Lecture 22

Question 1

What is Ischemia?

Answer 1

Inadequate local blood supply to a tissue

Question 2

What is hypoxia?

Answer 2

Deficiency of oxygen causing cell injury due to an inability of oxidative phosphorylation

Question 3

What is anoxia?

Answer 3

Complete lack of oxygen from a tissue

Question 4

What is infarction?

Answer 4

Necrosis due to ischemia

Question 5

What are the possible causes of ischemia?

Answer 5

Venous Obstruction
External Occlusion
Internal Occlusion
Spasm of Vessel wall
Capillary Blockage
Shock
Increased Demand for Oxygen

Question 6

What is the different sensitivity of different cell types to oxygen?

Answer 6

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)

Question 7

What factors does the outcome of vessel occlusion depend upon?

Answer 7

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

Question 8

What are the possible effects of iscahemia on a tissue?

Answer 8

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

Question 9

Where do most infarctions occur in practice?

Answer 9

Thrombotic or embolic effects

Question 10

What are the two types of infarcted tissue?

Answer 10

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

Question 11

What is the typical cause of ischaemic heart disease?

Answer 11

Atherosclerotic narrowing of coronary arteries

Question 12

What are the symptoms/effects of ischaemic heart disease?

Answer 12

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

Question 13

What is the typical timing of inflammation/repair seen in infarction?

Answer 13

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

Question 14

What are the vairous methods of treating myocardial infarction?

Answer 14

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

Question 15

What thrombolytic agents are used to treat myocardial infarction?

Answer 15

Streptokinase or tissue type plasminogen activator

Question 16

What is a mural thrombis?

Answer 16

A potential complication of myocardial infarction where a thrombus forms inside the heart causing embolisation potentially damaging the systemic circuit

Question 17

What are the potential complications for myocardial infarctions?

Answer 17

Mural thrombus formation
Dysrhythmias
Cardiac Rupture
Heart Failure

Question 18

What are the potential effects of ischaemia on cells?

Answer 18

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

Question 19

What signalling pathways are activated by ischaemic cell injury?

Answer 19

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

Question 20

What is reperfusion and how can it cause injury?

Answer 20

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

Question 21

How do Reactive Oxygen species cause damage in reperfusion injury?

Answer 21

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

Question 22

In which two clinical situations is reperfusion injury relevant and why?

Answer 22

Organ transplants as these have typically been ischaemic for a reasonable amount of time before transplantation
Myocardial Infarction

Question 23

How does reperfusion injury affect skeletal muscle?

Answer 23

Reperfusion causes tissue swelling within the enclosed fascia causing increased hydrostaticpressure, capillary compression, secondary ischaemia and necrosis

Question 24

How does reperfusion injury damage vascular endothelial cells?

Answer 24

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