EXAM1
Lecture: introduction
Disease an abnormality that causes loss of health, a set of features (signs, symptoms,
morphological and functional manifestations)
Systematic description:
- Epidemiology
- Cause (etiology)
- Pathogenesis (disease mechanisms)
- Symptoms, manifestations
- Complications & sequelae
- Prognosis
- Mortality
Biopsy process registration of the material that arrives at the department => cutting room =>
cutting => cassettes => tissue processing (=> fixation => dehydration => embedding => paraffin blocks
=> cutting => slides => H&E stain) => evaluation by residents and pathology specialists
Relevant information:
- Diagnosis
o Benign vs malignant
o Type of tumour
- Prognosis
o TNM classification
o Radicality
- Prediction
o Response to treatment
Lecture: Ch1 cell injury, cell death and adaptations
Etiology why a disease occurs.
Pathology essential in understanding disease, but is also the basis for developing rational
treatments.
Describing the organs microscopically
Iosin (C) stains tissue, HE
Lung carcinoma have a EGF mutation and are targetable
Necrosis or apoptosis are two ways for a cell to die.
Causes of cell injury:
- Etiology causes of disease.
o Hypoxia and ischemia
o Toxins
o Infections
o Abnormal immune reactions
o Genetic abnormalities
o Missense mutation
, - Pathogenesis mechanisms of disease, sequence of cellular, biochemical and molecular
events
o Biochemical changes
- Abnormalities in cells and tissues (genes)
o Missense mutation
- Clinical manifestations signs and symptoms of disease
Sequence of events in cell injury and cell death:
- Reversible cell injury:
o Morphologic correlates:
Cell will swell and increase in size when there occurs hypoxia or ischemia.
Fatty cells
ATPase failure leads to disbalance of osmose.
- Irreversible cell injury
o 3 phenomena:
o Inability to restore mitochondrial function.
o Altered structure and loss function of the plasma and intracellular membranes.
o Loss of structural integrity of DNA and chromatin
o => necrosis
Necrosis:
- Fall apart of cell membranes => leakage of enzymes => inflammatory reaction
- Always a pathologic phenomenon
- Morphologic patters
o Some severe injuries result in the death of many or all cells in a tissue or organ due to
ischemia, infection, inflammatory reactions.
Coagulative necrosis
o Usually secondary to ischemia
o Injury of structural proteins, but also of enzymes
o Wedge shape yellow discoloration, firm texture
o Tissue architecture is preserved for at least days after the injury.
o Over time: recruited leukocytes digest dead cells.
o Characteristic of infarcts in all solid organs except the brain
Liquefactive necrosis
o At sites of bacterial infections and sometimes fungal infections
Death tissue is visible as pus or an abscess.
o Ischemic necrosis in CNS
o Finally removed by phagocytes
Caseous necrosis
o Tuberculous infection
o Granulomatous inflammation
Obliteration of tissue architecture, cellular outlines
Granular, amorphous, pink cellular debris
Fat necrosis (saponification)
o Acute pancreatitis
Lipases eat the pancreas.
o Abdominal trauma
o Histology: fat cell necrosis, granular basophilic calcium deposits
Fibrinoid necrosis
o Immune-mediated diseases
o Deposition of immune complexes
, Antigen for example
Necrosis vs apoptosis
- Pro-inflammatory anti-inflammatory
- Pathologic part of normal physiology
- Cellular catastrophe, no regulation cellular suicide, under strict regulation
- Cell contents are released extracellularly cells contents are not released.
- Occurs now and then occurs continuously.
- Induces repair and defence no induction of repair.
Apoptosis programmed cell death, usually part of normal physiology.
- Cells activate enzymes that degrade their own nuclear DNA.
- Phagocytosis removes the apoptotic cell.
- Causes of apoptosis
o Physiologic conditions:
B cells in lymph node => Antibody formation
During embryogenesis
o Pathologic conditions:
DNA damage
Accumulation of misfolded proteins
infections
2 pathways:
o Regulated by biochemical pathways that control the balance of death- and survival-
inducing signals and ultimately the activation of enzymes called caspases.
Mitochondrial (intrinsic) pathway
o Responsible for apoptosis in most physiologic and pathologic situations
o Cytochrome c
Electron transport
Induction of apoptosis
Activates caspases 9.
o BCL2 (anti-apoptotic protein)
Important regulator
Keeps BAX or BAK in check.
Sensor proteins become activated.
Opening of BAX/BAK channel will release cytochrome c in cell.
B-cell (follicular) lymphoma loss of apoptosis response by overexpression
of BCL2 gene because BCL2 gene is brought under control of the promotor of
the heavy chain of immunoglobulin.
Death receptor (extrinsic) pathway
o Many cells express surface molecules, called death receptors, which trigger
apoptosis.
o Type 1 TNF receptor or FasL receptor
o Cytotoxic T cells are able to induce apoptosis.
o Leads to induction of caspase 8.
Caspase causes the breakdown of proteins and cytoskeleton and activation of enzymes
including endonuclease.
, Eventually both pathways stimulate the activation of enzymes called caspases.
- Execution phase and clearance
o
Mechanisms of cell injury and cell death: general principles
- The cellular response to injurious stimuli depends on the type of injury and its duration and
severity.
- The consequences of an injurious stimulus also depend on the type of cell and tis metabolic
state, adaptability and genetic makeup.
- Cell injury usually results from functional and biochemical abnormalities in one or more
essential cellular components
Mitochondrial dysfunction and damage
- Failure of oxidative phosphorylation, leading to: decreased ATP generation and ATP depletion
o Reduced activity of plasma membrane ATP-dependent sodium pumps
o Increase in anaerobic glycolysis
o Structural disruption and of the protein synthetic apparatus
- Abnormal oxidative phosphorylation leads to the formation of reactive oxygen species (ROS)
o Free radicals
o Many circumstances involve damage by free radicals:
Chemical/radiation injury, hypoxia, cellular aging, injury by inflammatory
cells, ischemia-reperfusion injury
o The accumulation of ROS is determined by their rates of production and removal
DNA damage
- Mutations and DNA breaks
- Indirect: ROS generation
- Direct effects of radiation or chemotherapeutic agents
- Lead to p53 accumulation => cell cycle arrest or triggers apoptosis
ER stress
- The accumulation of misfolded proteins in a cell can stress compensatory pathways in the Er
and lead to cell death by apoptosis
- Causes:
o Infections, changes in intracellular pH and redox state, aging (decreased capacity to
correct misfolding), deprivation of glucose and oxygen
Cellular adaptations to stress
Adaptations are reversible changes in size, number, phenotype, metabolic activity or function
of cells in response to changes in their environment: physiologic or pathologic
Hypertrophy increase in the size of cells, no increase in number of cells
- In tissues with limited capacity for replication (heart)
- May occur in concurrence with hyperplasia
- In pathological conditions:
o In heart hypertrophy can be problematic
Hyperplasia increase in the number of cells, not increase in the size
- Physiologic: e.g. tanner stages
- Pathologic:
o Benign prostate hypertrophy
o Abnormal menstrual bleeding
Atrophy Decrease of tissue due to cell size of cell number
Lecture: introduction
Disease an abnormality that causes loss of health, a set of features (signs, symptoms,
morphological and functional manifestations)
Systematic description:
- Epidemiology
- Cause (etiology)
- Pathogenesis (disease mechanisms)
- Symptoms, manifestations
- Complications & sequelae
- Prognosis
- Mortality
Biopsy process registration of the material that arrives at the department => cutting room =>
cutting => cassettes => tissue processing (=> fixation => dehydration => embedding => paraffin blocks
=> cutting => slides => H&E stain) => evaluation by residents and pathology specialists
Relevant information:
- Diagnosis
o Benign vs malignant
o Type of tumour
- Prognosis
o TNM classification
o Radicality
- Prediction
o Response to treatment
Lecture: Ch1 cell injury, cell death and adaptations
Etiology why a disease occurs.
Pathology essential in understanding disease, but is also the basis for developing rational
treatments.
Describing the organs microscopically
Iosin (C) stains tissue, HE
Lung carcinoma have a EGF mutation and are targetable
Necrosis or apoptosis are two ways for a cell to die.
Causes of cell injury:
- Etiology causes of disease.
o Hypoxia and ischemia
o Toxins
o Infections
o Abnormal immune reactions
o Genetic abnormalities
o Missense mutation
, - Pathogenesis mechanisms of disease, sequence of cellular, biochemical and molecular
events
o Biochemical changes
- Abnormalities in cells and tissues (genes)
o Missense mutation
- Clinical manifestations signs and symptoms of disease
Sequence of events in cell injury and cell death:
- Reversible cell injury:
o Morphologic correlates:
Cell will swell and increase in size when there occurs hypoxia or ischemia.
Fatty cells
ATPase failure leads to disbalance of osmose.
- Irreversible cell injury
o 3 phenomena:
o Inability to restore mitochondrial function.
o Altered structure and loss function of the plasma and intracellular membranes.
o Loss of structural integrity of DNA and chromatin
o => necrosis
Necrosis:
- Fall apart of cell membranes => leakage of enzymes => inflammatory reaction
- Always a pathologic phenomenon
- Morphologic patters
o Some severe injuries result in the death of many or all cells in a tissue or organ due to
ischemia, infection, inflammatory reactions.
Coagulative necrosis
o Usually secondary to ischemia
o Injury of structural proteins, but also of enzymes
o Wedge shape yellow discoloration, firm texture
o Tissue architecture is preserved for at least days after the injury.
o Over time: recruited leukocytes digest dead cells.
o Characteristic of infarcts in all solid organs except the brain
Liquefactive necrosis
o At sites of bacterial infections and sometimes fungal infections
Death tissue is visible as pus or an abscess.
o Ischemic necrosis in CNS
o Finally removed by phagocytes
Caseous necrosis
o Tuberculous infection
o Granulomatous inflammation
Obliteration of tissue architecture, cellular outlines
Granular, amorphous, pink cellular debris
Fat necrosis (saponification)
o Acute pancreatitis
Lipases eat the pancreas.
o Abdominal trauma
o Histology: fat cell necrosis, granular basophilic calcium deposits
Fibrinoid necrosis
o Immune-mediated diseases
o Deposition of immune complexes
, Antigen for example
Necrosis vs apoptosis
- Pro-inflammatory anti-inflammatory
- Pathologic part of normal physiology
- Cellular catastrophe, no regulation cellular suicide, under strict regulation
- Cell contents are released extracellularly cells contents are not released.
- Occurs now and then occurs continuously.
- Induces repair and defence no induction of repair.
Apoptosis programmed cell death, usually part of normal physiology.
- Cells activate enzymes that degrade their own nuclear DNA.
- Phagocytosis removes the apoptotic cell.
- Causes of apoptosis
o Physiologic conditions:
B cells in lymph node => Antibody formation
During embryogenesis
o Pathologic conditions:
DNA damage
Accumulation of misfolded proteins
infections
2 pathways:
o Regulated by biochemical pathways that control the balance of death- and survival-
inducing signals and ultimately the activation of enzymes called caspases.
Mitochondrial (intrinsic) pathway
o Responsible for apoptosis in most physiologic and pathologic situations
o Cytochrome c
Electron transport
Induction of apoptosis
Activates caspases 9.
o BCL2 (anti-apoptotic protein)
Important regulator
Keeps BAX or BAK in check.
Sensor proteins become activated.
Opening of BAX/BAK channel will release cytochrome c in cell.
B-cell (follicular) lymphoma loss of apoptosis response by overexpression
of BCL2 gene because BCL2 gene is brought under control of the promotor of
the heavy chain of immunoglobulin.
Death receptor (extrinsic) pathway
o Many cells express surface molecules, called death receptors, which trigger
apoptosis.
o Type 1 TNF receptor or FasL receptor
o Cytotoxic T cells are able to induce apoptosis.
o Leads to induction of caspase 8.
Caspase causes the breakdown of proteins and cytoskeleton and activation of enzymes
including endonuclease.
, Eventually both pathways stimulate the activation of enzymes called caspases.
- Execution phase and clearance
o
Mechanisms of cell injury and cell death: general principles
- The cellular response to injurious stimuli depends on the type of injury and its duration and
severity.
- The consequences of an injurious stimulus also depend on the type of cell and tis metabolic
state, adaptability and genetic makeup.
- Cell injury usually results from functional and biochemical abnormalities in one or more
essential cellular components
Mitochondrial dysfunction and damage
- Failure of oxidative phosphorylation, leading to: decreased ATP generation and ATP depletion
o Reduced activity of plasma membrane ATP-dependent sodium pumps
o Increase in anaerobic glycolysis
o Structural disruption and of the protein synthetic apparatus
- Abnormal oxidative phosphorylation leads to the formation of reactive oxygen species (ROS)
o Free radicals
o Many circumstances involve damage by free radicals:
Chemical/radiation injury, hypoxia, cellular aging, injury by inflammatory
cells, ischemia-reperfusion injury
o The accumulation of ROS is determined by their rates of production and removal
DNA damage
- Mutations and DNA breaks
- Indirect: ROS generation
- Direct effects of radiation or chemotherapeutic agents
- Lead to p53 accumulation => cell cycle arrest or triggers apoptosis
ER stress
- The accumulation of misfolded proteins in a cell can stress compensatory pathways in the Er
and lead to cell death by apoptosis
- Causes:
o Infections, changes in intracellular pH and redox state, aging (decreased capacity to
correct misfolding), deprivation of glucose and oxygen
Cellular adaptations to stress
Adaptations are reversible changes in size, number, phenotype, metabolic activity or function
of cells in response to changes in their environment: physiologic or pathologic
Hypertrophy increase in the size of cells, no increase in number of cells
- In tissues with limited capacity for replication (heart)
- May occur in concurrence with hyperplasia
- In pathological conditions:
o In heart hypertrophy can be problematic
Hyperplasia increase in the number of cells, not increase in the size
- Physiologic: e.g. tanner stages
- Pathologic:
o Benign prostate hypertrophy
o Abnormal menstrual bleeding
Atrophy Decrease of tissue due to cell size of cell number
