Tissue Ischemia and Reperfusion injury

This article doesn't meet WikiLectures quality standards.

This article seems to not fulfill most of the items on our Editorial Process checklist. As such, it's going to be deleted soon. To the author of this article: if you still work on this article, make sure to replace this template with the Under construction template. However, be aware that if you don't make any changes to the article after that soon enough, the article will still be deleted. To find out what you need to do to improve this article, read Help:Editorial process. Feel free to ask for help on Forum:Support. To see how articles on WikiLectures should look like, check out articles in Category:Finished articles. For more information, contact the user who inserted this template, you can find them in the Page History (under the "Actions" button). Last user who modified this page: ShadyMedic

Ischemia refers to a reduction or complete cessation of blood flow to a tissue or organ. This deprivation of blood leads to a sharp decrease in oxygen delivery, nutrient supply, and removal of metabolic waste. Because oxygen is essential for mitochondrial ATP production, ischemia rapidly causes failure of many energy-dependent cellular processes, eventually resulting in cell injury and necrosis if blood flow is not restored.

Degrees of Ischemic Injury

1. Mild or Short-Term Ischemia (Reversible Injury)

Short episodes of reduced blood flow usually cause transient functional disturbances. Cells remain viable because ATP depletion is not severe enough to cause membrane breakdown. Examples:

• Angina pectoris in the heart
• Transient ischemic attack in the brain

2. Prolonged or Severe Ischemia (Irreversible Injury)

If ischemia persists, ATP levels fall dramatically, ion pumps fail, membranes rupture, and cells progress to necrosis.

3. Infarction

An infarction is a region of dead tissue produced by prolonged continuous ischemia.

• Example: myocardial infarction caused by complete coronary artery occlusion (most likely due to ruptures atherosclerotic plaque)

Types of Ischemia

1. Acute Ischemia

Acute ischemia develops suddenly, causing immediate and severe cellular stress, quickly leading to necrosis. Most commonly due to:

• Thrombosis (rapid clot formation)
• Embolism (a clot or debris lodging downstream)
• Vasospasm (sudden intense vasoconstriction)
• Example: Acute coronary artery occlusion causing myocardial infarction

2. Chronic Ischemia

Chronic ischemia results from a slow, progressive decline in perfusion, often from long-standing atherosclerosis. The tissue adapts initially (e.g., forming collateral vessels), but prolonged low-grade ischemia eventually causes:

• Functional impairment
• Tissue atrophy
• Risk of ulceration or gangrene
• Example: Chronic limb ischemia in peripheral artery disease

3. Local Ischemia

Restricted to a specific localized tissue or organ. Examples:

• Cerebral ischemia resulting in stroke
• Renal ischemia due to renal artery stenosis
• Intestinal ischemia from mesenteric artery obstruction

4. Systemic Ischemia

Occurs when blood flow is reduced throughout the entire body, leading multi-organ failure. Usually due to:

• Severe hypotension
• Shock
• Cardiac arrest

Major Causes of Ischemia

1. Vascular Obstruction

Atherosclerosis - is a chronic disease in which arteries become narrowed and stiff due to plaque formation, in which this narrowing severely limits blood flow, especially during increased demand (e.g., exercise). Plaques contain:

• Lipids and cholesterol
• Macrophages (foam cells)
• Fibrous tissue forming a fibrous cap
• Calcium deposits that harden the vessel wall

Thrombosis - A thrombus is a clot that forms in situ in a vessel. In an artery, it reduces or completely blocks blood flow, leading to acute ischemia.

Embolism - An embolus is a piece of thrombus, fat, air, or tissue debris that travels through the bloodstream and blocks a distant vessel.

2. Vasospasm - is a sudden, intense contraction of the vascular smooth muscle, causing temporary severe narrowing of the artery. For example, Prinzmetal (variant) angina caused by spontaneous coronary artery spasm.

3. Reduced Cardiac Output

If the heart cannot pump enough blood, tissue perfusion decreases throughout the body, especially harmful to the brain, which is highly oxygen-dependent, leading to hypoxic-ischemic brain injury.

4. External Compression - Structures (tumors, enlarged cysts, edema, compartment syndrome) outside the vessel can compress it and reduce blood flow.

5. Systemic Hypotension (Shock)

In shock (e.g., hemorrhagic shock), blood pressure falls so low that organs no longer receive adequate perfusion, resulting in systemic ischemia affecting the kidneys, intestines, heart, and brain.

6. Blood Disorders

Abnormalities of blood cells can obstruct microcirculation. For example, sickled red blood cells in Sickle cell anemia become rigid and wedge into small vessels, causing repeated episodes of ischemia and pain.

7. Aneurysms

An aneurysm is an abnormal dilation of an artery due to weakening of its wall. Coomony caused in abdominal aorta or cerbrial arteries. Complications include:

• Rupture -> hemorrhage -> ischemia to downstream tissues
• Turbulent flow causing thrombus formation
• Embolization -> thrombus migrates and blocks smaller arteries

Pathophysiology of Ischemia

When blood flow to a tissue is reduced or completely interrupted, the delivery of oxygen and essential nutrients falls rapidly. Because cells rely on oxygen for mitochondrial oxidative phosphorylation, ischemia causes a sudden decline in ATP production. As ATP stores become depleted, the cell can no longer maintain its energy-dependent processes, leading to widespread metabolic dysfunction.

The cell attempts to compensate by switching from aerobic metabolism to anaerobic glycolysis. However, anaerobic glycolysis is inefficient and produces much less ATP, while simultaneously generating large amounts of lactic acid. As lactic acid accumulates, the intracellular pH decreases, causing an acidic environment that interferes with enzyme activity, disrupts the cytoskeleton, and damages cellular proteins.

The lack of ATP also leads to failure of the plasma membrane ion pumps, especially the Na⁺/K⁺-ATPase pump. When this pump stops functioning, sodium begins to accumulate inside the cell, and water follows the sodium into the cytoplasm. This results in cellular swelling, which is one of the earliest morphological signs of reversible cell injury. At the same time, calcium pumps also fail, allowing calcium to flood into the cell. Excess intracellular calcium activates destructive enzymes such as phospholipases, proteases, and endonucleases, which progressively damage cell membranes, cytoskeletal structures, and DNA. As ischemia persists, mitochondria become increasingly injured because their membranes become permeable and lose their ability to maintain membrane potential. Severe mitochondrial dysfunction leads to the release of pro-death molecules and the generation of harmful free radicals. At this stage, the cellular injury becomes irreversible, and the cell progresses toward necrosis.

Eventually, the plasma membrane and organelle membranes rupture. Enzymes and structural proteins leak out into the surrounding tissue and the bloodstream. This membrane breakdown marks the final stage of irreversible ischemic injury and leads to coagulative necrosis in most tissues, except in the brain, where ischemia produces liquefactive necrosis. If blood flow is restored after a period of ischemia, the tissue can paradoxically suffer additional damage known as reperfusion injury. The sudden reintroduction of oxygen leads to the rapid formation of reactive oxygen species, which attack lipids, proteins, and nucleic acids. Reperfusion also promotes inflammation by attracting neutrophils and activating the complement system. These combined effects can enlarge the area of injury beyond what ischemia alone would have caused.

Clinical Consequences of Ischemia

The clinical outcomes depend on the organ involved, duration, and severity.

1. Cardiovascular Consequences

• Angina Pectoris - Short-term myocardial ischemia causes chest pain due to lactic acid accumulation and sympathetic activation, not causing cell deat˙ (reversible injury).
• Myocardial Infarction (Heart Attack) - Prolonged ischemia (>20–30 minutes) leads to irreversible necrosis. Consequences include: arrhythmias, heart failure, cardiogenic shock, ventricular rupture, sudden cardiac death

2. Cerebral Consequences

• Transient Ischemic Attack - A brief period of reduced cerebral blood flow produces reversible neurological deficits.
• Ischemic Stroke - Prolonged brain ischemia leads to brain infarction, resulting in hemiparesis, speech deficits, vision problems and cognitive impairment. Also, brain tissue undergoes liquefactive necrosis rather than coagulative.

3. Gastrointestinal Consequences

Bowel Ischemia with consequences like severe abdominal pain, bloody diarrhea, intestinal necrosis, peritonitis, and sepsis.

4. Renal Consequences

Kidneys require high perfusion and are vulnerable to ischemia. Consequences include acute tubular necrosis, acute kidney injury, electrolyte imbalances, and oliguria or anuria.

5. Limb and Peripheral Ischemia

• Acute Limb Ischemia – pain, pallor, pulselessness, parathesias, paralysis, and cold limbs
• Chronic Limb Ischemia - pain when walking, non-healing ulcers, and gangrene (dry or wet)

6. Systemic Consequences

• Multi-Organ Failure - When systemic perfusion drops (e.g., during shock), major organs receive inadequate oxygen. Consequences include acute liver injury, renal failure, respiratory failure, myocardial ischemia, and encephalopathy.
• Metabolic Effects - Reduced blood supply and anaerobic metabolism lead to: Metabolic acidosis, Elevated lactate, and cellular dysfunction across multiple systems

7. Clinical Biomarkers of Ischemia - Ischemia causes cell membrane rupture and leakage of intracellular enzymes like Troponin I/T and CK-MB (heart), LDH (general tissue injury), AST/ALT (liver ischemia), and Creatinine (renal ischemia).

Reperfusion injury

Reperfusion injury refers to the paradoxical phenomenon in which restoring blood flow to previously ischemic tissue causes additional cellular damage rather than simply helping the tissue recover. Although reperfusion is necessary to prevent permanent injury, the sudden return of oxygen, inflammatory cells, and circulating molecules triggers events that can worsen tissue destruction.

1. Generation of Reactive oxygen species (ROS)

When oxygen suddenly re-enters previously ischemic cells, damaged mitochondria begin producing large amounts of free radicals rather than ATP.

• These ROS include superoxide, hydroxyl radicals, and hydrogen peroxide.
• Free radicals attack membrane lipids, proteins, and DNA, causing oxidative stress and structural damage.
• Lipid peroxidation destabilizes cell membranes and increases permeability.

2. Inflammation and neutrophil activation

Reperfusion brings inflammatory cells, especially neutrophils, into the area of injury.

• Ischemic tissues express adhesion molecules that recruit neutrophils.
• Neutrophils release enzymes such as proteases, elastase, and myeloperoxidase.
• These substances degrade extracellular matrix and damage cell membranes.
• Neutrophils also produce more ROS, compounding the oxidative injury.

3. Calcium overload

During ischemia, ion pumps fail, and reperfusion allows extracellular calcium to flood back into damaged cells.

• Calcium floods into cells that already lost pump function during ischemia.
• High intracellular calcium activates destructive enzymes including:
  • Phospholipases -> destroy membranes
  • Proteases -> break down cytoskeleton
  • Endonucleases -> fragment DNA
• Calcium overload is a major cause of irreversible injury.

4. Mitochondrial Permeability Transition (MPT)

Mitochondria are highly sensitive to ischemia and reperfusion.

• Reperfusion triggers opening of MPT pores.
• Loss of membrane potential halts ATP production completely.
• Damaged mitochondria leak pro-death factors, committing the cell to necrosis.

5. Complement Activation

The ischemic area expresses altered surface proteins that activate the complement system once oxygen and blood components return.

• Complement proteins (especially C5a) attract neutrophils.
• The membrane attack complex (MAC) forms pores in cell membranes.
• This amplifies inflammation and accelerates cell lysis.

References

Johnson, R. L. (2003). Robbins Basic Pathology. *Archives of Pathology & Laboratory Medicine*, 127(11), 1532. https://doi.org/10.5858/2003 127 1532 rbp

Sattar, H. A. (2025). Fundamentals of Pathology: Medical Course and Step 1 Review.