Inflammation 1 to 10
What is tissue hypertrophy?
- Increase in cellular size not number leading to overall organ/tissue size increase
- Cell size increased by more structural components and increased synthesis of cellular proteins
- Triggered by increased functional demand or stimulation by hormones or growth factors
- Can be selective hypertrophy of specific sub-organelles
- Bold points
What are examples of hypertrophy?
Prompt: How is it classified?
- Physiological skeletal muscle enhancement through training or uterus under influence of hormones such as oestrogen
- Pathological such as cardiomegaly in hypertension and CCF (has an upper limit after which regression occurs -> cell injury -> apoptosis/necrosis)
How is hyperplasia different form hypertrophy?
- Hyperplasia involves an increase in the number of cells
How do leucocytes get to an area of acute inflammation?
- Margination of WCC in vessels, rolling and adhesion to endothelium (pavementing) (Selectins)
- Migration and diapedesis across endothelium (PECAM1, CD31, Integrins)
- Migration towards chemotactic stimulus in tissue (bacterial products, cytokines, IL8, C5A)
- All bold
What is the role of leukocytes in acute inflammation?
- Recognition and attachment to materials (opsonins) mediated by receptors
- Killing of microbes: phagocytosis /engulfment /killing and degradation(H2O2-MPO-Halide)
- Release of products – Amplify the inflammatory reaction (lysosomal enzymes, reactive oxygen/nitrogen)
- 3 out of 5 bold
What is reperfusion injury?
- Further cell death in ischaemic tissues following restoration of blood flow
- Bold Points
What are the proposed mechanisms of reperfusion injury?
- Generation of oxygen free radicals – formed from incomplete reduction of in-coming O2 by damaged mitochondria in affected tissue and action of oxidases (generated from ischaemic cells and leucocytes)
- Associated inflammation – cytokines, adhesion molecules generated by hypoxic cells; they recruit neutrophils etc in re-perfused tissue; ensuing inflammation causes additional injury
- Activation of complement system – IgM Ab deposit in ischaemic tissue; restored blood flow brings complement proteins that bind to Ab and are activated; causing further cell injury and inflammation
- Mitochondrial permeability transition – via reactive O2 species – effects mitochondrial function – precludes recovery of ATP / energy supplies for the cell
- 2 out of 4
What is metaplasia and give some examples?
- Reversible change (Among differentiated cells such as epithelial or mesenchymal)
- Where one cell type is replaced by another by reprogramming of precursor stem cells or undifferentiated mesenchymal cells
- Respiratory tract: trachea and bronchi in respiratory tract – due to chronic irritation such as smoking; ciliated columnar to stratified squamous
- GIT: oesophagus – due to chronic gastric acid reflux; squamous to intestinal-like columnar “Barrett’s oesophagus”
- Bold PLUS 1 out of 2 examples
How may metaplasia progress?
Prompt: What is the potential undesirable outcome of metaplasia?
- Cells lose normal protective function
- Persistence of influence that initiated the metaplasia initiates malignant transformation (e.g. squamous cell lung ca; adenocarcinoma oesophagus)
- Bold to pass
What is hypertrophy?
- Increase in the size of cells – due to the synthesis of more structural components – resulting in an increase in the size of the organ; caused by increased functional demand or by hormonal stimulation. – pathological or physiological
- Bold to pass
Give examples of physiological and pathological hypertrophy.
- Skeletal muscle (gym etc – workload); Uterus in pregnancy (hormonal)
- Myocardium (due to hypertension, aortic stenosis – workload); BPH
- One example of each
Describe the process of skin wound healing by first intention.
- 24 hours: Scab; Neutrophils; Clot
- 3 to 7 days: Mitoses; Granulation tissue; Macrophage; Fibroblast; New capillary
- Weeks: Fibrous union
- <24 hours: neutrophils at the margins of the incision,. 24 to 48 hours: epithelial cells move from the wound edges and fuse in the midline beneath the surface scab, producing a continuous but thin epithelial layer that closes the wound.
- By day 3, neutrophils replaced by macrophages. Granulation tissue progressively invades the incision space. Collagen fibres in the margins of incision. Epithelial cell proliferation thickens the epidermal layer.
- By day 5, the incisional filled with granulation tissue. Neovascularization is maximal. Collagen bridges the incision. The epidermis recovers its normal thickness.
- During the second week, continued accumulation of collagen and proliferation of fibroblasts. The leukocytic infiltrate, oedema, and increased vascularity have largely disappeared.
- By the end of the first month, the scar is made up of a cellular connective tissue devoid of inflammatory infiltrate, covered now by intact epidermis.
- Timeline PLUS
- Inflammation (neutrophils + macrophages)
What are the morphological and chemical changes associated with early cell injury?
- Decreased generation of ATP
- Loss of cell membrane integrity
- Defects in protein synthesis
- Cytoskeletal damage
- DNA damage
- 3 out of 5 to pass
What are the phenomena that characterize irreversible cell injury?
- The first is the inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) even after resolution of the original injury
- The second is the development of profound disturbances in membranefunction
- Bold to pass
Can you give an example of a protein that leaks across degraded cell membranes?
- Cardiac muscle – contains a specific isoform of the enzyme creatine kinase and of the contractile protein troponin.
- Liver (and specifically bile duct epithelium) – contains a temperature-resistent isoform of the enzyme alkaline phosphatase.
- Hepatocytes – contain transaminases
- 1 example to pass
What is the difference between ischaemic and hypoxic injury?
- Ischaemic involves disruption or reduction in blood supply resulting in reduced oxygen delivery, reduced delivery of substrate and reduced removal of metabolic products
- Hypoxic involves reduced oxygen delivery only. I hypoxic, anaerobic (glycolytic metabolism can continue as new substrate is being delivered).
- As a result cellular, hence tissue injury is much more rapid in ischaemic injury
- Candidate to clearly differentiate the 2 processes
Describe the morphologic intracellular changes that occur in ischaemic injury.
- Reversible; Cell swelling, ultrastructural changes including loss of microvilli and cell surface ‘bleb’ formation. Swelling of ER and mitochondria, Myelin figure formation, and clumping of nuclear chromatin
- Irreversible; severe mitochondrial swelling, plasma membrane damage, swelling of lysosomes
- Mention of reversible & irreversible changes with examples from each
What is the complement system?
- Plasma protein system involved in immunity against microbes. Complement proteins numbered C1-9 are present in plasma in inactive forms
- Bold to pass
Describe the main pathways by which complement activation occurs.
- Classical pathway: involving an antigen-antibody complex
- Alternate pathway: triggered by microbial surface molecules (e.g. endotoxin). No antibody involvement.
- Lectin pathway: plasma mannose-binding lectin binds to carbohydrate on microbe
- All pathways result in cleavage and activation of C3 (most important and abundant complement component)
- Bold PLUS way activated
How do activated complement products mediate acute inflammation?
- Vascular effects: increased permeability; vasodilatation (via C3a, C5a mediated histamine release from mast cells)
- Leucocyte adhesion, chemotaxis and activation: via C5a
- Phagocytosis: C3b acts as opsonin on microbe and leads to phagocytosis
- Cell lysis by the membrane attack complex (MAC) – composed of multiple C9 molecules
- Vascular PLUS 1 other
Describe the sequence of cellular events in acute inflammation.
Prompt: What cells are involved in acute inflammation?
Prompt: How do these cells get from the blood vessels to the inflammatory site?
- Leucocytes are the major cell type involved. In first 6-24 hours neutrophils, and monocytes/macrophages in 24-48 hours
- Leucocytes line endothelial wall – margination
- First stasis of blood flow leading to increased leucocytes along endothelial wall
- Then leucocyte adhesion to endothelial wall and diapedesis or transmigration across into interstitium – extravasation
- Adhesion and transmigration and recruitment are mediated by various mediators such as histamine, PAF cytokines and various attraction molecules – variously called immunoglobulins, integrins, selectins, mucin-like glycoproteins
- Then leucocytes migrate to site of injury- chemotaxis
- Chemotaxis and activation is mediated thru various bacterial products, cytokines, chemical factors, Ag-Ab complexes products of necrosis
- Then leucocyte activation to enable phagocytosis and enzyme release
- Phagocytosis and release of various enzymes from leucocytes
- Bold to pass