Module 28 - Acute Inflammation Flashcards
Define inflammation.
A protective response intended to eliminate the cause and consequence (necrotic cells and tissue) of cell injury. It is induced by chemical mediators that are produced by host cells in response injurous stimuli.
Mention the fundamental signs of inflammation.
These manifestations occur as consequences of the vascular changes and leukocyte recruitment and activation.
- Heat (calor): Vasodilation; increased blood flow to the injured region
- Redness (rubor): Vasodilation and stasis (congestion/ hyperemia/ engorgement)
- Swelling (tumour): Vasodilation & vascular permeability leading to extravasation of fluid (transudate/ exudate/ edema)
- Pain (dolor): Compression of tissues or Direct effect of inflammatory mediators
- Loss of function (functio laesa): direct effect of injury, or due to pain/swelling
Differ between acute and chronic inflammation.
Acute:
- Rapid onset, short duration
- Fluid and plasma protein exudation
- Neutrophil (PMN) accumulation
Chronic:
- Insidious onset lasting days to years
- Lymphocytes and macrophages
- Scarring (more tissue destruction)
Mention the 5 essential steps in inflammation.
- Recognition
- Recruitment
- Removal
- Regulation
- Resolution
What happens during the recognition phase of inflammation?
Phagocytes and dendritic cells (cells that reside in the connective tissue of organs) and other cells (epithelial cells) express receptors that recognise microbes and necrotic cells.
These Pattern Recognition Receptors (PRR) includes:
- Toll-like receptors: recognize PAMPs - microbe receptors
- Inflammasome: recognize products of dead cells and microbial products DAMPs - cell damage sensors
What happens during the recruitment phase of inflammation with respect to vascular change?
Designed to initiate rapid delivery of leukocytes and plasma proteins from the circulation to the site of the injury.
Vascular changes includes:
- Transient vasoconstriction followed by arteriolar vasodilation: due to chemical mediators (histamines) -> increased blood flow -> engorgement of capillary beds -> formation of transudate
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Increased Vascular Permeability -> formation of exudate
- Either due to contraction or direct injury of endothelial
- Stasis: Increases RBC concentration, slowed blood flow -> accumulation of neutrophils
The lymphatic system then helps drain the edema fluid accumulated (increased lymph flow).
Describe the transudate mechanism.
Increased hydrostatic pressure or decreased colloid osmotic pressure leads to accumulation of interstitial fluid. However, the only ultrafiltrate can pass through the vessels, not a lot of protein or cells.
___________ line the entire blood and lymphatic vascular system and control the passage of materials into and out of the bloodstream.
Endothelial cells
Differ between vasoactive mediators that are responsible for the immediate/transient and slow/prolonged change in permeability.
Histamine, bradykinin, leukotrienes are responsible for the immediate and short-lived increase in vascular permeability through initiating endothelial cell contraction (gaps between endothelial cells)
Changes in cytoskeleton induced by IL-1 and TNF leads to prolonged permeability increase (larger gaps)
Explain how endothelial injury can also initiate vascular permeability.
Direct injury to the endothelium allows leakage and formation of exudate to start immediately and is sustained for several hours until the damaged blood vessels are thrombosed and repaired.
Explain how increased vascular permeability leads to exudate.
Due to the increase in vascular permeability, bigger things such as protein and cells are able to pass through, forming exudate (protein-rich fluid + cells) in the extravascular space.
This leads to a change in osmotic pressure causing an outflow of water and ions to extravascular space -> edema-fluid accumulation (swelling).
What happens during the recruitment phase of inflammation with respect to cellular change?
- Margination: slowed blood flow-stasis causes leukocytes to be pushed to the margins of the blood vessels
- Rolling: weak, transient adhesion between selectins and sialylated oligosaccharides (upregulated by immune mediators) in endothelial cells, reduce rolling velocity
- Adhesion: mediated by integrins, low affinity until activated by chemokines (also stimulate expression of integrin ligands I-CAM/V-CAM in endothelial cells)
- Transmigration: occurs in the post-capillary venules through diapedesis, in response to chemical gradient produces at the site of inflammation (PECAM1 - Platelet endothelial cell adhesion molecule 1) - Collagenase degrade basement membrane
- Migration/Chemotaxis: a chemical gradient produced by exogenous and endogenous sources, which binds to the surface receptors (chemokines) and initiates leukocyte movement
Describe the morphological types of acute inflammation.
Serous Inflammation: exudation of protein-poor fluid, located in body cavities (peritoneal, pleural, or pericardial)
Fibrinous inflammation: exudate contains large molecules (fibrinogen) forming fibrin, characteristic of inflammation of meninges, pericardium, and pleura
Suppurative (PUS): exudate consisting of edema fluid, prominent cellular components (neutrophils); associated with pyogenic bacterial infection, if occur inside tissue called abscess
Ulceration: necrosis and inflammation on or near the surface, shedding of tissue
What happens during the removal phase of inflammation?
- Recognition and Leukocyte Activation: engagement of receptors expressed on leukocyte surfaces by microbial products and mediators, PAMP/DAMP, cytokines, and opsonized particles
- Opsonization
- Phagocytosis: A form of endocytosis in which specialized endocytic vesicles (phagosome) are used to ingest
- Killing & Degradation
Describe the phagocytic receptors.
- Mannose Receptor - a lectin that binds glycolipids and glycoproteins that are unique to microbial cell walls
- Scavenger Receptors - recognize cellular debris (ie. acetylated LDL) and opsonized microbes.
- Opsonic receptors
Describe the mechanism of opsonization.
Below are examples of opsonins:
- Bacterial LPS activates complement pathway, generating C3b (deposited in the bacterial surface) with opsonizing properties.
- IgG antibodies binding to antigen also activates complement (acts as opsonins).
- Collectins (PRR) which bind to microbial cell wall sugar group.
- Mannose-binding lectins
Describe the mechanism of phagocytosis.
It involves the recognition of the particles to be ingested by the phagocytic receptors, which falls under two categories:
- Non-opsonic: Mannose receptor, Scavenger Receptor
- Opsonic: Complement receptor, FcR
- Requires opsonins coating the particle
This triggers engulfment, through receptor-initiated signalling, membrane remodelling, and cytoskeletal changes. Actin assembly to form phagosome.
It then fuses with lysosomes, resulting in the discharge of lysosomal contents into the phagolysosome. During this, the phagocyte also may release some granule contents into the extracellular space, damaging normal cells.
_________ occurs when phagolysosome is formed, leading to an increase in ROS. This process is mediated by _______.
Respiratory burst
Phagocyte oxidase/NADPH oxidase
What compounds are primarily used to destroy ingested particle in oxygen-dependent process? How is it manufactured inside lysosome?
Hypochlorous radical (HOCl•) - powerful oxidant and microbicidal. It is obtained through a reaction of H2O2 and Cl- in the presence of myeloperoxidase (MPO), which is present in the lysosome of neutrophils.
Nitric oxide is a short-lived, free radical gas. When it reacts with superoxide, it forms peroxynitrite (ONOO), a cytotoxic agent in macrophages - microbicidal and promotes vasodilation
Note: NADPH-oxidase activated in phagolysosome to produce superoxide ion -> H2O2
Mention the compounds that are responsible for degradation.
- Lysosomal acid hydrolases (function in low pH inside lysosome)
- Neutral proteases, elastase, collagenase, cathepsins ( regulated by antiproteases in ECM)
Mention the systems at which plasma-derived mediators are obtained. Explain the characteristics and advantages of these type of mediators.
Complement, Kinin, Coagulation, and Fibrinolytic systems are enzymatic cascades that produce plasma-derived mediators.
They are present as inactive precursors circulating in the plasma that needs to be activated at the site of inflammation. They are:
- Safer than active mediators
- Act to amplify the response
- A larger number of possible regulators can modulate the response
- Each step produces end products that can have different activities
Describe the mechanism of complement system producing plasma-derived mediator
Cell-derived chemical mediators may be produced by _________ (4). It can exist ________ or _____________.
- Tissue macrophages
- Mast cells
- Endothelial cells
- Leukocytes
Preformed or newly synthesized
Give an example of preformed and newly synthesized cellular mediators.
Preformed: Histamine -> released by a variety of stimuli (activation of complement. physical injury, binding of IgE etc) leading to vascular changes (dilation and increased permeability)
Newly Synthesized: Arachidonic Acid metabolites (prostaglandin and leukotrienes) -> AA cleaved from phospholipid, mediate most inflammatory step, short range and act locally (decay/enzymatic degradation)
______ and _______ target AA metabolite formation to reduce pain and fever.
Aspirin, NSAIDs (Non-steroidal inflammatory drugs)
Briefly recall endogenous inflammatory mediators and their common responses.
Describe what occurs during the resolution stage of acute inflammation.
Occurs when DAMP/PAMP is no longer present at the site of injury. Achieved through the following passive processes:
- Clearance of mediators and acute inflammatory cells (apoptosis)
- Regeneration of damaged tissue
- Normalization of vascular permeability
- Clearance of exudate (lymphatic drainage, macrophages ingestion)
Active process - Inhibitors of inflammation (Lipoxins): AA metabolite produced by leukocyte when entering tissue inhibits neutrophil (chemotaxis and adhesion) - negative regulators of leukotrienes
