Mechanisms ESA Stem

• 6 causes of cell injury– Hypoxia– Chemical (toxins)– Physical– Infection– Immune– Nutrition

• Mechanisms of cell injury– Reduced ATP synthesis/mitochondrial damage

• Reversible– Alterations in Ca homeostasis

• Irreversible– Metabolic derangements– Free radical production

• Name and describe the 2 types of cell death– Apoptosis• Programmed cell death• Not always pathological

– Necrosis• Death of contiguous cells in tissue or organ• Always pathological

• Name and briefly describe the types of necrosis– Coagulative

• Cells have died but basic architecture remains• Tissue retains solid consistency• Dead cells replaced by regeneration from neighbouring cells or fibrous scar

– Liquefactive necrosis• Complete dissolution of tissue

– Due to massive infiltration of neutrophils

– Caseous necrosis• Accumulation of amorphous debris within area of necrosis• Tissue architecture abolished• Characteristic of TB granulomas

– Fat necrosis• Lipase action results in free fatty acids precipitated as calcium soaps

– saponification

• What are clinical terms for necrosis and types of each– Gangrene – grossly visible and advanced necrosis

• Dry – coagulative necrosis• Wet – liquefactive necrosis

– Infarct• White

– Solid organs– Arterial occlusion where 1 artery supplies certain area

• Red– Loose tissues– Venous occlusion/dual blood supply

• Triggers of apoptosis– Withdrawal of growth stimuli– Death signals (TNF, Fas)– DNA damage (p53)

• Cellular consequences of chronic alcohol abuse– Liver – fat accumulation, hepatitis, cirrhosis– GIT – bleeding from gastritis/ulcer/varices– Thiamine deficiency

• Peripheral neuropathy• Wernicke-korsakoff syndrome

– Cerebral atrophy, cerebellar dengenration and optic neuropathy

– Cardiomyopathy– pancreatitis

• What is the pathology of paracetamol overdose– Metabolised to NAPQ1 through P450 system in

liver– Accumulates and causes hepatic necrosis

• How is it treated– N-acetylcysteine

• Causes of acute inflammation– Injury/insult– Hypersentivity reactions– Physical agents– Chemicals

• Clinical features of acute inflammation– Red, hot, swollen, painful

• Principle cells of acute inflammation– Polymorphonuclear granulocytes

• Neutrophils• Eosinophils• basophils

• Process of acute inflammation

• Inflammatory mediators cause vasodilation.

• Increased blood flow = red and hot.

Haemodynamic Changes

• Oedema.• Leaking fluid and protein• Caused by direct damage

to vessels , increased hydrostatic pressure, venule contraction.

Changes in Vessel Permeability • Polymorphonuclear

granulocytes recruited from blood.

• Mostly neutrophils.• Phagocytose (recognise,

engulf, kill)

Leukocyte Recruitment

• Describe the process of leukocyte recruitment and activation– Margination

• Stagnation in microcirculation displaces cells from central axis to periphery of blood vessels

– Adhesion• Expression of endothelial adhesion molecules leads to leukocyte binding

– Inflam causes P-selectin expression by endothelial cells– P-selectin tethers PMNs rolling along wall– Integrins on PMN upregulated and bind ICAM and VCAM-1 on endothelial cells

– Emigration• Adhesion activates pseudopodia in PMNs• Cell pushes through gaps between endothelial cells

– Chemotaxis• Directional movement of cells towards injury by following chemical messengers

– Phagocytosis• Destruction of foreign material

• Beneficial effects of acute inflam– entry of antibodies– nutrients and oxygen– deliver neutrophils– stimulation of the immune response– entry of drugs (makes membranes leaky)

• Negative side effects of acute inflam– destruction of normal tissue– swelling– blockage of tubes– loss of fluid– pain– inappropriate inflammation

• Outcomes of acute inflam– Resolution

• (elimination of stimulus, exudate drained, removal of debris, cells regenerate)– Suppuration

• (pus/abscess/empyema, can be v difficult to get rid of, can form sinuses/fistulae)

– organisation and repair • (stimulus eliminated but dead tissue not removed, heals via granulation with

scar tissue, causes adhesions)– chronic inflammation

• (persistant stimulus)– septicaemia– death

• Name 6 inflammatory mediators– Histamine– Serotonin– Prostaglandins– Leukotrienes– Cytokines– Nitric oxide– Bradykinin– complement

• Name and describe 2 inherited disorders of acute inflammation– Chronic granulomatous disease

• Failure of phagocytes to kill engulfed microbes due to lysosomal enzyme defects

• Recurrent infections– Hereditary angio-oedema

• Low levels (type 1) or dysfunctional (type 2) C1 esterase inhibitor

• Abnormal increase in complement activity• Non-pitting subdermal oedema

• Causes of chronic inflammation– Persistent infections– Prolonged exposure to toxins– Autoimmune disease– Non-resolving acute inflammation

• Complications of chronic inflammation– No resolution– Fibrosis– Scarring with dysfunction– Atrophy– metaplasia

• Main cells involved in chronic inflammation and their function– Macrophages (+ Giant cells)

• Phagocytosis and destruction• Cytokine release• Release tissue damaging agents and pro-fibrotic tissue repair factors

– Lymphocytes• B/plasma cells – antibody production• T-cells – cytotoxic

– Eosinophils• Membrane bound IgE

– Mast cells• Membrane bound IgE and cytokine release

• 3 patterns of chronic inflammation and an example of each– Lymphocytic – autoimmune thyroid disease– Mixed acute/chronic – ulcerative collitis– Granulomatous – Crohn’s

• Features of granulomatous inflammation– Presence of granulomas

• Collection of macrophages often with giant cells– Response to

• Persistant low grade antigen stimulation• Delayed hypersenitivity• Foreign material• Insoluble antigen

• Special types of chronic inflammation– TB – Caseating granulomas– Sarcoidosis – non-caseating granulomas– Crohn’s disease – granulomas– Foreign body reactions – multinucleated foreign

body giant cells– Syphillis – Gumma (lesion enclosing wall of

histiocytes)

• In terms of healing and repair what are the 3 categories of tissue– Labile• Continuously dividing

– Stable• Not normally dividing but retain ability

– Permanent• Terminally differentiated with no capacity to divide

• Describe the process of healing by regeneration– Cell migration• Leukocytes, fibroblasts, endothelial and epithelial cells• Via cell surface receptors/chemotaxis/binding ECM,etc

– Cell proliferation– Cell differentiation– Cell-ECM interaction

• Describe the process of healing by fibrosis– Angiogenesis– Migration and proliferation of fibroblasts (growth

factors)– Deposition of ECM• No of fibroblasts proliferating decreases and they start

secreting ECM• Granulation scaffold-scar-matures

– Remodelling of ECM

• Describe the phases of wound healing– Inflammatory phase

• Haemastasis– Vasoconstriction and clotting

• Inflammation– Cleansing of wound

– Proliferative phase• Granulation tissue• Contraction (wound edges pull together)• Epithelialisation (cells cross over moist surface)

– Maturation phase• Collagen forms (increases tensile strength)• Scar tissue (80% strength of original tissue)

• Describe healing by primary intention– Edges of wound opposed and fixed– Blood clot forms– Acute inflammation– Epithelium proliferation– Granulation tissue formation– Myofibroblast infiltrate and differentiate– Production of ECM which matures and contracts

further

• Describe healing by secondary intention– Larger defect = more extensive loss of cells/tissue– Initial wound contraction– Formation of eschar (scab)– Epidermis regenerates at base of wound with

granulation tissue bed– Myofibroblast infiltrate– Further wound contraction and ECM deposition

• Factors affecting wound healing– Site and size– Tissue type– Opposition and fixation– Infection and foreign material– Blood supple radiation damage– Age– Chronic disease– Steroids– Dietary deficiency

• Role of endothelial cell in normal conditions and response to damage– Normal – anti-coagulation

• Physical barrier• Secrete anti-coagulants

– Heparin sulphate, NO, prostacyclin (inhibit platelets)• Secrete tissue plasminogen activator

– Converts inactive plasminogen to plasmin = breakdown fibrin

– Damage – pro-coagulation• Barrier function loss = expose highly thrombotic collagen• Endothelin released (vasoconstrictor)• Express procoagulation molecules

– Platelet endothelial adhesion molecule – 1 and vWF• Tissue factor (III) released by exposure to subendothelial material• t-PA inhibitor secreted

• Describe the intrinsic and extrinsic coagulation cascades

• Describe the process of fibrinolysis– Plasminogen produced by the liver has affinity for

fibrin = incorporated into clot– Presence of t-PA and urokinase converts inactive

plasminogen into active plasmin– Plasmin causes breakdown of fibrin to fibrin

degradation products (FDPs)• Also produces more active forms of t-PA and urokinase

• What is the definition of a thrombus– Solid mass of blood constituents formed within

the vascular system during life• What are predisposing factors for thrombus

formation– Virchow’s triad• Abnormalities of vessel wall• Abnormalities of blood flow• Abnormality of blood constituents

• Risk factors for venous thrombosis– Surgery– Bed rest– Malignancy– Pregnancy and post partum– Obesity– Travel

• Possible outcomes of thrombosis– Propagation (in direction of blood flow)– Fibrinolysis– Organisation (scar tissue)– Recanalisation (macrophages)– embolism

• Definition of an embolism– A mass travelling through the vascular tree that becomes lodged

forming an obstruction• Name the different types of embolism

– Thromboembolism– Atheroma– Air– Amniotic fluid– Nitrogen– Tumour cells– Fat– Foreign material

• Name and describe 4 disorders of coagulation– Haemophillia

• X-linked recessive genetic disorder• Absence of types of clotting factors

– Disseminated intravascular coagulation (DIC)• Pathological activation of clotting mechanism

– Formation of clots in vessels throughout the body– Consumes platelets and coagulation proteins

– Thrombocytopenia• Too few platelets in the blood

– Thrombophilia• hypercoagulability

• What is the process of atheroma formation– Repetitive injury (loss of endothelial function)– Increased permeability and leukocyte adhesion– Infiltration of tunica intima by LDL and macrophages– Free radicals cause oxidation of LDL which is then taken

up by macrophages (become foam cells)– Foam cells produce cytokines and more free radicals

• Further leukocyte recruitment and oxidisation (visicious cycle)– SMC migration and proliferation– ECM secretion stabilises palque

• Name and describe the 3 types of atheroma morphology– Fatty streak

• Lipid deposits form slightly raised and yellow intimal disclouration– Fibro-fatty plaque

• Fibrous cap with central necrosis formed of extracellular lipids, SMCs and macrophages/foam cells

• Peripheral proliferating vessels within the lesion– Complicated plaque

• Same as fibro-fatty plaque but complicated by– Dystrophic calcification– Fissuring and ulceration of fibrous cap causing thrombus formation

• What are 3 major non-modifiable risk factors for atheroma– Age (40-60)– Gender (male)– Genetics

• What are 4 major modifiable risk factors for atheroma– Hyperlipdaemia– Hypertension (control)– Smoking– Diabetes mellitus (control)

• Factors controlling cellular growth– Presence of stimulatory or inhibitory signals– Cell-cell communication– Vascular/metabolic factors

• What are the phases in the cell cycle– G0 – resting

– G1 – gap 1 (checkpoint-DNA damaged/cell big enough)• If passes this checkpoint WILL complete cycle

– S – DNA synthesis/replication– G2 – gap 2 (checkpoint – all DNA replicated correctly)– M - mitosis

• Describe and list some physiological and pathological causes of hypertrophy– Increase in cell size and therefore organ/tissue size– Causes• Physiological

– Increased functional demand (e.g. Skeletal muscle)– Hormonal (uterus)

• Pathological– Increased functional demand (e.g cardiac muscle)

• Describe and list some physiological and pathological causes of hyperplasia– Increase in cell number and therefore organ/tissue

size– Causes• Physiological

– Hormonal (e.g. Endometrium)– Compensatory (e.g. Partial hepatectomy)

• Pathological– Chronic irritation

• Describe and list some physiological and pathological causes of atrophy– decrease in cell size by loss of cell substance –if

sufficient may result in decreased organ/tissue size– Causes

• Physiological– Reduced workload– ageing

• Pathological– Loss of nerve supply– Reduced blood supply

• Describe and list some physiological and pathological causes of metaplasia– Reversible change from 1 adult cell type to

another adult cell type– Causes• Physiological

– Hormonal (glandular to squamous cervix at puberty)• Pathological

– Barrett’s oesophagus– Glandular to squamous epithelium in bronchus of smokers

• Define neoplasm– Abnormal mass of tissue – Excess and uncoordinated growth– Growth persisting after removal of initial stimulus

• Changes in cell growth control causing neoplasm– Increased cell proliferation– Decreased cell death– Longer cellular lifespan– Altered growth factors/hormones and receptors– Altered cell-cell/ECM interaction

• Alterations essential for malignancy (malignificent 7)– Self-sufficiency in growth signals– Insensitivity to negative growth signals– Defects in DNA repair– Evasion of apoptosis– Limitless replicative potential– Sustained angiogenesis– Ability to invade and metastasis

• Describe the features of a benign tumour– No invasion or metastasis– cells retain function– Well defined edge– Minimal variation in nuclear size, shape and

chromasia– Low mitotic count– Retention of cellular specialisation– organised

• Describe the features of a malignant tumour– Invasion and metastases– Loss of function– Ill defined margin– Marked variation in nuclear size, shape and

chromasia (nuclear dysplasia)– May have high mitotic count– Loss of specialisation– disorganised

• Define dysplasia– Alteration in size, shape and organisation of adult

cells– Severe dysplasia = carcinoma in situ

• The cancer game (name the tissue each tumour is derived from and whether it is malignant or benign)– Fibroma – benign fibrous tissue– Chrondroma – benign cartilage– Leiosarcoma – malignant smooth muscle– Adenoma – benign glandular– Leukaemia – malignant blood– Teratoma – germ cells malignant+male, benign+female

• Define invasion– Ability of cells to break through normal barriers

and spread to surrounding tissue• Define metastasis– Ability of malignant cells to invade into

lymphatics/blood vessels/body cavities and spread to distant/non-contiguous sites

• Describe the mechanisms facilitating invasion and metastases– Detachment

• Altered cell adhesion - cadherins• Reduced expression/alterations in interaction allows cells to move apart

– Attachment• Altered cell adhesion – integrins• Reduced expression in malignant cells modifies ECM contact and allows

movement– Migration and ECM degradation

• Altered enzyme synthesis and interaction• Breakdown BM and stroma allows cells to break through and spread

• Describe the stages in metastasis– Invade BM (MMP/TIMP)– Passage through ECM (MMP/TIMP)– Intravasation (MMP/TIMP and altered integrins)– Immune reaction– Platelet adhesion– Adhesion to endothelium/BM– extravasation (MMP/TIMP and integrins)– angiogenesis

• What are the most common routes of metastasis– Blood– Lymphatics– Transcoelomic

• What are the most common sites of metastases– Lymph nodes– Lung– Liver– Bone – Brain– peritoneum

• What is cachexia– Progressive loss of body fat and lean body mass

accompanied by profound weakness, anorexia and anaemia

• What are paraneoplastic syndromes– Symptom complexes occurring in cancer patients

not readily explained by local or distant tumour spread

• List 5 types of carcinogens and give an example of each– Radiation

• UV or ionising– Chemical

• Aromatic amines or polycyclic aromatic hydrocarbons– Viruses

• HPV or EBV or hepatitis B– Micro-organisms

• Bacteria – H. Pylori• Fungi – aspergillus flavius• Parasites – schistosomiasis

– Hormones• Oestrogen – endometrial carcinoma• Anabolic steroids – hepatocellular tumours

• Normal functions of oncogenes and changes that occur in neoplasia– Normal = proto-oncogene• Products promote cell proliferation

– Oncogene (mutant proto-oncogene) • Function autonomously without requirement for

normal growth signals

• Describe the role of Ras and changes in function with mutation– Normal

• G protein that moves between active (GTP bound) and inactive state (GDP bound)• When active stimulates downstream regulators of

proliferation– Mutation

• Interfere with GTP hydrolysis enzymes – prevents inactivation of Ras– Trapped in active form

• Normal functions of tumour suppressor genes and changes that occur in neoplasia– Normal = protective gene• Prevent cell replicating with damaged DNA and

stimulate apoptosis– Mutation (requires loss of both genes)• Loss of “stop” mechanisms resulting in uncontrolled

replication (failure of apoptosis) and unrepaired DNA damage

• Describe the role of p53 and changes in function with mutation– Normal• Senses DNA damage and assists repair by causing G1

arrest and inducing DNA repair genes– If damage too severe induce apoptosis

– Mutation• DNA damage goes unrepaired and mutations become

fixed in dividing cells– Cells set on pathway to malignant transformation

• What is xeroderma pigmentosum– Inherited inability to repair DNA damage caused

by UV radiation – develop skin cancer• What is ataxia telangiactasia– Autosomal recessive inherited defect in detecting

DNA breaks (ATM gene)– Leads to abnormal cell death in areas of body

(including cerebellum – ataxia)

• How are malignant tumours staged– T – extent of tumour (1-4)– N – lymph nodes (0-3)– M – metastases (0-1)

• How is rectal cancer staged– Duke’s staging

• How is hodgkins lymphoma staged– Ann Arbor staging

• What is tumour grading a measure of– The differentiation of the tumour

• What is the mechanism of action and main side effects of radiotherapy– Kills cells by using ionising radiation to damage

DNA– Ischaemic necrosis and fibrosis

• What are tumour markers– Products liberated from tumour into blood

• What type of tumour do the following markers indicate– α-foetoprotein = germ cell or liver cell tumours– CA 125 = ovary– CA19-9 = pancreas or colon– CA15-3 = breast