1. Pathophysiology of the cell- causes and mechanisms of cell injury.
Causes:
- chemical factors: toxics, mercury, cyanamide
- physical factors: electric current, hyperthermia, trauma, pressure
- nutritional factors: de ciency, ischemia
- toxic factors: free radicals through radiation damage
- aging
- genetic factors
Mechanisms of cell injury:
The cellular response to injurious stimuli depends on the nature of the injury, its duration and its severity.
Small doses of toxin or ischemia may cause reversible injury wile a larger dose may cause an irreversible
injury.
The consequences also depends on several factors such as the nutritional status, the hormonal status and
the metabolic needs of the cell.
1) Depletion of ATP:
Mitochondrial damage and a reduction of ATP are associated with hypoxia and toxic injury of the cell. The
major cause of ATP depletion are reduced supply of oxygen and nutrients. mitochondrial damage and the
action of some toxing ( eg. cynamide). Further complications might occur:
- Na+- K+- ATPase is reduced which follows an accumulation of NA+ inside the cell leading to cell
swelling
- cellular energy metabolism is altered—> if the cell gets less oxygen due to an ischemia, less ATP is
provided and the cell switches to anaerobic glycolysis generating ATP through metabolism of glucose
derived from glycogen.
- Failure of the Ca2+ pump ( decr
- structural disruption of the protein synthetic apparatus
- misfolding of proteins in ER—> unfolded protein response
- irreversible damage to mitochondrial and lysosomal membranes and the cell undergoes necrosis
2) In ux of calcium and loss of calcium homeostasis:
Calcium concentrations are only accepted in a very low cytosolic amount. Therefore, ischemia and certain
toxins cause an increase in cytosolic calcium concentration, because of the release of Ca2+ from
intracellular stores and later through increased in ux across the plasma membrane.
- Failure of the Ca2+ pump
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, - structural disruption of the protein synthetic apparatus
- misfolding of proteins in ER—> unfolded protein response
- irreversible damage to mitochondrial and lysosomal membranes and the cell undergoes necrosi
- accumulation in mitochondria: opening of permeability transition pore and failure of ATP generation
- increased cytosolic Ca2+: activates number of enzymes a ecting cells as follows: (picture).
- induction of apoptosis
3) Accumulation of oxygen- derived free radicals
( oxidative stress):
Cell injury induced by free radicals is an important
mechanism of cell damage:
- chemicals
- radiation
- ischemia reperfusion injury
- aging
- microbial killing
Free radicals attack adjacent molecules such as
proteins, lipids or carbs. Some of these components
are autocatalytic meaning they even turn into free
radicals after being attacked.
- ROS: - increased production can lead to oxidative
stress ( cell injury, cancer, aging, Alzheimers
disease)
- also produced by activated leukocytes
( neutrophils and macrophages)
2. E ects and responses.
Responses
The adaptive response may consist of an increase in
the size of cells ( hypertrophy) and functional activity,
an increase in their number ( hyperplasia), a decease in the
size and metabolic activity of cells ( atrophy), or a change in
the phenotype of cells ( metaplasia). When the stress is
eliminated, the cell can recover to its original state without
having su ered any harmful consequences.
It can also be irreversible and lead to a cell death.
Hypertrophy: increase in size of cells
Hyperplasia: increase in number
Atrophy: reduction in the size
Metaplasia: reversible change in cell type
E ects:
- cloudy swelling
- fatty change
- cell size / number
ff ff ff ff
,3. Apoptosis.
Apoptosis is associated with programmed cell death. It is done by a tightly regulated suicide program in
which cells destined to die activate intrinsic enzymes that degrade the cells own nuclear DNA and nuclear
and cytoplasmic proteins.
Causes in physiological conditions:
- destruction of cells during embryogenesis
- involution of hormone- dependent tissues upon hormone withdrawal
- cell loss in proliferating cell populations
- elimination o potentially harmful self- reactive lymphocytes
- death of host cells that hav served their useful purpose
Causes in pathological conditions:
- DNA damage
- accumulation of misfolded proteins
- cell death in certain infections
- pathologic atrophy in parenchymal organs after duct obstruction
Endogenous pathway: genetic factors or immunity
or
exogenous pathway: death- receptor initiated
, 4. Free radicals.
Generation of free radicals:
- absorption of radiant energy
- in leukocytes due to in ammation
- enzymatic metabolism of exogenous chemicals or drugs
- transition metals: iron, copper
- Nitric oxide
Removal of free radicals:
- antioxidants
- enzymes
Pathologic e ects:
- lipid peroxidation in membranes
- oxidative modi cation of proteins
- lesions in DNA
3) defects in membrane permeability:
- ROS-> lipid peroxidation
- increased phospholipid breakdown
- cytoskeletal abnormalities
Consequences:
- mt membrane damage
- plasma membrane damage
- injury to lysosomal membranes—> release of enzymes which degrade needed cellular components
5. Mechanism of cell death.
Necrosis
Types:
- coagulation necrosis
- liqui dation necrosis
Characteristics:
- membrane integrity
- leakage of cellular content
- induced in ammation because lsot cells release content and after that a scar is formed
- can be reversible or irreversible
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fl ff fi fl
Causes:
- chemical factors: toxics, mercury, cyanamide
- physical factors: electric current, hyperthermia, trauma, pressure
- nutritional factors: de ciency, ischemia
- toxic factors: free radicals through radiation damage
- aging
- genetic factors
Mechanisms of cell injury:
The cellular response to injurious stimuli depends on the nature of the injury, its duration and its severity.
Small doses of toxin or ischemia may cause reversible injury wile a larger dose may cause an irreversible
injury.
The consequences also depends on several factors such as the nutritional status, the hormonal status and
the metabolic needs of the cell.
1) Depletion of ATP:
Mitochondrial damage and a reduction of ATP are associated with hypoxia and toxic injury of the cell. The
major cause of ATP depletion are reduced supply of oxygen and nutrients. mitochondrial damage and the
action of some toxing ( eg. cynamide). Further complications might occur:
- Na+- K+- ATPase is reduced which follows an accumulation of NA+ inside the cell leading to cell
swelling
- cellular energy metabolism is altered—> if the cell gets less oxygen due to an ischemia, less ATP is
provided and the cell switches to anaerobic glycolysis generating ATP through metabolism of glucose
derived from glycogen.
- Failure of the Ca2+ pump ( decr
- structural disruption of the protein synthetic apparatus
- misfolding of proteins in ER—> unfolded protein response
- irreversible damage to mitochondrial and lysosomal membranes and the cell undergoes necrosis
2) In ux of calcium and loss of calcium homeostasis:
Calcium concentrations are only accepted in a very low cytosolic amount. Therefore, ischemia and certain
toxins cause an increase in cytosolic calcium concentration, because of the release of Ca2+ from
intracellular stores and later through increased in ux across the plasma membrane.
- Failure of the Ca2+ pump
fl fi fl
, - structural disruption of the protein synthetic apparatus
- misfolding of proteins in ER—> unfolded protein response
- irreversible damage to mitochondrial and lysosomal membranes and the cell undergoes necrosi
- accumulation in mitochondria: opening of permeability transition pore and failure of ATP generation
- increased cytosolic Ca2+: activates number of enzymes a ecting cells as follows: (picture).
- induction of apoptosis
3) Accumulation of oxygen- derived free radicals
( oxidative stress):
Cell injury induced by free radicals is an important
mechanism of cell damage:
- chemicals
- radiation
- ischemia reperfusion injury
- aging
- microbial killing
Free radicals attack adjacent molecules such as
proteins, lipids or carbs. Some of these components
are autocatalytic meaning they even turn into free
radicals after being attacked.
- ROS: - increased production can lead to oxidative
stress ( cell injury, cancer, aging, Alzheimers
disease)
- also produced by activated leukocytes
( neutrophils and macrophages)
2. E ects and responses.
Responses
The adaptive response may consist of an increase in
the size of cells ( hypertrophy) and functional activity,
an increase in their number ( hyperplasia), a decease in the
size and metabolic activity of cells ( atrophy), or a change in
the phenotype of cells ( metaplasia). When the stress is
eliminated, the cell can recover to its original state without
having su ered any harmful consequences.
It can also be irreversible and lead to a cell death.
Hypertrophy: increase in size of cells
Hyperplasia: increase in number
Atrophy: reduction in the size
Metaplasia: reversible change in cell type
E ects:
- cloudy swelling
- fatty change
- cell size / number
ff ff ff ff
,3. Apoptosis.
Apoptosis is associated with programmed cell death. It is done by a tightly regulated suicide program in
which cells destined to die activate intrinsic enzymes that degrade the cells own nuclear DNA and nuclear
and cytoplasmic proteins.
Causes in physiological conditions:
- destruction of cells during embryogenesis
- involution of hormone- dependent tissues upon hormone withdrawal
- cell loss in proliferating cell populations
- elimination o potentially harmful self- reactive lymphocytes
- death of host cells that hav served their useful purpose
Causes in pathological conditions:
- DNA damage
- accumulation of misfolded proteins
- cell death in certain infections
- pathologic atrophy in parenchymal organs after duct obstruction
Endogenous pathway: genetic factors or immunity
or
exogenous pathway: death- receptor initiated
, 4. Free radicals.
Generation of free radicals:
- absorption of radiant energy
- in leukocytes due to in ammation
- enzymatic metabolism of exogenous chemicals or drugs
- transition metals: iron, copper
- Nitric oxide
Removal of free radicals:
- antioxidants
- enzymes
Pathologic e ects:
- lipid peroxidation in membranes
- oxidative modi cation of proteins
- lesions in DNA
3) defects in membrane permeability:
- ROS-> lipid peroxidation
- increased phospholipid breakdown
- cytoskeletal abnormalities
Consequences:
- mt membrane damage
- plasma membrane damage
- injury to lysosomal membranes—> release of enzymes which degrade needed cellular components
5. Mechanism of cell death.
Necrosis
Types:
- coagulation necrosis
- liqui dation necrosis
Characteristics:
- membrane integrity
- leakage of cellular content
- induced in ammation because lsot cells release content and after that a scar is formed
- can be reversible or irreversible
fi
fl ff fi fl
