BMI2606 – CLINICAL PATHOLOGY
QUESTION 1 [20]
Distinguish between labile, stable, and permanent cells, and place each of the following cell/tissue types into the
appropriate category:
1. hematopoietic
2. glandular
3. glial
4. osseous
5. scar tissue.
LABILE CELLS
Labile (continuously dividing) tissues. Cells of these tissues are continuously being lost and replaced by maturation from
tissue stem cells and by proliferation of mature cells.
• hematopoietic cells in the bone marrow
• most surface epithelia,
• such as the stratified squamous epithelia of the skin, oral cavity, vagina, and cervix; the cuboidal epithelia of the
ducts draining exocrine organs (e.g., salivary glands, pancreas, biliary tract); the columnar epithelium of the
gastrointestinal tract, uterus, and fallopian tubes; and the transitional epithelium of the urinary tract. These
tissues can readily regenerate after injury if the pool of stem cells is preserved.
STABLE CELL
• Stable tissues. Cells of these tissues are quiescent (in the G0 stage of the cell cycle) and have only minimal
proliferative activity in their normal state.
• These cells can divide in response to injury or loss of tissue mass.
• Stable cells constitute the parenchyma of most solid tissues, such as liver, kidney, and pancreas.
• They also include endothelial cells, fibroblasts, and smooth muscle cells; the proliferation of these cells is
particularly important in wound healing.
• Except for liver, stable tissues have a limited capacity to regenerate after injury.
PERMANENT CELL
• Permanent tissues. The cells of these tissues are terminally differentiated and non-proliferative in postnatal life.
• Most neurons and cardiac muscle cells belong to this category.
• Thus, injury to the brain or heart is irreversible and results in a scar because neurons and cardiac myocytes
cannot regenerate.
• Limited stem cell replication and differentiation occur in some areas of the adult brain, and there is some
evidence that heart muscle cells may proliferate after myocardial necrosis.
• Nevertheless, whatever proliferative capacity may exist in these tissues, it is insufficient to produce tissue
regeneration after injury.
• Skeletal muscle is usually classified as a permanent tissue, but satellite cells attached to the endomysia sheath
provide some regenerative capacity for muscle. In permanent tissues, repair is typically dominated by scar
formation.
CATEGORIZING DIFFERENT CELL:
1. hematopoietic – Labile cell
, 2. glandular – Stable cell
3. glial – Permanent cell
4. osseous – Stable cell
5. scar tissue - Permanent cell
QUESTION 2 [20]
Discuss the formation of free radicals and their impact on cell and tissue health.
Free radicals are highly reactive anions with an unpaired outer orbital electron. They react with inorganic or organic
chemicals to form further free radicals. Important examples are:
• Reactive oxygen species (ROS): hydrogen peroxide (H2O2), superoxide anion radical (O2−⋅) and hydroxyl radical
(⋅OH).
• Nitric oxide (NO) made by endothelium, macrophages, neurons, and other cells.
Formation
• During normal cellular energy generation by oxygen reduction and electron transfer.
• Killing of pathogens by phagocytes: ROS are performed in a membrane complex.
• Unwanted by-product of intracellular oxidase reactions.
• Radiation (generates hydroxyl and hydrogen free radicals by ionizing water).
• Toxic by-product of drug/chemical metabolism by cellular enzymes, e.g., in the liver.
Harmful effects
• Lipid membrane damage by peroxidation (affects the cell membrane and the membranes of organelles).
• Protein damage by amino acid oxidation, cross-linkages, or protein breakdown, e.g., microtubule aggregation.
• DNA damage can cause mutations and cancer.
• They are also induced by several external agents. A classic example is carbon tetrachloride (CCI4). It is believed
that CCI4 causes hepatic toxicity by free radical attack.
QUESTION 3 [20]
Write an essay comparing cell death by necrosis and apoptosis. Ensure that you describe the sequence of events
within the cell associated with each type of cell death and the causes of each.
Apoptosis
often called ‘programmed cell death’, occurs during embryological development, as new tissues are formed and
remodeled, or in physiological cycles such as the menstrual cycle. Apoptosis is characterized by the orderly breakdown of
cellular constituents, which are packaged into membrane-bound vesicles and tagged for collection by phagocytes. This
requires energy. The initiation of apoptosis is as follows.
• Binding of a ‘death ligand’ (e.g., TNFR1 or Fas) on the cell surface, e.g., direct binding by T cells or NK cells, or
tumor necrosis factor (TNF) secretion by immune cells.
• Membrane disruption by perforin, then intracellular injection of granzyme B by a cytotoxic T cell.
• Release of pro-apoptotic proteins, e.g., cytochrome c, from leaky mitochondrial membranes, a process largely
regulated by pro- and anti-apoptotic proteins of the Bcl-2 family.
• TP53, a ‘gatekeeper’ gene in the cell cycle. p53 protein instigates apoptosis if there is a failure to repair DNA
damage.
Once started, apoptosis is generally irreversible, involving a final common pathway of an intracellular cascade of caspases.
Proteolytic cleavage of cell contents and water loss causes cell shrinkage. Fragments bud off, enveloped by cell membrane,
which expresses new ligands. Apoptosis does not stimulate an acute inflammatory response; instead, macrophages and
adjacent cells bind the new ligands and phagocytose the fragments
, Necrosis
The type of necrosis is dependent on the nature, intensity and duration of the injurious agent, and the type of cell involved.
Note that initial membrane damage allows Ca+2 leakage with subsequent activation of Ca-dependent phosphatases and
lipases. Coagulative necrosis – cytoplasm of the necrosed cells becomes eosinophilic and persists for many days
(myocardial infarction) Colliquative necrosis – cells undergo lysis rapidly (brain infarcts) Caseous necrosis – Mycobacterium
tuberculosis interacts with macrophages Gangrenous necrosis – primary (bacterial toxins) or secondary (ischemia,
infection) Fibrinoid necrosis – smooth muscle necrosis, fibrin release (malignant hypertension) Fat necrosis – inflammatory
response to liberated fat Æ fibrosis
There are also nuclear changes related to necrosis:
• Margination of chromatin – chromatin condensing around the periphery of the nucleus
• Pyknosis – small and dense nuclei
• Karyolysis – complete lysis of the nuclei
• Karyorrhexis – fragmented nuclei (generally seen in apoptosis)
Irreversible cell injury is typically accompanied by: Release of intracellular enzymes: Cardiac muscle – creatine kinase (MB
isoform), aspartate transaminase, lactate dehydrogenase Hepatocytes – alanine transaminase Striated muscle – creatine
kinase (MM isoform) Exocrine pancreas – amylase Loss of membrane selectivity – may be helpful in diagnosis through
uptake of dyes Inflammatory response – initiated by products (mediators) of the necrotic cell
QUESTION 4 [20]
Discuss the different types and causes of shock. Also, explain the effects of shock on the kidneys, lungs, GIT, adrenal
glands, brain, and heart.
QUESTION 1 [20]
Distinguish between labile, stable, and permanent cells, and place each of the following cell/tissue types into the
appropriate category:
1. hematopoietic
2. glandular
3. glial
4. osseous
5. scar tissue.
LABILE CELLS
Labile (continuously dividing) tissues. Cells of these tissues are continuously being lost and replaced by maturation from
tissue stem cells and by proliferation of mature cells.
• hematopoietic cells in the bone marrow
• most surface epithelia,
• such as the stratified squamous epithelia of the skin, oral cavity, vagina, and cervix; the cuboidal epithelia of the
ducts draining exocrine organs (e.g., salivary glands, pancreas, biliary tract); the columnar epithelium of the
gastrointestinal tract, uterus, and fallopian tubes; and the transitional epithelium of the urinary tract. These
tissues can readily regenerate after injury if the pool of stem cells is preserved.
STABLE CELL
• Stable tissues. Cells of these tissues are quiescent (in the G0 stage of the cell cycle) and have only minimal
proliferative activity in their normal state.
• These cells can divide in response to injury or loss of tissue mass.
• Stable cells constitute the parenchyma of most solid tissues, such as liver, kidney, and pancreas.
• They also include endothelial cells, fibroblasts, and smooth muscle cells; the proliferation of these cells is
particularly important in wound healing.
• Except for liver, stable tissues have a limited capacity to regenerate after injury.
PERMANENT CELL
• Permanent tissues. The cells of these tissues are terminally differentiated and non-proliferative in postnatal life.
• Most neurons and cardiac muscle cells belong to this category.
• Thus, injury to the brain or heart is irreversible and results in a scar because neurons and cardiac myocytes
cannot regenerate.
• Limited stem cell replication and differentiation occur in some areas of the adult brain, and there is some
evidence that heart muscle cells may proliferate after myocardial necrosis.
• Nevertheless, whatever proliferative capacity may exist in these tissues, it is insufficient to produce tissue
regeneration after injury.
• Skeletal muscle is usually classified as a permanent tissue, but satellite cells attached to the endomysia sheath
provide some regenerative capacity for muscle. In permanent tissues, repair is typically dominated by scar
formation.
CATEGORIZING DIFFERENT CELL:
1. hematopoietic – Labile cell
, 2. glandular – Stable cell
3. glial – Permanent cell
4. osseous – Stable cell
5. scar tissue - Permanent cell
QUESTION 2 [20]
Discuss the formation of free radicals and their impact on cell and tissue health.
Free radicals are highly reactive anions with an unpaired outer orbital electron. They react with inorganic or organic
chemicals to form further free radicals. Important examples are:
• Reactive oxygen species (ROS): hydrogen peroxide (H2O2), superoxide anion radical (O2−⋅) and hydroxyl radical
(⋅OH).
• Nitric oxide (NO) made by endothelium, macrophages, neurons, and other cells.
Formation
• During normal cellular energy generation by oxygen reduction and electron transfer.
• Killing of pathogens by phagocytes: ROS are performed in a membrane complex.
• Unwanted by-product of intracellular oxidase reactions.
• Radiation (generates hydroxyl and hydrogen free radicals by ionizing water).
• Toxic by-product of drug/chemical metabolism by cellular enzymes, e.g., in the liver.
Harmful effects
• Lipid membrane damage by peroxidation (affects the cell membrane and the membranes of organelles).
• Protein damage by amino acid oxidation, cross-linkages, or protein breakdown, e.g., microtubule aggregation.
• DNA damage can cause mutations and cancer.
• They are also induced by several external agents. A classic example is carbon tetrachloride (CCI4). It is believed
that CCI4 causes hepatic toxicity by free radical attack.
QUESTION 3 [20]
Write an essay comparing cell death by necrosis and apoptosis. Ensure that you describe the sequence of events
within the cell associated with each type of cell death and the causes of each.
Apoptosis
often called ‘programmed cell death’, occurs during embryological development, as new tissues are formed and
remodeled, or in physiological cycles such as the menstrual cycle. Apoptosis is characterized by the orderly breakdown of
cellular constituents, which are packaged into membrane-bound vesicles and tagged for collection by phagocytes. This
requires energy. The initiation of apoptosis is as follows.
• Binding of a ‘death ligand’ (e.g., TNFR1 or Fas) on the cell surface, e.g., direct binding by T cells or NK cells, or
tumor necrosis factor (TNF) secretion by immune cells.
• Membrane disruption by perforin, then intracellular injection of granzyme B by a cytotoxic T cell.
• Release of pro-apoptotic proteins, e.g., cytochrome c, from leaky mitochondrial membranes, a process largely
regulated by pro- and anti-apoptotic proteins of the Bcl-2 family.
• TP53, a ‘gatekeeper’ gene in the cell cycle. p53 protein instigates apoptosis if there is a failure to repair DNA
damage.
Once started, apoptosis is generally irreversible, involving a final common pathway of an intracellular cascade of caspases.
Proteolytic cleavage of cell contents and water loss causes cell shrinkage. Fragments bud off, enveloped by cell membrane,
which expresses new ligands. Apoptosis does not stimulate an acute inflammatory response; instead, macrophages and
adjacent cells bind the new ligands and phagocytose the fragments
, Necrosis
The type of necrosis is dependent on the nature, intensity and duration of the injurious agent, and the type of cell involved.
Note that initial membrane damage allows Ca+2 leakage with subsequent activation of Ca-dependent phosphatases and
lipases. Coagulative necrosis – cytoplasm of the necrosed cells becomes eosinophilic and persists for many days
(myocardial infarction) Colliquative necrosis – cells undergo lysis rapidly (brain infarcts) Caseous necrosis – Mycobacterium
tuberculosis interacts with macrophages Gangrenous necrosis – primary (bacterial toxins) or secondary (ischemia,
infection) Fibrinoid necrosis – smooth muscle necrosis, fibrin release (malignant hypertension) Fat necrosis – inflammatory
response to liberated fat Æ fibrosis
There are also nuclear changes related to necrosis:
• Margination of chromatin – chromatin condensing around the periphery of the nucleus
• Pyknosis – small and dense nuclei
• Karyolysis – complete lysis of the nuclei
• Karyorrhexis – fragmented nuclei (generally seen in apoptosis)
Irreversible cell injury is typically accompanied by: Release of intracellular enzymes: Cardiac muscle – creatine kinase (MB
isoform), aspartate transaminase, lactate dehydrogenase Hepatocytes – alanine transaminase Striated muscle – creatine
kinase (MM isoform) Exocrine pancreas – amylase Loss of membrane selectivity – may be helpful in diagnosis through
uptake of dyes Inflammatory response – initiated by products (mediators) of the necrotic cell
QUESTION 4 [20]
Discuss the different types and causes of shock. Also, explain the effects of shock on the kidneys, lungs, GIT, adrenal
glands, brain, and heart.
