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Summary Pathology lectures
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- Rijksuniversiteit Groningen (RuG)
Summary of all Pathology lectures
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Pathology lecture elaborationsChapter 2 Adaptation, cell death and injury
Etiology are the causes of disease. Having a disease can have various reasons:
- Toxins
- Infectious agents
- Genetic abnormalities
- Physical agents
- Nutritional imbalances
- Immunologic reactions
- Hypoxia and ischemia
- Aging
Hyposia and ischemia are the most common causes of cell injury. Hypoxia occurs when there is not
enough oxygen in the blood because of the low concentration of oxygen. This causes oxygen
deprivation in tissue which will lead to CO poisoning, anemia, respiratory problems or altitude
sickness. Ischemia occurs when there is not enough oxygen due to reduced blood supply. This causes
oxygen deprivation, deficiency of essential nutrients and a build up of toxic metabolites. Due to this
occlusion of an artery or vene could occur. Anoxia is when there is no oxygen supply at all. When
aging the function of cells decreases, this is due to stress and chronic diseases. A way to prevent
cellular aging is to perform physical activity and to have a calorie restriction. When aging there is a
progressive decline in life span and functional activity of cells. The telomeres of chromosomes will
shorten when aging, when telomerase is reactivated this causes cancer. Diminished ability of cells to
respond to stress is the cellular senescence.
All forms of cellular adaptation are reversible, these can be; changes in number, size, phenotype,
metabolic activity or the functions of cells. Physiological adaptations are stimulated by hormones or
by endogenous chemical mediators. Pathological adaptations are responses to stress that allow cells
to modulate their structure and function and thus escape injury but at the expense of normal
function. There are several known forms of cellular adaptation:
Hypertrophy is the increase in cell size (so no new cells are
formed), which causes an increase in organ size. This is
associated with increased amounts of structural proteins
and organelles. Caused due to an increased functional
demand or due to growth factor or hormone stimulation. It occurs in cells that have a limited dividing
capacity, heart and muscle cells. This is a reversible process but if stress is too much or not relieved
and the organ cannot enlarge further, than it will cause progression towards more degenerative
organ changes. Physiologic hypertrophy is for example when you
have an increased work load
striated muscle cells. Pathological
hypertrophy is for example the
cardiac enlargement resulting
from hypertension or aortic valve
disease.
,Hyperplasia is an increase in cell number, rapid increase in the amount of cells
(proliferation). This happens in cells that are capable of replication and can be
stimulated by growth factors or hormones. Physiological hyperplasia can be
proliferation of glandular epithelium of the female breast at puberty and pregnancy
(hormonal hyperplasia) or can be residual tissue growth after loss of part of an
organ (compensatory hyperplasia). Pathological hyperplasia can be the benign prostatic hyperplasia;
papilloma virus induced wart formation or mucosal lesions. This is again reversible, but if it is persists
it is a fertile soil for cancer; when a patient has hyperplasia of endometrium; there is an increased
risk of developing endometrial cancer.
Hyperplasia and hypertrophy can occur together resulting in an enlarged organ. This is the case in for
example pregnancy, the smooth muscle in the uterus will enlarge.
Atrophy is a decrease in cell size, that will lead to a decrease in organ
size. This will cause a diminished cell function but not cell death. It is
associated with decreased protein synthesis and increased protein
degradation. Atrophy is often associated with autophagy. Common causes of atrophy are decreased
work load, loss of innervation, diminished blood supply, inadequate nutrition, loss of endocrine
stimulation and aging (it is then called senile atrophy). Physiologic atrophy can be a decrease in work
load. Pathological atrophy can be aging and a reduced blood supply. The degradation that is
associated with atrophy can occur in two cellular compartments; the lysosomes and proteasomes.
Autophagy is the adaptation to nutrient deprivation; a survival mechanism. The body is self-eating;
lysosomal digestion of the
cell’s own organelles and
recycling in order to
provide energy and
nutrients. Autophagy is
seen in starvation, ischemic
injury and in some types of
myopathies like cancer.
When the stress is too
severe apoptosis will take
place. Proteasome
degradation via the
ubiquitin pathway causes
the break down from
proteins into amino acids.
Metaplasia is reversible, there is a change in phenotype of differentiated
cells which is often a response to chronic irritation. The cells will change
so that they are better able to withstand the adverse environment.
These changes will apply to epithelial cells or
mesenchymal cells. An example of this is the
change in lung epithelium due to the smoking
of cigarettes. There is a reduced function or
increased propensity for malignant
transformation. There is a variety of types of
epithelial cells which can all vary is size and
disorders.
,Reversible injury has two morphological characteristics, cellular swelling
due to the uptake of water which causes a failure of energy dependent
ion pumps in the plasma membrane and fatty change principally in
organs involved in lipid metabolism, liver. The accumulation of water
and of fat are thus changed. The point at which an injury is not
reversible anymore is when the cell is unable to restore mitochondrial
function (oxidative phosphorylation and ATP generation), loss of
structure and functions of the plasma membrane an intracellular
membrane and loss of DNA and chromatin structural integrity. An
irreversible injury will lead to cell death; depending on the nature and
severity of the insult necrosis or apoptosis will take place. Necrosis is
the major part of cell death. It is encountered in many injuries such as,
ischemia, exposure to toxins, infections and trauma. Apoptosis happens
when the injury is less severe or cells need to be eliminated during
normal processes. A set of molecular pathways will be activated which
leads to cell death; also called the programmed cell death.
Necrosis is a form of cell death in which cellular membranes fall apart and cellular enzymes leak out
and digest the cell. The fate of the necrotic cells are either phagocytosis by other cells or further
degradation into fatty acids, these fatty acids will then bind calcium salts which leads to calcification.
Necrosis is often associated with inflammation. The characteristics are cytoplasmic changes,
eosinophilia and vacuolated, and nuclear changes, pyknosis, karyorrhexis and karyolysis. Pyknosis is
when there is eosinophilia (denatured proteins and loss of lighter stained glycogen particles) in the
cytoplasm and condensation (reduced DNA transcription) in the nucleus. Karyorrhexis is degradation
(DNases, cleaves the backbone of the DNA) in the nucleus. Karyolysis is when vacuoles eat the
organelles and the nucleus is in dissolution.
Apoptosis is programmed cell death, the activation of enzymes that degrade the cells own nuclear
DNA and nuclear and cytoplasmic proteins. The point of no return is when the mitochondrial
membrane is permeable. The plasma membrane will remain intact and the apoptotic bodies will
cause the phagocytosis. There are two ways apoptosis can occur; the mitochondrial pathways and
the death receptor pathway. The mitochondrial pathway will cause the mitochondria, after injury, to
produce cytochrome c and other pro-apoptotic proteins which will lead to the activation of caspase
and to the endonuclease activation. The death receptor pathway will start when something is bound
to the TNF receptor, this will lead to caspase activation and thus into the breakdown of the
cytoskeleton. The mechanism of apoptosis in
general is the induction phase, the effector phase,
the degradation phase and the phagocytic phase.
In the induction phase the proteases disrupt cell
connections. The effector phase will allow the
permeability of mitochondria which will initiate
the release of cytochrome c where after there is
no return. The degradation phase will be the
activation of all the caspases and the phagocytic
phase will be the clearance of the cell fragments.
, Pathogenesis is the mechanism of cell injury and of cell death.
The final response depends on the type of injury, its duration and
its severity. Cell injury is the result of functional and biochemical
abnormalities. ATP is necessary for membrane transport, protein
synthesis, lipogenesis and acylation reactions for phospholipid
turnover. The loss of ATP will lead to reduced activity of Na/K/Ca membrane pumps, the Na/K lack
will cause water to go into the cell which will result in the swelling of the entire cell and thus into
vacuolisation. The failure of the Ca pumps will lead to an increased concentration of Ca in the cell,
too much Ca inside the cell will lead to destruction in the cell. There will be an increase in anaerobic
glycolysis and structural disruption of the protein synthetic apparatus.
Another type of damage that causes cell
injury is multiple injurious stimuli, also
called oxidative stress, which leads to
damage to lipids, proteins and nucleic
acids. The damage is induced by ROS
(reactive oxygen species) which will form
free radicals. These radicals are extremely
unstable and very reactive with various cellular molecules, it can cause membrane damage, cause
protein misfolding or breakdown and can cause mutations in the DNA. The major pathways of ROS
production are via mitochondrial respiration, this can
happen in all cells but only in small amounts, and via
phagocytic leukocytes, this can only take place in a
phagosome or a phagolysosome and happens in large
amounts, it is a weapon for the destruction of
microbes. The removal of free radicals happens via
enzymatic systems such as superoxide dismutase,
glutathione peroxidase and catalase but also via non
enzymatic systems like vitamin A, C and E and beta-
carotene.
Due to mutations, cell stress and infections proteins can misfold in the ER, this will lead to apoptosis.
Misfolded proteins can lead to neurodegenerative diseases: Alzheimer disease, Huntington disease
and Parkinson disease. The gathering of misfolded proteins in cells causes stress in the ER. This will
lead to an unfolded protein response trying to restore homeostasis in the cell. To this response the
cell can adapt well or fail to adapt. When it is able to adapt in a proper way the protein synthesis will
go down and the production of
chaperones will go up which will result in
proper folded proteins. When a cell fails
to adapt this will lead to apoptosis of the
cell. A cell is mostly unable to adapt
when there is severe ER stress so that
caspases will be activated. Mild stress
can be adapted to.
Other causes of cell injury can be radiation or other insults which will lead to DNA damage in the
nucleus of a cell. When this is recognised by the cell there will be apoptosis. Infections or
immunologic disorders can cause inflammation which will lead to the production of toxic molecules,
this will be shut down by either necrosis or apoptosis.
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