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

1. Hypoxia2. Physical agents3. Chemical agents4. Micro-organisms5. Immune mechanisms

List 5 causes of cell injury

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.

Activity 1 - Structural changes of cell injury

Define necrosis and apoptosis

Necrosis Apoptosis• Always pathological• Passive process• Affects contiguous cells• Membranes breach with loss

of cytoplasm into the ECF• Inflammatory response

• Physiological or pathological• Active process• Affects single cells• Membrane integrity is

preserved• No inflammatory response

Differentiate between apoptosis & necrosis

Describe the structural changes of necrosis

• 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

List the 4 major types of necrosis, citing an example for each

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

Acute inflammation

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

How to remember neutrophil margination & migration

Mr AA

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

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

List some major chemical mediators of acute inflammation and their effects

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 TBQ2. What is the causative agent of this disease and how is it spread?A2. Mycobacterium tuberculosis spread via inhalation of droplets in the airQ3. What are the lesions causing the apical shadowing likely to be?A3. Granulomas/Ghon focusQ4. What type of cells are most likely to be seen on the biopsy specimen?A4. Epithelioid cells and langhans-type giant cells

Chronic inflammation

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)

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)

Describe the complications of chronic inflammation

• Continued chronic inflammation• Change in tissue function• Catastrophe• Scarring & dysfunction• Calcification• Resolution

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)

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 cells e.g lymphocytes, fibroblasts, giant cells, plasma cells. In response to a chronic insult

What is a granuloma? (4)

• Granuloma is a multicellular aggregate of macrophages

• A giant cell is a single fused mutlinucleate cell

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.

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.

Q1. What is the most likely diagnosis?A. Crohn’s diseaseQ2. Name 3 pathological features of Crohn’s diseaseA. Non-caseating granulomas, Fissuring & Fistula formation, Mucosal inflammation, causing transmural inflammationQ2. What are the most common complications of this disease?A. Malabsorption, fibrous strictures, perforation, fistulae

Healing & Repair

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)

Local SystemicSite & Size AgeTissue Type Chronic diseases (DM)Apposition & Fixation Drugs (steroids)Infection Cardiovascular statusBlood supply Dietary deficiencyRadiation damage Systemic infection

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

Define and describe the terms labile, stable and permanent tissues

There are two outcomes of repair, what are they? (2)

• Resolution/regeneration– Requires an intact BM

• Fibroplasia/fibrosis– Permanent scar formation

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)

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

Cellular Non-cellular Endothelial cells Fibroblasts Macrophages

Fibrin ECM proteins Oedema

Describe the process of fracture healing (6)

1. Haematoma2. Organisation (granulation tissue)3. Callus formation (osteoblasts)4. Laying down of Woven bone5. Ossification of woven bone into laminar bone6. Remodelling

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