2C - The chemical Mediators of Inflammation and Immunity Flashcards
Three major types of chemical mediators
Preformed chemicals, synthesized, plasma proteins
Preformed chemicals
such as histamine - stored in granules - rapid release and action
Synthesized chemicals
cytokines and prostaglandin are formed after an inflammatory cell has injured or activated
Plasma Proteins
that become activated once an inflammatory process has already started
Checks and balances of the immune system
◦ Chemical mediators of inflammation all have
‣ Short half lives and decay rapidly
‣ Are destroyed enzymatically
‣ Are scavenged by protective mechanisms such as anti-oxidants
‣ Are blocked by endogenous inhibitors
Why is histamine an example of preformed chemical mediator
the effects are almost immediate but do not last long
◦ Histamine is found in the granules of mast cells and basophils
‣ Increase vascular permeability, vasodilation (hyperemia), pain and itching
‣ Effects are almost immediate (w/in 1-2min) transient (lasts only 30 min)
Cytokine
• Cells communicate via chemical messengers called cytokines, that are synthesized in response to tissue damage
◦ Cytokines regulate cells involved in the immune response
◦ Cytokines are produced by many cell types including lymphocytes, macrophages, and other inflammatory cells, endothelial cells and epithelial cells and connective tissues cells
• Cytokines modulate (enhance or suppress) the expression of other cell activities during inflammation
Chemokine
A chemokine is a cytokine that attracts cells to the site of injury
Chemotaxis
attraction of cells to the site of injury via chemokine
Examples of cytokines and their functions
‣ IL-2 activates T-lymphocytes
‣ IL-3 activates bone marrow to produce more white blood cells
‣ IL-4 suppresses the immune response
‣ IL-17 receipts macrophages and neutrophils to the site of inflammation
‣ Interferons (IFNα) are released by cells in response to viruses and neoplasia to protect neighboring cells
Complement Proteins
plasma proteins that are made in the liver and are normally inactive in the blood
◦ Activated by both innate and adaptive immune response
Difference of Complement Proteins when they are activated by the different sides of the immune system
‣ Adaptive
• Complement is activated by Antibody-Antigen complexes (the Classic Pathway)
‣ Innate
• Complement is activated bacterial and fungal products
◦ The alternative pathway
◦ The mannose binding lectin pathway
Activated complement proteins
◦ Opsonins
◦ Attract leukocytes (chemotaxis)
◦ Directly attack bacteria
◦ Stimulate histamine release from mast cells
‣ Many components of complement bind together to form the membrane attack complex
MAC
membrane attack complex (MAC) - forms a hole in the cell membrane
Arachidonic Acid
(AA) is a 20 carbon polyunsaturated fatty acid derived from linoleum acid present in a cell membranes
Steps to create Arachidonic Acid Metabolites
◦ Cell damage and other chemical mediators of inflammation, like complement and IL-1 activate phospholipase
◦ Arachidonic acid metabolites are released from cell membranes by phospholipase
◦ Different AA metabolites are released from the cell membranes of different cells
The two pathways to create AA metabolites
‣ COX (cyclo-oxygenase) → prostaglandins and thromboxjnes
‣ Lipoxygenase → leukotrienes and lipoxins
Important AA products
◦ PGI1 (Prostacyclin) is released from endothelial cells (line BV) and reduces blood clotting
◦ TXA2 (Thromoboxane) is released from platelets-promotes clot formation
◦ PGF2α from endothelial cells causes vasoconstriction of smooth muscle
◦ PGE2 released from epithelial cells, fibroblasts and smooth muscle cells promotes fever
◦ The leukotrienes and lipoxins released from mast cells and macrophages - increase chemotaxis and promote vascular permeability and vasodilation
Fever benefits and side-effects
• Fever is one of the benefits and one of the side effects of inflammation and the products of the AA pathway called PGE2
◦ Benefits : an increase in body temperature, causes vasodilation (increase blood flow to the area) and also inhibits the replication of some microbial agents
◦ Side-effects : makes you feel bad and if prolonged can be detrimental to health tissues
‣ Animals go off their food and decrease production
Difference between fever and hyperthermia
• Fever is different form hyperthermia and results from resetting of the hypothalamic temperature center
◦ The effect of PGE2 affects the hypothalamus to reset the body’s thermostat, telling the body to heat up → animal shiver and seek warmth with blankets and hot showers to elevate the body temp
‣ They will feel warmer than normal to touch
◦ Hyperthermia → body wants to cool
◦ Fever → body wants to be warmer
NSAIDS function
◦ Non steroidal anti-inflammatory drugs, NSAIDS, are used to treat the symptoms of fever in humans and animals
‣ NSAIDS block the cyclooxygenase (COX) pathways of the arachidonic acid metabolism
‣ Aspirin, ibuprofen and naproxen are COX 1 and COX 2 inhibitors
‣ Highly selective - newer generation NAIDS such as Meloxicam only COX-2 → less side effects
COX 1 inhibitor
constitutively expressed and present in almost all tissues
‣ Housekeeping enzyme with roles in homeostasis, protects the renal medulla, and helps protect the gastric mucosa from acid by increasing mucous production
COX 2 inhibitor
induced by exogenous and endogenous stimuli and is present in leukocytes, endothelial cells of blood vessels and synovial fibroblasts
The role of corticosteroids
◦ Corticosteroids act right at the beginning of the pathway → many side effects
The Role of omega three fatty acids
◦ It is though that omega 3 fatty acids may be protective-chemical mediators produced from this pathway are resolving and protecting
transferrin lactoferrin
• Other important chemical mediators are iron binding proteins called transferrin lactoferrin
◦ Iron is an essential nutrient for bacterial replication
◦ These host proteins present in body secretions such as saliva and milk bind iron and make it unavailable to bacteria
◦ Some bacteria counteract this with Siderophores that chelate iron and remove it from the iron binding proteins
Chemical mediators of the acute inflammatory response
◦ Kinins - tachykinin and Brady kinin are peptides that act on blood vessels
◦ Platelet activating factor
◦ Oxygen derived free radicals and nitric oxide
◦ Antimicrobial peptides - defensins
◦ Acute phase proteins - produced by the liver that increase in concentration during inflammation
‣ Eg C-reactive protein and fibrinogen
‣ Elevated fibrinogen concentration in the blood of cattle is one of the earliest indicators of acute inflammation
