Chapter 1: The inflammatory Response Flashcards
What cells produce TNF-α?
Activated M1 macrophages are a major source of TNF-alpha.
Also made by:Monocytes, macrophages, neutrophils, NK cells, and several others (T, B, fibroblasts).
What is stimulated by the release of TNF-α?
Production of proinflammatory cytokines (e.g., IL-6), reactive oxygen intermediates, chemotaxins, and endothelial adhesion molecules (all facilitate the recruitment of cells at the site of inflammation).
The main effect of TNF-α is stimulation of cytokines (IL-6, ROS, etc.) that facilitate cell recruitment at the site of inflammation. What are three additional effects of TNF-α?
Activation of natural killer cells, proliferation of cytotoxic T-cells, and T-cell apoptosis.
What are released from the cell surface to reduce the activity of TNF-α?
Tumor necrosis factor soluble receptors
Found constitutively at low levels in the blood but are increased in inflammatory conditions such as sepsis. The solubilized receptors bind to TNF-α and effectively reduce the cytokine’s activity.
TNF-α has both beneficial and deleterious effects. Name some of each:
Beneficial - protects against mycobacterial infection, blocking it in septic patients increases mortality
Deleterious - causes all the classic signs of shock (hypotension, metabolic acidosis), causes inflammation (inflammatory diseases like Crohns).
What is TNF-α?
A membrane-bound surface protein, cleaved by metalloproteases, that is released in soluble form.
Corticosteroids and recombinant TNFR receptors (Enbrel, a treatment for RA/Crohn’s) inhibit TNF-α, which increases risk of what?
Recrudescence of pulmonary mycobacterial infections and infectious complications after orthopedic surgeries.
True or False: Activated M1 macrophages produce proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and prostaglandins, enhancing the inflammatory response?
True
True or False: M2 macrophages are activated in response to proinflammatory cytokines?
False. M2 macrophages are activated in response to anti-inflammatory cytokines (IL-4, IL-13, and IL-10). They then secrete growth factors like PDGF or TGF-β, which stimulate fibroblasts to produce collagen, aiding in wound healing and further dampening the inflammatory response.
True or False: M1 macrophages are activated by infectious agents or proinflammatory cytokines?
True. M1 macrophages are activated by infectious agents or proinflammatory cytokines (interferon-gamma [IFN-γ] or TNF-α). They then produce more proinflammatory cytokines and prostaglandins to increase inflammation.
As the acute inflammatory response resolves, macrophages produce factors that stimulate fibroblasts to produce ________, aiding in wound repair and healing of the inflamed tissue?
Collagen! Fibroblasts are the most common cell that produce collagen.
Prostaglandins are produced in the __________ pathway?
Prostaglandins are produced in the cyclooxygenase (COX) pathway.
What is the starting molecule for prostaglandins?
Arachidonic acid (metabolized along the cyclooxygenase pathway containing COX enzymes).
COX-2 expression is induced by what?
Trauma, growth factors, proinflammatory cytokines, and other mediators.
True or False: COX-1 is constitutively expressed (always present)?
True. It is involved in homeostasis and is present in the majority of mature cells.
What is the precursor to all prostaglandins and thromboxanes?
PGH2 (Prostaglandin H2).
Describe the arachidonic acid pathway?
AA -> through COX -> PGG2 -> releases free oxygen radicals to become -> PGH2 -> ENZYMES = Thromboxane A2 and B2, PGE2, PGF2, and PGI2 (prostacyclin).
Tell me about the hepatotoxicity of carprofen?
- Acute hepatic necrosis.
- Idiosyncratic (not dose or time on med dependent)
- Of 1 million dogs receiving carprofen, an incidence of 0.2% suspected side effects was reported, with 0.02% involving the liver.
- At least 70% of affected animals were considered geriatric.
- Animals receiving phenobarbital have been anecdotally reported to be more susceptible to carprofen hepatotoxicity.
How do you treat a suspected carprofen hepatotoxicity?
- Stop the drug
- Use of hepatoprotective agents such as N-acetylcysteine (a glutathione precursor) or SAMe may be beneficial during initial or continued hepatic damage.
How long does oral carprofen take to reach steady state?
1 hour. Oral carprofen is rapidly and almost completely absorbed; greater than 90% bioavailability.
What is the half life of carprofen?
About 10 hours, long enough to be approved for once daily dosing.
Where is carprofen metabolized?
How is carprofen excreted?
All NSAIDs undergo hepatic metabolism so the liver is exposed to a high concentration of parent drug and metabolites.
Between 70% and 80% of carprofen metabolites are excreted in the feces, with the remainder in the urine.
Is NSAID hepatotoxicity dose-dependent?
No. Reactions to drugs other than aspirin and acetaminophen tend to be idiosyncratic- unpredictable and non-dose related.
True or False: Giving liver protective supplements reduces risk of NSAID induced liver injury?
False. No supplements help protect against liver injury. May actually decrease liver metabolism and clearance. (But after/if injury occurs can use as therapy).
