Cell Injury Flashcards
Define the term ‘disease’
Disease - a consequence of failed homeostasis
Describe the terms ‘hypoxaemia’, ‘anaemic’ ‘ischaemic’ and histiocytic’ in terms of hypoxia
Hypoxaemic - arterial content of oxygen is low e.g. reduced inspired oxygen at altitude
Anaemic - decreased ability of Hb to carry oxygen e.g. anaemia, carbon monoxide poisoning
Ischaemic - interruption to blood supply e.g. blockage of a vessel, heart failure
Histiocytic - inability to utilise oxygen in cells due to disabled oxidative phosphorylation enzymes e.g. cyanide poisoning
List the causes of cell injury and death
Hypoxia (hypoxaemic, anaemic, ischaemic, histiocytic), toxins, heat, cold, trauma, radiation, microorganisms, immune mechanisms, dietary insufficiency or deficiency, genetic abnormalities
Define the terms ‘oncosis’, ‘necrosis’ and ‘apoptosis’
Oncosis - cell death will swelling, the spectrum of changes that occur in injured cells prior to death
Necrosis - the morphological changes that follow cell death in living tissue
Apoptosis - programmed cell death with shrinkage, a cell activates enzymes that degrade its own nuclear DNA and proteins
Describe the cellular events associated with apoptosis
Initiation:
Apoptosis is triggered by two mechanisms (intrinsic and extrinsic) which culminate in the activation of caspases. Caspases are proteins that mediate the cellular effects of apoptosis. They cleave proteins, breaking up the cytoskeleton and initiating degradation of DNA.
Execution:
Intrinsic - all the apoptosis material is within the cell –> release of cytochrome c from mitochondria which interacts with APAF1 and caspase 9 to form an apoptosome that activates downstream caspases.
Extrinsic - caused by external ligands such as TRAIL and Fas that bind to death receptors –> caspases activation independently of mitochondria.
Degradation:
The cell breaks into membrane bound fragments called apoptotic bodies. They induce phagocytosis.
Describe the structural changes of apoptosis - microscopic, electron microscopic
Microscopic - shrunken apoptotic cells, intensely eosinophilic, cell shrinkage, chromatin condensation, pyknosis, nuclear fragmentation.
Electron microscopic - cytoplasmic blebbing, apoptotic bodies contain cytoplasm, organelles and nuclear fragments.
Describe the cellular events associated with the two main types of necrosis
Coagulative - denaturation of proteins dominates over release of active proteases, dead tissue has a solid consistency, cellular architecture creates a ‘ghost outline’, incites acute inflammatory response
Liquefactive - active enzyme degradation dominates denaturation, enzymatic digestion of tissues, seen in massive neutrophil infiltration, bacterial infections
Describe caseous and fat necrosis
Caseous - cheesy appearance, amorphous debris, associated with granulomatous inflammation, associated with TB
Fat - destruction of adipose tissue, releases free fatty acids which can react with calcium to leave chalky deposits (calcium soaps) in fatty tissue, consequence of acute pancreatitis (release of lipases from acinar cells), can occur after direct trauma to fatty tissue e.g. breast (leaves an irregular scar that mimics a nodule of breast cancer)
Describe reversible hypoxic injury
Lack of oxygen –> decreased production of ATP by oxidative phosphorylation
Loss of activity of Na+/K+ pump –> cell and organelles swell up, Ca2+ damages cell components
Accumulation of lactic acid –> reduces pH –> chromatin clumping
Ribosomes detach from ER –> disrupted protein synthesis –> intracellular accumulations of fat, denatured proteins
Describe irreversible hypoxic injury
Massive cytosolic accumulations
Potent enzymes activated - ATPases (decrease ATP), proteases (breakdown membranes and cytoskeleton proteins), endonucleases (damage DNA)
Intracellular substances leak out into the circulation
Explain how free radicals cause cell damage
Free radicals are reactive oxygen species with a single unpaired ion. They are particularly released in chemical and radiation injury, ischaemia reperfusion injury, cellular aging and at high oxygen temperatures.
Free radicals attack lipids in cell membranes (lipid peroxidation), damage protein and nucleic acid, are mutagenic.
Three important free radicals are OH., H2O2-, O2-
Describe the anti-oxidant system
Enzymes (SOD, catalases, peroxidases)
Free radical scavengers (vit. A, C, E, glutathione)
Storage proteins - transferrin, ceruloplasmin (sequester transmission metals)
Explain the changes to cells during cell injury microscopically
Light microscope - reduced pink staining (accumulation of water), followed by increased pink staining (detachment and loss of ribosomes), clumped chromatin, pyknosis, karryohexis, karryolysis
Electron microscope - swelling, cytoplasmic blebs, clumped chromatin, ribosome separation, nuclear changes, swelling and rupture of lysosomes, myelin figures
Which cellular changes are reversible and which are irreversible
Reversible - reduced pink staining, chromosome clumping, swelling, cytoplasmic blebs, ribosome separation.
Irreversible - accumulation of denatured proteins, pyknosis, karryohexis, karryolysis, myelin figures, lysis of ER
Define the terms ‘pyknosis’ karryohexis’ and ‘karryolysis’
Pyknosis - nuclear shrinkage
Karryohexis - nuclear fragmentation
Karryolysis - nuclear dissolution
Explain the difference between a red and white infarct
Red - extensive haemorrhaging into dead tissue (dual blood supply, numerous anastomoses, loose tissue, raised venous pressure e.g. in lungs
White - in solid organs after occlusion of an end artery, limits amount if haemorrhage, wedge shapes, coagulative necrosis e.g. in heart, spleen, kidneys
Explain the histological and biochemical consequences of chronic, excessive alcohol intake and aspirin and paracetamol overdose
Alcohol - ethanol –> acetaldehyde (alcohol dehydrogenase, cytochrome p450 enzyme CYP2E1) –> acetic acid (aldehyde dehydrogenase). Metabolic tolerance occurs due to induction to CYP2E1. Leads to hepatomegaly, acute alcohol hepatitis (jaundice, fever, mallory body), cirrhosis (micronodules of regenerating hepatocytes surrounded by bands of collagen).
Aspirin - acetylates platelet cyclooxygenase, blocks platelets’ ability to make thromboxane A2 (which activates aggregation). Leads to respiratory alkalosis, increase in lactate, pyruvate, ketone bodies, acute erosive gastritis –> GI bleeding.
Paracetamol - detoxified by sulphonation, glucuronidation, metabolised by CYP 2E1 to NAPQI. NAPQI is detoxified by glutathione. Overdose - glutathione depletes, NAPQI accumulates, binds with sulphydryl groups on liver cell membranes –> hepatocytes necrosis, liver failure. Antidote (NAC) increases availability of hepatic glutathione. Prothrombin time is a guide to liver damage severity.
Explain abnormal cellular accumulations
Lipids:
Steatosis - accumulation of triglycerides, liver steatosis due to alcohol abuse, diabetes mellitus, obesity, toxins.
Cholesterol - accumulates in smooth muscle cells and macrophages within atherosclerotic plaques, skin, tendons.
Proteins:
Mallory’s hyaline - altered keratin filaments, seen in hepatocytes in alcoholic liver disease
a1 antitrypsin deficiency - incorrectly folded protein can’t be packaged by ER so accumulates, patents develop emphysema
Pigments:
Exogenous - carbon/coal dust causes blackened lung tissue –> fibrotic lungs, tattoos
Endogenous - lipofusin (brown pigment in ageing cells), haemosiderin (yellow/brown, bruises), billirubin (bile pigment causes jaundice)
Explain the term ‘gangrene’
A clinical term used to describe necrosis visible to the naked eye.
It can be dry (coagulative) or wet (liquefactive).
Wet gangrene can lead to septicaemia.
Gangrenous tissue is dead and cannot be salvaged.
