L13 Notes Flashcards
What is the role for inflammation?
Body’s defense against infection
What are routes for infection and what is the response?
Inflammation protects us from pathogens
- When u cut your skin → bacteria enters the cut → causes inflammatory response (swelling/edema, redness)
RESPONSE:
-
Sensory nerves
- Rapidly release peptides (eg. Substance P)
- attract immune cells
- Plasma extravasation
- Rapidly release peptides (eg. Substance P)
-
Innate immune system
- Preprogrammed to recognize pathogen
- increasing cytokines and cell proliferation
- Adaptive immune system
Innate immune systems
Resident in tissue that responds to characteristic features of bacteria, parasites, and viruses.
(Eg: toll receptors recognize bacterial cell wall)
- Mast cells
- secrete histamine
- natural killer cells
- Macrophages/dendritic cells
- Macrophages produce oxygen radicals and several inflammatory cytokines
-
Dendritic Cells: Present antigens to naïve T cells
- Mediate new immune responses
- Granulocytes (eg neutrophils) and monocytes recruited to infected tissue
- Complement (circulating proteins → activated by pathogens)
- Anti-microbial peptides
Adaptive immune systems
Highly selective defense and antigen-specific:
- antibodies
- cell-mediated immunity (viral infected cells)
*Usually takes a few days to be activated
EXPLAIN
Cellular inflammatory signaling via arachidonic acid COX enzymes
- Tissue injury or infection causes the release of lipids (arachidonic acid)
- COX metabolizes arachidonic acid and produces prostanoids
- prostaglandins and thromboxanes
COX-1
Responsible for ‘housekeeping’ PG biosynthesis constitutively produced in most tissues in the body.
- low concentration
- cell proliteraltion, self help
COX-2
Not normally produced in most tissues but is induced by a wide spectrum of growth factors and pro-inflammatory cytokines in specific pathophysiological conditions.
- usually low levels
- but hella upregulated during inflammation
Pharmacology of NSAIDs
NSAIDs block COX metabolism of arachidonic acid
- aspirin (inhibits COX 1 and modifies COX 2 can also be an anticoagulant to prevent clotting)
- ibuprofen (blocks both COX 1 and COX 2 reversibly)
- indomethacin
- Acetaminophen (Paracetamol) NOT NSAID
Side Effects:
- gastric mucosa (ulcers)
- PGs produced by COX-1 stimulate cell growth/proliferation and repair
- anti-platelet action (increase risk of bleeding)
What is ASPRIN?
Irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2.
Normally COX produces prostaglandins, most of which are pro-inflammatory, and thromboxanes, which promote clotting.
Also used as an anticoagulant
- Low dose Asprin → inhibit platelets bc they don’t have nucleus and cant replace the COX enzyme
- Won’t trigger coagulation
What is ACETAMINOPHEN?
“Tylenol” is a contraction of para-acetylaminophenol
- Analgesic- via CNS effects
- Does not significantly block COX in peripheral tissues
- Not anti-inflammatory
Not an NSAID!
Pharmacology of Corticosteroids
Prevents the liberation of lipids from the site of injury (AA) and therefore no COX 2 and no inflammation
- Cortisol is released from the adrenal gland in the fight or flight response
- GC binds to GC receptor in cytoplasm → dimerizes and translocate to the nucleus
- THEN, binds to GC response elements (GRE) on GC genes → Increases transcription of gene coding for anti-inflammatory proteins
- GCs stimulate expression of lipocortin-1, which has an inhibitory effect on phospholipase A2 and therefore inhibits the production of lipid mediators.
- GCs also inhibit genes coding for COX-2.
- Powerful anti-inflammatory and immunosuppressive actions
- Permissive for many physiological functions (adrenergic and nor-adrenergic signaling)
- Major component of stress response, gluconeogenesis
- IMMUNE SUPPRESSANT bc they inhibit cytokine levels.
Side effects:
- hyperglycemia
- diabetes
- osteoporosis
- CA transpot in gut impaired
- bone cells (osteoblast /cast laying down bone are also impacted)
- Lipid metabolism alterations (Cushings syndrome)
- Infection
- Cause ur blocking all these immune cells
- Peptic ulcers (wound repair impaired
- Adrenal insufficiency (therefore patients weaned off with tapering doses)
What is Cortisol?
Naturally occurring steroid released from adrenal Cortex.
- Major component of stress response, gluconeogenesis
- Permissive for many physiological functions eg. Adrenergic and nor-adrenergic signaling.
Pharmacology of Anti-Histamines
Antagonizes CNS Histamine GPCR Receptor (H1)
- One of the most widely used drugs
- Used in the treatment of allergies and insect stings
- Are antagonists
- H1 receptors are GPCRs
- Inhibition of CNS H1 receptors → sedation
- Old antihistamines used to cause drowsiness because of CNS receptors
- Terfenadine blocks K channel in the heart and could cause heart problems especially in women
- Fecifenadine (allegra) is a metabolite
- Terfenadine blocks K channel in the heart and could cause heart problems especially in women
- New antihistamines work around the CNS and are non-drowsy
- Peripheral selective blockers: non drowsy (don’t go into the CNS)
Pharmacology of immunosuppressants
1. T cell inhibitors
- Used to prevent transplant rejection and severe auto-immune condition
- block immunue system (T-cells) from rejecting new organ
- Cyclosporin; FK506
- Block calcineurin which causes de-phosphorylation of “nuclear factor of activated T cells” (NFAT) required for translocation into nucleus and Interleukin 2 (IL-2) transcription & T cell proliferation
2. Anti-CD3 antibodies (TINDER FOR CELLS)
- prevents transplant rejection by stimulating only 1 of two necessary signals (CD3 & CD80) for T cell activation -> inactivates T cell
-
Muromonab-CD3: inactivated T cell activation and is used for transplant rejection
- A dendritic cell is like “here’s an antigen” to T cell (first). Costimulation → “there is danger!!” → eats part of virus and rushes to lymph nodes
- NEED BOTH
- Binding to the T cell receptor → preventing that dendritic cell from working (COCK BLOCK)
3. Anti-CD80 antibodies
-
Abatacept: blocks co-stimulation and prevents T cell activation.
- Used for severe RA
Anti-cytokine strategies
Tumor necrosis factor (TNF-alpha) released from macrophages
- Originally discovered as tumor suppressor
- critical immune stimulant
TNF-alpha antibodies: Highly promising treatment for rheumatoid arthritis, inflammatory bowel disease
(colitis, Crohns disease)
- Adalimumab
- Etanercept
- infliximab
