Inflammation 31 to 40
Describe the vascular changes that occur in acute inflammation.
- Vasodilation & increased blood flow mediated by histamine and NO, action on vascular smooth muscle
- Increased permeability
- Stasis – incr blood viscosity and concentration of RBCs
- Accumulation of leukocytes on vascular endothelium
Pass: Need 1 + 2 and 1 other
What are the causes of the increased vascular permeability?
- Gaps due to endothelial contraction via mediators (“immediate transient response”): histamine (fast), bradykinin, sub P, leukotrienes, cytokines(longer). Venules,
- Direct injury to vessel: (“immediate sustained”)
- “Delayed prolonged” 2-12 hrs burn, radiation, toxins
- Leukocyte mediated injury: venules, palm caps, hours
- Incr transcytosis: vesicles, vacuoles, incr channels VEGF
- New vessel formation; new bvs leaky; VEGF, mediators
Pass: Need 1 and 2 others
Describe the types of damage that occur inside a cell after severe ischaemia.
Prompt: What would happen to energy production in the cell?
- ATP depletion leading to Na.K. pump failure, anaerobic metabolism, Ca pump failure, reduced protein synthesis and protein misfolding
- Membrane damage – mitochondria, lysosomes and plasma membrane
- Increased intracellular Ca–/ loss Cahomeostasis
- Accumulation of reactive 02 species
- Defects in membrane permeability
Pass: 3/5 bold
What factors lead to formation of a thrombus?
Prompt: What is Virchow’s triad?
- Endothelial injury: dominant influence, by itself can lead to thrombosis, especially in high flow circulation (e.g. arterial circulation; cardiac chambers). Any alteration in dynamic balance of pro- and anti-thrombotic effects of endothelium can influence clotting
- Stasis or turbulence: Turbulence contributes to thrombosis by causing endothelial injury or dysfunction, and local pockets of stasis. Disrupts laminar flow and bring platelets into contact with endothelium; prevents dilution of clotting factors by fresh flowing blood; retards inflow of clotting factor inhibitors. Stasis is a major factor in development of venous thrombi.
- Blood hypercoagulability: Less frequent. Any alteration of the coagulation pathways that predisposes to thrombosis. Primary: Genetic mutations (e.g. Factor V gene; prothrombin gene); genetic deficiencies (e.g. antithrombin III; protein C; protein S) Secondary (acquired): High risk for thrombosis (prolonged bed rest; immobilisation; MI; AF; tissue damage; cancer; DIC; HITS; APLA); lower risk (cardiomyopathy; nephritic syndrome; hyperestrogenic states / pregnancy; OCP use; sickle cell anaemia; smoking)
Pass: All three plus brief description to pass
What is 'Reperfusion injury' after blood flow is restored to an ischaemic tissue?
New damaging processes are triggered by reperfusion which effect additional cell injury and necrosis to that caused by the period of ischaemia itself.
What mechanisms are involved?
- Oxygen free radical generation
- Increased “Mitochondria’ permeability transition” -> mitochondria’ failure and loss of intracellular energy production.
- Inflammatory response with neutrophil influx (in response to cytokines and increased expression adhesion molecules)
- Activation of complement
Pass: At least one
What is the causative organism of salmonella dysentery?
1. Salmonella enteritidis, typhimurium
2. Gram negative, flagellated
What is the pathogenesis of salmonella dysentery?
- Invades epithelium (low oxygen environment)
- Taken up by macrophages
- Gut wall inflammation
- Neural reflex pathway
Pass: Inflammation plus one
Describe the vascular changes in acute inflammation.
- Transient vasoconstriction sometimes.
- Vasodilatation, arterioles first then capillary beds resulting in increased local blood flow.
- Increased vascular leakage 1 permeability resulting in oedema formation and increased blood viscosity.
- Circulatory slowing with stasis and neutrophil margination
What mechanisms cause increased vascular leakage in acute inflammation?
- Formation of gaps in venules due to endothelial contraction
- Direct endothelial injury
- Leukocyte-mediated injury
- Increased transcytosis
- Leakage from new blood vessels
Describe the mechanisms of ischaemic cell injury.
Hypoxia —›Loss of Ox Phos and decreased ATP in mitochondria
Failure of Na pump, loss of glycogen and decreased protein synthesis
Cellular swelling, loss of microvilli, ER swelling, cell surface blebs, myelin figures
Irreversible changes — swollen mitochondria, plasma membrane damage, lysosome swelling, Ca influx
Pass: 3 of 4
What are the differences between ischaemic cell injury and hypoxic cell injury?
Ischaemia prevents delivery of energy substrates, while hypoxic tissue can still produce energy by anaerobic glycolysis
Ischaemia tends to injure tissues faster than hypoxia
What are the possible mechanisms for ischaemia- reperfusion injury?
Prompt: Talk about reperfusion injury
O2 free radicals from cells and leukocytes
Mitochondria’ permeability transition
Inflammation from cytokines and expression of adhesion molecules
Pass: 2 of 4
Describe how oxygen free radicals contribute to this injury.
Derived for parenchymal cells, endothelial cells and leucocytes
– damaged mitochondria
– action of oxidases
Pass: 1 of 2
What is apoptosis?
Programmed cell death
Describe the mechanisms that result in apoptosis.
- Extrinsic (Death Receptor-initiated) pathway TNF receptor family (TNFR1 & Fas)
Activation of caspase leading to execution phase
- Intrinsic (Mitochondrial pathway)
Increased mitochondrial permeability releases pro-apoptotic molecules into cytoplasm which lead to caspase activation
- Execution phase
Proteolytic cascade mediated by activated caspases. Cleave cytoskeletal and nuclear matrix proteins Cleavage of DNA in nuclei
- Removal of dead cells by phagocytosis prior to inflammation
Describe the process of fracture healing.
- Haematoma formation / fibrin mesh
- Ingrowth of inflammatory cells / Activation of osteoprogenitor cells (procallus) *
- Woven Bone *
- Callus Formation *
- Remodelling times extra
Pass: 3/4 stages required
What factors may interfere with fracture healing?
- Displaced / Comminuted
- Foreign Bodies
- Inadequate immobilization
- Nutrition: Calcium / Phosphate
- Diabetes / Systemic Illness
Pass: 3 of the 6 stages required