Causes of inflammation
Defense mechanism by the body deals with an insult
- Foreign particles
- Necrotic tissue
- Hypersitivity reactions
- Physical agents
What are the cardinal signs of inflammation?
Calor - Hear
Rubor - Redness
Dolor - Pain
Tumor - Swelling
(and loss of function)
What are the three types of exudate?
Fibrinous - large amounts of fibrinogen due to increase in vascular permeability
Purulent - pyogenic bacterial infections. Rich in neutrophils, cell debris and bacteria
Transudate - low protein content, caused by alteration in hydrstatic or oncotic pressure
Name 5 possible outcomes of an acute inflammatory response
Organisation and repair
Name 6 inflammatory mediators
Platelet activating factor
Cytokines - TNF alpha, ILs
Complement system – esp C5a
What is the role of histamine in inflammation?
Causes vascular dilatation, and is the main effector of immediate phase vascular permeability
Released from preformed granules in mast cells in response to trauma, cold, antibodies, cytokines.
Role of PAF in inflammation
Released from leukocytes and mast cells. Causes vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst. 1000 times more potent than histamine
What is the role of prostaglandins in acute inflammation?
Released from mast cells and leukocytes. Causes vasodilation, pain and fever.
What are leukotrienes?
Amino Acid metabolites
Released from mast cells and leukocytes. Vaso-active (increase permeability).
LTB4 chemotactic & stimulates leukocyte adhesion to endothelium, also generation of free radicals & release of lysosomal enzymes
Which cytokines are involved in acute inflammation?
IL-1, TNF-alpha. Released by macrophages, endothelial cells and mast cells.
Cause local endothelial activation (expression of adhesion molecules)
Chemotaxis of neutrophils
Decreased vascular resistance (shock)
What is the role of complement in inflammation?
Complement products (C5a, C3a, C4a) are produced in liver and secreted into the plasma
Complement can be activated by necrosis, Ag/Ab complexes, endotoxin or fibrinolytic systems.
Cause leukocyte chemotaxis and activation, vasodilation (mast cell stimulation), cell lysis via the MAC and opsonisation of pathogens
What are the problems that are caused by acute inflammation?
destruction of normal tissue
blockage of tubes
loss of fluid
What are the three stages of acute inflammation?
Increase in blood flow,
Structural changes in the microvasculature that permit plasma proteins and leukocytes to leave the circulation,
Emigration of the leukocytes from the microcirculation to the tissue and activation to eliminate the offending agent
What are the systemic effects of acute inflammation?
Fever - enogenous pyrogens e.g IL-2
Leukocytosis - bacterial infections (neutrophils), viral (lymphocytes)
Acute phase resposne (high CRP, ESR)
What are the three steps of extravasation?
Vascular endothelium in its normal, unactivated state does not bind circulating cells or impede their passage.
- Endothelium is activated expresses adhesion molecules which bind to receptors on leukocytes, causing margination, rolling, and adhesion to endothelium.
- Migration across the endothelium and vessel wall
- Migration in the tissues toward a chemotactic stimulus
What is the function of neutrophils?
In most forms of acute inflammation neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours and are replaced by monocytes in 24 to 48 hours.
Allows destruction of foreign material & removal of damaged tissue
Neutrophils recognise dead tissue and foreign material either directly via mannose receptors or via Opsonins & Fc and C3b receptors, then bind to it
Engulf material (phagocytosis/pinocytosis)
Descibe the process of extravasation
Vasodilation slows the blood flow (stasis) and reduces shear stress. Leukocytes redistribute along the endothelial surface (margination).
Endothelial cells are activated by cytokines to express express E-selectin and P-selectin, this binds to receptors expressed on leukocytes and cause adherence which causes the leukocytes to roll along the vessel wall. TNF and IL-1 induce the expression of integrins, which cause leukocytes to adhere tightly to the endothelium (patenting).
Chemokines produced at the site of injury activate the leukocytes and stimulate migration through endothelial spaces toward the sie of infection. After traversing the endothelium, leukocytes pierce the basement membrane, by secreting collagenases and enzymes, and enter the extravascular tissue.
Once inside the tissue, cells migrate to areas of inflammation by chemotaxis.
What is the purpose of inflammation?
Inflammation is a protective response, designed to rid the organism of both the initial cause of cell injury (e.g. microbes, toxins) and the consequences of such injury (e.g., necrotic cells and tissues).
What factors comprise the anti-oxidant defence system?
What is the effect of aspirin on inflammation?
Aspirin irreversible acetylates and inhibits COX-1 and COX-2 enzymes. These convert arachadonic acid to PGH2 which is a precursor for other prostaglandins.
Prostaglandins are involved in the vascular and systemic reactions of inflammation, particularly TXA2 which is a potent platelet activator.
How do corticosteroids modify acute inflammation?
Corticosteroids suppress the immune system.
Produces an anti-inflammatory response. Can act by reducing the transcription of genes encoding COX-2, phospholipase A2, pro-inflammatory cytokines (such as IL-1 and TNF), and iNOS.
How does inflammation help produce an effective response to injury?
Inflammation causes cellular reactions (stimulates the immune response), which promote destuction and removal of the damaging agent.
Increased vascular permeability increases delivery of antibodies, nutrients and oxygen to cells.
destroys and removes dead or foreign material and promotes repair process.
What are the microscpic features of acute inflammation? How do they occur?
Oedema, fibrin and neutrophil infiltration
Causes by haemodynamic changes (vasodilation slow blood flow)
Increased vascular permeability (leading to the escape of a protein-rich exudate into the extravascular tissue)
Recruitment and migration of neutrophils
What are the underlying processes that result in the signs of inflammation?
Rubor (redness) is caused by increased circulation and vasodilation in the injured tissues
calor (warmth) is the heat given off by the increased flow of blood;
tumor (swelling) is caused by increased fluid escaping into the tissues;
dolor (pain) is caused by the stimulation of nerve endings.
Combined, these events often cause the temporary loss of function of the afflicted tissue (functio laesa)
Name one inherited disorder of acute inflammation
Inherited angio-oedema: defective gene means immune system not regulated causing spontanous angioedema
Chronic granulamous disesase
Describe 3 possible outcomes of acute inflammation
Resolution: Once the injurious agent has been neutralised, the site of acute inflammation is restored to normal. This is the usual outcome when the injury is limited or short-lived or when there has been little tissue destruction and the damaged parenchymal cells can regenerate. Resolution involves removal of cellular debris and microbes by macrophages, resorption of fluid by lymphatics, fibrin degraded by plasmin, apoptosis of neutrophils.
Suppuration: Pus formation due to resistant organism. Results in abscess formation, empyema and fistulae
Organisation: This occurs after substantial tissue destruction, when the inflammatory injury involves tissues that are incapable of regeneration, or when there is abundant fibrin exudation in tissue or serous cavities (pleura, peritoneum) that cannot be adequately cleared. In all these situations, connective tissue grows into the area of damage or exudate, converting it into a mass of fibrous scar tissue.
Chronic inflammation: If acute inflammation cannot be resolved or if the injury persists the healing process is impaired. Causes fibrosis and long term tissue damage
What are the three main funciton sof the acute inflammatory response?
Transport of cells and proteins from local blood vessels which promote a defensive response.
Destruction and removal of foreign agent (e.g. bacteria, material)
Destruction and removal of damaged tissue and debris
What are the contents of acute inflammatory exudate?
Fluid: containing salts, Ig, proteins
Fibrin: filamentous protein which polymerises into form clots
Cells: neutrophils, lymphocytes, macrophages
What are the underlying processes that produce the cardinal signs of inflammation?
The redness and heat of acute inflammation are the result of vesel dilation and icnreased blood flow into the inflamed part.
Swelling is caused by the accumulation of exudate, particularly the fluid component.
Pain is due to the direct effects of certain chemical mediators and pressure on the nerve endings caused by swelling
When swelling is marked, there is a loss of function of the inflamed structure.
What is an abscess?
A mass of necrotic tissue with dead and viable neutrophils, suspended in the fluid products of tissue breakdown.