MoD Flashcards
What are the eight causes of cell injury?
Hypoxia Toxins Heat Cold Trauma Radiation Micro-organisms Immune reactions
What is hypoxia?
Oxygen deprivation causing atrophy (wasting), cell injury or cell death
What is ischaemia?
Loss of blood supply due to decreased arterial supply or decreased venous drainage
What occurs in cell injury that causes depletion of mitochondrial nucleotides and ATP?
- Decreased oxygen = decreased ATP production in mitochondria
- Loss of activity of Na/K pump = increase in intracellular Na = increased H2O
- Ca enters cell
- Increase in anaerobic respiration = increase in lactic acid = decrease pH = effects enzymes = chromatin clumping
- Ribosomes detach from ER = disruption of protein synthesis
What are free radicals and what are the main three?
Molecules with a single unpaired electron
OH’, O2-, H2O2
What negative effects do free radicals elicit?
Attack lipids in membranes = lipid peroxidation
Damage proteins and nucleic acids = mutagenic
What positive effects do free radicals elicit?
Produced by leukocytes for killing bacteria
What are the four defence mechanisms against free radicals?
- Superoxide dismutase (SOD enzyme) = O2- to H2O2
- Catalases and peroxidases = H2O2 to O2 + H2O
- Savenger radicals = Vitamin A, C, E & glutathione
- Storage proteins sequester transition metals (e.g. Fe and Cu) as they catalyse formation of free radicals
What is the function of heat shock proteins?
Ensure correct refolding of proteins that have undergone denaturing due to cell injury
Define oncosis
Changes that occur in injured cells prior to death
Define necrosis
Morphologic changes that follow cell death, largely due to progressive degradative action of enzymes on cell
Define apoptosis
Cell death induced by regulated intracellular programme - cells activate enzymes that degrade cells’ own nuclear DNA and proteins
What are the cellular events seen in necrosis?
Cell unable to maintain membrane integrity, contents leak out.
Often causes inflammation
Lysosomal enzymes are released
Dystrophic calcification occurs
How is necrotic tissue removed?
Enzymatic degradation & phagocytosis by white cells
What are the two types of necrosis?
Coagulative & Liquifactive
What is coagulative necrosis?
Protein denaturing which then cause clumping and solidity of dead cells
What is coagulative necrosis most common in?
Ischaemia
What is seen under the microscope in coagulative necrosis?
Ghost outline of cells as cellular architecture is preserved
What is liquifactive necrosis?
Release of active enzymes which generate a viscous mass via enzymatic degradation
When is liquifactive necrosis most common?
Associated with massive neutrophil infiltration
Also seen in the brain as it is a fragile tissue with minimal support from robust collagenous matrix
What are the other two, less common, types of necrosis?
Caseous necrosis
Fat necrosis
What is caseous necrosis and when does it occur?
Cheese-like appearance - amorphous debris
Highly associated with TB
What is fat necrosis and when does it occur?
Destruction of adipose tissue
Typically seen with acute pancreatitis (inflammation causes release of lipases)
What can also occur with fat necrosis?
Release of free fatty acids that can react with Ca can causes chalky deposits
What is gangrene?
Term used to describe necrosis visible to the naked eye
What are the two types of gangrene and what causes them?
Dry gangrene - coagulative necrosis - ischaemic limbs
Wet gangrene - liquifactive necrosis - infection
What is an infarction and what are the two types?
Refers to the cause of necrosis
Red or white infarct
What are the most common causes of an infarct?
Thrombosis/embolism, external compression of vessel, twisting of vessel
What occurs in a white infarct and where do they occur?
Coagulative necrosis
Occurs in solid organs with good stromal support, after end artery - limits amount of haemorrhage that can occur
Heart, spleen, kidneys
What occurs in a red infarct?
Extensive haemorrhage into dead tissue
What are the five instances that red infarcts occur?
- Organs with dual blood supply - e.g. lungs
- Where capillary beds of 2 separate arterial supplies merge - e.g. intestines
- Loose tissue - poor stromal support for capillaries
- Previous congestion - e.g. congestive cardiac failure
- Raised venous pressure
What are the cellular events associated with apoptosis?
Nuclear chromatin condensation and fragmentation.
Cytoplasmic budding and phagocytosis of apoptotic bodies
No leakage of cell contents therefore no inflammation
What are the macroscopic structural changes of necrosis?
Firm or soft
Pale or heamorrhagic
What are the microscopic structural changes of necrosis?
Pykinosis (Condensation of chromatin)
Karyorrhexis (Destructive fragmentation of nucleus)
Karyolysis (Complete dissolution of chromatin by endonucleases)
Leading to disappearing of nucleus
Glassy, homogenous cells left
What are the electron microscopic changes of necrosis?
Discontinuities in plasma and organelle membranes
Dilation of mitochondria and large amorphous densities
Membrane blebs
What are the mircoscopic changes seen in apoptosis?
Single cells or small clusters Intensely eosinophilic (lots of chemical mediators) Dense nuclear fragments Cell shrinkage Chromatin condensation Nuclear fragmentations Phagocytosis by macrophages
What are the electron microscopic changes seen in apoptosis?
Cytoplasmic blebs
Fragmentation into membane-bound apoptotic bodies
What occurs in cell injury caused by alterations in calcium homeostasis?
Raised intracellular calcium due to influx across plasma membrane and release from mitochondria and endoplasmic reticulum
Causes enzyme activation which produces cell injury
What are the six main causes of acute inflammation?
Foreign bodies Immune reactions Infections & microbial toxins Tissue necrosis Trauma Physical and chemical agents
What is the biological purpose of acute inflammation?
Response of living tissue to injury, initiated to limit the tissue damage
What are the clinical features of acute inflammation?
Rubor - redness Tumour - swelling Color - heat Dolor - pain Loss of function
What are the changes in tissues that occur
Vascular phase - vasodilation, increased permeability, vascular stasis
Cellular phase - infiltration of inflammatory cells (fibrin, neutrophils)
What occurs in vasodilation in acute inflammation and what are the chemical mediators?
Initial vasoconstriction followed by vasodilation to increase blood flow for protein delivery and hydrostatic pressure
Mediated by histamine, prostagladins
What occurs in increased permeability of blood vessels
Vasodilation causes gaps in membrane therefore escape of protein-rich fluid (exudate)
Mediated by histamine, leukotrienes
What are the two types of oedema?
Transudate - Low protein content (due to hydrostatic pressure imbalance only)
Exudate - High protein content (types that occurs inflammation)
What occurs during neutrophil margination and migration?
Neutrophils to line up at the edge of blood vessels (endothelium) = margination
Neutrophils then roll along endothelium, sticking to it intermittently = rolling
Stick more avidly = adhersion
Emigration of neutrophils through blood vessel wall = migration (chemotaxis)
Mediated by C5a and leukotriene B4
What type of neutrophils are seen in acute inflammation?
Polymorphonuclear leucocytes
What do neutrophils do in acute inflammation?
Phagocytosis
Release toxic metabolites and enzymes damaging host tissue
What chemical mediators cause neutrophil chemotaxis?
C5a, LTB4, bacterial peptides
What chemical mediators enhance phagocytosis?
Opsonins - C3b
What are the hallmarks of acute inflammation?
Exudate of fluid
Infiltrate of inflammatory cells
How does exudation of fluid combat injury?
Delivers plasma proteins to area of injury
Dilutes toxins
Increases lymphatic drainage
How does pain and loss of function combat injury?
Enforces rests, reduces chance of further trauma
What are the local complications of acute inflammation?
Swelling - blocking of tubes
Exudate - compression
Loss of fluid - burns
Pain and loss of function
What are the systemic complications of acute inflammation?
Fever - endogenous pyrogens produced, increase prostaglandins
Leukocytosis - increased release from bone marrow
Acute phase response - decreased appetite, raised pulse rate, altered sleep patterns, changes in plasma concentrations of CRP, alpha-1-antitrypsin, fibrinogen
Septic shock
What are the sequelae of acute inflammation?
Complete resolution (changes gradually reverse) - if collagen framework still intact
Chronic inflammation and fibrous repair, tissue regeneration - if collagen framework not intact
Continued acute inflammation with chronic inflammation - abscess (acute around the edge, chronic in the middle)
Death
Give clinical examples of acute inflammation
Lobar pneumonia
Acute appendicitis
Give one inherited disorder of acute inflammatory process
Alpha-1-antitrypsin deficiency
Autosomal recessive disorder - low levels of alpha-1-antitrypsin therefore decreased trypsin breakdown. Trypsin catalyses conversion of proelastase to elastase which breaks down elastin, destorying alveolar walls.
How does aspirin modify acute inflammation?
Inhibits cyclooxygenase and blocks prostaglandin synthesis resulting in decreased fever, pain and vasodilatation
What is chronic inflammation?
Chronic response to injury with associated fibrosis
How does chronic inflammation arise?
- Take over from acute inflammation
- Arise de novo (no preceeding acute inflammation)
- Develop alongside acute inflammation
What are the microscopic appearances of chronic inflammation?
Macrophages - phagocytosis, presentation of antigen to immune system, synthesis of cytokines and complement
Lymphocytes - B lymphocytes produce antibodies, T lymphocytes produce cytotoxic functions
Plasma cells - differentiated antibody-producing B lymphcytes
Eosinophils - allergic reactions
Fibroblasts/myofibroblasts - recruited by macrophages
Giant cells - multinucleate cells made by fusion of macrophages, frustrated phagocytosis
What are the different types of giant cells recognised?
Langhans - TB
Touton - Fat necrosis
Foreign body type
What are the effects of chronic inflammation?
Fibrosis e.g. chronic cholecystitis
Impaired function of tissue e.g. Inflammatory bowel disease
Atrophy e.g. gastric mucosa
Stimulation of immune response e.g. rheumatoid arthritis
What is granulomatous inflammation?
Chronic inflammation with granulomas (collection of immune cells, macrophages = epithelioid histiocytes)
When do granulomas arise?
Persistent low-grade antigenic stimulation
Hypersensitivity
What are the main causes of granulomatous inflammation?
Mildly irritant ‘foreign’ material
Infections - Mycobacterium (TB), leprosy
Unknown causes - sarcoidosis
What is regeneration?
Replacement of dead or damaged cells by functional, differentiated cells
What is the difference, in terms of regeneration of labile, stable and permanent cells?
Labile - rapid proliferation (epithelial, heamatopoietic)
Stable (resting state) - speed of regeneration variable (hepatocytes, osteoblasts, fibroblasts)
Permanent (Unable to divide) - neurones, cardiac myocytes
What is fibrous repair?
Replacement of functional tissue by scar tissue
What are the key components of fibrous repair?
- Cell migration
- Blood vessels
- Extracellular matrix production and remodelling
What are the cell types involved in fibrous repair?
Inflammatory cells - phagocytosis (neutorphils, macrophages), chemical mediators (lymphocytes, macrophages)
Endothelial cells - angiogenesis
Fibroblasts/myofibroblasts - extracellular matrix proteins, wound contraction
What are the defects of collagen synthesis?
Vitamin C deficiency (Scurvy) - inadequate hydroxylation of alpha chains leading to defective helix formation
Ehler-Danlos syndrome - Defective conversion of procollagen to tropocollagen
Osteogenesis imperfecta - mutation in collagen gene
What is chronic granulomatous disease?
Deficiency of NADPH oxidase therefore unable to produce reactive oxygen species and cannot degrade pathogens engulfed. Causes formation of granulomas (frustrated macrophages forming giant cells)
What is angiooedema?
Mutation causing deficiency of C1-inhibitor protein
Leads to abnormal activation of complement system by unopposed activation of contact pathway resulting in large amounts of bradykinin causing vasodilation and increase permeability
