Week 2: Cell Injury Flashcards
Rudolf Virchow
Father of cellular pathology
19th century German scientist
“Diseases arise in CELLS, not tissues or organs. Every cell comes from another cell like it”
Revolutionized how we define disease/treat it
Pathogenesis
Mechanism/development of disease
Aortic valve stenosis
Because the valve does not work, the heart must pump HARDER which causes myocytes to become super big.
This adaptation of the heart = injury
Disease
Results when adaptive mechanisms fail OR become harmful
Vulnerable cell components
Cell membrane (critical for ionic/osmotic homeostasis)
Mitochondria (generation of energy via ATP)
Protein synthesis
Cellular DNA
What is atrophy? State its causes.
Decrease in mass due to decrease in cell size
Due to: decreased blood supply, decreased endocrine stimulation, decreased innervation, workload, aging
Lysosomes and ubiquitin-proteasome pathway play a role too; autophagy (the recycling of cellular components)
What is hypertrophy? State its causes and provide a few examples.
Increase in cell size due to the synthesis of organelles/proteins
Due to: Increasing functional demand, hormone stimulation
Uterus in pregnancy, aortic valve stenosis, cardiomegaly
Occurs in conjunction with hyperplasia
Hyperplasia
Increase in cell number
Due to: increased cell division
Breast during pregnancy (hormonal), liver if you cut some of it out (compensatory)
If there is too much estrogen, you make too many cells and cells become unresponsive to cues
Metaplasia
Change to a different cell type
Results in decreased function or increased chances of malignancy (in resp. system, ciliated columnar –> squamous with injury; doesn’t respond to cell signals)
Tissue usually reverts to its resting state if you remove the stimulus
Dysplasia
Abnormal cells from hyperplasia (more division and proliferation) and metaplasia (more change means more room for DNA replication mistakes) that CAN become cancerous
ALWAYS PATHOLOGIC
Duration of Injury vs. Effect
After cell death –> ultrastructural changes –> light micro changes –> gross morphological changes
If someone dies very fast of heart attack, heart will appear normal
If someone dies slowly, you will see necrosis
Reversible Injury
Acute/mild stress or stimulus that is reversible if the stimulus is removed (reduced oxphos, ATP depletion, cellular swelling)
Reversible Injury - Hydropic Swelling
Increase in cell volume. Large, pale cytoplasm, normally located nucleus
Causes: chemical/biological toxin, viral/bacterial infections, ischemia/hypoxia, excessive heat/cold –> causes ion imbalance –> swelling
Impairment of cellular volume regulation causes mitochondria to swell, ER cisternae dilation, blebs on PM
Reversible Injury - Fatty Change (Steatosis)
Disruptions in fatty metabolism following hypoxia/chemical poisoning. Abnormal accumulation of fats
Cause: A) increased delivery of fat (starvation), B) fat metabolism impairment (alcoholism), C) decreased synthesis of transport proteins (CCl4 deficiency)
Alcohol = most common cause (alteration in uptake of fatty acids)
Big vacuoles that push the nucleus out of the way; small vacuoles of fat appear throughout cytoplasm (or form one large vacuole)
Liver, heart, kidney, skeletal muscle
Explain the causes of intracellular accumulations and give an example.
Causes: inadequate rate of metabolism, genetic defects in metabolism, and the presence of abnormal exogenous substances
Steatosis/fatty change
State the causes of intracellular accumulations and provide an example
Due to: Genetic/acquired defects in metabolism
Proteins accumulate if you cannot break them down, causing tissues to break down from too many misfolded proteins
Intracellular Accumulations - Pigments
Can be exogenous or endogenous
Endogenous pigments:
-Lipofuscin (wear and tear)
-Hemosiderin (blood broken down)
-Melanin (skin colour; protects from UV)
Exogenous pigments:
-Smoke (lungs; macrophages gobble up smoke)
-Tattoos (skin; macrophages gobble up ink)
What is ischemia? State some of its causes
Reduced blood flow to tissues downstream. Injures you FASTER than hypoxia (because waste products are not removed/circulated away)
Can lead to hypoxia and cellular swelling
Causes:
-Hypotension
-Vasoconstriction
-Thrombus/embolus
-Atherosclerosis (plaque)
Hypoxia
Reduced state of oxygen availability. Glycolytic energy production continues during hypoxia because it is anaerobic.
Ischemic and Hypoxic Cell Injury Effects
Decreased Oxygen
Decreased ATP (cannot pump ions; sodium accumulates; lactic acid accumulates)
Pump failure (increases calcium = enzymes that attack cellular proteins)
Increased Sodium (rupture cell PM, blebs)
Decreased pH (causes ribosomes to detach from RER, less protein synthesis)
Ischemia-reperfusion Injury
Continued injury AFTER reperfusion (opening up the vessel) due to:
1. Influx of calcium
2. Oxygen free radicals from damaged mitochondria
3. Compromised antioxidant defense mechanisms
4. Inflammation
5. Activation of complement pathway
Irreversible Cell Injury
Acute, severe stress OR prolonged, unrelieved stress
Inability to reverse mitochondrial dysfunction, severe disruption of membrane function
Necrosis
Necrosis is ONLY PATHOLOGICAL insult
Severe/prolonged injury; cell cannot adapt
Morphological changes: eosinophilia, nuclear changes (pyknosis, karyorrhexis, karyolysis), inflammatory infiltration
Pyknosis
Shrinkage of nucleus
Karyorrhexis
Breakup of nuclear material
Karyolysis
Dissolution of the nucleus
Coagulative Necrosis
Most common type of necrosis
Due to: Ischemic injury
Found in: Heart and kidneys because they are closely related to blood flow
Appearance: Pink, pyknosis, karyorrhexis, karyolysis -> ghost cells (no nuclei)
Texture: Firm
What is liquefactive necrosis? State some of its causes and the resulting texture of the tissue.
Digestion of dead cells due to inflammatory response (like basic necrosis) -> only here is there a rapid loss of tissue architecture; the cell turns into mush
Due to: Ischemic injury, bacterial damage -> hydrolytic enzymes act
Found in: CNS, lungs, or in the presence of bacteria
Tissue texture: Mushy
Caseous Necrosis
Cheese-like (goat cheese)
-soft and friable
-Found in tuberculosis!!!!
Fat Necrosis
Enzymes digest fat, which then combines with calcium = white, chalky deposits
Found in: Pancreatitis, breast tissue damage
Enzymes from pancreas leak out
Fibrinoid Necrosis
Fibrin in the blood seeps out the walls of the blood vessel, destroying it
Found in: blood vessels
Gangrenous Necrosis
Occurs in the limbs!!
Is due to compromised vascular supply
-wet gangrene - liquefactive component
-dry gangrene - mummified tissue (dry)
Apoptosis
Programmed cell death that can be physiologic OR pathologic
-ATP dependent process
-uses caspases and endogenous endonucleases to break down cell nucleus and cytoskeleton
-apoptotic cells are engulfed by phagocytic cells
-TIGHTLY regulated
Characterized by nuclear dissolution without complete loss of membrane integrity (cell contents are broken down with the membrane still intact)
Necrosis vs. Apoptosis
-Severe damage = necrosis
-Immune-mediated damage = apoptosis
-ATP gets too low = necrosis
-Fast cell loss/turnover = necrosis
Intrinsic Mechanism of Apoptosis
Mitochondrial pathway (BCL2 activation)
Extrinsic Mechanism of Apoptosis
Death receptor pathway (TNF, executioner caspases, phagocytes)
Calcification
Physiologic or pathologic; could be malignant or dystrophic if pathologic
Dystrophic Calcification
-Deposition of calcium in necrotic or degenerative tissue
-You can have normal calcium levels in the blood because the problem is that the calcium is even going to those tissues in the first place, not the amount of calcium
Malignant Calcification
-Deposition of calcium in normal tissue
-High blood calcium levels (problem is with the very high CALCIUM levels, not the TISSUE)
-E.g. happens due to increased parathyroid hormone
