Lecture 1+2: Cell Injury Flashcards
Cellular responses to stress and injurious stimuli
-homeostasis
-adaptation
-cell injury
-cell death
homeostasis
-cells maintain intracellular environment within range of physiological parameters
adaptation
-cells achieving a new steady state and preserving viability by changing size, number, and form
Adaptation responses
-hypertrophy (size)
-hyperplasia (number)
-atrophy (size)
-metaplasia (form)
-dysplasia (organization)
cell injury
-when cells are stressed to the point where they can NOT adapt
-reversible or subcellular alterations
cell death
-most crucial event in evolution of disease in a tissue or organ
Response of myocardial cells to overload and ischemia
-adaptation: leads to hypertrophy
-cell injury: leads to ischemia, reversible injured monocyte and cell death
Hypertrophy
-increase in the size of cells
=increase in size of organ
*only increase cell size NOT cell number
Hypertrophy affects
-only cells INcapable of dividing
-striated muscle cells in skeletal and cardiac muscle
Hypertrophy causes
-increased workload
-physiological stimuli (estrogen enlarging uterus during pregnancy)
-pathological (hypertension)
Hypertrophy is characterized by
-increase protein synthesis
-mechanical triggers (stretching)
-hormonal triggers
Physiological hypertrophy
-caused by growth signal
-adaptive
pathological hypertrophy
-stress signal (hypertension, MI)
-sarcomere mutation
-decompensation
-maladaptive
Hyperplasia
-increase in NUMBER of cells
-physiologic or pathologic
Hyperplasia examples
-physiologic hormonal
-proliferation of connective tissue during wound healing
-physiologic compensatory
physiologic hormonal hyperplasia
-proliferation of female mammary epithelium during puberty
physiologic compensatory hyperplasia
-regeneration of partially resected liver by remaining haptocytes
Impact of female hormones on mammary gland (PHYSIOlogical)
-estrogen: form TEBs and ductal elongation (puberty)
-progesterone: side branching (adult) and alveologenesis and lactogenic differentiation
-prolactin: alveologenesis and lactogenic differentiation (pregnancy)
Role of hormones in breast cancer (PATHOlogical)
-hormone imbalance?
Atrophy
-shrinkage in cell size due to loss of substance
=smaller organ
Atrophy causes
-decreased workload
-loss of innervation
-reduced blood supply
-inadequate nutrition
-aging (senile atrophy)
Decreased cell size in atrophy is caused by
-increased protein degradation
-reduced protein synthesis
Metaplasia
-reversible
-one adult cell type is replace by another adult cell type
Metaplasia cause
-often response to chronic irritation and inflammation that make cells better able to withstand stress
Metaplasia examples
-Cilliated columnar epithelial cells of trachea and bronchi clear foreign materials and mucous
-REPLACED by squamous epithelial cells in smokers (vit A deficiency)
=coughing and infections
-also barret’s esophagus
barret’s esophagus
?
Dysplasia
-deranged cell growth of specific tissue that results in cells that VARY in SIZE, NUMBER, SHAPE, and ORGANIZATION
-adaptive in that it is potentially reversible after irritating
cause has been removed
-strongly implicated as a precursor (precancerous
lesion) of cancer.
Dysplasia causes
-chronic inflammation and irritation
Dysplasia location
-metaplastic squamous epithelium in respiratory tract and uterine cervix
PAP smear
-early detection of cervical cancer
-look at cervical cells under microscope
-every 3 years starting at age 21
-30-65: every 3-5 years with HPV test
8 Causes of cell injury
- Oxygen deprivation
- Chemical agents – poisons, air pollutants, CO, asbestos
- Infectious agents – viruses, bacteria, fungi, parasites
- Immunological reactions – autoimmune diseases
- Genetic defects – sickle cell anemia, familial hypercholesterolemia
- Physical agents – trauma, heat, cold, electric shock
- Nutritional imbalances
- Aging
Causes of oxygen deprivation
-hypoxia
-ischemia
hypoxia
-oxygen deficiency
-inadequate oxygenation of blood = pneumonia
-reduction in oxygen-carrying capacity of the blood (blood loss anemia or carbon monoxide poisoning in which CO forms stable complex with hemoglobin that prevents oxygen binding
ischemia
-loss of oxygenated blood supply to tissues
nutritional imbalances
-typically indirect causes of injury
-nutritional deficiencies (caloric or vitamin)
-excess nutrition
-diabetes
-artheroclerosis
Diabetes
-can be caused by obesity
-excess blood sugar levels can damage cells
Artherosclerosis
-can be caused by diet rich in fats
-can result in blockage of coronary arteries
Aging
-accumulation of damage by ROS
-loss of telomerase function
Uterus enlargement during pregnancy is mainly caused by:
-hormone-induced hypertrophy of uterus smooth muscle cells
Which of the following may develop into cancer?
-hyperplasia
-hypertrophy
-metaplasia
-hyperplasia and metaplasia
Hyperplasia is likely caused by:
-Increased workload
-Increased growth factors or hormones
-Chronic irritation
-Increased protein synthesis
The liver has a very high capacity to regenerate after surgical
resection. This is caused by:
an increased proliferation of the remaining hepatocytes
Reversible cell injury
-decrease in cell function
irreversible cell injury
-cell death
-structural changes
-microscopic changes
-gross morphologic changes
Metaplasia is a precursor to
-malignancy
-May be caused by reprogramming of stem cells rather than by
transdifferentiation of mature cells
What kind of
metaplasia in
stomach may occur
if pyloric sphincter is weak?
-intestinal metaplasia
Pathologic hyperplasia
– typically the result of excessive hormonal or growth factor
stimulation
– hyperplastic tissue may eventually become malignant
Ischemia in myocardial cells
-noncontractile after 1-2 min
-cell death after 20-30 min
-appear dead by electron microscope at 2-3 hours
-appear dead by light microscope at 6-12 hours
characteristics of REVERSIBLE injury
-cellular swelling
-fatty change
cellular swelling
-result of failure of energy-dependent ion pumps in the plasma membrane
=inability to maintain ionic and fluid homeostasis
fatty change
-occurs in hypoxic injury and various forms of toxic or metabolic injury
-manifested by appearance of small or large lipid vacuoles in cytoplasm
-mainly occurs in cells involved in metabolism such as hepatocytes and myocardial cells
Characteristics of Irreversible injury
-Inability to reverse mitochondrial dysfunction (lack of oxidative
phosphorylation and ATP generation)
-Profound disturbances in membrane function (membrane
dysfunction)
Reversible cell injury mech
-cell is injured
-swelling of ER and mitochondria
-memnrane blebs
-clumping of chromatin
-recovery = normal cell
PIC
Mechanisms of Cell Injury
-ATP depletion
-damage to mitochondria
-influx of calcium
-increased oxidative stress
ATP depletion
-ischemia decreases oxidative phosphorylation in mitochondria
=decrease ATP
=ER swelling, loss of microvilli, blebs (calcium)
=clumping of chromatiin (anaerobic glycolysis decreases pH)
=decrease protein synthesis
Damage to mitochondria by
-increased Ca2+
-ROS
-lipid peroxidation
Damage to mitochondria results in
-necrosis due to inability to generate ATP (loss of membrane potential)
-apoptosis by cytochrome c
2 ways to increase cytosolic calcium concentration
-release from intracellular calcium stores
-influx across plasma membrane
Influx of calcium mech of damage
-activate various enzymes
=decreased ATP, membrane damage, chromatin damage
Increased oxidative stress
-generation of ROS by:
-inflammation
-radiation
-chemicals
-reperfusion injury
PIC
Mechs of OFR and ROS damage
-lipid peroxidation
-DNA fragmentation
-protein oxidation and cross-linking
lipid peroxidation of membranes
-C=C bonds attacked
-peroxidated membrane lipids are less hydrophobic
=converts lipids to detergents
=membrane integrity reduced
DNA fragmentation
-Thymine (per)oxidation: base pairing between T and A altered = mutation from repair
-ssDNA breaks: breakage of phosphodiester backbone = reduced replication and transcription
Protein oxidation and cross-linking (C&M residues)
-altered protein structure
-increased protein degradation
-loss of enzymatic activity
Cellular mechanisms to deal with OFRs and ROS
-superoxide dismutase
-glutathione peroxidase
-catalase
-antioxidants
-sequestration of free ionized iron and copper
superoxide dismutase
radical to peroxide
glutathione peroxidase
catalase
antioxidants
-scavenge (react with) free radicals
-many sold as dietary supplements
-vitamin C and E, B-carotene
sequestration of free ionized iron and copper
-free ionized iron and copper can cause ROS and oxygen free radical production via fenton reaction
-transferrin, ferritin, and ceruloplasmin sequester these metal ions and prevent them from causing ROS and OFR production
Defects in membrane permeability
-mitochondrial, plasma, lysosomal membrane damage
mitochondrial membrane damage
-decreased ATP production
-necrosis and apoptosis
plasma membrane damage
-loss of osmotic balance
-influx of fluids and ions
-loss of cellular contents
lysosomal membrane damage
-leakage of enzymes into cytoplasm
-activation of acid hydrolases in acid pH of injured cells
Apoptosis
-pathway of cell death
-cells destined to die activate enzymes capable of degrading cells DNA and proteins
Physiological causes of apoptosis
-programmed destruction of cells during embryogenesis
-involution of hormone-dependent tissue upon hormone deprivation: endometrial cell breakdown during menstrual cycle
-cell loss in proliferating cell populations: intestinal crypt epithelia
-elimination of potentially harmful self-reactive lymphocytes: before or after their maturation
-cell death induced by cytotoxic T lymphocytes
Pathological causes of apoptosis
-DNA damage
-accumulation of misfolded proteins
-cell injury in infection
-pathological atrophy in parenchymal organs after duct obstruction
Mechanisms of Apoptosis
-intrinsic (mitochondrial)
-extrinsic (death receptor)
Mitochondrial (intrinsic) pathway of apoptosis
-cell injury
-Bcl-2 effectors interact with mitochondria = dysfunction
-release cytochrome c and pro-apoptotic proteins
Death receptor (extrinsic pathway of apoptosis
Dimerization and oligomerization of Bax or Bak
-increases mitochondrial membrane permeability and cytochrome c release
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