise in [[Pulmonary artery hypertension|pulmonary artery pressure]] and a subsequent increase in [[Lung|pulmonary]] [[Microvascular bed|microvascular]] permeability.


* ''[[Leukotriene|Leukotrienes]]''
* ''[[Leukotriene|Leukotrienes]]''
**[[Leukotriene|Leukotrienes]] are also synthesized from arachidonic acid.<ref name="pmid8169854">{{cite journal |vauthors=Mangino MJ, Murphy MK, Anderson CB |title=Effects of the arachidonate 5-lipoxygenase synthesis inhibitor A-64077 in intestinal ischemia-reperfusion injury |journal=J. Pharmacol. Exp. Ther. |volume=269 |issue=1 |pages=75–81 |date=April 1994 |pmid=8169854 |doi= |url=}}</ref> [[Leukotriene]]<nowiki/>s acts directly in the [[endothelial cells]], [[smooth muscle]] and indirectly on the [[neutrophils]]. The [[Leukotriene|leukotrienes]] C<sub>4</sub>, D<sub>4,</sub> and E<sub>4</sub> alters the endothelial [[cytoskeleton]], resulting in  increased [[vascular]] permeability and [[smooth muscle]] contraction, and finally leading to [[vasoconstriction]].
**[[Leukotriene|Leukotrienes]] are also synthesized from arachidonic acid. [[Leukotriene]]<nowiki/>s acts directly in the [[endothelial cells]], [[smooth muscle]] and indirectly on the [[neutrophils]]. The [[Leukotriene|leukotrienes]] C<sub>4</sub>, D<sub>4,</sub> and E<sub>4</sub> alters the endothelial [[cytoskeleton]], resulting in  increased [[vascular]] permeability and [[smooth muscle]] contraction, and finally leading to [[vasoconstriction]].


==== Nitric oxide ====
==== Nitric oxide ====
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* ENO S- [[Endothelial|Endothelia]]<nowiki/>l nitric oxide synthase enzyme
* ENO S- [[Endothelial|Endothelia]]<nowiki/>l nitric oxide synthase enzyme


In the first 15 minutes of ischemia [[Nitric oxide|NO]] level rises due to transient ENOS activation.<ref name="pmid15961106">{{cite journal |vauthors=Khanna A, Cowled PA, Fitridge RA |title=Nitric oxide and skeletal muscle reperfusion injury: current controversies (research review) |journal=J. Surg. Res. |volume=128 |issue=1 |pages=98–107 |date=September 2005 |pmid=15961106 |doi=10.1016/j.jss.2005.04.020 |url=}}</ref> As said this elevation is transient so ultimately after few minutes there will be general decline in [[Endothelium|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 [[Reperfusion injury|IRI]].
In the first 15 minutes of ischemia [[Nitric oxide|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 [[Endothelium|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 [[Reperfusion injury|IRI]].
[[File:Neutrophils involved in tissue destruction.jpg|thumb|400x400px|Neutrophils, attachment, rolling and extravasation]]
[[File:Neutrophils involved in tissue destruction.jpg|thumb|400x400px|Neutrophils, attachment, rolling and extravasation]]


==== Endothelin ====
==== Endothelin ====
These are peptide [[Vasoconstrictor|vasoconstrictors]] mainly produced from the [[endothelium]]. They mainly mediate [[vasoconstriction]] through Ca<sup>2+</sup>-mediated [[vasoconstriction]].<ref name="pmid19135850">{{cite journal |vauthors=Kiriş I, Narin C, Gülmen S, Yilmaz N, Sütçü R, Kapucuoğlu N |title=Endothelin receptor antagonism by tezosentan attenuates lung injury induced by aortic ischemia-reperfusion |journal=Ann Vasc Surg |volume=23 |issue=3 |pages=382–91 |date=2009 |pmid=19135850 |doi=10.1016/j.avsg.2008.10.003 |url=}}</ref> [[Endothelin-1|Endothelin -1]] levels increase during [[Ischemia-reperfusion injury|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]].
These are peptide [[Vasoconstrictor|vasoconstrictors]] mainly produced from the [[endothelium]]. They mainly mediate [[vasoconstriction]] through Ca<sup>2+</sup>-mediated [[vasoconstriction]]. [[Endothelin-1|Endothelin -1]] levels increase during [[Ischemia-reperfusion injury|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 ====
==== Cytokines ====
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* [[Tumor necrosis factor-alpha|TNF-a]]
* [[Tumor necrosis factor-alpha|TNF-a]]
** Elevated levels detected during [[cerebral]] and [[skeletal]] IRI. it can also induce generation of ROS and enhance the susceptibility of vascular [[endothelium]] to neutrophil mediated injury by increasing the expression of [[ICAM-1]] which helps in binding of [[Neutrophil|neutrophils]] to the [[endothelium]].<ref name="pmid20509932">{{cite journal |vauthors=Lutz J, Thürmel K, Heemann U |title=Anti-inflammatory treatment strategies for ischemia/reperfusion injury in transplantation |journal=J Inflamm (Lond) |volume=7 |issue= |pages=27 |date=May 2010 |pmid=20509932 |pmc=2894818 |doi=10.1186/1476-9255-7-27 |url=}}</ref>
** Elevated levels detected during [[cerebral]] and [[skeletal]] IRI. it can also induce generation of ROS and enhance the susceptibility of vascular [[endothelium]] to neutrophil mediated injury by increasing the expression of [[ICAM-1]] which helps in binding of [[Neutrophil|neutrophils]] to the [[endothelium]].
* [[IL-1|IL-1, IL-6, IL-8]]
* [[IL-1|IL-1, IL-6, IL-8]]
** IL-6 is a proinflammatory [[cytokine]] produces in large amounts in hypo perfused [[Tissue (biology)|tissues]].
** IL-6 is a proinflammatory [[cytokine]] produces in large amounts in hypo perfused [[Tissue (biology)|tissues]].
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==== Neutrophils and endothelial interactions ====
==== Neutrophils and endothelial interactions ====
[[Neutrophil|Neutrophils]] plays Important role in the tissue damage.<ref name="pmid11914015">{{cite journal |vauthors=Roach DM, Fitridge RA, Laws PE, Millard SH, Varelias A, Cowled PA |title=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 |journal=Eur J Vasc Endovasc Surg |volume=23 |issue=3 |pages=260–9 |date=March 2002 |pmid=11914015 |doi=10.1053/ejvs.2002.1598 |url=}}</ref> Activated neutrophils secrete [[Protease|proteases]], [[metalloproteinase]], that results in the degradation of [[basement membrane]] and contributes to tissue damage. [[Selectin|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 [[Neutrophil|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.
[[Neutrophil|Neutrophils]] plays Important role in the tissue damage. Activated neutrophils secrete [[Protease|proteases]], [[metalloproteinase]], that results in the degradation of [[basement membrane]] and contributes to tissue damage. [[Selectin|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 [[Neutrophil|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 ====
==== Complement activation ====
Contributes in the pathogenesis of IRI. [[Reperfusion]] is usually associated with depletion of [[Complement|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|osmotic lysis.]]<ref name="pmid10600778">{{cite journal |vauthors=Kyriakides C, Austen W, Wang Y, Favuzza J, Kobzik L, Moore FD, Hechtman HB |title=Skeletal muscle reperfusion injury is mediated by neutrophils and the complement membrane attack complex |journal=Am. J. Physiol. |volume=277 |issue=6 |pages=C1263–8 |date=December 1999 |pmid=10600778 |doi=10.1152/ajpcell.1999.277.6.C1263 |url=}}</ref>
Contributes in the pathogenesis of IRI. [[Reperfusion]] is usually associated with depletion of [[Complement|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|osmotic lysis.]]
<br />
<br />
===Specific organs affected by reperfusion injury===
===Main Central organs affected in reperfusion injury.===


==== CNS ====
==== Central Nervous System ====
[[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 [[wound healing|heal]] of [[chronic wound]]s such as [[pressure sore]]s and [[diabetic foot]] [[ulcer]]s.  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]]
Reperfusion injury is a major pathophysiological mechanism involved in ischemia related injury to the central nervous system consequently resulting the patients to land up with complications of stoke , TIA and other neurological problems. A lot of studies regarding this are still under pipe line.
 
<br />
==== CVS ( Myocardium) ====
Restoration of [[epicardial]] patency can be associated with r[[Reperfusion injury|eperfusion injury]] in the [[myocardium]].  This can manifest clinically as [[Cardiac arrhythmia|arrhythmia]], microvascular dysfunction, [[Stunned myocardium|myocardial stunning]], and myocyte death.


Microvascular dysfunction, or "no reflow," as well as [[Stunned myocardium|myocardial stunning]], are the possible consequences of [[reperfusion injury]]. [[Stunned myocardium|Myocardial stunning]], may to some extent be mediated by impaired [[Microvascular bed|microvascular function]].
==== Cardiovascular system ====
In cardiovascular system the most common complications studied are arrhythmias, and myocardial stunning and myocardial cell also. According to various studies done so far, Impaired microvascular function is the main reason behind the myocardial stunning


==References==
==References==

Revision as of 23:16, 19 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 (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.

Main Central 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 the patients to land up with complications of stoke , TIA and other neurological problems. A lot of studies regarding this are still under pipe line.

Cardiovascular system

In cardiovascular system the most common complications studied are arrhythmias, and myocardial stunning and myocardial cell also. According to various studies done so far, Impaired microvascular function is the main reason behind the myocardial stunning

References