Lipid Mediators Flashcards
what does inflammatory response to injury and/or infection cause?
1) Redness (rubor)
2) Heat (calor)
3) Swelling (Tumor)
4) Pain (Dolor)
Redness (rubor) due to?
due to capillary dilation resulting in increased blood flow
Heat (calor) due to?
due to capillary dilation resulting in increased blood flow
Swelling (Tumor) due to?
-due to passage of plasma from the blood stream into the damaged tissue
Pain (dolor)
-due to tissue destruction, swelling and chemical mediators of inflammation
inflammation process regulation?
- inflammation is regulated by specific molecules
- is carefully choreographed dance between tissue & immune cells triggered by pathogens/iinjury
Chemical Mediators of inflammation?
-regulate initiation, progression and resolution of inflammatory response to pathogen and/or injury
What molecules tend to be drug targets for therapeutic regulation of inflammatory process?
the chemical mediators of inflammation
chronic inflammation?how prevent it?
- more is not always better if go from acute to chronic have side effects
- can lead to neutrophils during hole in tissue (abcess) or fibrosis (scaring) & loss of function
- target key points in the inflammatory cycle to control chronic inflammation
what are the two sources of chemical mediators for inflammation?
1) cellular
2) from plasma (the liver)
Two forms of inflamamtion mediators from the cell?
1) Preformed proteins: are packaged in vesicles/granules of the cells (like a neutrophil). when activated just have to secrete them
2) Newly synthesized: is slower, have to take time go to nucleus do trxn/trans then can secrete
Plasma/liver mediators follow what two pathways?
- mediators made in Liver (on occasion other organs) then released into plasma.
- then can do:
1) Factor XII activation (Hageman factor)
2) Complement Activation
In what state are Plasma/liver mediators in?
-secrete the mediators in inactive form, are quickly activated by enzymes etc. when needed
Do these chemical mediators of inflammation cause damage?
-yes; most have potential to cause damage to self
are newly synthesized mediator products in the cell always proteins/peptide?
-no; can be lipids, O2 species or many other molecules
What is the source of leukocyte derived mediators? What are some leukocyte derived mediators?
1) cytokines
2) Nitric Oxide
3) ROS
source is leukocyte cell and they are newly synthesized as needed
6 reactions that occur in inflammation? how do mediators affect them?
1) vasoldialtion
2) vasopermeabilty
3) chemotaxis, leukocyte recruitment & activation
4) fever
5) pain
6) tissue damage
- specific mediators regulate different steps in inflammation*
vasoldialtion
-is about altering smooth muscle function, relaxing smooth muscle to make the vessel wider
vasopermeabilty
- different than vasodilation
- involves making epithelium less leaky, have to make less water tight
chemotaxis
-chemoattractants/ that attract/recruit things from to an area of inflammation
fever response
- causes increase in temperature, makes molecular actions go faster & burn through more ATP
- means body becomes deficient in ATP and pathogens will die from protein denaturation and lack of ATP
3 broad classes of chemical mediators of inflammation?
1) Lipid mediators
2) Plasma proteins
3) Cytokines & chemokines
What are lipid mediators?
-all lipid mediators are autocoids; but not all autocoids= lipid mediators
Eicosanoids
a chemically diverse family of arachidonic acid (AA) derived autacoids
Autacoids
-substances that are rapidly synthesized in response to specific stimuli, act quickly at the immediate locality, and remain active only short time before degradation
Lipid Mediator pathway step 1
1) cleave arachidonic acid (AA) from plasma membrane
2) can choose between 2 pathways; 5-Lipoxygenase or Cyclooxygenase
arms of the pathway?
- different arms have opposing pathways
ex: vasodilation vs constriction even though are downstream from same source
can all lipid mediator products be made in same cell?
-no, each product will be cell type dependent in production because not all enzymes are present in all cells at all times
what is arachidonic acid (AA)? what derived from?
- 20 carbon polyunsaturated fatty acid
- derived from dietary sources or by conversion from the essential fatty acid linoleic acid
Does AA occur free in the cell?
- NO
- exists esterified in the plasma membrane
- must be liberated from the plasma membrane
what liberates AA from plasma membrane? When is it liberated? Why?
- Phospholipase A2 releases AA from membrane phospholipids
- receptor on PM gets bound/ activated, activates PL2A which cleaves AA
- is regulatory system
PL2A four categories based on?
1) Structure and size 2) Substrate specificity
3) Calcium requirement 4)Tissue distribution
What are the four PL2A categories? Which use Ca?
1) Secretory (Ca)
2) Cytoplasmic (Ca)
3) iPLA2 (no Ca)
4) PAF acetyl Hydrolases
PLA2 only role cleaving AA from membrane?
-no; has many roles and many classes but cleaning AA is one of primary roles
PLA2 target for anti-inflammatory therapeutics? steroids?
- no
- it’s heterogeneity and size of family makes not great target for therapeutic intervention
- PLA2 involved in too many body processes, would have too many side effects
- steroids do act here but steroids act everywhere*
AA is cleaved from the membrane: Now what?
Two pathways
1) Lipoxygenase pathway
2) Cyclooxygenase pathway
- once decide cannot go back
Lipoxygenase pathway
-Initial products produced by 3 different lipoxygenases, present in only a few cell types
-5-lipoxygenase is one of the 3; & the primary enzyme in neutrophils
is the primary enzyme in neutrophils
5-lipoxygenase and main product?
- made from AA, is the Lipoxygenase pathway
- primary enzyme in neutrophils, so LOX5 & products are PRO-INFLAMMATORY
- main product is 5-HPETE
5-lipoxygenase in many cell types? what does this tell us?
- very few cells have ability to make them
- means most cells aren’t in danger of making radical pro-inflammatory molecules
5-HETE
- main product of 5-lipoxygenase; is intermediate to final products of LOX-5 pathway
- converted into a family of compounds called leukotrines
5’-LOX –> 5-HETE; now what?
2 separate pathways
1) Cysteinyl LTs
2) LTA4 hydrolase
Cysteinyl LTs (CLTs)
-made of LTC4, LTD4 & LTE4
-1000x more potent in inducing bronchospasm than histamine
-involved in many chronic inflamm disorders in body
(inflamm bowl disease & asthma)
why are antihistamines only partially helpful in severe allergic reactions?
-if reactions include CLTs then only dealing with one half of the problem (histamine) not other part
LTA4 hydrolase
-product of 5-Lox pathway
-powerful chemotactic agent, recruits leukocytes
to areas of inflammation
Leukotrienes associated with
- leukotrienes= major family of compounds that were converted from HETE-5
- Leukotrienes associated with:
1) Asthma
2) Inflammatory Bowel Disease
3) Glomerulonephritis
A) what does 5-Lox pathway make x2?
B) what cell type makes them?
1) 5-LOX–>5-HETE–>
Leukotrienes (LT)
(vasoconstriction)
2)5-LOX–>5-HETE–> 12-LOX–> Lipoxins (vasodilation)
B) leukocytes
When have AA, what determines the end product we get?
-actual product get is dependent on enzymes present in the specific cells & tissue
Transcellular leukotriene biosynthesis?
- adds another layer of regulation in 5-LOx pathway
- sequesters different synthetic steps in separate cells
- is how make Lipoxin
Lipoxin transcellular biosynthesis mechanism?
1) AA liberated, activate 5-HETE –>5-LOX pathway in neutrophil, can make LTA4
2) attract platelets, when have sufficient quantities where plates & neutrophil touching, LTA4 can be moved into platlet
3) once in platelet, can synthesize 12-LOX
4) 12-LOX makes anti-infammatory Lipoxins
why can’t synthesize 12-LOX in neutrophil? Why can’t synthesize in platelet by itself?
- it makes Lipoxins which are anti-inflammatory, neutrophils are pro-inflammatory
- neutrophil lacks the enzymes to make 12-LOX; platelet lack machinery to 5-LOC so can’t make LTA4
- FOR REGULATION
What is the process of Transcellular Leukotriene Biosynthesis used for?
-to produce Lipoxins and stop the inflammatory reaction
Lipoxin actions
1) Inhibit leukocyte recruitment
2) Inhibit neutrophil chemotaxis and adhesion
3) May be negative regulators of leukotriene synthesis
how do you block lipoxin production?
-blocking cell:cell adhesion blocks lipoxin production
how cycloxygenase pathway initiated?
by two diff enzymes that regulate 2 diff pathways
1) Cox-1: constitutively expressed
2) Cox-2: inducibly expressed
how cycloxygenase pathway lead to?
-production of prostaglandins
What is COX?
-also known as prostaglandin H synthase, - a heme-containing enzyme that catalyzes two sequential enzymatic reactions
two sequential enzymatic reactions of COX?
1) the bis-oxygenation of AA leading to production of PGG2 (COX reaction) 2) reduction of 15-hydroperoxide of PGG2 leading to formation of PGH2 (hydroperoxidase reaction)
* then separate into 2 diff pathways
Normal functions mediated by cycle-oxygenase (COX)?(5 big ones)
what drives these processes?
1) Angiogenesis
2) Ovulation
3) Implantation
4) Wound healing
5) Temp Regulation
prosteglandins
How are prostaglandins synthesized?
- in a cell-type specific manner, not made in all cells all the time
- dependent on enzymes present in specific tissue type
How do prostaglandins function?
- paracrine and autocrine mechanisms
- many produce effects by acting through distinct GPCRs
How can same prostaglandins produce a different effects?
- depends on what GPCR is in the specific tissue
- tissue can expresses receptors linked to activating or inhibiting intracellular signaling pathways
How target specific prostaglandin pathways therapeutically?
- use Prostanoid Agonists
1) agonists drugs will have ligands that bind receptors and cause opposite to occur
2) inducers: have ligands that bind receptors and induce something to prohibit pathway
3 outcomes of the COX (cyclo-oxygenase) pathway?
AA–> Cycloendoperoxides
1) thromboxane (COX-1); vasoconstricting
2) prostacyclin (COX-2):
vasodilation
3) Prostaglandins; 2 types, do both constriction & dilation
Why hard to target COX or 5-lox pathway therapeutically?
-because have so many roles in many different pathways nearly impossible to target the single one you want
What does Asprin/NSAID block?
- COX pathway
- COX-1 10-100X more than Cox 2
How block the entire process (COX & LOX)?
-steroids that block PLA2 which prevents cleavage of AA from the membrane
How block entire LOX pathway?
- Lipoxigenase inhibitors
How block just leukotriene production?
-Leukotriene receptor agonists
