Cell Injury and its Adaptation part 2

Cell Injury II

1. Know the definitions of necrosis, apoptosis, autolysis, heterolysis, atrophy, hypertrophy, hyperplasia, and metaplasia.
a. Necrosis: a sequence of morphological changes that follow irreversible injury and cell death in a tissue
b. Apoptosis: programmed cell death
c. Autolysis: occurs when the source of the hydrolytic enzymes is from the dead cells themselves
d. Heterolysis: occurs when the enzymes originate from inflammatory cells that invade the necrotic focus
e. Atrophy: decrease in cell size
f. Hypertrophy: increase in cell size
g. Hyperplasia: increase in mitosis resulting in a greater number of cells
h. Metaplasia: chang in the state of differentiation of a cell in response to a stress, most commonly an irritation

2. Know the 2 biochemical components of necrosis and understand which prevails in different forms of necrosis.
a. Enzymatic digestion: produces liquefactive necrosis
b. Denaturation of proteins: produces coagulation necrosis

3. Understand the morphology, etiology and common tissue sites of coagulation, liquefactive, caseous, gangrenous, and fat necrosis.
a. Coagulation necrosis: the most common form of necrosis and occurs in a number of solid organs.
i. Hypoxic death of cells in all tissues except the brain will result in coagulation necrosis.
ii. The structural outline of elements of the tissue is preserved for days.
iii. Necrotic tissue contains eosinophilic ghosts of structures or cells that are devoid of nuclear detail.
iv. The necrotic area may have an inflammatory infiltrate.
b. Liquefactive necrosis: occurs in any tissue where there is a focus of bacterial or fungal infection (abscess).
c. Gangrenous necrosis: normally involves the distal region of the limb (usually the leg)
i. Loss of blood supply initiates a coagulative necrosis with a superimposed bacterial infection (wet gangrene)
d. Caseous necrosis: a form of coagulation necrosis at the focus of a tuberculous infection.
i. The necrotic area is white and cheesy and devoid of structure but surrounded by a ring of granulomatous inflammation.
ii. Once resolved, this too leaves cavities at the site.
e. Fat necrosis: may be seen in focal areas of the peritoneal cavity and caused by release of pancreatic enzymes into the peritoneum.
i. The pancreatic lipases attack the fat associated with the mesenteries and omentum, hydrolyzing triglyceride esters to release fatty acids.
ii. The fatty acids combine with calcium to form chalky white areas (fat saponification).
iii. Traumatic fat necrosis is also seen in the breast.

4. Know the differences between dystrophic and metastatic calcification.
a. Dystrophic calcification: occurs in areas of necrosis despite normal circulating levels of calcium
i. Crystal formation begins as calcium combines with phosphate to form a hydroxyapatite-like deposit in the dead cells or mitochondria of the necrotic tissues.
ii. In some cases, these sites may initiate heterotopic bone formation
iii. This can also contribute to further organ dysfunction.
b. Metastatic calcification: occurs in normal tissues
i. Abnormally high levels of circulating calcium (hypercalcemia) due to endocrine dysfunction or a tumor causing bone destruction are the cause of this sort of calcium deposition.

5. Understand the difference between cell death by necrosis and apoptosis.  When do you see each and how do they differ in morphology?
a. Necrotic cell death always follows injury.
i. Whole tissues may be affected
b. Apoptotic cell death is a well-planned and highly-regulated process that may follow injury but also occurs in normal tissues.
i. Apoptotic cells are often isolated and seen in smaller numbers
ii. Not accompanied or followed by inflammation
iii. Occurrences:
1. During embryogenesis (limb bud development)
2. Hormone-regulated cell changes involve apoptosis.  (shedding of the endometrium)
3. Cell deletion in tumors or normal proliferating populations of cells.
4. Selective removal of cells with DNA damage.
iv. Stimulation, signaling and activation:
1. Extrinsic signals act as stimuli, including specific growth factors, alterations in hormone levels, and specific receptor-ligand interactions (TNF, FAS)
2. Injurious agents may also trigger signals, resulting in a cascade of enzymatic reactions involving caspases leading to DNA degradation and cell and nuclear fragmentation.
3. Generally programmed intrinsic signals may also result in activation of the execution caspases.
v. Regulation:
1. Apoptosis is controlled by the BCL-2 family of proteins, involving the mitochondrion and regulation of the permeability transition pore (PTP).
2. Bcl-2 and others inhibit apoptotic cell death by stabilizing the pore complex to prevent leakage of cytochrome c and also stabilizes Apaf-1 protein so that it is not available to interact with procaspase 9.
3. Bax and others promote apoptosis by binding Bcl-2 and modulating this anti-apoptotic effect.
vi. Morphology:
1. Nucleus exhibits distinctive condensation of chromatin, followed by formation of nuclear fragments.
2. Plasma membrane is intact and packaged budding cytoplasmic fragments containing organelles and nuclear fragments into discrete apoptotic bodies are quickly phagocytosed by macrophages and other cells without inflammation.
3. If DNA is isolated from apoptotic cells, necrotic cells, and viable cells:
a. Control DNA runs as a single band.
b. DNA from necrotic cells will travel as a streaked band due to general degradation.
c. DNA from apoptotic cells forms distinct subunits or fragments that “ladder” along the band of the gel.

6. Know why substances may accumulate in cells.  What are some of the defects responsible for accumulation of endogenous substances?
a. Accumulation of substances may be an adaptation to stress or these substances may be normal constituents of the cell (endogenous substances) or abnormal substances (exogenous).
b. Accumulations of normal endogenous materials may occur when that substance is produced by the cell at normal or greater than normal rates where the removal is inadequate to prevent accumulation.
i. Ex: fatty liver and protein accumulations in proximal tubule cells
c. Both normal and abnormal endogenous substances may accumulate if the cell has defects in the metabolic pathway necessary to process the substance as in lysosomal storage diseases.
d. Exogenous substances accumulate in cells because there is simply no biological mechanism for their removal.
i. Ex: carbon in the lung and associated lymph nodes (anthracosis leading to emphysema) and tattoos
e. Endogenous accumulations:
i. Fat: accumulation of triglycerides due to blockage of steps in triglyceride metabolism.  Lipids accumulate in small vesicles surrounding the nucleus and then coalesce to form large intracellular lipid vacuoles that displace the hepatocyte nucleus and may cause rupture of the cell. (hepatocytes in fatty liver)
ii. Proteins:
1. When greater than normal amounts of protein escape in the glomerular filtrate in glomerulonephritis, the proximal tubule cells fill with eosinophilic droplets.
2. A plasma cell neoplasm (multiple myeloma) produces excess amounts of immunoglobulins and may form inclusion bodies with the RER called Russell bodies.
iii. Glycogen: may accumulate in diabetic individuals due to altered glucose metabolism.
1. Defect in glucose-6-phosphate results in accumulation of glycogen in the liver and hepatomegaly.
2. Defect in lysosomal glucosidase results in glycogen stores in the cardiac muscle cells and cardiomegaly.
iv. Cholesterol: Following endothelial injury, macrophages and smooth muscle cells filled with lipid (foam cells) may accumulate in developing atherosclerotic plaques.
1. When the lipid containing cells die, the extracellular lipids form the cholesterol core of the atheroma.
v. Pigments:
1. Bilirubin: When concentrations of bile in the blood exceed 2.0 mg/dL, jaundice occurs.  Dubin-Johnson disease involves a defect in the hepatic excretion of bilirubin.
2. Hemosiderin: hemoglobin-derived, iron-containing pigment.
a. Local excesses founding focal hemorrhage in a bruise or in the congested lungs of heart failure patients.
b. Systemic excesses in multiple organ systems due to massive doses of dietary iron or impaired iron usage causing hemosiderosis snd extreme iron overload found in hemochromatosis.
3. Lipofuscin: “wear and tear” pigment that accumulates with age or atrophy
4. Melanin: synthesized by oxidation of tyrosine in melanosomes of the melanocyte

7. Know the causes of atrophy, hypertrophy, hyperplasia, and metaplasia.  How may they contribute to organ size?
a. Atrophy: decrease in cell size leading to a reduction in organ size if enough cells atrophy.
i. Cause: decreased work load, decreased blood supply to an organ, alteration in nutritional status, change in hormonal stimulation, or aging in general
b. Hypertrophy: increase in cell size leading to an increase in organ size if enough cells hypertrophy.
i. Cause: increased physical or mechanical demand or hormonal stimulation
c. Hyperplasia: due to increase in the rate of mitosis resulting in a greater number of cells.  Can contribute to increased organ size.
i. Cause: growth factor stimulation (compensatory) as in hyperplasia of one kidney following unilateral nephrectomy, change in hormonal stimulation as in prostatic hyperplasia with advancing age as estrogens increase and testosterone decreases
ii. Hyperplasia may be a precursor for neoplasia.
d. Metaplasia: change in the state of differentiation of a cell in response to stress, usually irritation.
i. Cause: In response to potentially damaging irritant, growth factors signal to reserve stem cells to produce a population of cells better suited to handle the stress.
1. Respiratory epithelium that is chronically irritated may respond by metaplastic change to stratified squamous.
2. Esophageal reflux disease leads to replacement of squamous epithelium in areas of the lower esophagus by a columnar epithelial cell type with characteristics of the stomach or intestinal mucosa (Barrett’s esophagus).