1 / 60

Mechanisms ESA Stem

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.

binh
Download Presentation

Mechanisms ESA Stem

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Mechanisms ESA Stem

  2. 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

  3. 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

  4. 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

  5. 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)

  6. 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

  7. 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

  8. 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

  9. Process of acute inflammation

  10. 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

  11. 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

  12. 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

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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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)

  19. 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

  20. 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

  21. 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

  22. 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)

  23. 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

  24. 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

  25. 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

  26. 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

  27. Describe the intrinsic and extrinsic coagulation cascades

  28. 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

  29. 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

  30. 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

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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)

  36. 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

  37. 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)

  38. 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

  39. 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

  40. 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

  41. 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

  42. 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

  43. 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

  44. 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

  45. Define dysplasia • Alteration in size, shape and organisation of adult cells • Severe dysplasia = carcinoma in situ

  46. 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

  47. 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

  48. 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

  49. 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

  50. 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

More Related