Lesson 1 Flashcards
What are causes of cell injury?
Hypoxia Chemical agents and drugs Infections Immune-mediated process Nutritional imbalance Genetic derangement Physical agents
What are four main types of hypoxia?
Hypoxaemic
Anaemic
Ischaemic
Histiocytic
What is hypoxaemic hypoxia?
Low arterial O2 content t e.g. cardiorespiratory failure or in reduced inspired O2 at high altitudes
What is anaemic hypoxia?
Decreased O2 carrying capacity in blood e.g. anaemia or CO poisoning
What is ischaemic hypoxia?
Interruption to blood supply e.g. blocked vessel or heart failure
What is histiocytic hypoxia?
unable to use O2 due to disabled oxidative phosphorylation enzymes e.g. cyanide or paracetamol poisoning
What are some chemical agents and/or drugs that can cause cell injury?
Oxygen in high/low conc.
Glucose and salt in hypertonic concentrations
Trace amounts of poisons: cyanide and arsenic
Daily exposures: air and environmental pollutants, insecticides and asbestos
Drugs: recreational (alcohol) and therapeutic drugs
What are some immune mediated processes that can cause cell injury?
- Reaction to endogenous self antigens (autoimmune disease)
- Hypersensitivity reaction as a result of vigorous immune reaction results in host tissue damage (utricaria and hives)
What are some nutritional imbalances that can cause cell injury?
•Dietary insufficiency ‒Malnourished states in deprived populations -self imposed insufficiency (anorexia nervosa) •Dietary excess ‒Obesity ‒Diabetes ‒Atherosclerosis ‒Cancer
What are some physical agents that can cause cell injury?
- Mechanical trauma
- Extremes of temperature (burns and deep cold) •Sudden change in atmospheric pressure
- Radiation
- Electric shock
What are examples of free radicals (that are of biological significance)?
• OH• (hydroxyl ions) -the most dangerous
• O2- (superoxide anion radical)
• H2O2 (hydrogen peroxide)
• Reactive oxygen species (ROS)
• Nitric oxide (NO) made by microphages, endothelia, and
neurones
What is the purpose of biological free radicals (in low conc. in normal state)?
Required for; killing bacteria, cell signaling, attack lipids in cell membranes, damages proteins, carbohydrates and nucleic acids
What are some causes of free radical production?
- Chemical and radiation injury
- Ischaemia – reperfusion injury
- Cellular ageing
- High oxygen concentrations
- Killing of pathogens by phagocytes (ROS)
What are some ultra structural changes that are responsible for morphological changes?
- Cell Membranes – plasma membrane and organelle membranes
- Nucleus - DNA
- Proteins – structural (enzymes)
- Mitochondria – oxidative phosphorylation
How is ATP produced?
- produced in mitochondria via oxidative phosphorylation
- produced by glycolysis pathway in absence of oxygen from glucose in body fluids or as a result of hydrolysis of glycogen
How can free radicals be produced?
- Chemical and radiation injury
- Ischaemia – reperfusion injury
- Cellular ageing
- High oxygen concentrations
- Killing of pathogens by phagocytes (ROS)
How do heat proteins (HSP) protect against cell injury?
- heat shock response aims to ‘mend’ misfolded proteins/maintain cell viability.
- Many HSP’s are Chaperonins – provide optimal conditions for denatured protein folding, preventing protein aggregation, label misfolded proteins for degradation.
- e.g ubiquitin
What are the two main processes seen in necrosis?
- Desaturation of intracellular proteins
- Enzymatic digestion by lysosomes inherent to the dying cell and lysosomes of leukocytes that are part of inflammatory reaction
What is an approximate time necrosis may be developing?
4-12hr after necrosis onset
What are types of necrosis?
- Coagulative necrosis - protein denaturation
- Liquefactive necrosis
- Caseous necrosis
- Fat necrosis
- Fibrinoid necrosis
Provide information on coagulative necrosis?
- Most common form
- Occurs in most organs
- A result of protein denaturation
- Gross: Firm, pale wedge of tissue, can be soft later on
- Microscopy – “ Ghost cells”. Neutrophils can infiltrate but NOT a prominent feature
Provide information on liquefaction necrosis?
- Usually seen in brain
- Seen in infections resulting in abscess formation
- Degradation of tissue by enzymes.
- Necrotic material - creamy yellow because of dead leukocytes -> pus (NEUTROPHILS)
Provide information on caseous necrosis?
- “Cheese like” gross appearance
* Amorphous debris surrounded by histiocytes -> granulomatous inflammation
Provide information on fat necrosis?
- Destruction to adipocytes (consequence of trauma) or secondary to release of lipases from damaged pancreatic tissue.
- Fat necrosis causes fatty acids which react with calcium -> white deposits in fatty tissue
- Can mimic breast tumour on radiology and is biopsied to exclude cancer.
Provide information of fibrinoid necrosis
- Seen in immune reactions involving blood vessels.
- Deposits of “immune complexes” + fibrin that has leaked out of vessels.
- Bright pink and amorphous appearance in H&E stains, called “fibrinoid” (fibrin-like) by pathologists
Describe white infarct
- Solid organ- Robust stromal support limits haemorrhage into necrotic area from adjacent capillaries
- Arterial insufficiency
- End artery
- Common site: heart, spleen , kidney
Describe red infarct (haemorrhaging infarct)
- Organs with dual blood supply /numerous anastamoses between capillary beds
- Organs that have loose stromal support
- Raised venous pressure leading to increased capillary pressure/tissue pressure -> in arterial insufficiency
What are three types of gangrene?
- Wet gangrene (necrosis modified by bacteria)
- Dry gangrene (necrosis modified by air)
- Gas gangrene (necrosis modified by gas from bacteria)
Clinical term to describe Visible Necrosis
Describe apoptosis?
- Energy dependent programmed cell death
- Characteristic non random internucleosomal cleavage of DNA
- Distinct morphological features
- Does not result in an inflammatory response
- Apoptosis can be physiological or pathological
Explain physiological apoptosis
- Embryogenesis and fetal development (loss of webbing as hand develops).
- Hormone dependent involution e.g. shedding of endometrium at menstruation
- Cell deletion in proliferating cell populations e.g. regulation of immune system or intestinal crypts
- Death of cells that have served their function (neutrophils/lymphocytes).
Explain pathological apoptosis
- Neoplasia
- Autoimmune conditions (failure of induction of apoptosis in lymphoid cells directed against host antigens)
- AIDS - HIV proteins may activate CD4 on uninfected T helper lymphocytes with apoptosis -> immunodepletion
What are some ways in which apoptosis can be regulated?
- Genes
- Inhibitors - growth factors, extracellular cell matrix, sex steroids, some viral proteins
- Inducers - growth factor withdrawal, loss of extracellular matrix attachment, glucocorticoids, viruses, free radicals, ionising radiation
What is the mechanism of apoptosis?
- Activation of a cascade of caspases (cysteine-dependent aspartate-directed proteases)
- 2 pathways resulting in activated caspase 3 which cleave proteins -> chromatin condensation, nuclear fragmentation, blebbing
- Extrinsic pathway – external “death receptors” (TNF receptors or Fas receptors) are activated by a ligand
- Intrinsic pathway – withdrawal of growth factors or hormones causes molecules to be released from mitochondria (e.g. Bcl2, Bax, p53)
- Apoptotic cell eventually phagocytised by macrophages/histiocytes/neighbouring cells -> no acute inflammation
Compare necrosis and apoptosis in relation to their pattern, cell size, nucleus and plasma membrane
Pattern: • N - contiguous groups of cells • A - single cells Cell size: • N - enlarged (swelling) • A - reduced (shrinkage) Nucleus: • N - pyknosis, karyorrhexis, karyolysis • A - fragmentation into nucleosome sized fragments Plasma membrane: • N - disrupted, early lysis • A - intact; altered structure (orientation of lipids)
Compare necrosis and apoptosis in relation to their cellular contents, adjacent inflammation and physiologic/pathological role
Cellular contents:
• N - enzymatic digestion (may leak out of cell)
• A - intact (may release into apoptotic bodies)
Adjacent inflammation:
• N - frequent
• A - no
Physiologic or pathological role:
• N - invariably pathologic
• A - often physiologic (eliminating unwanted cells), pathologic (some forms of cell injury - DNA damage)
What are molecules that are released as a result of cell injury and death?
- Potassium
- Enzymes
- Myoglobin
What can happen to the body as a result of molecules released as a result of cell injury?
- Can cause local inflammation
- May have general toxic effects on body
- May appear in high concentrations in blood and can aid in diagnosis
Explain rhabdomyolysis
This can be serious without myoglobin as a breakdown product of muscle causing damage to the kidneys/renal failure -> dialysis
Typical brown urine in myoglobinuria
What are mechanisms of intracellular accumulations?
• Abnormalmetabolism • Alterationsinproteinfolding and transport • Deficiency of critical enzymes • Inability to degrade phagocytosed particles
What can intracellular accumulations be?
- Water and electrolytes • Lipids
- Carbohydrates
- Proteins
- Pigments
What are the names of some disease as a result of endogenous pigments (abnormal accumulations)?
- Haemosiderin
- Haemosiderosis
- Hereditary haemochromatosis
- Bilirubin
What is pathological calcification - metastatic?
- Parathyroid overactivity – tumour or hyperplasia
- Vitamin D overdosage
- Malignant tumours e.g. breast and lung, bone
- Paget’s disease •Prolonged immobilisation
