MoD Session 1: cell injury Flashcards
Causes of cell injury and death
Hypoxia Toxins Radiation Microorganisms Immune mechanisms (autoimmune, hypersensitivity) Dietary deficiency or excess Genetic abnormalities Physical agents: trauma, extreme temperature, pressure, electric current
What is the result of hypoxia and how does tolerance vary between cells?
Reduced aerobic respiration.
Fibroblasts can tolerate it for a few hours, neurones only a few minutes
What are the causes of hypoxia?
- Hypoxaemic hypoxia: at altitude or reduced oxygen absorption in lungs
- Anaemic hypoxia: less ability of Hb to carry oxygen due to anaemia or carbon monoxide poisoning
- Histiocytic anaemia: problem with oxidative phosphorylation enzymes e.g. cyanide poisoning
- Ischaemic hypoxia: interruption to arterial blood supply or decreased venous drainage. Reduces oxygen and metabolic substances so injury more rapid and severe
What toxins can cause cell injury?
Glucose and salt in hypertonic solutions High oxygen Insecticides, herbicides, pollutants etc Asbestos Narcotics, alcohol, medicines
Hypersensitivity reactions?
Host tissue damaged after overly vigorous immune reaction, e.g. urticaria (hives)
Autoimmune reactions?
Immune system fails to distinguish self from non-self, e.g. Grave’s disease
What are the targets for cell damage?
Membranes
Nucleus
Proteins
Mitochondria
Describe the events in reversible hypoxic injury
Decreased oxidative phos so decreased ATP
Loss of activity of Na+/K+ ATPase (as needs ATP)
[Na+]i increases, water enters, cell swells
Ca2+ enters, damages cell components
Anaerobic glycolysis produces lactate-affects enzymes as low pH
Ribosomes detach from ER causing disrupted protein synthesis
Describe irreversible hypoxic injury
Not known exactly when injury becomes irreverible
Accumulation of Ca2+ causes activation of enzymes
Lysosomes are broken down and release more lytic enzymes
All cell membranes are damaged and start to show blebbing, and at some point die
Which enzymes does Ca2+ activate in irreversible hypoxic injury?
ATPases (decreases ATP further)
Phospholipases (more membrane damage)
Proteases (break down membranes and cytoskeletal proteins)
Endonucleases (damage DNA)
Ischaemia-reperfusion injury?
Blood flow returned to tissue that has had ischaemia but not yet necrotic, damage can be worse than if blood not restored
May be due to:
1. Increased production of free radicals with the reoxygenation
2. More neutrophils causing more inflammation and injury
3. Activation of the complement pathway
What are free radicals and when are they produced?
Molecules with a singular unpaired electron (so unstable)
Produced in: chemical/radiation injury, cellular ageing, ischaemia reperfusion, high oxygen concentrations
OH radical (hydroxyl radical): most dangerous
O2- (superoxide)
H2O2 (hydrogen peroxide)
Produced in Fenton reaction: Fe2+ + H2O2 –> Fe3+ + OH- + hydroxyl radical
Also in Haber-Weiss reaction: O2 radical + H+ + H2O2 –> O2 + H2O + hydroxyl radical
Effects of free radicals?
Chain reactions causing production of more free radicals Lipid peroxidation of cell membranes Damaged proteins, CHOs and nucleic acids Kill bacteria Used in cell signalling
Antioxidant system
Superoxide dismutase: makes O2- into H2O2 so less damaging
Catalases and peroxidases: make H2O2 into O2 + H2O
Free radical scavengers: vitamins A,C,E and gluathione
Storage proteins
Heat shock proteins
Unfoldases or chaperones
E.g. ubiquitin
Mend misfolded proteins and maintain cell viability
Triggered by any form of injury
Dye exclusion technique
Morphological criteria for light microscopy to see if cell dead: put dye in cells medium and if cell takes it up cell is dead because membrane is permeable to something it wouldn’t normally be
Cytoplasmic changes seen with cell swelling from oncosis light microscope
Decreased staining of cytoplasm due to H2O accumulation (reversible)
then
Increased staining due to loss of ribosomes from the ER (irreversible)
May also see abnormal intracellular accumulations
Nuclear changes seen with cell swelling from oncosis light microscope
Chromatin subtly clumped (reversible)
then
Pyknosis (shrinkage), karryohexis (fragmentation), and karryolysis (dissolution) (irreversible)
Reversible changes seen with electron microscope
Swelling
Cytoplasmic blebs
Clumped chromatin
Ribosome separation from ER
Irreversible changes seen with electron microscope
Swelling Nuclear changes: pyknosis, karryohexis, karryolysis Membrane defects Swelling and rupture of lysosomes ER lysis Amorphous densities in mitochondria
Oncosis?
Cell death with swelling. Spectrum of changes prior to cell death. Morphologically most cells die by karyohexis or karyolysis
Apoptosis?
Cell death with shrinkage induced by a regulated intracellular program. Membrane integrity preserved
Physiological apoptosis?
Normal response to maintain steady state. Cytotoxic T cell killing.
Occurs in embryogenesis (limb sculpting) and insect metamorphis
Process pathological apoptosis
Initiation: caspase activation
Execution: shrinkage, budding, chomatin condensation, see apoptotic bodies
Degradation: express molecules on surface that induce phagocytosis. No inflammation
Important apoptotic molecules
p53: mediates apoptosis when DNA damaged
cytochome C, APAF 1, caspase 9: apoptosome
Bcl-2: prevents cytochrome C release from mitochondria so inhibits apoptosis
TRAIL: death ligand
TRAIL-R: death receptor
caspases: effector molecules of apoptosis
Necrosis?
Morphological changes that occur after a cell is dead for some time. An appearance not a process: due to progressive degradation by enzymes
Main types coag and liq
Coagulative necrosis?
Mainly denaturation of proteins. ‘Ghost outline’ of cells as slightly preserved.
Proteins become less soluble
Incites acute inflammation: neutrophils then phagocytes
Liquefactive necrosis?
Mainly active enzyme degradation. Enzymatic digestion (liquefaction) of tissues.
Seen in massive neutrophil infiltration (e.g. abscess) as neutrophils release proteases
Seen in brain as fragile tissue without robust collagen network
Tissue becomes a viscous mass so actue inflammation so pus
Caseous necrosis?
‘Cottage cheese’
Amorphous debris
Seen in infections especially TB
Fat necrosis?
Destruction of adipose tissue
Often in acute pancreatitis: release lipases from injured acinar cells
Act on fat in abdominal cavity, release of free FAs, react with Ca2+ to form chalky deposits
Seen on X-rays and with naked eye in surgery/autopsy
Can occur after direct trauma to fatty tissue
Gangrene?
Often seen in ischaemic limbs, tissue can’t be saved
Not a type of necrosis but a clinical term to describe necrosis visible to the naked eye
Dry gangrene?
Exposure to air causes drying of necrosis
E.g. dry crisp appearance of umbilical cord stump after birth, gangrenous toes, autumn leaves
Wet gangrene?
Infection with a mixed bacterial culture, liquefactive necrosis, very serious as bacteria can cause septicaemia.
Gas gangrene a form of this: tissue infected with anaerobic bacteria, produces visible and palpable gas bubbles. E.g. limb crushed in an accident, tissue loses blood supply becoming necrotic, anaerobic bacteria enter
Infarction?
Ischaemia that causes necrosis.
Causes: thrombosis, embolism, compression of a vessel or twisting of vessels
Colour indicates how much haemorrhage in the infarct
Consequences depend on alternative blood supply, ischaemia spread, hypoxia vulnerability and O2 of blood
White infarct?
In ‘solid’ organs with good stromal support, after occlusion of an end artery
Limited bleeding from capillaries due to solidity
Tissue supplied by end artery dies and pale
Mostly wedge-shaped with occluded artery at apex
Usually coagulative
In HEART, SPLEEN and KIDNEYS
Red infarct?
Bleeding into dead tissue
In organs with dual blood supply, main artery occuluded, second artery insufficient to rescue tissue but allows some blood to enter. E.g. LUNG
Numerous anastomoses e.g. INTESTINES
Loose tissues e.g. LUNG where poor stromal support for capillaries
Where previous congestion occurred
Raised venous pressure, transmitted to capillary bed, infarction then engorged with blood
Molecules released by injured cells?
Potassium
Enzymes
Myoglobin
Abnormal cellular accumulations
Carbohydrates
Water and electrolytes
Lipids: steatosis (fatty change due to more TAG, increase organ size) and cholesterol (skin and tendons in hyperlipidaemia, also in atheromas as taken up by foam cells)
Proteins: Mallory’s hyaline (abnormal keratin seen in alcoholic liver disease), alpha 1 antitrypsin deficiency (genetic, systemic deficiency so proteases act unchecked on lung breaking down tissue)
Exogenous pigments: carbon/coal dust/soot/tattoos. Phagocytosed by aleveolar marophages but accumulate in lung tissue can cause fibrosis
Endogenous pigmets: lipofuscin (brown, ageing, non injury), haemosiderin (yellow/brown, iron storage), bilirubin (breakdown of haem, toxic, jaundice)
Pathological calcification?
Abnormal deposition of calcium salts in tissues
- Dystrophic: common, local. Atherosclerotic plaques, damaged heart valves (not pulmonary valve), ageing, TB lymph nodes. No abnormality in Ca2+ metabolism. Nucleation of hydroxyapatite crystals, can cause organ dysfunction
- Metastatic: body-wide. Hydroxyapatite crystals deposited in normal tissues when hypercalcaemia due to metabolism issues. Usually asymptomatic but can be lethal
Replicative senescence?
Decrease in replication during cellular ageing. Each replication shortens telomeres, eventually too short to replicate. Germ and stem cells contain telomerase which maintains length
Changes seen in chronic excessive alcohol intake in the liver
- Fatty change: steatosis. Reversible and asymptomatic
- Acute alcoholic hepatitis: direct toxicity of alcohol causes focal hepatocytic necrosis, formation of mallory bodies and neutrophil infiltrate. Fever, liver tenderness and jaundice. Usually reversible
- Cirrhosis: hard, shrunken liver. Micronodule of regenerating hepatocytes surrounded by bands of collagen. Irreversible and sometimes fatal
Enzymes raised in alcoholic liver disease
AST, ALT, albumin, bilirubin, GGT, ALP
Enzymes raised in acute pancreatitis
Bilirubin, AST, ALT: indicate gallstones which are a common cause
Enzymes raised in myocardial infarction
Cardiac troponins-T and I
Creatine kinase-a few hours after
Myoglobin levels after a couple of hours
