Moskovitz Immune system Flashcards
Physiologic Roots of Inflammation
A controlled inflammatory response is generally considered? But?
Acut inflammatory response:
Delivery of?
Triggered by?
Production of?
____ killing of pathogens
If neutrophils fail?
The cyclooxtgenase pathway
The COX pathway produces? 2 things
COX isoforms?
COX-1 activity is typically present and expressed by? Produces what with “housekeeping” function
Examples of these function 4 things
Prostaglandins
What common chemical structure is shared?
4 bioactive ones?
Each cell type generates one or two dominant producted which act as?
Prostaglandin production is typically?
When is production increased?
Glucocorticoids
Name some
Inhibit the action of ____ in what 3 ways?
used to treat patients with?
PGE2
One of the most? During inflammation what is it responsible for 3?
What do some of these stem from?
What about the other response?
Clinical relevance? Plays a role in the development of?
Case study continued NSAIDs and GI Toxicity
Which factors are important in determining the risk for the development of NSAID induced GI bleeding?
What has been developed to prevent this?
Oxicams
Meloxicam- kinetics?
Selective for?
Fenamates
Meclofenamate
Tx of?
High incidence of?
Microbial Inducers and Sensors
Exogenous inducers can be microbial or non microbial
Pathogen-associated molecular patterns (PAMPs)? What are they who carries them?
Virulence factors:
Unlike PAMPs they are not?
These factors cause what two negative affects which in turn causes?
Inflammasome
What is the inflammasome sensitive to?
Case study NSAIDs and GI toxicity
Endogenous Inducers: clinical relevance
Advanced glycation end products (AGEs)
The glycation of long lived proteins, such as collagen can result in?
AGEs are recognized alone by the receptor?
What situation would you expect the accumulations of AGEs?
Propanoic Acids
Naproxen (Aleve) and Ibuprofen (Advil)
High doses may have less?
Ibuprofen has a short? Naproxen?
Prostaglandins as therapeutic targets
THe NSAIDs
What do they do?
Prevent generation of?
Limits?
SEs associated with chronic glucocorticoid use
• Given the vast array of biological effects mediated by prostaglandins, the use of prostaglandins blocking drugs should be considered based on the individual condition
Lipid Mediators: Arachidonic Acid
Comes from what precursor? Only obtained?
Released from phospholipids by what enzyme?
This enzyme is stimulated by?
What type of drugs inhibit this?
Lipocortins? Another family? Suppression of?
____ supresses phospholipase A2 and?
Overview of Eicosanoid Functions
Examples of their function?
Regulation of what 3 things?
Inflammatory Mediators Overview
Mediators can be classified into 7 groups according to their biochemical properties
Vasoactive amines (_____)
- Secreted in what manner and when?
- What 2 things can it cause?
Vasoactive molecules (_____)
- Stored in what form or generated by?
- Cause what 2 things?
Complement proteins
- Produced by?
- ___ promotes ____ recruittment and Induce what type of degranulation? This affects?
Inflammatory cytokines
- What are 3 examples?
- Produced by many cell types but what are the two important ones?
- Have many roles but activation and induction of what is the example?
Chemokines
- Produced by? Control what 2 things towards the affected tissue?
Proteolytic Enzymes
- Degrades what things?
- Important roles in what 3 things?
Lipid Mediators
- Derived from?
- Why are these important?
Arachidonic Acid
- Synthesized from? Linked to?
- Different pathways can form different?
- – Vasoactive amines (histamine)
- Secreted in all-or-none manner when mast cells and platelets degranulate
- Can cause vasodilation and increased vascular permeability –
- Vasoactive molecules (serotonin)
- Stored in active form in secretory vesicle or generated by proteolytic processing of inactive precursors
- Cause vasodilation and increased vascular permeability
- Complement proteins
- Complement fragments are produced by several pathways
- C5a promotes leukocyte recruitment and induce mast-cell degranulation, affecting the vasculature
- Inflammatory cytokines
- Examples include tumor-necrosis factor-α (TNF-α), IL-1, IL-6, and many others
- Produced by many cell types, but most importantly by macrophage and mast cells
- Have several roles, including activation of the endothelium and leukocytes and induction of the acute-phase response
- Chemokines
- Produced by many cell types, and controls leukocytes extravasation and chemotaxis towards the affected tissues
- Proteolytic enzymes
- Degrades the extracellular matrix and basement-membrane proteins
- Have important roles in host defense, tissue modeling, and leukocyte migration
- Lipid mediators:
- These are derived from phospholipids that are present in cellular membranes
- These mediators represent an important focus of discussion, as they represent current targets of anti-inflammatory therapies
- Arachidonic Acid (AA)
- AA is synthesized from fatty acids, and is linked to membrane phospholipids
- Different pathways can form different metabolites of AA, as shown on the next slide
PGD2
Sythesized in? What 2 things does it regulate?
What other places?
Involved in what type of reponse?
Clinical relevance?
Salicylates (nonacetylated)
Diflunisal and Salsalate
No significant effect on?
Less frequent?
Generally tolerated by?
Relatively slow?
The Inflammatory Pathway
Inducers
Sensors
Mediators
Non Microbial Inducers and Sensors
Exogenous Examples? Think of? The sensors for allergens?
Asbestos
Endogenous inducers of inflammation- Signals are produced by? Sensors are able to detect?
How are cells and tissues able to distinguish between normal and stressed, damaged, or dysfunction states? What can they detect?
“separation strategy”
Examples supporting the things
Acetic Acids
Diclofenac (Voltaren) and Indomethacin (indocin)
Diclo
Available as? When would this be useful?
Indomethacin?
Useful for the tx of?, potently? SEs?
Nonacidic- Nabumetone only drug in class
Kinetics? Selective for?
Celecoxib?
Reduction in? Why is this?
What risks are dose related?
PGF2a
Acts in the female?
Important role in?
Recent studies show important activity in 4 things?
Leads to? Suppressed by?
Clincial relevance in 3 disease states?
Inflammasome case
Given the preceding information, what molecule(s) could be acting like inducers of inflammation (DAMPs or PAMPs) in the setting of atherosclerosis?
Endogenous Inducers: Clinical relevance
Example of an inducer involved in chronic inflammation:
____ is cause by a build up of _______ crystals in joints, bones, and soft tissue
Hyperuricemia?
At higher concentrations?
When urate crystals reach a certain size, they are?
Phagocytosis triggers activation of?
Inflammasome case
Activation of the inflammasome has been strongly linked to Know this one you can answer the rest?
Inflammation is thought to promote?
Where would you expect inflammation to take place?
What might be inducers of the inflammation?
Case Study the Inflammasome
Inflammasomes are systems of innate immune receptors/ sensors: That are responsible for?
Inflammasomes have been linked to a variety of diseases?
Thromboxane
TXA2 is an unstable metabolite of? Half life?
TXA2 functions?
Mediates platelet?
Mediates smooth muscle?
Activates?
Clinical Relevance?
PGI2
Important regulator in?
What are 3 major sources of PGI2
PGI2 is an important mediator of? Associated with acute inflammation
CLincial relevance:
Mediators and Effectors of Inflammation
Inducers trigger? What can these be derived from? Many of these affect?
Cellular Mediators? Produced by? Some are stored in?
Other mediators?
Salicylate
Aspirin
High doses are limited by?
Used infrequently for?
What is different compared to other NSAIDs?
Cyclo pathyway
COX-2
Expression is?
As inflammation progresses what happens?
Both isoforms generate? who cares?
Common themes of all NSAIDs
Most have the option of?
Have a dose and age related risk of?
Can cause or worsen?
Avoided in what patients?
Use with caution in?
From Atachidonic Acids
_____ are lipid signalling molecules derived from?
AA can be enzymatically metabolized by what 3 pathways?
