Acute inflammation Flashcards
What is acute inflammation?
A response by vascularized tissue to infections & necrotic tissue damage
brings leukocytes & plasma proteins from circulation to the site needed.
It’s a protective response to remove the cause of cell injury e.g. microbes & the consequences of injury e.g. necrotic cells.
Caused by necrosis (DAMPs) or iinfection (PAMPs/MAMPs).
Which cell characterises acute inflammation?
Neutrophil
What are the 5 cardinal signs of infection?
Heat (calor)
Redness (rubor)
Swelling (tumor)
Pain (dolor)
Loss of function (functio laesa)
Describe sequence of events in acute inflammation?
- Stimulus - PAMPs or DAMPs are produced.
- Recognition by sential cells - macrophages, dendritic cells & mast cells that have toll-like receptors.
- Cytokines produced by sential cells e.g. IL-1.
- Recruitment of leukocytes by IL-1 - neutrophils & monocytes.
- Inflammation induced - vasodilation & increased vascular permability, leading to oedema.
- Phagocytosis by neutrophils & macrophages (the macrophages develop from the monocytes).
- Regulation - cytokines switch from inflammatory to healing & growth factors.
- Resolution- where homeostasis is restored.
What is the vascular reaction in a nutshell?
Changes in blood flow
Changes in permeability of vessels
Maximizes movement of plasma proteins & leukocytes (WBCs)
Describe the changes in blood flow seen in acute inflammation? What induces this reaction?
Vasodilation:
- Induced by histamine & prostaglandins I2 & D2 (& other mediators e.g. Bradykinin & Serotonin) on vascular smooth muscle.
- First involves arterioles & then capillaries.
- Slows blood
- Results in increased blood flow to affected area = causes heat & redness of site of inflammation.
Increased permeability:
- Causes an outpouring of exudate.
- The exudate is high in proteins, including immunoglobulins & coagulation factors e.g. fibrin.
- Inflammatory oedema - the combined increase in hydrostatic pressure & decrease in plasma oncotic prrssure causes net movement of fluid from the blood plasma into tissues.
How does increased vascular permeability occur?
Bradykinin
Retraction of endothelial cells:
- Results in the opening of interendothelial spaces.
- Initiated by histamine, bradykinin, leukotriene B4 & nitric oxide.
- Mainly occurs in post capillary venules.
- This is fast (15-30 mins) & short lived.
Endothelial injury:
- Leakage due to damage by burns or induced by microbes/microbial toxins.
- Starts immediately after damage & is sustained for several hours until damage is repaired.
Name the advantages of inflammatory oedema
- Brings antibodies & fibrin to site of infection,
- Fibrin mesh provides a scaffold for WBCs & prevents spread of microorganisms.
- Contains non-specific immune cells that oponise pathogens for neutrophil-mediated phagocytosis.
- Fluid dilutes & modifies the actions of toxins
- The exudate circulates in the lymphatic system, aiding antigen presentation
Describe leukocytes recruitment & activation?
- Margination:
- Vasodilation slows blood in the venules.
- Causes cells to marginate from the centre of the vessel to the periphery - Endothelial cells activated by cytokines express adhesion molecules called selectins.
- Leukocytes attach loosely to the selectins (using Sialyl-Lewis X modified glycoprotein)
- The leukocytes bind & detach = roll along endothelial surface. - Adhesion
- Chemokines activate integrins – which are found on the surface of neutrophils.
- Integrins undergo conformational changes & cluster together.
- This increases the affinity for selectins that are present on surface of endothelial cells.
- At the same time, TNF & IL-1 upregulate expression of ICAM & VCAM ( integrin ligands found on endothelial cells). i.e. they bind to integrins. - Transmigration
- Leukocytes migrate through endothelial surface by squeezing between cells at intercellular junctions.
- Mainly occurs in post-capillary venules.
- Platelet endothelial cell adhesion molecule-1 (PECAM-1) mediates transmigration of leukocytes. - Chemotaxis:
- locomotion along a chemical gradient.
- Chemoattractants include: bacterial products, IL-8, C5a, leukotriene B4.
- These activate the contractile protein actin w/in leukocyte, causing cell to move. - Phagocytosis & O₂ dependant killing
- Pathogen Recognition Receptors (PRRs) e.g.toll-like receptors on phagocyte bind to PAMPs
- Bacterium becomes attached to membrane evaginations called pseudopodia which are part of the cytoplasm.
- Phagocyte engulf bacterium forming phagosome.
7.Destruction of phagocytosed material:
- Phagosome fuses w/ lysosome (phagolysosome), which contains digestive enzymes (lysosomal proteases).
- The lysosomal enzymes break down bacteria into particles.
- In activated neutrophils, cytoplasmic components of phagocyte oxidase enzyme assemble in membrane of the phagosome to form an active enzyme.
- This enzyme catalyses conversion of oxygen to superoxide + hydrogen peroxide.
- Myeloperoxidase (enzyme present in granules of neutrophils) then converts hydrogen peroxide into hypochlorite (bleach).
- Reactive oxygen species, acid & nitric oxide kill ingested microbes, too.
- Those digestion products are exocytosed from cell & some are used for antigen presentation.
- Resolution
- Neutrophils die by apoptosis & disappear w/ 24 hours after stimulus has been eliminated.
- Anti-inflammatory cytokines e.g. transforming growth factor beta (TGF-β) & IL-10.
- Anti-inflammatory lipoxins released (arachidonic acid metabolite).
Name the important mediators of acute inflammation
Hageman factor
Bradykinin
Histamine
Arachidonic acid metabolites
Complement system
Cytokines
Chemokines
What is Hageman factor? What is its actions?
A clotting factor found in blood & produced liver
- Activated by contact w. collagen or microbes
- Also called Factor XII
Actions:
- Activates the coagulation cascade.
- Activates complement system.
- Activates kinin system - causes Bradykinin production.
How is Bradykinin produces? What are its actions?
Hageman factor cleaves plasma kallikrein which then cleaves high molecular weight (HMW) kininogen to produce Bradykinin.
Actions:
- Increases vascular permeability
- Dilates blood vessels
- Causes contraction of smooth muscle i.e. in endothelial contraction.
- Causes PAIN
What are the actions of Histamine?
Actions:
- Vasodilation
- Increased vascular permeability
-Endothelial activation
how are arachidonic acid metabolites produces? What do they do?
Phospholipids are converted to arachidonic acid by enzyme Phospholipase
- Prostaglandins & leukotrienes are produced from arachidonic acid
Actions:
Arachidonic acid may be acted on by cyclo-oxygenase 1 & 2 (COX I & II) to form prostaglandins
- PGI₂ & PGD₂ cause vasodilation & vascular permeability
- PGE₂ causes pain & fever (does this by raising temp set point in hypothalamus).
Arachidonic acid can also be acted on by 5-lipoxygenase to form leukotrienes
- LTC₄, LTD₄, LTE₄ cause vasoconstriction, bronchospasm & vascular permeability.
- LTB₄ causes neutrophil attraction & activation.
NOTE: Steroids reduce transcription of genes that code for Phospholipase, COX-II, TNF, IL-1, nitric oxide synthase = blocks arachidonic acid formation
NOTE: Aspirin & other NSAIDs are COX inhibitors = blocks prostaglandin formation from arachidonic acid.
What pathways activate complement system? Why are the products of complement system?
3 pathways for activating complement:
1. Classical pathway - activated by C1 attaching to an antibody (IgM or IgG) that has combined w/ an antigen.
2. Alternative pathway - triggered by microbial surface molecules, in the abscence of an antibody.
3. Lectin pathway - plasma mannose-binding lectin binds to carbohydrates on microbe & directly activates C1.
All 3 pathways result in the formation of C3 convertase!
C3 convertase splits C3 into C3a & C3b
- C3a recruits & activates leukocytes.
- C3b acts as “eat me signal” for phagocytes by covering pathogen’s surface. Oponization & phagocytosis.
- C3b can also bind more C3b to form C5 convertase
C5 convertase splits C5 into C5a & C5b.
- C5a stimulates histamine release from mast cells.
- C5b binds C6-C9 to form membrane attack complexes.
- C6, C7, C8 & C9 form membrane attack complexes = tunnel through bacterial cell walls. Cells become permable to water = cell death from lysis
