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Mechanisms of Disease

Mechanisms of Disease . Cell Injury, acute and chronic inflammation. Learning objectives from handbook. Question based upon learning objectives. The basics. Discuss and list the causes of cell injury and death. Hypoxia Physical agents Chemical agents Micro-organisms Immune mechanisms.

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Mechanisms of Disease

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  1. Mechanisms of Disease Cell Injury, acute and chronic inflammation

  2. Learning objectives from handbook Question based upon learning objectives

  3. The basics

  4. Discuss and list the causes of cell injury and death • Hypoxia • Physical agents • Chemical agents • Micro-organisms • Immune mechanisms List 5 causes of cell injury

  5. Describe the mechanisms of cell injury • Reduced ATP synthesis or mitochondrial damage • Loss of calcium homeostasis ([Ca2]i), • disruption of membrane permeability • and the production of free radicals.

  6. Activity 1 - Structural changes of cell injury

  7. Define necrosis and apoptosis Differentiate between apoptosis & necrosis

  8. Describe the structural changes of necrosis List the 4 major types of necrosis, citing an example for each • Coagulative necrosis • Myocardial infarction, Acute tubular necrosis • Liquefactive necrosis • Stroke/TIA, acute pancreatitis • Caseous necrosis • Granulomatous inflammation of TB, fungal infections • Fat necrosis • Pancreatitis, trauma

  9. A 62-year-old man returns home from playing bingo, complaining of midline abdominal pain. He denies being hit or suffering any other trauma. Over the next few hours the pain does not remit but becomes more severe and is localized to the lower right quadrant. On examination, he has a temperature of 38.8°C and appears ill. His abdomen is mildly distended and has hypoactive bowel sounds. The abdomen is diffusely tender to palpation, particularly in the right lower quadrant. What is the most likely diagnosis? Acute appendicitis What is the cause of his raised temperature? Pyrexia due to IL-1/IL-2, TNF-alpha and prostaglandins He undergoes an appendectomy describe the most likely macroscopic appearance of the excised appexdix Suppurative (purulent) inflammation, enlarged erythematous, pus covered

  10. Acute inflammation

  11. List the major causes & purposes of acute inflammation Describe the macroscopic features of acute inflammation Describe the microscopic features of acute inflammation How do the microscopic changes relate to the macroscopic Explain why the changes constitute an effective response to injury

  12. How to remember neutrophil margination & migration Mr AA 

  13. Describe the 6 events that begins with neutrophils in blood vessels and ends with them accumulating at an inflammatory site

  14. Activity 2 – What do neutrophils do, and briefly how do they do it?

  15. List some major chemical mediators of acute inflammation and their effects

  16. A 75-year-old woman is brought to the emergency department because of massive hemoptysis. Her CXR shows apical shadowing. Despite appropriate measures, including volume replacement and circulatory support, she dies. Postmortem examination reveals hilar lymphadenopathy with caseous necrosis and infiltration and destruction of a large pulmonary artery by this process. The lungs show extensive consolidation with other areas of caseous necrosis. Q1. What is the most likely diagnosis? A1. Pulmonary TB Q2. What is the causative agent of this disease and how is it spread? A2. Mycobacterium tuberculosis spread via inhalation of droplets in the air Q3. What are the lesions causing the apical shadowing likely to be? A3. Granulomas/Ghon focus Q4. What type of cells are most likely to be seen on the biopsy specimen? A4. Epithelioid cells and langhans-type giant cells

  17. Chronic inflammation

  18. Describe the cells principally involved in c. inflammation and the role of each • Macrophages • Lymphocytes • Plasma cells • Eosinophil’s List the cells that characterise histologically chronic inflammation (4)

  19. Describe the central role of the macrophage, and its many functions • Phagocytosis • APC • Cytokine production • Tissue destruction/repair What are the major functions of macrophages? (4)

  20. Describe the complications of chronic inflammation • Continued chronic inflammation • Change in tissue function • Catastrophe • Scarring & dysfunction • Calcification • Resolution

  21. What is the role of opsonins in phagocytosis? Give an example (2) • Bind to and label a target material for phagocytosis • IgG, IgA, Complement (C3b)

  22. What is a granuloma? (4) What is the difference between a granuloma and a giant cell? (2) • A collection of epithelioid cells (activated macrophages) clumped together usually with a variable number of other inflammatory cellse.g lymphocytes, fibroblasts, giant cells, plasma cells. In response to a chronic insult • Granuloma is a multicellular aggregate of macrophages • A giant cell is a single fused mutlinucleate cell

  23. A 22-year-old woman has had recurrent episodes of diarrhoea, crampy abdominal pain, and slight fever over the last 2 years. At first the episodes, which usually last 1 or 2 weeks, were several months apart, but recently they have occurred more frequently. Q1. What is the most likely diagnosis? • Crohn’s disease Q2. Name 3 pathological features of Crohn’s disease A. Non-caseating granulomas, Fissuring & Fistula formation, Mucosal inflammation, causing transmural inflammation Q2. What are the most common complications of this disease? A. Malabsorption, fibrous strictures, perforation, fistulae On at least one occasion, her stool has been guaiac-positive, indicating the presence of occult blood. Colonoscopy reveals several sharply delineated areas with thickening of the bowel wall and mucosal ulceration. Areas adjacent to these lesions appear normal. Biopsies of the affected areas show full-thickness inflammation of the bowel wall and several noncaseating granulomas.

  24. Healing & Repair

  25. The patient in the previous question undergoes surgery, you note in the post-op notes that it is taking a surprisingly long time for her to recover from surgery. What are the general systemic factors that can affect the rate of wound healing? (5)

  26. Define and describe the terms labile, stable and permanent tissues Define the terms below and give an example of each (6) • Labile cell – continuously dividing • Epithelia of….. Skin, GI tract, cervix, endometrium, UT • Stable cell – Can undergo rapid division in response to certain stimuli • Liver and kidney • Permanent cell – cannot divide in postnatal life • Cardiac myocytes, neurones, skeletal muscle

  27. There are two outcomes of repair, what are they? (2) • Resolution/regeneration • Requiresan intact BM • Fibroplasia/fibrosis • Permanent scar formation

  28. Give four complications of repair (4) • Loss of tissue architecture and function e.g cirrhosis • Deficient scar formation e.g hernia, ulceration • Excessive formation of repair components e.g keloid scars • Contracture e.g intestinal strictures (crohn’s)

  29. What are the cellular and non-cellular constituents of granulation tissue? (6)

  30. Describe the process of fracture healing (6) • Haematoma • Organisation (granulation tissue) • Callus formation (osteoblasts) • Laying down of Woven bone • Ossification of woven bone into laminar bone • Remodelling

  31. Activity 3 – The whole process of healing from injury to resolution!

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