Inflammation 41 to 50
How do cancers invade the extracellular matrix?
- Loosening of intercellular junctions
- Downregulation of E-cadherin expression
- Mutations in gene for catenins
- Attachment to BM / interstitial connective tissue components
- Idensity of laminin and intregrins
- Degradation of ECM
- Proteases – by tumour cells or induced stroma cells
- 3 classes – serine, cysteine, matrix metalloproteases (MMPs)
- type IV collagenases (eg MMP9), plasminogen activators
- Migration of tumour cells
- Within circulation, aggregate in clumps – homotypic / tumour-plt aggreg’s
- arrest and extravasation of tumour emboli at distant sites
- adhesion to endothelium, egress through BM (same mechanisms as above)
Pass: 3 out of 4
What is the importance of matrix metalloproteinases in this process?
1. collagenases produced by tumour cells or surrounding stromal tissue
2. cleave type IV collagen of epithelial and vascular BMs
3. generate, from ECM, factors that promote angiogenesis, tumour growth
Describe the process of 'Primary Wound Repair'
- Immediate: Blood clot (dehydration of the surface dot forms the “scab”)
- Within 24 hours: neutrophils move towards the fibrin clot
- 24 – 48 hours: wound closure by spurs of epithelial cells
- By Day 3: neutrophils replaced by macrophages, granulation tissue, collagen fibres
- By Day 5: Incisional space filled with granulation tissue, neovascularization maximal, bridging collagen fibres. Epidermis normal thickness, surface keratinization
- During second week: continued accumulation of collagen & proliferation of fibroblasts. Blanching. …… …10% strength
- By the end of the first month: cellular connective tissue devoid of inflammatory infiltrate
- Ensuing months: full tensile strength takes many months 70-80% strength
Pass: 5 of 8
How does a scar form?
- Induction of inflammatory process in response to initial injury with removal of damaged and dead tissue
- Proliferation and migration of parenchymal and connective tissue cells
- Formation of new blood vessels (angiogenesis) and granulation tissue
- Synthesis of ECM proteins and collagen deposition
- Tissue remodelling
- Wound contraction
- Acquisition of wound strength
What factors influence scar formation?
- Tissue environment and extent of tissue damage
- Intensity and duration of stimulus
- Conditions that inhibit repair: foreign bodies or inadequate blood supply, infection
- Disease states that inhibit repair: diabetes / steroids
- Genetic – keloid
Describe the morphological changes that occur in cells during acute ischaemia.
Cellular Swelling: failure to maintain ionic and fluid haemostasis; organs become swollen;
1. plasma membrane blebs, intramembranous aggregations
2. mitochondrial swelling, small densities.
3. distended segments of ER; dispersion of ribosomes ‘vacuolar degeneration.
4. Clumping of nuclear chromatin. Fatty change: lipid vacuoles in cytoplasm.
Cell membrane defects:
Myelin figures in cytoplasm, rupture of lysosymes and autodigestion
Mitochondrial large densities, lysis of ER Nuclear pyknosis, karyolysis or karyorrhexis.
Pass: Need both reversible & irreversible changes to pass, need 5 or 6 points to pass.
Describe the processes involved in healing by first intention.
Prompt: Say in chronological order
Within 48 hrs: space filled by clotted blood/fibrin, neutrophils at margins, epidermis thickens at cut edges due to mitotic activity of basal cells, dehydration of surface clot forms scab, spurs of epithelial cells from edges migrate and grow along cut margins of dermis and deposit BM components, epithelial cells fuse in midline producing continuous thin epithelial layer.
3-7 days: neutrophils replaced by macrophages, granulation tissue invades incision space, collagen fibrils at margins then bridge incision, neovascularisation, differentiation of surface cells produces mature epidermal architecture weeks: proliferation of fibroblasts and collagen, regression of vascular channels, disappearance of leukocytic infiltrate and oedema and loss of increased vascularity.
What is metaplasia?
Reversible change where one adult cell type is replaced by another adult cell type
May be adaptive-sensitive cell type replaced by resistant cell type
The influences that predispose to metaplasia can induce cancerous transformation
Please give examples of metaplasia.
Columnar to squamous epithelium in the resp tract secondary to chronic irritation
Stones in pancreas, salivary or bile ducts – squamous epithelium from columnar
Barrett esophagitis squamous – columnar epithelium
Connective tissue metaplasia. Cartilage, bone or adipose tissue forms in other tissues
Pass: 1 example
What causes metaplasia?
Reprogramming of stem cells
May be due to cytokines, growth factors, and extracellular matrix components.
Tissue specific and differentiation genes influenced to lead to cellular differentiation
Known factors include, chronic irritation, Vit A deficiency and excess, cytostatic drugs
Describe the biochemical features of cell injury.
1. Depletion of ATP – sodium pump reduction – Na into cells, K+ out. Inc.
catabolites in cells – inc. osmotic load – swelling.
Anaerobic metabolism. – lactic acid, initially decreased pH then normalisation or increased pH.
2. Free oxygen radical formation
3. Increased intracellular Ca
4. Defects of membrane permeability-leakage of intracellular substances- myoglobin, CK, troponin, other enzymes
5. Mitochondrial damage
Decreased protein synthesis
Increased Lipid breakdown products
Decreased Intracellular glycine
Pass: At least 3
Describe the process of fibrosis and scar formation.
- Formation of new blood vessels (angiogenesis) – pre-existing vessels send out capillary buds/sprouts
- Migration and proliferation of fibroblasts – within granulation tissue framework
- Deposition of extracellular matrix (ECM) – fibrillar collagens, spindle shaped fibroblasts, elastic tissue
- Maturation and organisation of fibrous tissue (tissue remodelling) – changes in composition of CM, degradation of collagen and other ECM proteins by matrix metalloproteinases
Pass: 2 points
What is the difference between dystrophic and metastatic calcification?
Dystrophic calcification has normal calcium level in damaged tissue while metastatic calcification has high calcium level in damaged tissue.
What are the causes of metastatic calcification?
hyperparathyroidism, vitamin D intoxication, systemic sarcoidosis, milk alkali syndrome, hyperthyroidism, idiopathic hypercalcaemia.
Renal failure, destructive bone disease
What tissues are most commonly affected by metastatic calcification?
What is apoptosis?
Programmed cell death, occurs in single cells or clusters of cells, not associated with tissue inflammation.
Give some examples of apoptosis.
Endometrial cells during menstruation, GIT epithelium, Killer T Cell action, embryo development, tumours, neutrophils in acute inflammation, atrophy following duct obstruction, viral hepatitis, low does noxious stimuli : heat, radiation, hypoxia, cytotoxics, aging
Pass: 2 examples