Cell Death and Perfusion Disorders 1 Flashcards
What is a malfunctioning organ the product of?
Malfunctioning cells.
-may not malfunction organ or cause dx
Why don’t malfunctioning cells always result in a malfunctioning organ?
- redundancy in structure and function
- self correcting physiologic/metabolic feedback loops
Define pathogenesis
How a disease state develops
Define degeneration
Cell injury that falls short of cell death, usually reversible
Define programmed cell death (PCD)
Regulated, controlled cell death. Not messy, doesn’t stimulate inflammatory response.
Define apoptosis
A specific form of PCD, may be pathological or physiological.
Define necrosis
Pathological cell death in the tissues of a living animal due to lethal cell injury.
Define autolysis
Cell death that occurs after an animal dies.
Define putrefaction
Bacterial lysis and fermentation of tissue in a dead animal.
What does the cellular response depend on?
The type, duration, and severity of the injurious stimulus, and the type of cell.
How are metabolically active cells susceptible to injury?
Constant import, export and synthesis of molecules. Sublethal injury may shift metabolic pathways such that these molecules accumulate in large amounts, called intracellular inclusions.
What is the pathway caused by an intracellular inclusion?
ATP -> reduction in Na+ K+ ATPase, H2O influx, cell swelling.
Are all intracellular inclusions the result of cell damage?
No, many accumulate in cells carrying out normal functions, such as hepatocytes and macrophages, and in aging cells, or they are biological agents.
What are the 6 mechanisms of cell accumulation?
- increased biosynthesis
- decreased excretion/secretion
- diminished intracellular consumption
- reduced metabolism/decreased transformation of a precursor molecules into its product, resulting in an accumulation of the precursor
- Increased uptake from the extracellular compartment
- Inability to enzymatically degrade endogenous or exogenous (phagocytosed substances)
What are some examples of extracellular material?
- normal cellular molecules accumulated to excess
- foreigh substances such as exogenous non-degradable material
- pigments
- metal ions that accumulate to excess or are not excreted properly
- calcium in necrotic cells
- microbial structures
What are some normal cellular molecules that may accumulate in excess?
water (cell swelling), lipids, glycogen, proteins, carbohydrates
Give 2 examples of foreign substances that are exogenous, non-degradable material
Carbon from smoke (anthracosis), inhaled mineral particles (pneumoconiosis)
Give examples of pigments (intracellular material)
- products of normal metabolism (bilirubin, hemosiderin) that are normally mobilized and disappear over time
- products of normal metabolism/catabolism that accumulate (ceroid, lipofuscin -aging pigments) and are stored
How does hepatic lipidosis (fatty liver) occur?
Sublethal injury: cells lose ability to properly process and export fats - so triglycerides accumulate in vacuoles in the cytoplasm.
-fatty acids taken up, may turn to triglycerides but need apoprotein, rate limiting step to turn to lipoprotein to be stored, accumulate TGLs if not enough apoprotein
What does fat metabolism require?
- enzymes, ATP, carbohydrate metabolites
- excretion requires apoprotein and lipoprotein synthesis
What is the differences between macrovesicular lipidosis/steatosis and micro vesicular lipidosis/steatosis?
Macrovesicular: single large fat vesicle in cell, nucleus pushed to side but normal nucleus.
Microvesicular: Many small fat vesicles in cytoplasm, nucleus stays in middle.
What is the gross appearance of a fatty liver?
- floats in water, fat floats
- swollen rounded edges, enlarged
- yellow
- greasy, fatty liver
- decreased strength (friable)
- colour and texture of fat and the enlargement of cells are reflected in gross appearance
Is a kidney normally fatty?
In cats, renal cortical tubular epithelial cells are lipidotic so cat kidneys are often pale and yellow
What does physiologic cell death look like?
Normal cell death. One example is skin cells that die as they mature from the dermis. Divide in basal layer and mature as they move up, eventually turn to keratin.
What are the causes of cell injury and death?
- chaotropic chemical and physical insults
- lytic cell insults
- hypoxia and ischemia
- Impaired cell membrane function or integrity
- damage to nucleic acids
- ligand receptor mediated signals
What are examples of chaotropic chemical and physical insults?
Protoplasmic poisons like thermal, caustic, ionic, detergents, etc.
What are examples of lytic cell insults?
Lysis: viral infections
Pores: Complement, cytotoxic T cells, hemolysins
What are hypoxia and Ischemia? What can they cause?
Hypoxia is oxygen deprivation, ischemia is loss of blood supply. These can both cause infarction and severe anemia.
What are examples of things that can cause impaired cell membrane function or integrity?
- phospholipid peroxidation
- phospholipases (bacterial exotoxins)
- Ionophores
What can cause damage to nucleic acids?
genotoxic chemicals, radiation, some viruses, etc
What is an example of a ligand receptor mediated signal?
Fas ligand binding to fas receptor
What are the features of apoptosis?
- cell shrinks
- cytoplasm/organelles -> blebs
- nucleus condenses
- membrane stays intact (entire process stays in membranes)
- membranes become recognizable
- process is orchestrated
- requires energy (ATP) and organization
- mediated by enzymes (caspases)
- stimulates no inflammation
- cellular contents do not leak
What is apoptosis important for?
- involution
- atrophy
- T cell removal
- embryogenesis
- glucocorticoids
- tumours
- Injurious stimuli that are too weak to cause necrosis
What are the four phases of apoptosis?
-signalling
-control/integration
-execution phase
-phagocytosis
no inflammation
Where does apoptosis signalling occur?
Transmembrane or intracellular; numerous signals
What dictates the outcome of the signal in the control/integration phase of apoptosis?
Biochemical integration of pro and anti-apoptotic factors in the cell
What mediates the execution phase of apoptosis?
Death program mediated mainly by caspases; cysteine-aspartic residues, bioamplification system
What occurs in phagocytosis during apoptosis?
Membrane flipping - cell displays signals on the surface to neighbouring cells that say eat me -> phagocytosed.
What are the four main mechanisms of cell injury?
- depletion of ATP
- damage to nucleic acid, especially DNA
- Interference with protein synthesis
- Injury to cell membranes
How does cell injury result in recovery or necrosis?
Degeneration is reversible. Injury can cause swelling of ER and mitochondria, clumping of chromatin. Examples of sublethal injury are hydropic degeneration or fatty degeneration.
If stimulus continues, get swelling and eventually death. ln irreversible injury, also get loss of ribosomes, lysosome rupture, membrane blebs, nuclear condensation which leads to necrosis.
What role does calcium have in injured cells?
Injured cells accumulate calcium. Many cells have loss of membrane integrity resulting in an influx of large amounts of calcium which is toxic to the cell. Can look for calcium inside cell as evidence for necrosis.
What is white muscle disease?
Pale necrotic muscle; granular pallor due to calcium inside dead muscle cells. Gritty to cut.
See basophilic granular calcium in necrotic myofibrils microscopically. White material grossly.
What is dystrophic calcification?
When necrotic tissue calcifies.
How long does it take before the hallmarks of necrosis are visible microscopically?
6 to 8 hours
Do cells that have passed the metabolic point of no return appear necrotic right away?
Not necessarily
What are the microscopic hallmarks of necrosis?
- hypereosinophilia and homogeneity of cytoplasm (look pink, cytoplasm swollen)
- nuclear changes (more important) like pyknosis, karyorrhexis, karyolysis)
Define pyknosis
The most commonly seen nuclear change in necrosis. A shrunken dark blue (hyper chromatic) nucleus. Probably due to tight coiling of DNA at low cellular pH. Cytoplasm intact, indistinct cell borders.
Define karyorrhexis
Fragmentation of the nucleus, seen frequently when necrosis is caused by infectious agents.
Multiple nuclear fragments, dissolution or disruption of cell borders, increased eosinophilia in cytoplasm.
Define karyolysis
Dissolution or fading away of the nucleus, due to dissolution of DNA by DNAases released at low pH. Fragments hard to see.
What are the characteristics of necrosis?
- swells
- coagulates or liquefies
- membrane fragmented
- disorganized, chaotic
- ATP depleted
- contents leak
- Inflammation
- messy
What are the characteristics of apoptosis?
- shrinks
- cytoplasm packed into blebs/bodies
- membrane intact
- organized
- ATP required
- no leaks
- no inflammation
- clean
What starts to infiltrate necrotic tissue?
Leukocytes. They surround the regions of necrosis The line of leukocytes would appear white glossy.
What are the three macroscopic appearances of necrotic tissue?
- coagulation necrosis
- liquefactive necrosis
- caseation necrosis
What are the characteristics of coagulation necrosis?
- retains architectural resemblance to normal
- pale, swollen, friable
What are the characteristics of liquefactive necrosis?
- architecture lost
- pale, liquid but texture may vary
- eg in brain where relatively little ECM or large numbers of neutrophils that may debride tissue
- necrotic tissue becomes liquefied by the action of enzymes released by leukocytes or bacteria, the liquified tissue may leave behind a hollow cavity
- liquefaction also occurs in bacterial infections that produce pus within abscesses by inducing an influx of neutrophils
What are the characteristics of caseation necrosis?
- architecture lost
- dry or cheese like consistency, friable
Do macrophages liquefy dead tissue?
Not usually
What does pus consist of?
Dead leukocytes (mainly neutrophils) and bacteria.
