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8 classes of agents that cause cell injury and death
1. Chemical agents
2. Free radicals
3. Genetic factors
4. Immunological reactions
5. Infectious agents
6. Lack of blood supply
7. Nutritional imbalance
8. Physical and mechanical factors
role of Ca2+
floods cell with leaky membrane, activates proteases, nitric oxide synthase, phospholipases and endonuclease (cytoskeleton disruption, membrane damage, activation of inflammation, DNA degradation, eventual cell death). Also, an eventual drop in pH caused by the loss of oxidative phosphorylation and resultant glycolysis combines with leaky membrane to induce lysosomal membrane injury. Can also lead to NT disruption.
2 events that characterize irreversible damage:
1. lack of ATP generation because of mitochondrial dysfunction
2. major disturbances and damage in membrane function
Free radical modes of damage
1. Lipid peroxidation: destruction of saturated fatty acids in lipid membrane.
2. Alterations in proteins: fragmentation
3. Alterations of DNA: incl' breakage of single strand
Converted to CCl3 free radical by liver cell. 10 - 15 min: blockage of triglyceride (lipoprotein) secretion by rough ER means a fatty liver (enlarged and pale 10 - 12 hours later). It all starts by CCl3 production from CCl4 in the smooth ER. So much lipid is contained that it overwhelms the cell, vacuoles form and it eventually overruns the entire organ. The free radical produced by the smooth ER also leads to membrane permeability, influx of calcium, mitochondrial swelling and influx of calcium, loss of oxidative phosphorylation, Na+, Cl- and H2O into cell, K+ out of cell, all other forms of Ca2+ influenced damage.
2 forms of chemical injury
1. Direct toxicity
2. Reactive free radical and lipid peroxidation (e.g. CCl4)
- neurological impairments (learning disabilities and attention problems)

- kidney impairments (proximal tubule dysfuntion). Leads to glucosuria, aminoaciduria and hyperphosphaturia.

- GI irritability and N, V, cramping

Cellular levels of Ca2+ increase and we all know what that can lead to.
headache, giddiness, tinnitus, N, V, and weakness
Hypothermic injury
- intracellular ion imbalances (slowing of Na+, K+ ATPase), high Na+ and Ca2+ concentrations.

- ROS increase

- gradual: first vasoconstriction then vasomotor loss and vasodilation, increased capillary permeability...

- acute: vasoconstriction and increased blood viscosity. thrombosis (gangrene from ischemia).
Heat cramps: cramps from water loss

heat exhaustion: hypovolemia, hypotension, cardiovascular failure after trying to compensate for it.

heat stroke: +106o rectal temp. thermoregulatory failures. life threatening.
fatty acids released from adipose tissue. Can lead to lowered pH.
Kidneys, heart and adrenal glands. coagulation of albumin caused from hypoxia (from ischemia).
Tb pulmonary infections. Combo of coagulative and liquefactive. cheesey appearance.
Neurons and glial cells. Ischemic injuries or bacterial infections. Cells are injured by own hydrolytic enzymes (from neutrophils in bacterial). Contained in cysts.
Fat necrosis
breast, pancreas, other abdominal.

Lipases break down triglycerides into free fatty acids which saponify making the tissue opaque and chalk white.
Gangrenous necrosis
secondary to hypoxemia. dry is coagulative, wet is liquefactive (from neutrophil pus), gas is from Clostridium.
Caspases are proteases involved. Very neat and tidy programmed cell death.
Systemic manifestations of cell injury
1. Fever - pyrogens from bacteria or macrophage are endogenous and released.
2. Increased heart rate - increase in oxidative metabolic processes resulting from fever
3. Increase in leukocytes - WBC count increases (leukocytosis) due to infection.
4. Pain - variety of reasons (e.g. bradykinins, obstruction, pressure)
5. Presence of cellular enzymes in extracellular fluid - released from cells of damaged tissue.
Purines vs. Pyrimidine
Purines: Adenine and Guanine

Pyrimidines: Cytosine, Thyamine, Uracil (RNA replacement for Adenine)

A-T (RNA is U-T); G-C
Heart muscle ischemia results (1-5 min)
1 min heart muscle appears pale
3-5 min: stops contracting
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