Fundamentals: Pathology - Acute and chronic inflammation Flashcards
Describe the sequence of events in acute inflammation
- Vascular changes:
- Mediators including histamine and NO induce vasodilation (sometimes follows transient vasoconstriction), resulting in increased blood flow and erythema
- Increased vascular permeability occurs via a variety of mechanisms, leading to oedema
- Stasis of blood flow causes vascular congestion and activation by a variety of mediators causes endothelial cells to increase expression of adhesion molecules - Lymphatic changes:
- Lymph flow is increased
- Hyperplasia of lymphoid follicles occurs in lymph tissue, with increased numbers of lymphocytes and macrophages - Leukocyte changes:
- Leukocytes extravasate into the interstitial space via margination, rolling, and adhesion to endothelium followed by migration across the vessel wall and towards the chemotactic stimulus
- Leukocytes recognise offending agents via receptors, triggering their removal via phagocytosis and intracellular killing
Describe the mechanisms of increased vascular permeability in inflammation, where each occurs, their respective triggers, and their duration
- Retraction of endothelial cells (occurs in venules, triggered by mediators including histamine and NO, rapid and short-lived i.e. minutes)
- Endothelial injury (occurs in arterioles, capillaries and venules; caused by burns and some microbial toxins; rapid and may be long-lived i.e. hours to days)
- Leukocyte-mediated vascular injury (occurs in venules and pulmonary capillaries, associated with late stages of inflammation, long-lived i.e. hours)
- Transcytosis (occurs in venules, induced by VEGF)
Describe the steps involved in leukocyte recruitment and activation
- Margination: stasis pushes leukocytes to the periphery, they align along the endothelial surface
- Rolling: leukocytes transiently bind to endothelial adhesion molecules via receptors called selectins, detach and bind again thereby slowing down
- Adhesion: leukocytes bind more firmly to receptors called integrins
- Migration/diapedesis: leukocytes migrate through interendothelial spaces via binding to adhesion molecules including PECAM-1 (aka CD-31)
- Chemotaxis: locomotion of leukocytes through tissues to the site of inflammation, in the direction of the gradient of various chemoattractants
- Recognition of microbes and dead tissue: leukocytes are activated when they bind microbial products (via TLRs or via GPCRs recognising N-formylmethylpeptides), opsonins (e.g. Ab, complement proteins, lectins) or cytokes (e.g. IFN-y)
- Leukocyte activation: signaling pathways are triggered by receptor binding resulting in phagocytosis and intracellular killing of the offending agent
Give some examples of exogenous and endogenous chemoattractants
Exogenous: microbial products
Endogenous: cytokines (e.g. IL-8), complement system components (e.g. C5a), arachidonic acid metabolites (e.g. leukotriene B4)
Describe the process of phagocytosis
- Leukocytes bind offending agent (directly or via opsonins or cytokines)
- Leukocytes engulf offending agent in phagosome
- Phagosome fuses with lysosome to form phagolysosome
- Offending agent is degraded via lysosomal enzyme activity and directly via ROS/NO
Identify 7 cell-derived chemical mediators of inflammation
- Vasoactive amines: histamine, serotonin
- Arachidonic acid metabolites: leukotrienes, prostaglandins, lipoxins (which unlike other two inhibit inflammation)
- Platelet-activating factor
- ROS
- NO
- Cytokines
- Chemokines
What cells release histamine?
Mast cells
Basophils
Platelets
What cells release serotonin as part of the inflammatory response?
Platelets
What cells release prostaglandins and leukotrienes?
Mast cells
Leukocytes
What cells release platelet-activating factor?
Mast cells
Leukocytes
What cells release ROS?
Leukocytes
What cells release NO?
Endothelium
Macrophages
What cells release cytokines?
Mast cells
Endothelium
Macrophages
What cells release chemokines?
Leukocytes
Activated macrophages
Identify 3 plasma protein-derived chemical mediators of inflammation
- Complement products (C5a, C3a, C4a)
- Kinins
- Proteases activated during coagulation (e.g. thrombin)
Where are the plasma protein-derived chemical mediators of inflammation produced?
In the liver
Which chemical mediators of inflammation induce vasodilation?
Histamine
Prostaglandins
NO
Which chemical mediators of inflammation increase vascular permeability?
Histamine and serotonin
C3a and C5a (indirectly via inducing release of vasoactive amines from mast and other cells)
Bradykinin
Leukotrienes (C4, D4, E4)
PAF
Substance P
Which chemical mediators of inflammation induce chemotaxis and leukocyte recruitment and activation?
TNF and IL-1
Chemokines
C3a and C5a
Leukotriene B4
Bacterial products (e.g. N-formylmethylpeptides)
Which chemical mediators of inflammation produce fever?
TNF and IL-1
Prostaglandins
Which chemical mediators of inflammation induce pain?
Prostaglandins
Bradykinin
Which chemical mediators of inflammation are responsible for tissue damage?
Lysosomal enzymes of leukocytes
ROS
NO
What role does histamine play in the inflammatory response?
Vasodilation
Increased vascular permeability
Endothelial activation
What role does seratonin play in the inflammatory response?
Vasodilation
Increased vascular permeability
What role do prostaglandins play in the inflammatory response?
Vasodilation
Pain
Fever
What role do leukotrienes play in the inflammatory response?
Increased vascular permeability
Chemotaxis
Leukocyte adhesion and activation
What role does platelet-activating factor play in the inflammatory response?
Vasodilation
Increased vascular permeability
Chemotaxis
Leukocyte adhesion
Degranulation
Oxidative burst
What role does ROS play in the inflammatory response?
Killing of microbes
Tissue damage
What role does NO play in the inflammatory response?
Vascular smooth muscle relaxation
Killing of microbes
What role do cytokines play in the inflammatory response?
Local endothelial activation (increased adhesion molecules)
Fever
Pain
Anorexia
Hypotension
Decreased vascular resistance leading to shock
What role do chemokines play in the inflammatory response?
Chemotaxis
Leukocyte activation
What role do complement proteins play in the inflammatory response?
Vasodilation via mast cell stimulation
Chemotaxis
Leukocyte activation
What role do kinins play in the inflammatory response?
Vasodilation
Increased vascular permeability
Pain
Smooth muscle contraction
What role do coagulation cascade proteases (e.g. thrombin) play in the inflammatory response?
Endothelial activation
Leukocyte recruitment
List 4 important cytokines involved in acute inflammation
TNF
IL-1
IL-6
Chemokines