Flashcards in Cell Injury 2 Deck (21)
CAUSES OF CELL INJURY
-Immunologic reactions- The body's immune system defends against pathogens but also causes cell injury when it reacts. Autoimmune diseases can occur in reaction to endogenous self antigens.
-Nutritional deficiencies and imbalances.
TARGETS OF CELLULAR INJURY
-DECREASED ENERGY PRODUCTION- Decreased ATP, can be due to mitochondrial damage. Decreased ATP has multiple downstream effects, mitochondrial damage causes leakage of proapoptotic proteins.
-CALCIUM HOMEOSTASIS- Entry of Ca in to cells causes increased mitochondrial permeability and activation of multiple cellular enzymes.
IMPORTANT IN TRANSITION FROM REVERSIBLE TO IRREVERSIBLE CELL DAMAGE.
-OXIDATIVE DAMAGE- Increases ROSs, leading to damage of lipids, proteins and DNA.
-MEMBRANE DAMAGE- Reduced membrane integrity of plasma and lysosomal membranes leads to loss of cellular components and enzymatic digestion of cellular components by released lysosomal enzymes.
-DNA DAMAGE- Causes activation of proapoptotic proteins.
-PROTEIN MISFOLDING- Due to stress on ER, also leads to activation of proapoptotic proteins.
The above mechanisms do not all occur at the same time.
REVERSIBLE CELL INJURY
Cells can recover if injurious stimulus is removed.
A decrease in cell function is seen.
IRREVERSIBLE CELL INJURY
Cell function has decreased to the extent that the cell can no longer recover.
Progressive increase in biochemical alterations eventually lead to cell death.
Increasing ultrastructural changes.
Increasing light microscopic changes.
Increasing gross morphologic changes.
(Not all at same time! Timeline- See lecture slide 7)
Caused by increased Ca in to cell, increased ROSs from oxidative stress, lipid peroxidation.
Causes a DECREASE in ATP production.
1. Mitochondrial permeability transition -> loss of membrane potential -> inability to generate ATP -> NECROSIS
2. Leakage of cytochrome c and other proapoptotic proteins -> APOPTOSIS.
DECREASED ATP PRODUCTION
Leads to a decrease in critical function of cell.
-Impaired fucntion of Na/K pump.
-Increased glycolysis -> decreased pH -> chromatin clumping.
-Decreased protein synthesis.
-Release of proapoptotic factor cytochrome c.
Important part of oxidative phosphorylation; involved in electron transfer.
Becomes proapoptotic if it enters the cytoplasm (ie. in cell injury)
Injury to a cell causes hypoxia, leading to reduced ATP production and a malfunctioning Na/K pump.
Na and water pass in to cell, K moves out. This INCREASES OSMOTIC PRESSURE, which draws more water in to the cell.
The cisternae of the ER distend and rupture to form vacuoles, and the cytoplasm swells.
Entry of much water in to the cell causes degeneration.
HYDROPIC DEGENERATION- GROSS APPEARANCE
Organs are enlarged, pale and turgid.
HYDROPIC DEGENERATION- MICROSCOPIC DEGENERATION
Pale, finely vacuolated cytoplasm- Cloudy swelling.
Nuclei often remain central.
Organelles swell and disintegrate
eg. Dog with hepatocutaneous syndrome. Cellular imbalances lead to liver degeneration (hepatocellular hydropic degeneration) and skin lesions.
Hepatocyte swelling is seen microscopically.
Extreme hydropic degeneration. Cytoplasm appears as clear, swollen space.
Swollen, degenerated cells.
WHAT HAPPENS TO INTRACELLULAR Ca ON CELL INJURY?
It increases in response to injury.
-Sources: Extracellular space, mitochondria and smooth endoplasmic reticulum.
-Consequences: Activation of cellular enzymes- Phospholipase, proteases, endonucleases, ATPase.
-Outcomes- Membrane damage, nuclear damage and AP depletion.
This is cell injury induced by free radicals/reactive oxygen species (ROSs)
ROS: Superoxide anion
A partial reduction in the oxygen concentration supplied to cells or tissues.
Anaerobic glycolysis continues during this.
Complete reduction in oxygen concentration supplied to cells or tissues.
HEPATOCYTE SENSITIVITY TO HYPOXIA
Hepatocytes (liver cells) are made up of of hexagonal shaped lobules, with a central vein and peripheral triads.
Triads are made up of a branch of the hepatic artery, portal vein, and a bile ductule.
Zone 1- Outer zone, nearest to triad.
Zone 2- Middle.
Zone 3- Centrilobular.
AS WE MOVE FROM ZONE 1 TO ZONE 3, SENSITIVITY TO HYPOXIA INCREASES.
HEPATIC CIRCULATORY DISTURBANCES
1. PASSIVE VENOUS CONGESTION- Increased pressure in hepatic veins and venules, relative to portal venules.
Possible causes- Congestive heart failure (underlying cardiac or pericardial disease)
- Partial obstruction of larger hepatic veins or caudal vena cava (eg. due to abscess, neoplasm, thrombus, heartworm disease (dirofilariasis)).
2. CHRONIC PASSIVE CONGESTION- Nutmeg liver. Red central zones of congestion with loss of hepatocytes (necrosis)
Pale swollen periportal hepatocytes with fatty degeneration.
Particularly seen in ruminants and horses.
3. ACUTE PASSIVE CONGESTION- Sudden engorgement with blood (eg. due to shock, anaphylaxis or other acute insults)
Reduction or loss of blood supply.
Can be partial- Due to local impairment of blood flow.
Or complete- Due to total impairment of blood flow.
-Mechanical interference with blood flow caused by space-occupying lesions compressing blood vessels, or by displacement of organs causing stretching and torsion of vessels with impairment of blood flow.
Necrosis caused by ischaemia.
Renal infarcts have a typical wedge shape in gross cross section, with a pale central necrotic area and peripheral haemorrhagic area.
Caused by ischaemia.
Ischaemia causes hypoxia and loss of cell volume regulation -> calcium influx due to inadequate ATP to run ion pumps.
If blood flow is restored, there is a MASSIVE INFLUX OF CALCIUM.
Damage is often accelerated- White blood cell influx, plasma protein influx, complement cascade, added membrane damage.