Lecture 22 Flashcards
What is Ischemia?
Inadequate local blood supply to a tissue
What is hypoxia?
Deficiency of oxygen causing cell injury due to an inability of oxidative phosphorylation
What is anoxia?
Complete lack of oxygen from a tissue
What is infarction?
Necrosis due to ischemia
What are the possible causes of ischemia?
Venous Obstruction External Occlusion Internal Occlusion Spasm of Vessel wall Capillary Blockage Shock Increased Demand for Oxygen
What is the different sensitivity of different cell types to oxygen?
Neuron are most sensitive, permanent damage occurs after 3 min anoxia
Renal proximal tubular epithelium is sensitive as ion transport is rapidly impaired
Myocardium is sensitive permanent damage takes 20 minutes to occur but functional impairment takes only a minute
Skeletal muscle is less sensitive as it can undergo anoxic work
Fibroblasts and macrophages are insensitive to anoxia
Neutrophils have a LONGER lifespan in hypoxia (this may aid in repair of damaged anoxic tissues)
What factors does the outcome of vessel occlusion depend upon?
The anatomy of the blood supply as collateral circulation may be present
The size of the occluded vessel as a larger vessle indicates there will be a larger block of ischaemic tissue
The speed of onset as if it is slow collateral compensation vessels might develop
The duration of occlusion as some cells may survive brief periods of occlusions (although reperfusion injury may occur)
Metabolic demands of the tissue when ischemia occurs
The adequacy of the circulatory system
What are the possible effects of iscahemia on a tissue?
No effect
Functional Defect caused by oxygen supplies being below optimum
Reversible damage to isolated cells
Apoptosis of isolated cells (uncommon though as this is an energy dependent process)
Infarction caused by necrosis as the cells are overwhelmed by the injury
Where do most infarctions occur in practice?
Thrombotic or embolic effects
What are the two types of infarcted tissue?
Red infarct occurs in tissues where there is a dual blood supply or blood flow as become re-established
White infarct where there is only a single artery to a tissue, these often form a wedge shape
What is the typical cause of ischaemic heart disease?
Atherosclerotic narrowing of coronary arteries
What are the symptoms/effects of ischaemic heart disease?
Angina Pectoris which is pain due to transient recurrant myocardial ischaemia
Chronic ischaemic heart disease leading to heart failure
Myocardial infarct caused by the sudden rupture or blockage of a coronary artery
Cerebral Ischaemic injury can develop from this as the brain is extremely dependent on oxygen and neurons are highly susceptible to anoxia/hypoxia
What is the typical timing of inflammation/repair seen in infarction?
Within 24 hours neutrophil migration occurs
In 1-3 days macrophages and lymphocytes appear
Granulation Tissues is formed
within 6-8 weeks the infarct is replaced by scar tissue or regenerative tisue
What are the vairous methods of treating myocardial infarction?
Use of thrombolytic agents to turn on the fibrinolytic cascade
Angioplasty or stenting which re-expands an occluded vessel
Coronary artery bypass grafting
These treatments may potentially cause reperfusion injury
What thrombolytic agents are used to treat myocardial infarction?
Streptokinase or tissue type plasminogen activator
What is a mural thrombis?
A potential complication of myocardial infarction where a thrombus forms inside the heart causing embolisation potentially damaging the systemic circuit
What are the potential complications for myocardial infarctions?
Mural thrombus formation
Dysrhythmias
Cardiac Rupture
Heart Failure
What are the potential effects of ischaemia on cells?
Attempts at repair (where heat shock proteins and other repair mechanisms are activated)
Cell Atrophy (Volume reduced by proteasome mediated proteolysis and autophagy)
Cell shut down (where DNA/RNA/Protein synthesis is repressed along with all non-essential reactions)
Apoptosis (may occur but uncommon due to energy dependence)
Necrosis
What signalling pathways are activated by ischaemic cell injury?
Stress Kinases which initiate phosphorylation cascades (e.g. p38 MAP Kinase and Jun N-Terminal kinase pathways)
Heat Shock Factors (act as transcription factors to induce the production of heat shock proteins)
Heat Shock proteins
What is reperfusion and how can it cause injury?
Reperfusion is the re-establishment of blood flow after a period of ischaemia
If there was only a brief period of ischaemia then complete recovery may result
If there was a long period of ischaemia then the increased blood flow may release damaging reactive oxygen species
How do Reactive Oxygen species cause damage in reperfusion injury?
Attacking double bonds in unsaturated fatty acids causes lipid peroxidation
They can oxidise amino acid side chains causing enzyme damage
They can cause DNA damage through reactions with thymine
In which two clinical situations is reperfusion injury relevant and why?
Organ transplants as these have typically been ischaemic for a reasonable amount of time before transplantation
Myocardial Infarction
How does reperfusion injury affect skeletal muscle?
Reperfusion causes tissue swelling within the enclosed fascia causing increased hydrostaticpressure, capillary compression, secondary ischaemia and necrosis
How does reperfusion injury damage vascular endothelial cells?
During Ischaemia no nitric oxide is produced resulting in vasoconstriction, platelet aggregation and increased adhesion for leukocytes
The introduced ROS by reperfusion worsen this situation as they promote the upregulation of receptors for leukocytes resulting in increased leukocyte migration where they cause damaging acute inflammation
