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Richard Anderson, MD
M2 Pathology Course
Lectures #2 and #3
Thursday August 23, 2001
8:30 a.m. and 9:30 a.m.
Lecture Goals:
I.
II.
III.
IV.
V.
Give visual examples of cellular apoptosis and explain some of the genetic
controls over programmed cell death
Definition of Terms:
Pathology
Cellular adaptation
Cellular injury
Hypertrophy
Hyperplasia
Metaplasia
Dysplasia
Necrosis
Apoptosis
The most important thing to remember is that after withdrawal of the stress, theses changes are completely
reversible.
atrophy
hypertrophy
Hyperplasia
metaplasia
dysplasia
intracellular deposits
Atrophy:
Atrophy is a decrease in the size and function of a cell. Causes and examples of atrophy include:
1. Reduced functional demand:
2. Ischemia:
Hypertrophy:
Hypertrophy is an increase in the size of a cell and organ. Causes and examples of hypertrophy include:
1. Physiologic hormonal hypertrophy:
myocardial hypertrophy
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alcoholic hepatitis
Hyperplasia:
Hyperplasia is an increase in the number of cells in an organ, which usually results in an increase in size of
the organ. Causes and examples of hyperplasia include:
1. Physiologic hormonal hyperplasia:
gynecomastia
Metaplasia:
Metaplasia is a reversible change in which one cell type is replaced by another, which is usually more apt
to withstand stress. Though most of the time, metaplasia is a harmless process (e.g., squamous metaplasia
of the cervix), there are certain types of metaplasia (Barretts esophagus incomplete intestinal metaplasia)
which carry an increased risk of malignant transformation. Metaplasia is under genetic control. An
example of this is the differential expression of mucin genes (MUC1-MUC7) in normal respiratory
epithelium, metaplastic respiratory epithelium and malignant epidermoid carcinoma of the respiratory tract
(Copin MC, et al. 2000. Int J Cancer; 86:162-168.) Metaplasia is usually fully reversible. Examples of
metaplasia include:
1. Endocervical squamous metaplasia
2. Barretts specialized intestinal metaplasia.
Dysplasia:
Cellular dysplasia refers to an alteration in the size, shape and organization of the cellular components of a
tissue. Dysplasia is a preneoplastic condition. In dysplasia, there is increased cell proliferation
accompanied by abnormalities in cell size, configuration and orientation. In mucinous epithelium (e.g.,
colon) the following changes may be observed in dysplastic epithelium:
As one would expect, dysplasia is also under genetic control. In adenomatous polyps (tubular adenomata)
of the colon, aneuploidy can be detected in about 35% of cases, p53 expression is found in a minority of
cases and bcl-2 immunoreactivity is present in virtually all cases. Fearon and Vogelstein (1990. Cell;
61:759-767) have proposed a genetic model for transformation of normal colonic epithelium to dysplastic
epithelium to carcinoma (the so-called adenoma-carcinoma sequence). Examples of dysplasia include:
1. Adenomatous colonic polyp
2. Cervical intraepithelial neoplasia
3. Barretts specialized intestinal metaplasia with dysplasia
Intracellular storage:
Intracellular storage is a normal cellular function. However, abnormal or excessive accumulations are
seen in certain disease states as well as a consequence of inborn errors in metabolism. Examples of
intracellular storage include:
1. Alcoholic and non-alcoholic steatohepatitis:
2. Liquefactive necrosis:
3. Fat necrosis:
4. Casseous necrosis:
pulmonary tuberculosis
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Reperfusion injury:
This is a somewhat paradoxical response involving the damaging effect of oxygen to a cell that has
suffered irreversible cell injury. Clinically, this is an extremely important event which occurs during
myocardial infarction as well as cardioplegic arrest during cardiac surgery. Principle mediators of this
phenomenon are oxygen radicals (O2-, H2O2, -OH) and neutrophils. Reperfusion of postischemic tissue
is accompanied by generation of large amounts of oxygen radicals formed by a number of mechanisms:
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mitochondrial respiration
xanthine oxidase activity
byproduct of neutrophil activation
Apoptosis:
Apoptosis is a genetically determined and biologically meaningful process in which cells that are
immunologically reactive against self, infected or genetically damaged are removed to protect the host.
There is phagocytosis though no associated inflammatory response. Morphologically, there is nuclear
condensation and fragmentation. The surface membrane becomes irregular and the cell fragments into
membrane-bound bodies which may or may not contain nuclear material. These are phagocytized.
Apoptosis can be triggered by a variety of extrinsic and intrinsic signals. It appears to be carried out
through the activation of endogenous proteases which disrupt the integrity of the cytoskeleton and
endonucleases which degrade nuclear DNA. The key feature of apoptosis is that the plasma membrane
remains intact.
Apoptosis is genetically regulated. Early experiments to identify genes that regulated cell death during the
development of the nematode Caenorhabditis elegans led to the discovery of 3 genes (CED-9, CED-4 and
CED-3). It was found that if CED-9 was mutated, apoptosis was prevented. Mammalian homologs for all
three genes have been found. When CED-9 was cloned, it was found to be related to the mammalian
oncogene, bcl-2. This gene is present on chromosome 18 and was originally identified because of its
involvement in a 14:18 translocation present in 85% of follicular non-Hodgkins lymphoma. CED-3 is an
endogenous protease. The mammalian counterpart include the caspases,, which are intracellular cysteine
proteases that have the novel ability to cleave proteins after an aspartate residue (hence the name).
The rate at which apoptotic signaling events initiate or amplify caspase activity is regulated by proteins of
the Bcl-2 family. A number of Bcl-2-related proteins have been identified. Paradoxically, some of these
proteins have been shown to promote apoptosis (Bax, Bak) whereas others inhibit apoptosis (Bcl-2).
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http://www.kumc.edu/instruction/medicine/pathology/ed/ch_path_850.html
An excellent site with full lectures and slides.
http://www.pathguy.com/lectures.htm
This is a huge site with a lot of information. It is maintained by one unique individual.
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