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Week 11 (Inflammation (Receptors (GPCR (Recognises N-formyl-methionyl…

- - - - Three outcomes of cellular stress/injury
        
        Non-lethal stress (hyperplasia, hypertrophy, atrophy, metaplasia, metabolic derangement, intracellular accumulation (adaptation)
        
        Lethal/irreversible injury (necrosis, apoptosis, autophagy) (cell death)
        
        Non-lethal, reversible injury (swelling, membrane damage, organelle damage) (return to normal state)
    - - Causes of cell injury
        
        Oxygen deprivation (hypoxia, ischaemia)
        
        Physical agents (trauma, heat/cold/pressure/radiation/electric shock)
        
        Chemical agents (drugs, toxins)
        
        Immunologic reactions (autoimmunity, excessive/uncontrolled inflammation)
        
        Nutritional imbalances (deficiency, excess)
        
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        Cellular mechanisms
        
        Mitochondrial damage: decreased ATP (multiple downstream effects) or increased reactive oxygen species (damage to lipids, proteins, DNA)
        
        Entry of calcium ions (increased mitochondrial permeability; activation of multiple cellular enzymes)
        
        Membrane damage: plasma membrane (loss of cellular components) or lysosomal membrane (enzymatic digestion of cellular components)
        
        Protein misfolding and DNA damage: activation of pro-apoptotic proteins
  - - - If the cell is not irreversibly injured, restoration of normal structure/function
        
        Hypertrophy
        
        Increase in size of cells, resulting in increase in size of organ
        
        Simultaneous hyperplasia/hypertrophy
        
        In obesity, or in bladder muscle hypertrophy secondary to prostatic hyperplasia/urinary outflow obstruction
        
        Both caused by growth factors in response to mechanical stress, hormone/chemical stimulation
        
        Occurs in tissues where cells have limited capacity to divide (skeletal muscle, cardiac muscle, uterus)
        
        Hyperplasia
        
        Increase in number of cells that may also lead to increase in size of organ
        
        Pathological
        
        Benign prostatic hyperplasia; adrenal hyperplasia in Cushing’s disease; Paget’s disease of bone; fibrocystic disease of breast
        
        Physiological
        
        e.g. Reactive changes in lymph nodes during infection; thickening of endometrium during proliferative phase of menstrual cycle; increase in glandular tissue of breast when breastfeeding
        
        Atrophy
        
        Shrinkage in size of cells by loss of cell substance (or shrinkage in size of organ by loss of cell numbers/size)
        
        Results from decreased protein synthesis and +/- increased protein degradation (ubiquitin-proteasome pathway; often associated with autophagy)
        
        Causes: decreased workload, disuse, denervation, loss of blood supply, malnutrition, cachexia, hormonal abnormalities
        
        Metaplasia
        
        One adult cell type is induced to be a replaced another adult cell type
        
        Stem cells are ‘reprogrammed’; may be physiological (e.g. cervix) or pathological
        
        Increases likelihood of further alterations in cells (development of dysplasia/neoplasia)
        
        Examples: intestinal metaplasia in Barrett’s oesophagus, squamous metaplasia of upper respiratory tract in smoker
        
        Causes: stresses that require special adaptation (usually chronic irritation)
    - - Cell injury impedes function of energy dependent ion pumps in the plasma membrane
        
        Increased permeability leading to cell swelling (+/- vacuolar change, membrane blebs, increased eosinophilia of cytoplasm)
        
        Altered cellular metabolism (+/- fatty change, +/- intracellular accumulation)
        
        Intracellular accumulation
        
        Even if changes have been reversed, some damaged cells/tissues may accumulate byproducts
        
        Lipids (fatty change), proteins (e.g. neurofibrillary tangles in AD, amyloid), glycogen (e.g. in diabetes), exogenous pigment (anthracosis in lung), endogenous pigment (melanin in skin/lymph nodes, haemosiderin from old blood), calcium (affinity of calcium for membrane phospholipids)
        
        Caused by: altered physiologic stimuli, some non-lethal injurious stimuli, metabolic alternations, chronic injury
  - - - Variants: necroptosis (regulated), pyroptosis (pro-inflammatory)
      - Necrosis
        
        End result of severe damage (acute or chronic), i.e. irreversible cell injury
        
        Cellular changes
        
        Nuclear
        
        Breakdown of DNA
        
        Pyknosis
        
        Shrinkage and increased basophilia; DNA condenses into dark shrunken mass
        
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        Cytoplasmic
        
        Increased eosinophilia, ‘glassy’ cytoplasm, loss of organelles, accumulation of breakdown products (can lead to vacuolation of cytoplasm); necrotic cells may persist or be rapidly digested and disappear
        
        Not regulated by specific signals or biochemical mechanisms, i.e. accidental event when injury is too severe to be repaired and cellular constituents fail or fall apart
        
        Myocardial infarction
        
        Local tissue death of heart muscle due to obstruction of blood supply (irreversible ischaemia); loosely, 'heart attack'
        
        Ischaemic event
        
        Death of myocytes in ischaemic area
        
        Vulnerable myocytes left at periphery
        
        Acute inflammation
        
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        Reduced blood flow to tissues, esp. obstruction of blood vessel (thrombosis, embolus)
        
        Cell damage is a combination of decreased ATP generation and failure of Na pump
        
        May be reversible or irreversible (infarct)
        
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        Patterns
        
        Coagulative
        
        Affected cells retain their shape but lose their nuclei (‘ghost cells)’
        
        Defined area (often wedge shaped), usually due to loss of blood supply
        
        As scaffolding is still present, healing is by scar formation
        
        Liquefactive
        
        Damaged tissue is cleared, there is no scar formation, and hence cavity forms
        
        Particularly in CNS (infarct, abscess)
        
        Caseous
        
        ‘Cheese-like’ necrosis: mixture of coagulative and liquefactive necrosis, caused by constant inflammation that cannot cleared
        
        Pathognomonic of tuberculosis
        
        Fat necrosis
        
        ‘Foamy’ macrophages and calcification due to accumulation and saponification of lipids
        
        Often secondary to trauma or chemical injury (pancreatitis, breast, post-surgery)
        
        Fibrinoid necrosis
        
        Looks like fibrin in walls of blood vessels, immunologic injury to vascular smooth muscle
        
        Gangrene
        
        Form of coagulative necrosis where tissue turns black (necrosis is usually white)
        
        Dry gangrene
        
        Black, dead, dry tissue caused by chronic ischaemia often seen in the toes of patients with severe atherosclerosis
        
        Wet gangrene
        
        Follows infection of dead, anoxic tissue by gas-forming organisms
- - - - Leukocytes and plasma proteins are recruited from the circulation to the site where the offending agent is located
        
        .
        
        The leukocytes and proteins are activated and work together to destroy ad eliminate the offending substance
        
        The reaction is controlled and terminated
        
        The damaged tissue is repaired
      - Cellular receptors exist in membrane, endosomes, and cytoplasm; act as sensors of cell damage (inflammasomes) w/ help of circulating proteins (complement system, collectins)
  - - - Patterns
        
        Abscess
        
        Collection of pus in tissue; empyema is collection of puss in anatomical space e.g. pleura, gallbladder
        
        Serous
        
        Protein-rich exudate at serous surfaces e.g. peritonitis, pleuritis
        
        Purulent/suppurative
        
        Pus-forming, i.e. dead/dying neutrophils, macrophages, bacteria, proteins
        
        Ulcerative
        
        Inflammation leading to or associated with erosion of a mucosal surface e.g. bowel, stomach
        
        Fibrinous
        
        Similar to serous, but with marked leakage and activation of large plasma proteins including fibrin
  - - - Signs of Celsus: tumour, rubor, calor, dolor
      - Virchow: loss of function
    - - Fever (leading to sepsis), acute phase response, leucocytosis, and shivering/chills/anorexia/somnolence/malaise
    - - Induced by histamine and other mediators; rapid and short-lived (minutes)
  - - - Increased permeability of microvasculature (plasma proteins and leukocytes leave circulation; both active and passive process)
        
        Attraction (chemotaxis) and emigration of leukocytes (particularly neutrophils) to site of injury: activation of numerous receptors including pain
        
        Causes oedema due to increased fluid in interstitial tissue leading to swelling
        
        Due to histamine, kinins, and other mediators
      - Causes stasis or congestion of blood (redness and heat)
      - Due to histamine and other mediators
  - - - Recognises N-formyl-methionyl peptides, chemokines, and lipid mediators
      - Induces cytoskeletal changes and signal transduction
      - Results in increased integrin avidity (hence adhestion to endothelium) and chemotaxis (hence migration into tissues)
    - - Recognises microbes (LPS, CD14)
      - Induces production of mediators such as arachidonic acid metabolites and cytokines, leading to amplification of the inflammatory reaction
      - Induces production of reactive oxygen species and lysosomal enzymes, leading to microbicidal activity of leukocytes and hence killing of microbes
    - - Recognises cytokines e.g. IFN-gamma
    - - Induces phagocytosis of microbe into phagosome and production of ROS/lyososomal enzymes
      - Leads to microbicidal activity of leukocytes and hence killing of microbes
      - Phagocytosis
        
        Recognition and attachment: microbes bind to phagocyte receptors
        
        Engulfment: phagocyte membrane zips up around microbe; microbe is ingested in phagosome; phagosome fuses with lysosome
        
        Killing and degradation: microbe is killed by ROS and NO (involves arginine and phagocyte oxidase); degradation of microbes by lysosomal enzymes in phagolysosome
  - - - Lymphocytes mediate adaptive immunity but also secrete cytokines that prolong inflammatory response
      - Tissue destruction occurs due to injurious agent or by inflammatory cells (macrophages)
      - Infiltration of mononuclear cells (macrophages, lymphocytes, and plasma cells)
      - Attempts at healing include angiogenesis (formation of granulation tissue) and fibrosis (scar formation)
    - - Induced by T-cell and macrophage activation where infectious agent or foreign body cannot be eradicated
      - Characterised by clusters of histiocytes (tissue macrophages) with variable cuff of surrounding lymphocytes +/- giant cells (multinucleate macrophages)
      - May be necrotising (usually infectious) or non-necrotising (usually non-infectious)
      - Mycobacterial/fungal infection, foreign body (particularly lung/skin), idiopathic (e.g. Crohn’s disease of bowel)
    - - Responses
        
        Resolution: tissue returns to pre-injury state
        
        Regeneration: tissue regrows to replace damaged area (skin, liver, nerves, bone)
        
        Repair: scar formation through connective tissue; abnormalities include Keloid or Contracture
      - Depends on injury
        
        First intention: neater scar
        
        Second intention: greater loss of tissue
      - Bone healing
        
        Fibrocartilaginous callus formation: internal callus (fibrous tissue and cartilage), spongy bone trabeculae, new blood vessels, external callus
        
        Bony callus formation: bony callus of spongy bone
        
        Haematoma formation
        
        Bone remodelling: healed fracture
      - Factors
        
        Local
        
        Extent of injury (esp. tissue loss)
        
        Mechanical factors (tension)
        
        Foreign material (including dead tissue)
        
        Poor perfusion
        
        Infection
        
        Systemic
        
        Glucocorticoids (steroids - stress/exogenous)
        
        Hypoxia
        
        Nutritional status
        
        Diabetes
        
        Sepsis
        
        Other
        
        Specific mediators (complement, clotting, fibrinolytic cascades)
        
        Cell functions (esp. in cell-mediated immunity)
        
        Auto-immunity/other harmful effects
- - - - Swellings (not neoplasm)
        
        Hydrocoele
        
        Hernia
        
        Lymphoedema
        
        Inflammatory pseudotumour
        
        Abscess
      - Haematoma
        
        Tumour that is not a neoplasm; a mass formed of cells native to the tissue, but with a disorganised arrangement
        
        Ectopia
        
        Tumour that is not a neoplasma; normal tissue, usually normal architecture, but at the wrong site e.g. accessory spleen
    - - Neoplastic cells - clonal
        
        Reactive stroma (connective tissue, blood vessels, often inflammatory cells)
        
        Desmoplasia is the formation of abundant fibrous stroma by invasive tumour
        
        Angiogenesis is new blood vessels, critical in formation of rapid growing tumours and metastases
  - - - Degeneration; high proliferation; may progress to malignancy
        
        Typically named according to the tissue type, e.g. fibroma, adenoma, chondroma, leiomyoma, rhabdomyoma, schwannoma
    - - Clonal; identifiable genetic abnormalities
        
        Abnormal architecture or cytomorphology
        
        Mild changes
    - - Atypical lesion (i.e. has some nuclear features of malignancy) and/or shows abnormal architectural features such as loss of normal maturation
        
        May be pre-malignant (i.e. represent a step midway along the process), but not always, and difficult to predict; may arise in normal, hyperplastic or metaplastic epithelium
      - Categorised based on cytological atypia and architecture
        
        High grade dysplasia is generally on a continuum with carcinoma in situ and reflects underlying mutations that are similar to cancer, without evidence of invasion or metastatic spread
        
        Progression rates: Cervix: about 30% at 30 years; Colon: about 1% per year; Oesophagus: 1-5% per year
      - Examples
        
        Actinic (solar) keratosis
        
        Tubular adenoma (in the GI tract, ‘adenoma’ means dysplasia is present; this is not true for all systems e.g. thyroid, ovary)
- - - - Triggered by loss of survival signals, DNA damage, and accumulation of misfolded proteins (ER stress)
        
        Leakage of pro-apoptotic proteins from mitochondrial membrane into the cytoplasm, triggers caspase activation
        
        Inhibited by anti-apoptotic members of the Bcl family, which are induced by survival signals including growth factors
  - - - Cells are rapidly cleared by phagocytes (before inflammation), recruited by pro-phagocytic signals many of which are on the internal part of the cell membrane
  - - - Responsible for elimination of self-reactive lymphocytes
        
        Initiated by the engagement of death receptors (members of the TNF receptor family) by ligands on adjacent cells (particularly FasL)
- - - - Acts as a survival mechanism in times of nutrient deprivation, so that the starved cell can live by eating its own contents and recycling these to provide nutrients and energy
  - - - Intracellular organelles and portions of cytosol sequestered within ER-derived vacuole
        
        Vacuole fuses with lysosome to form autophagolysosome in which lysosomal enzymes digest cellular components
- - - - Mutations include translocations, aneuploidy, deletions, amplifications or point mutations
- - - - Acquisition of genomic instability: initiated precursor – mutation affecting genomic integrity – precursor with mutator phenotype
        
        .
        
        Acquisition of cancer hallmarks: precursor with mutator phenotype – additional driver mutations – founding cancer cell
        
        Further genetic evolution + accumulation of driver and passenger mutations: founding cancer cell – additional mutations, emergence of subclones – genetically heterogeneous cancer
        
        Diagnosis
- - - - Unconstrained proliferative tending to lead to the death of the patient
  - - - Tumours benign in some and malignant in others: teratoma
        
        .
        
        Tumours with unpredictable behaviour: ovarian, smooth muscle, endocrine, mesenchymal tumours
        
        Invades but does not metastasise: basal cell carcinoma of the skin, some brain tumours
  - - - Atypia (pleomorphism, nuclear hyperchromasia, large nucleoli, cytomegaly/nucleomegaly, anisonucleosis
      - Increased mitotic activity or apoptosis; inclusions
    - - Inclusions, increased cytoplasmic products (melanin, mucin, glycogen, mitochondria)
  - - - Metastases (tumours elsewhere), lymph node enlargement, weight loss/cachexia, and paraneoplastic syndromes (hormonal effects of substances produced by tumours)
      - Clinical
        
        Diagnosis: Clinical (signs and symptoms), imaging, histopathology/cytopathology, immunopathology, cancer markers (biochemical and genetic), autopsy, malignancy of unknown primary
        
        Grading & staging: Tumour/nodes/metastases, some organ specific systems (Gleason/ISUP for prostate, WHO for brain, lymphoma/leukaemia), ensures consistency of treatment, and evidence base
  - - - Pathways to spread
        
        Direct: tumour grows to directly invade adjacent structures. E.g. lung Ca involving chest wall, pancreas invading spleen and small intestine
        
        Haematogenous: tumour invades blood vessels and spreads to other vascularised organs. E.g. capillaries, arteries, veins, tumour emboli, metastasis to most vascular organs (lung, liver, brain, bone)
        
        Lymphatic: tumour invades lymphatics in adjacent normal tissue; tumour then spreads to lymph nodes following local lymphatic drainage
        
        Transcoelomic: direct seeding of body cavities (usually peritoneum). Commonly seen with appendiceal, gastric, and ovarian carcinoma
        
        Normal, PanIN-1 (KRAS), PanIN-2 (CDKN2A), PanIN-3 (TP53 and SMAD4), infiltration, dissemination, and metastasis
      - Poorly differentiated (complete loss = anaplasia) tumours tend to behave worse