Biomedical Engineering Reference
In-Depth Information
MECHANISM OF TISSUE DAMAGE BY HR INJURY
Once in the tissue, activated leukocytes can subsequently enhance the localized
inl ammatory response by releasing toxic metabolites such as proteases (e.g.,
elastase and methyloproteinases) and ROS resulting in damage to the surrounding
tissue. h e toxic ROS include superoxide anions (O
-
), hydroxyl radicals (OH
-
),
hypochlorous acid (HOCl
-
), and hydrogen peroxide (H
2
O
2
). ROS are potent
oxidizing and reducing agents that directly damage cellular membranes by lipid
peroxidation. h e released proteases degrade the subendothelial extracellular
matrix, enabling more leukocytes to migrate to the site of injury while ROS degrade
matrix components, resulting in loss of structural integrity of the af ected tissue.
ROS have long been recognized as important components in host defence as well
as contributors to the pathogenesis of inl ammatory disease. In addition, ROS
stimulate leukocyte activation and chemotaxis by activating plasma membrane
phospholipase A2 to form arachidonic acid, an important precursor for eicosanoid
synthesis (e.g., thromboxane A2 and leukotriene B4).
ROS also stimulate leukocyte adhesion molecule and cytokine gene expression
via activation of transcription factors such as nuclear factor-kB. In addition to
causing direct cell injury, ROS thus increases leukocyte activation, chemotaxis,
and leukocyte-endothelial adherence at er HR.
Ischaemia reperfusion results in complement activation and the formation of
several pro-inl ammatory mediators that alter vascular homeostasis. Particularly
important are C3a and C5a, and complement components iC3b and C5b-9. In
addition to stimulating leukocyte activation and chemotaxis, C5a may further
amplify the inl ammatory response by inducing production of the cytokines
monocyte chemoattractant protein 1, TNFα, IL-1, and IL-6. C3b is a specii c
ligand for leukocyte adhesion to the vascular endothelium via the β
2
integrin,
CD11b/CD18. In addition, C5b-9 may activate endothelial NF-κB to increase
leukocyte adhesion molecule transcription and expression. C5b-9 also promotes
leukocyte activation and chemotaxis by inducing endothelial IL8 and monocyte
chemoattractant protein 1 secretion. C5b-9 may also alter vascular tone by inhibiting
endothelium-dependent relaxation and decreasing endothelial cyclic guanosine
monophosphate (Mark
et al.
1989, Collard
et al.
1999). h us, complement may
compromise blood l ow to an ischaemic organ by altering vascular homeostasis
and increasing leukocyte-endothelial adherence.
SUMMARY
• Hypoxia reperfusion injury has been recognized to play a key role in the
pathogenesis of many kinds of organ dysfunction.
• Reperfusion of ischaemic tissues is associated with microvascular
dysfunction that causes leukocyte migration into intrestisuum.
