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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.
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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
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 – Caseatinggranulomas • Sarcoidosis – non-caseatinggranulomas • 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 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 intimaldisclouration • 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