1. Oxygen deficit: Hypoxia and ischemia

2. Free Radicals

3. Chemical Injury

4. Physical Injury

5. Nutritional Injury

6. Mechanical Injury

7. Infection

8. Immunological/inflammatory injury

9. Genetic defects

1. Hypoxic Injury

Definitions: Hypoxia, Anoxia, Hypoxemia, Ischemia

Gas exchange takes place in the alveoli (between air and blood) and at tissues (between blood and cells)

Hypoxic injury can occur as a result of:

– Lack of oxygen in the air

o E.g. High altitude, being trapped in an enclosed space such as an elevator or underground.

– Problems with oxygen transport:

o E.g. Conditions affecting RBC formation and structure, and subsequent oxygen carrying capacity.

o E.g. decreased RBCs production (erythropoiesis).

– Disease of the respiratory and/or cardiovascular system:

o Blood is not getting pumped/circulated adequately.

o Poor gas (oxygen) exchange in the lungs and/or delivery to tissues.

– Narrowing of an artery or vein

o E.g. atherosclerosis.

– Obstruction of an artery or vein

o E.g. blood clot (thrombosis).

Myocardial Infarction (MI)

Acute obstruction of coronary artery leading to myocardial cell death.

There is hypoxia, which progresses to anoxia if blood flow is not restored.

– In response to hypoxia, the heart modifies its method of oxygen uptake and utilizes myoglobin stores [Remember: Myoglobin = hemoglobin in heart]

– Myoglobin stores are limited and eventually run out.

– The heart becomes anoxic and cardiac cells decrease their metabolism to conserve energy until eventually no ATP is produced.

– The Na-K pump fails due to lack of ATP.

– Na and water leak into cell causing it to swell and burst.

Diagnostic Testing

Troponin and cardiac enzyme test, ECG

o Elevated troponin I is a marker for MI, however, depending on the timing in relation to onset of chest pain, levels may not be elevated. For this reason, Troponin is repeated in 4 hours for patients with suspected MI.

o Elevated Troponin I after 4 hours is indicative of MI

– ECGs are critical to determine treatment approach.

o Do an ECG for any suspected MI*

o *In practice, ECGs are completed on most adults presenting with sudden onset chest pain, especially with cardiac features, to rule out MI

o Extra consideration should be taken for persistent, generalized, radiating pain in women with no apparent cause of onset as women with MI often present atypically from males

• This includes generalized abdominal pain, back pain, neck, that is not reproducible with specific movements or is related to a specific diagnosis or injury

Reperfusion:

– Restoration of blood flow to an obstructed area.

– This occurs via collateral circulation.

Reperfusion Injury:

– Cellular damage caused by restoration of blood flow to obstructed area

– Occurs due to an increase in intracellular calcium and formation of free radicals:

o Calcium damages mitochondria → Therefore no ATP production

o Calcium increases cellular enzyme activities causing membrane damage, nucleus damage, and further decrease in ATP production.

o Free radical causes further cell membrane damage and release of calcium stores contributing to mitochondrial calcium overload.

– Cells attempt to detoxify radicals but they may fail:

o Toxic free radicals can be stabilized by donating or accepting an electron from another molecule (antioxidants).

o With significant free radical formation, there are not enough antioxidant molecules to stabilize all the unstable oxygen species.

Free radicals come from many sources such as:

– Aging, respiration, metabolism

– Infection, cancer

– Reperfusion, inflammation

– Drugs, chemicals, radiation.

Unstable and highly reactive, therefore called reactive oxygen species (ROS).

Free radical injury has many effects, including:

– Lipid peroxidation.

– Alteration to proteins → impaired enzymatic activity and folding

Free radicals must accept or donate an electron from another molecule to become stable, and they do this by binding to other molecules

– This binding can be injurious if these ROS bind to molecules such as proteins, lipids, and

carbohydrates, as well as those key to survival such as molecules of cellular membranes and nucleic acids (DNA)

– ROS set of a chain reaction as they bind to stable molecules, in turn making these previously stable molecules unstable free radicals.

Peroxisome is the cell that detoxifies the free radical by adding something to make them safe and “stable”.

Antioxidants can also act as binding molecules to stabilize free radicals and prevent their binding to other body molecules.

– Free radicals can be eliminated by Antioxidants (vitamins A,C,E), spontaneously, or via enzymes. These enzymes include:

o Superoxide dismutase (in the mitochondria) O2 + 2H → H2O2

o Catalase (in peroxisomes): 2 H2O → 2 H2O + O2

o Glutathione peroxidase (in cytoplasm): H2O2 or 2 OH + 2 GSH → 2 H2O + GSSH

Antioxidants stabilize, peroxisomes detoxify

-Oxidative Stress: When excess ROS production overwhelms endogenous antioxidant systems leading to cellular injury.

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