CELLULAR INJURY, INFLAMMATION AND HEALING VIVAS

Sample VivaWhat is reperfusion injury?COMMENTSPOINTS1 Further injury to ischaemic tissue that occurs after restoration of blood flow.Must give conceptPROMPTSSECOND QUESTIONWhat are the proposed mechanisms of reperfusion injury.POINTS1 Oxygen free radicals2/42 Mitochondrial permeability transition3 Inflammation: cytokine production and increased expression of adhesion molecules, recruitment polymorphs4 Complement pathway activation

Sample VivaCOMMENTSOPENING QUESTIONDescribe the role of complement in inflammation.COMMENTSPOINTS1 Vascular phenomena3/32 Leucocyte adhesion, chemotaxis and activation3 PhagocytosisPROMPTSSECOND QUESTIONOf the complement components, which are the most important inflammatory mediators?Must name bothPOINTS1 C32 C5

2011-2What leukocytes types are characteristic of acute inflammation- Initially Neutrophils first 6-24 hours- Then replaced by monocytes 24-48 hours- Neutrophils may last longer (4 days) in pseudomonas Lymphocytes in viral - Eosinophils in hypersensitivity

How do leucocytes get to an area of acute inflammationExtravasation – 3 steps:1. Margination of WCC in vessels, rolling and adhesion to endothelium (pavementing) (Selectins)2. Transmigration and diapedesis across endothelium (PECAM1, CD31, Integrins) 3. Migration towards chemotactic stimulus in tissue (bacterial products, cytokines, IL8, C5A)

Why do neutrophils predominate in the inflammatory response in the first 6-24 hours1. More numerous in the blood 2. Respond more rapidly to chemokines, 3. May attach more firmly to adhesion molecules, especially those expressed early4. Neutrophils are short lived - disappear after 24-48 hrs (monocytes live longer)

2011-2What are the characteristics of chronic inflammation- Prolonged process (weeks or more) in which active inflammation, tissue destruction and healing

all occur together.Morphologic features:1. Infiltration with mononuclear inflammatory cells

- Macrophages- Lymphocytes- Plasma cells

2. Tissue destruction3. Attempts at healing by connective tissue replacement

- Angiogenesis- Fibrosis

What are the causes of chronic inflammationCauses:1. Persistent infection by intracellular microbes of low direct toxicity (e.g. TB, viruses)2. Immune reactions

- Against own tissues especially i.e. auto-immune (RA, lupus)- Against host flora (e.g. inflammatory bowel disease)- Against benign environmental substance (allergies)

3. Prolonged exposure to potentially toxic substances- Exogenous (e.g. silica)- Endogenous (e.g. lipids -> atherosclerosis)

Why does macrophage accumulation persist in chronic inflammation1. Continued recruitment of monocytes due to continued expression of adhesion molecules and

chemotactic factors) 2. Local proliferation of macrophages3. Immobilisation of macrophages

2011-2Describe the pathogenesis of FibrosisFibrosis = excess deposition of collagen & ECM in chronic disease

1. Frustrated healing/chronic inflammation -> 2. Persistent stimulus (infections, autoimmune, trauma) Macrophage/Lymphocyte activation ->3. Growth factors: especially TGF-, PDGF, FGF -> 4. Proliferation of fibroblasts, endothelial cells, specifically fibrogenic cells

Alternatively activated macrophages - by IL- 4, IL-13, cytokines from TH2 , Mast, eosinophils- produce TGF-- act to suppress microbicidal function, stimulate angiogenesis and scar formation- vs. classically activated by TH1 cells (IFN- and TNF) -> micobicidal and phagocytic

TGF-β almost always involved:- Monocyte attractant (L/Mac) - Fibroblast activation/proliferation - Increased collagen fibronectin synthesis/secretion - Inhibition of metalloproteinases

OPN (osteopontin) also important in recent studies

Please provide some examplesCirrhosis, chronic pancreatitis, pulmonary fibrosis Pneumoconiosis, constrictive pericarditis, Glomerulonephritis

2011-1What are the stages of ischaemic cell injury • Initial Reversible • Irreversible (prolonged ischaemia injury and necrosis)2. Describe the sequence of events thatoccurs in reversible ischaemic cellular injury.PROMPTS What occurs in the cell?What happens to pH?• Due to loss of oxidative phosphorylation à decreased ATP àfailure of sodium pump à loss ofK+; influx of Na+ and H2O à iso-osmotic cell swelling. • Increase in Ca++ initially release from intracellular stores then influx of Ca++ across plasmamembrane à failure of ATP generation, activation of enzymes, induction of apoptosis àmembrane and nuclear damage• Decreased cellular pH due to increased lactate (increased anaerobic metabolism) • Loss of glycogen, decreased protein synthesis • Loss of microvilli, formation of cell surface blebs, myelin figures, mitochondria + ER swelling, ribosome detachment clumping of nuclear chromatin fatty change3. Describe the morphological changes ofirreversible ischaemic injury• Severe swelling of mitochondria • Extensive damage to plasma membrane • Swelling of lysosomes • Cell death by necrosis/apoptosis

2011-11.What is atrophy?

Shrinkage in the size of an organ or tissue due to decrease in cell size and number.2. What are the causes ofatrophy?

• Disuse • Denervation • Diminished blood supply • Inadequate nutrition • Loss of endocrine stimulation • Pressure

2.Give some examples of atrophy3.• Fracture disuse • damage to nerves causing muscle atrophy • breast/reproductive

organs from oestrogen lack

2011-11. Describe the cellular changes in necrosis

Usually irreversible injury Often adjacent inflammation Swollen cells Increased eosinophilia Myelin figures (whorls of cell membrane bits) Nucleus fades (karyolysis), may shrink (pyknosis) and then fragments (karyorrhexis)

1. Organelle disruption à amorphous mass Cell membrane disrupted, contents released

2. What are the patterns of tissue necrosis?Coagulative (architecture preserved) Liquefactive (digestion à liquid viscous mass) Caseous (friable white ) *Gangrenous (usually applied to limb. Typically coagulative. Superimposed liquefaction from infectionà‘wet gangrene’) *Fat necrosis (focal areas of fat destruction) Fibrinoid (microscopic feature of Ag-Ab complexes in vessel walls from immune mediated)

2011-1

1. Which mediators of inflammation are derived from cells?PreformedVasoactive amines § Histamines § SerotoninNewly synthesizedo Arachidonic metabolites § Prostaglandins§ Leukotrienes

1. § Lipoxins o Reactive Oxygen Species o Platelet activating factors o Nitric Oxide oCytokines (TNF, IL1)& Chemokines

2. Which cells release histamine?

Widely distributed in tissues, richest sources:1. • Mast cells • Basophils • Platelets2. What are the effects of histamines in an inflammatory response?

• • •1. Dilation of the arterioles Increased vascular permeability of the venules Can cause

constriction of large arteries

2010-21. Describe the vascular changes in acuteinflammation1.1. Vasodilatation: opening of arterioles and capillary beds mediated by histamine and Nitric Oxide leading to increased blood flow1.2. Increased vascular permeability1.3. Stasis: due to PP permeability and increased viscosityWhat are the mechanisms of increased vascular permeability?2. 2.1. Endothelial contraction / retraction: gaps in venules due to histamine and leukotrienes < 30mins, immediate transientresponse eg.ultraviolet radiation and kinins and leukotrienes 2-12hrs, delayed prolonged leakage eg. late appearingsunburn 2.2. Direct vascular endothelial injury eg. in severe burns, microbial toxin injury, amplified by neutrophil activation, rapidonset but may last days 2.3. Leukocyte mediated leakage, in venules and pulm capillaries, long lasting for hours 2.4. Trancytosis increased Tx of fluid and protein thru endothelial cell, VEGF

2010-21. What is tissue hypertrophy?

1.1. Increase in cellular size not number leading to overall organ/tissue size increase 1.2. Cell size increased by more structural components and increased synthesis of cellular proteins 1.3.

Triggered by increased functional demand or stimulation by hormones or growth factors 1.4.Can be selective hypertrophy of specific sub-organelles

2. What are examples of hypertrophy (Prompt: How is it classified??)3. 2.1. Physiological skeletal muscle enhancement through training or uterus under influence

of hormones such as4. oestrogen 2.2. Pathological such as cardiomegaly in hypertension and CCF (has an

upper limit after which regression occurs ->5. cell injury -> apoptosis/necrosis)2. How is hyperplasia different form hypertrophy?3. 3. Hyperplasia involves an increase in the number of cells.

2010-2What is angiogenesis?1. The process of blood vessel formation in the adult. 2 methods1.1. Branching and extension of existing vessels 1.2. Recruitment of endothelial progenitor cells (EPCs)

Please give some examples?3. Wound healing, chronic inflammation, proliferating endometrium, tumours, etc

What steps are involved in angiogenesis from pre existing vessels?3. Steps in angiogenesis 3.1. Vasodilation 3.2. Proteolytic degradation of basement membrane 3.3. Endothelial cells migrate to angiogenic stimuli 3.4. Maturation 3.5. Capillary formation 3.6. Recruitment of periendothelial cells for support structure formation4. Inhibitors such as endostatin are released by proteinases (This is a small fragment of collagen that inhibits endothelial proliferation and also angiogenesis)

2010-2How do leucocytes get to an area of acuteinflammation?1.1 Margination of WCC in vessels, rolling and adhesion to endothelium (pavementing) (Selectins) 1.2 Migration and diapedesis across endothelium (PECAM1, CD31, Integrins) 1.3 Migration towards chemotactic stimulus in tissue (bacterial products, cytokines, IL8, C5A)

. What is the role of leukocytes in acuteinflammation?2.1 Recognition and attachment to materials (opsonins) mediated by receptors 2.2 Killing of microbes: phagocytosis /engulfment /killing and degradation (H2O2-MPO-Halide) 2.3 Release of products – Amplify the inflammatory reaction (lysosomal enzymes, reactive oxygen/nitrogen)

2010-1What is reperfusion injuryWhat are the proposed mechanisms of reperfusion injury

2010-1What is apoptosisList some important stimuli for apoptosis

2010-1What is metaplasia and give some examples

How may metaplasia progress

2010-1What systemic factors affect wound healingWhat local factors impede wound healing

2010-1What is hypertrophyGive examples of physiologic and pathologic hypertrophy

2009-2What cells are present in chronic inflammationWhat processes mediate the persistent accumulation of macrophages seen in chronic inflammationWhat products are released by macrophages in chronic inflammation

2009-2Describe the process of skin wound healing by first intention

2009-2What are the morphological and chemical changes associated with early cell injuryWhat are the phenomena that characterize irreversible cell injuryCan you give an example of a protein the leaks across degraded cell membranes

2009-1Describe the vascular changes that occur in acute inflammationWhat are the causes of the increased vascular permeability

2009-1Describe the types of damage that occur inside a cell after severe ischaemia

2008-21. 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).

1. As a result cellular, hence tissue injury is much more rapid in ischaemic injury.

2. 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

2008-2What is the complement system?

1. Plasma protein system involved in immunity against microbes. Complement proteins numbered C1-9 are present in plasma in inactive forms.

Describe the main pathways by which complement activation occurs1. Classical pathway: involving an antigen-antibody complex 2. Alternate pathway: triggered

by microbial surface molecules (e.g. endotoxin). No antibody involvement. 3. 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)

How do activated complement products mediate acute inflammation?1. Vascular effects: increased permeability; vasodilatation (via C3a, C5a mediated histamine

release from mast cells) 2. Leucocyte adhesion, chemotaxis and activation: via C5a 3. Phagocytosis: C3b acts as opsonin on microbe and leads to phagocytosis4. Cell lysis by the membrane attack complex (MAC) –– composed of multiple C9 molecules

2008-2Describe the factors that affect wound healing(Table 3-5) Local: blood supply, denervation, local infection, FB, haematoma, mechanical stress, necrotic tissue, protection, surgical technique, tissue type Systemic: Age, anaemia, drugs, genetic disorders, hormones, diabetes, malignant disease, malnutrition, obesity, systemic infection, temperature, trauma, hypovolaemia, hypoxia, uraemia, vitamin deficiency (C), trace metal deficiency (Cu, Zn)

2008-2Describe the sequence of cellular events in acute inflammationLeucocytes 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 glycoproteinsThen leucocytes migrate to site of injury- chemotaxis

␣ Chemotaxis and activation is mediated thru various bacterial products, cytokines, chemical factors, Ag-Ab complexes products of necrosisThen leucocyte activation to enable phagocytosis and enzyme releasePhagocytosis and release of various enzymes from leucocytes

2008-1What are the differences between hyperplasia and hypertrophy? Hyperplasia - increase in number of cells in organ/tissue- usually resulting in increase in volume - occurs if cellular population capable of synthesising

DNA thus permitting mitotic division.Hypertrophy increase in size of cells causes increase in size of organs.Hypertrophy and hyperplasia often co-exist.

Describe the different types of hyperplasia and give an example of each.Physiologic: Hormonal, Compensatory. growth factors e.g. proliferation of connective tissue cellsand blood vessels in aiding wound repair.Pathological hormonal stimulation excessive e.g. oestrogen and effect on uterus, benign prostatic hypertrophy caused by androgens

2008-1Please describe the 2 different forms of pathological calcification and give an example of each.Dystrophic calcification – normal serum calcium - in necrotic or dying tissueMetastatic calcification - normal tissue - abnormal (raised) calciumDystrophic calcification – atherosclerosis; calcific aortic stenosis; tuberculous nodeMetastatic calcification – nephrocalcinosis; pulmonary calcinosis; gastric mucosal

“Describe the different principal pathological causes of hypercalcaemia, with some clinical examples.1. Increased PTH secretion + bone resorption - hyperparathyroidism2. Destruction of bone tissue – skeletal metastases, myeloma, Paget’s3. Vit-D related disorders – sarcoidosis, hypervitaminosis D4. Renal failure – secondary hyperparathyroidism + phosphate retention

2008-1

What is apoptosis?1.Pathway of cell death. 2.Induced by tightly regulated intracellular programme 3. Cells that are destined to die activate enzymes that degrade the cells’ own nuclear DNA and nuclear/cytoplasmic proteins. 4. The cell’s plasma membrane remains intact. 5. Apoptotic cell becomes target for phagocytosis. 6. Dead cell rapidly cleared before contents leak out so this does not elicit an inflammatory reaction in the host. 7. Cell shrinks

Describe the physiologic situations where apoptosis occurs.1.Programmed destruction of cells during embryogenesis. 2. Hormone dependent involution in adult such as endometrial breakdown. 3. Cell deletion in proliferating cell populations e.g. intestinal crypt cells. 4. Death of host cells that have served their purpose e.g. neutrophils in acute inflammation. 5. Elimination of potentially harmful self reactive lymphocytes. 6. Cell death induced by cytotoxic T cells.

2008-1Describe how angiogenesis occurs.1)Mobilisation of Endothelial precursor cells (EPC) from the bone marrow & from pre-existing vessels. 2)EPC migrate to a site of injury or tumour growth. 3) EPC differentiate & form a mature network by linking with existing vessels.4)Stabilisation: Endothelial cells from pre-existing vessels become motile & proliferate to form capillary sprouts. 5)Vessels mature involving pericytes & smooth muscle cells to form periendothelial layer.

1. Haemangioblast generates haemopoietic stem cells and angioblasts. Angioblasts like EPC are stored in adult bone marrow initiate antiogenesis. Participate in replacing lost endothelial cells, in vascular impant endothelization and in neovascularising ischaemic organs, cutaneous wounds and tumours.2. Vasodilatation of pre-existing vessels, increased permeability, degradation of basement membrane, disruption of endothelial cell to cell contact, proliferation and migration towards angiogenic stimulus, and endothelial cell maturation/growth inhibition/remodelling capillary beds.

Factors:Receptors:VEFGAngioproteins 1 and 2PDGFTGFBVEGFR-2 FGF-2EC receptor Tie 2

2008-1What are the phases involved in scar formation?Fibroblast migration and proliferation Extracellular matrix (ECM) deposition Tissue remodeling

What are the local triggers of fibroblast migration and proliferation (at the site of an injury)?Growth Factors- TGF-β; PDGF; EGF; FGFCytokines – IL-1; TNF

What are the sources of these local triggers?1. 2.Platelets Macrophages and other inflamm cells such as mast cells, eosinophils, lymphocytesEndothelium

2007-2What is metaplasiaA reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by anotherAn adaptive change brought on by chronic stress such as chemical or physical irritation so that cells

change to other cell types that are better able to withstand the adverse environmentCan you give examplesMost common is columnar -> squamous epithelium- trachea in smoking- salivary, pancreatic and biliary ducts by stones (secretory columnar changed to non-secreting

sqaumous)- vitamin A def may cause squamous metaplasia in reipiratory, or corneal, renal- vitamin A excess may stimulate osteoclast formation -> bone resorption and fractures

Metaplasia of squamous to columnar- Barretts oesophagus (in reponse to acid, predisposing to adenocarcinoma)

Metaplasia of one connective tissue type to another eg muscle -> bone or cartilage e.g myositis ossificans

What is the mechanism causing metaplasiaA reprogramming of epithelial stem cells or undifferentiated mesebchymal cells- involves signals from cytokines, growth factors, ECM components, genes, and DNA methylation

2007-2What are the defining pathological characteristics od chronic inflammationList some causes of chronic inflammation

2007-1What are the differences between hyperplasia and hypertrophy?Hyperplasia

Increase in number of cells in organ/tissueUsually resulting in increase in volumeoccurs if cellular population capable of synthesising DNA thus permitting mitotic

division.Hypertrophy

Increase in size of cellsCauses increase in size of organs.

Hypertrophy and hyperplasia often co-exist

Describe the different types of hyperplasia and give an example of each.Physiologic:HormonalCompensatory.PathologicalHormonal stimulation excessive e.g. oestrogen and effect on uterus, benign prostatic

hypertrophy caused by androgensGrowth factors e.g. proliferation of connective tissue cells and blood vessels in aiding

wound repair.

2007-1Describe the 2 different forms of pathological calcification and give an example of each

Dystrophic calcificationNormal serum calciumIn necrotic or dying tissue

Metastatic calcificationAbnormal (raised) calciumNormal tissue

 Give examples of each.

Dystrophic calcification:AtherosclerosisCalcific aortic stenosisTuberculous node.Metastatic calcificationNephrocalcinosisPulmonary calcinosisGastric mucosal

Describe the different principal pathological causes of hypercalcaemia, with some clinical examples.

Increased PTH secretion + bone resorption – hyperparathyroidismDestruction of bone tissue – skeletal metastases, myeloma, Paget’sVit-D related disorders – sarcoidosis, hypervitaminosis DRenal failure – secondary hyperparathyroidism + phosphate retention

2007-1What is atrophy? 2. What are the pathological types of atrophy? Prompt: What are the causes? 3. Give some examples of atrophy

Shrinkage in the size of the cell by loss of cell substanceDisuse, Denervation, Diminished blood supply, Inadequate nutrition, Loss of endocrine stimulation, Ageing, PressureFracture disuse, damage to nerves causing muscle atrophy, breast/reproductive organs from oestrogen lack.

2007-1Please describe the main vascular changes that occur with acute inflammationWhat are the major mechanisms for the increased vascular permeability that occurs with inflammation?Prompt: “What mediators affect vascular permeability”

1.Vasodilation & incr blood flow via mediators eg histamine, NO action on vasc smooth muscle 2. Increased permeability 3.Stasis (mins)4 Accumulation of leukocytes on vasc endothelium 1. Gaps due to endothelial contrac via mediators (immediate transient): histamine (fast), bradykinin, sub P, leukotrienes, cytokines(longer). Venules. 2. Direct injury to vessel: immediate sustained eg burns, lytic bact 3. Delayed prolonged 2-12 hrs burn, radiation, toxins mech unclear 4.. Leukocyte-dep injury: venules, pul caps, hours 5. Incr transcytosis: vesicles, vacuoles, incr channels VEGF 6. New vessel formation; new bvs leaky; VEGF, mediators

2007-1. What is hypertrophy?2. What are the types of hypertrophy?3. Give examples of physiologic and pathologic hypertrophy.

Increase in the size of the cells, due to synthesis of morestructural components, resulting in an increase in the size of the organ (no new cells, just larger cells) Physiological or pathological in response to increased functional demand or specific hormonal stimulationCan occur in both dividing and non-dividing cells Physiological Pathological 1. Physiologic: Enlarged skeletal muscles in labourers (workload), Enlarged uterus in pregnancy (hormonal), Enlarged breasts in lactation

Pathological: Enlarged prostate in BPH, Enlarged heart in valve disease or chronic hypertension (workload)

2007-11. Describe the causes of oedema formation2. How does increased hydrostatic pressure causes oedema?Prompt: What are some examples?What is the pathogenesis of cardiac oedema?1. Hydrostatic pressure; 2. Decreased plasma oncotic pressure; 3. Lymphatic obstruction; 4. Sodium and water retention; 5. Inflammation1. Local: Impaired venous outflow – Thrombosis, External pressure, Prolonged dependency with inactivity 2. Generalised impaired venous return – CCF, Constrictive pericarditis, Ascites3. Arteriolar dilatation – Heat, Neurohumeral dysregulation Decreased cardiac output, Decreased renal perfusion, Secondary aldosteronism, Increased blood vol, inc venous pressure

2006-2Describe the role of complement in inflammation.COMMENTSPOINTS REQUIRED1 Vascular phenomena3/3 to pass2 Leucocyte adhesion, chemotaxis and activation3 Phagocytosis

Of the complement components, which are the most important inflammatory mediatorsC3C5

2006-2COMMENTSOPENING QUESTIONWhat is reperfusion injury?COMMENTSPOINTS REQUIRED1 Further injury to ischaemic tissue that occurs after restoration of blood flow.Must give conceptPROMPTSSECOND QUESTION (if needed)What are the proprosed mechanisms of reperfusion injury.POINTS REQUIRED1 Oxygen free radicals2/4 to pass2 Mitochondrial permeability transition3 Inflammation: cytokine production and increased expression of adhesion molecules,

recruitment polymorphs4 Complement pathway activation

2006-2What is apoptosis?COMMENTSPOINTS REQUIRED1 Programmed deathMust give conceptPROMPTSSECOND QUESTION (if needed)

Under what conditions may apoptosis occur.Must be able to give at least one example of each group to passPOINTS REQUIRED1 Physiological: embryogenesis, hormone-dependent involution in adult, cell deletion, elimination of potentially harmful self-reactive lymphocytes, cell death induced by cytotoxic T cells2 Pathological: cell death secondary to radiation injury or cytotoxins, viral hepatitis, pathologic atrophy after duct obstruction in pancreas, parotid or kidney, cell death in tumoursPROMPTSGive an example of physiological (or pathological ) apoptosisTHIRD QUESTION (if needed)What happens at a cellular level?POINTS REQUIRED1 Cell shrinkage2 Chromatin condensation3 Formation of cytoplasmic blabs and apoptotic bodies4 Phagocytosis of apoptotic cells or cell bodies, usually by macrophages

2006-1What is reperfusion injuryWhat mechanisms are involved

2006-1What is irreversible injury in cells after a period of ischaemiaWhat changes are observed in these cell’s structure and contents

2006-1Describe the vascular changes in acute inflammationWhat mechanisms cause increased vascular leakage in acute inflammation

2005-2Describe the mechanisms of ischemic cell injuryWhat are the differences between ischemic cell injury and hypoxic cell injury

2005-2What are the possible mechanisms for ischaemia-reperfusion injuryDescribe how oxygen free radicals contribute to this injury

2005-2What is apoptosisDescribe the mechanism that result in apoptosis

2005-1Describe the process of primary wound repair

2005-1How does a scar formWhat factors influence scar formation

2004-2Describe the morphological changes that occur in cells during acute ischaemia.PROMPTSCOMMENTSPOINTS REQUIREDReversible changes Cellular Swelling: failure to maintain ionic and fluid haemostasis; organs become swollen; 1. plasma membrane blebs,

intramembranous aggregations 2.mitochondrial swelling, smalldensities. 3. distended segments of ER;dispersion of ribosomes ‘vacuolardegeneration. 4. Clumping of nuclear chromatin.Fatty change: lipid vacuoles in cytoplasm.Irreversible changes Cell membrane defects, Myelin figures in cytoplasm, rupture of lysosymes and autodigestion Mitochondrial large densities, lysis of ER Nuclear pyknosis, karyolysis or karyorrhexis.

2004-2Describe the processes involved in healing by first intention.COMMENTSPOINTS REQUIRED1. 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 layerGet candidate to say in chronological order2. 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 architecture3. weeks: proliferation of fibroblasts and collagen, regression of vascular channels, disappearance of leukocytic infiltrate and oedema and loss of increased vascularity

2004-2What is metaplasia?PROMPTSCOMMENTSPOINTS REQUIREDReversible change where one adult cell type is replaced by another adult cell typeMust say this point to passMay be adaptive- sensitive cell type replaced by resistant cell typeThe influences that predispose to metaplasia can induce cancerous transformationSECOND QUESTION (if needed)Please give examples of metaplasia.Give 1 example to passPOINTS REQUIREDColumnar to squamous epithelium in the resp tract secondary to chronic irritationStones in pancreas, salivary or bile ducts Þ squamous epithelium from columnarBarrett esophagitis squamous Þ columnar epitheliumConnective tissue metaplasia. Cartilage, bone or adipose tissue forms in other tissuesTHIRD QUESTION (if needed)What causes metaplasia?OptionalPOINTS REQUIREDReprogramming of stem cellsMay be due to cytokines, growth factors, and extracellular matrix components.Tissue specific and differentiation genes influenced to lead to cellular differentiationKnown factors include, chronic irritation, Vit A deficiency and excess, cytostatic drugs

2004-2Describe the biochemical features of cell injury.PROMPTSCOMMENTSPOINTS REQUIRED

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 ↓ pH then normalisation or ↑ pH. 2. Free oxygen radical formation 3. ↑ intracellular Ca4. Defects of membrane permeability- leakage of intracellular substances - myoglobin, CK, troponin, other enzymes 5. Mitochondrial damageDecreased protein synthesis ↑ Lipid breakdown products↓ Intracellular glycine

2004-2Describe the process of fibrosis and scar formation.COMMENTSPOINTS REQUIRED1 Formation of new blood vessels (angiogenesis) – pre- existing vessels send out capillary buds/sproutsNeed 2 points to pass.2 Migration and proliferation of fibroblasts – within granulation tissue framework3 Deposition of extracellular matrix (ECM) – fibrillar collagens, spindle shaped fibroblasts, elastic tissue4 Maturation and organisation of fibrous tissue (tissue remodelling) – changes in composition of ECM, degradation of collagen and other ECM proteins by matrix metalloproteinase’s

2004-2What is the difference between dystrophic and metastatic calcification?PROMPTSCOMMENTSPOINTS REQUIREDDystrophic calcification has normal calcium level in damaged tissue while metastatic calcification has high calcium level in damaged tissue.SECOND QUESTIONWhat are the causes of metastatic calcification?POINTS REQUIREDhyperparathyroidism, vitamin D intoxication, systemic sarcoidosis, milk alkali syndrome,

hyperthyroidism, idiopathic hypercalcaemia.Renal failure, destructive bone diseaseNeed 3 to passTHIRD QUESTION (if needed)What tissues are most commonly affected by metastatic calcification?Need 1 to passPOINTS REQUIREDGastric mucosaKidneysLungsSystemic arteriesPulmonary veins

2004-2What is apoptosis?PROMPTSCOMMENTSPOINTS REQUIREDProgrammed cell death, occurs in single cells or clusters of cells, not associated with tissue inflammationSECOND QUESTION (if needed)Give some examples of apoptosis.Need 2 to pass

POINTS REQUIREDEndometrial 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

2004-2Describe the steps involved in angiogenesis.COMMENTSPOINTS REQUIRED1 Proteolysis of basement membrane of parent vessel – allows formation of capillary sprout and subsequent cell migrationNeed 2 to pass2 Migration and chemotaxis of endothelial cells – towards angiogenic stimulus3 Proliferation of endothelial cells4 Lumen formation, maturation, inhibition of growth/remodelling – of endothelial cells, remodelling into capillary tubes5 Increased permeability through gaps and transcytosis – recruitment of periendothelial cells to support endothelial tubes, providing maintenance and accessory cell function

2004-2What is steatosis?PROMPTSCOMMENTSPOINTS REQUIREDAbnormal accumulations of triglycerides within parenchymal cellsSECOND QUESTION (if needed)Which organs are commonly involved in steatosis?Need 2 to passPOINTS REQUIREDLiverHeart, muscle, kidneysTHIRD QUESTION (if needed)What are the causes of hepatic steatosis?Need 2 to passPOINTS REQUIREDAlcohol abuseToxins (CCl4), protein malnutrition, diabetes mellitus, obesity, anoxia, starvationIn the liver it results from defects in any one of the events in the sequence from fatty acid entry to lipoprotein exit (FFA- esterified to triglycerides- converted into cholesterol and phospholipids or oxidized to ketone bodies- associated with apoproteins to form lipoproteins and released into the circulation)

2003-2Describe the morphological changes seen in cells with reversible ischaemia.What metabolic changes occur in reversible ischaemia?Cellular swelling: failure to maintain ionic and fluid homeostasis; organelles become swollen; 1.plasma membrane alterations. 2. mitochondrial changes. 2/4 3. distended segments of ER; ‘vacuolar’ degeneration. 4. nuclear alterations. Fatty change: lipid vacuoles in cytoplasm.Depletion of ATP –> sodium pump reduction –> swelling, Na into cells. Increased. catabolites in cells –> increased. osmotic load –> swelling. Anaerobic metabolism. –> lactic acidosis, decreased pH. Detachment of ribosomes from ER –> decreased protein synthesis

2003-2Describe the vascular response in acute inflammationWhat are the mechanisms of increased vascular permeability in acute inflammation?

Changes in vascular flow and caliber:-> transient constriction –> dilation –> heat and redness. Increased vascular permeability: -> slowing of circulation, hemoconcentration –> stasis –> leucocyte margination, adherence to endothelium -> oedema.Vascular leakage – endothelial contraction; cytoskeletal reorganisation; direct injury; leucocyte injury; increased. Transcytosis

2003-2Describe the morphological changes seen in cells with irreversible ischaemia.What metabolic changes occur in irreversible ischaemia?Mitochondrial swelling: influx of Ca, loss of proteins, enzymes, RNA, through hyperpermeable membranes. Lysosomal injury – leakage of enzymes into cytoplasm. – autodigestion. Cell membrane leakage in both directions, fluid in, eg CK,Trop out.. Nuclear changes (pyknosis/karyolysis/karyolexis).Inability to reverse mitochondrial dysfunction causing ATP depletion. Disturbances of cell membrane. Contributing mechanisms: mitochondrial dysfunction; loss of membrane phospholipids; cytoskeletal abnormalities; reactive oxygen species; lipid breakdown products; loss of intracellular amino aids.

2003-1Describe the process of peripheral nerve repair following traumatic injuryCOMMENTSPOINTS REQUIRED1 Death of distal part (+/- some of proximal)2 Axonal Cone of Growth 1-2 mm per day3 Growth through Schwann cell structure4 regenerating Clusters