Inflammation 2 Flashcards
What are cytokines?
intercellular messenger substances secreted by cells of the immune systems (innate or acquired) that tell other cells what to do, but they don’t travel too far or else they would be hormones.
How does the molecular mediation of sepsis begin?
With toll-like receptors on macrophages, neutrophils and endothelial cells; G-coupled receptors; and nucleotide oligomerization domain proteins 1 and 2 (NOD1-2); bind to various microbial cell wall and internal elements to activate them and produce TNF and many IL molecules, HMGB1, interferon-gamma and other pro-inflammatory cytokines.
Where are most of the inflammation-associated cytokines produced?
Mononuclear phagocytic cells.
What are the main cytokines involved in the acute phase response?
IL-1, IL-6, TNF-alpha, interferon-gamma, and TGF-beta
Which cytokines are the main stimulators of fever?
IL-1 and TNF
What does IL-6 stimulate?
increased production of most acute phase reactant proteins.
What cytokines stimulate Kupffer cells to amplify the cytokine response?
IL-1, IL-6 and TNF
Can cytokines act on monocytes? fibroblasts? endothelial cells?
Yes to all. This further magnifies the cytokine response.
How does the CNS participate in the acute phase response?
it mediates fever by secreting adrenocorticotrophic hormone (ACTH).
Is pain a sign or symptom?
symptom. It is subjective
Is fever a symptom? What about elevated body temperature?
Fever is a symptom, elevated body temperature is a sign.
Which is likely more applicable to an older patient: Occam’s razor or Hickams’s dictum?
Hickam’s dictum. patients tend to accumulate chronic diseases as they get older.
What does cronic inflmmation usually consist of?
active inflammation with tissue destruction and attempted repair.
What are some common causes of chronic inflammation?
persistent infection like TB, prolonged toxin exposure as in silicosis, autoimmunity, conditions of unknown etiology, such as atherosclerosis, sarcoidosis and Alzheimer disease.
What are the key cellular players in chronic inflammation?
macrophages. They are activated by cytokines such as interferon-gamma and bacterial endotoxins.
What do macrophages secrete during chronic inflammation?
neutrophil chemotactic factor and growth factors TGF-beta, PDGF, and FGF. They also leak proteases and reactive oxygen species at sites of chronic inflammation.
What draws macrophages to sites of chronic inflammation?
MCP-1, C5a, PDGF, TGF-alpha, fibrinonectin and fibrinopeptide fragments draw macrophages by chemotaxis.
Which cytokine do macrophages release that stimulates T cells?
IL-12
What do activated T-cells secrete? What does this secretion do?
interferon-gamma. Activates macrophages.
Are atherosclerosis, subacute phase pneumonia, Gaucher disease, gout and interstitial pneumonia usually macrophoge or lymphocyte predominant diseases?
Macrophage
What is a granuloma?
aggregate of activated macrophages working together.
What is a common example of a granulomatous disease?
TB, leprosy, syphilis, cat-strach disease, sarcoidoisis.
Are thyroiditis, rheumatoid arthritis and myocarditis usually macrophage or lymphocyte predominant diseases?
lymphocyte
What is lymphangitis?
inflammation of lymphatic channels.
What is lymphadenitis?
inflammation of lymph nodes
What is lymphadenophaty?
enlargement of lymph nodes.
Why does inflammation tend to spread to lymph nodes?
because they are the processing centers of the immune system in the lymphatic sewer system of the body
What are the systemic effects of chronic inflammation?
increase in ESR (erythrocyte sedimentation rate).
Anemia
and the usual increase in body temp, heart rate, RR and WBC.
Which systemic effect is characteristic of chronic inflammation but not acute?
anemia (unless there is bleeding, hemolysis or disseminated intravascular coagulation)
What are pyrogens?
fever producing substances from the mononuclear phagocyte system
What aer the main endogenous pyrogens? What is there release mediated by?
IL-1 and TNF-alpha.
Their release is mediated by protaglandins, mainly PGE2, which acts on the hypothalamus.
What are the common causes of fever?
infection, infarction, tumors, inon-infectious inflammation, hemorrhage, brain damage, drug reactions and heatstroke.
Why is heatstroke so dangerous?
because after reaching about 104 degrees, the heat regulating center becomes depressed and the temperature continues to rise in a positive feedback loop until death.
What does progesterone do to body temp?
it can increase it.
What does poikilothermic mean? When does this occur?
ambient temperature. occurs in fully anesthetized patients.
Who is inflammatory response hypothermia most common in?
in neonates and the very elderly
What causes anemia in chronic diseases?
Iron is taken up and hidden to prevent bacteria growth, but this also hinder RBC production. This happens even if the disease is not bacteria-related.
What do interferon, lipopolysaccharide and TNF-alpha do to the expression of ferroprtin?
they downregulate its expression
What is ferroportin?
It is the only iron export protein in iron-transporting cells. Decreasing it would decrease the release of iron from cells.
How does hepcidin affect iron stores?
inhibits duodenal absorption of iron and macrophage iron recycling. It also binds to and degrades ferroportin.
What cytokines will increase transferrin-receptor-mediated uptake of transferrin bound iron into monocytes?
IL-10
Which cytokines increase expression of divalent metal transporter1 on macrophages and stimulate uptake of ferrous iron (Fe2+)?
Interferon-gamma and lipoplysaccharide
Which cytokine further induces digestion of RBCs by macrophages?
TNF-alpha.
Which cytokines downregulate the expression of the macrophage iron-transporter ferroprotein 1 and inhibit iron export from macrophages?
hepcidin, interferon-gamma, and lipopolysaccharide
Which cytokines stimulate ferritin expression and storage and retention of iron within macrophages?
TNF-alpha, IL-1, IL-6, IL-10
Which cytokines inhibit differentiation and proliferation of erythroid progenitor cells?
TNF-alpha, interferon-gamma, and IL-1
If a patient has a hemoglobin below 10 mg/dL, is it likely due to chronic disease?
No. chronic disease induced anemia tends to hit a minimum hemoglobin level of 10 mg/dL. Look for bleeding if it drops below this.
What can chronic excess stimulation of TNF release cause?
cachexia
What is cachexia?
the loss of body mass that cannot be reversed nutritionally
What is arachidonic acid?
a cell membrane fatty acid whose metabolites are short-acting intracellular and short-range extracellular mediators of inflammation
What do lipoxygenases convert arachidonic acid into?
precursors for a group of inflammatory mediators and inhibitors, the leukotrienes and lipoxins.
What does cyclooxygenase do to arachidonic acid?
converts it to prostaglandins
What do corticosteroids do?
they block production of arachidonic acid and all the metabolites that are made from it. This can mask inflammation, causing opportunistic infections and a whole host of other side effects.
What do non-steroidal anti-inflammatory drugs do?
they block only protaglandin production and have morel limited side-effects
Why do corticosteroids have such a larger number of serious side effects?
they block an important metabolic pathway at its start; the production of arachidonic acid and all its metabolites, which are crucial inflammatory inhibitors and mediators
What do prostaglandins do?
They mediate much of the pain, fever and other signs and symptoms of inflammation.
What are NSAIDS?
non-steroidal anti-inflammatory drugs. They are pain killers and antipyretics, but interfere with prostaglandin-mediated gastric mucosal protection and can cause gastric bleeding.
They also block cyclooxygenase.
Is aspirin a reversible or irreversible cyclooxygenase inhibitor?
irreversible, very long acting
What does cyclooxygenase in edothelial cells do?
makes prostacyclin, a vasodilator and inhibitor of platelet aggregation
What does cyclooxygenase in platelets do?
makes thromboxane, which is a vasoconstrictor and platelet aggregation promotor.
If cyclooxygenase in endothelial cells causes vasodilation and inhibits clotting, why would inactivating it irreversibly be good for patients at risk for thrombosis?
In platelets, cyclooxygenase makes thrombaxane, which promotes vasoconstriction and aggregation. All of the cyclooxygenase, in both endothelial and platelets is irreversibly inhibited, but endothelial cells are quickly replaced, whereas platelets live for up to 10 days.
Why are drugs that affect inflammation dangerous?
most inflammation factors that are targeted, are also important in clotting. Messing with one can and often does affect the other.
