What is the mechanism of ischemia- reperfusion injury?
increased ROS from inflammatory cells –> compromised antioxidant defense –> increased inflammation from leukocyte influx and compliment system activation
What is ischemia reperfusion injury?
O2 is restored following ischemia
Inflammatory response worsens situation by increasing ROS
What is the direct cytotoxic effect?
Chemical injury- inhibits cellular transport and increases membrane permeability
What is indirect toxicity?
Chemical injury- chemicals converted into toxic metabolites then act on target cells
What is Necrosis?
pathological messy cell death
What causes necrosis?
ischemia, toxins, infections, and trauma
What happens with necrosis?
cell membrane loses integrity
contents leak out
inflammatory response reacts to remove dead cells
Morphologic changes in necrosis:
eosinophillic staining glassy homogenous appearance Vacuolated cytoplasm (moth eaten look) myelin figures in cytoplasm (whorl like structures from damaged membranes) nuclear dissolution
then phagocytosis
Necrosis changes include:
Karyolysis: chromatin fades (DNAase activity)
Pykonosis: Nucleus shrinks
Karyorrhexis: nucleus fragments
What is autophagy?
“to eat oneself”
digested of dead cells mediated by lysosomes
What is heterophagy?
Digestion within the invading inflammatory cell
substance taken in by phagocytosis
What is dystrophic calcification?
If necrotic cells are not eliminated they attract calcium and other minerals leading to calcification
Types of Necrosis:
Coagulative necrosis: Phagocytosis- common in ischemia and infarction.
Liquefactive necrosis: Enzyme digestion by lysosomes. Focal bacteria and fungal infections.
Gangrenous necrosis: Can be coagulative (limbs due to ischemia) or liquefactive necrosis (wet gangrene).
Caseous necrosis: cheesy yellow white necrosis enclosed within granulomatous ring of inflammatory cells.
Fat Necrosis: Fat destruction. Chalky white
Fibrinoid Necrosis: In blood vessels. Immune reactions- Antigen-AB complexes deposit in arteries.
What is apoptosis?
Clean programmed cell death (“cell suicide”)
no inflammatory reaction
Apoptotic Pathway:
death ligand binds to death receptor on membrane –> TNF (tumor necrosis factor) secreted –> Cytochrome c activates caspases –> pro-apoptotic pathway initiated –> DNA damage + nuclear fragmentation –> cell death.
What are anti-apoptotic sensors?
growth factors that prevent apoptosis
What can intracellular accumulations cause?
reduced metabolic rate
Genetic/ acquired defects in metabolism
inherited defective enzyme (fail to degrade a metabolite)
Lack of enzymatic machinery to degrade exogenous substance
What is Steatosis (fatty changes)?
Abnormal accumulations of triglycerides
causes: toxins, diabetes mellitus, alcohol abuse, etc.
What are cholesterol and cholesteryl esters?
accumulations in phagocytic cells or macrophages.
foam cells accumulate
What are xanthomas?
accumulations in foam cells in skin or tendons
What is more common: protein or lipid accumulations?
Protein
Examples of protein accumulations:
Nephrotic syndrome
Mallory body in alcohol liver disease
Alzheimer’s disease
Histological appearance of protein accumulations:
pink hyaline cytoplasmic droplets
Where can glycogen accumulate in diabetes mellitus?
Renal tubular epithelium, cardiac monocytes, and B cells of islets of langerhans
