Inflammation Cont’d Flashcards
What are the sources of chemical mediator? What is their function/life span? (Inflammation)
Cell
Plasma (usually synthesized by liver)
Biological activity to regulate inflammatory response through receptor or direct acting
Short lived (inactivated by enzymes or inhibited)
Describe the cell derived chemical mediator-Histamine.
Preformed (mast cells, basophils, platelets, amoung first released)
Function- vasodilation and vascular permeability
Release from mast cells caused by:
Physical agents (trauma & heat)
Immunologic reactions involving binding of IgE antibodies to mast cells
Complement fragments C3a and C5a (anaphylatoxins) Neuropeptide (substance P)
Cytokines (IL-1 & IL-8)
What are arachidonic acid metabolites (eicosanoids)?
From leukocytes, mast cells, endothelial cells and platelets
Two major classes of enzymes
Cyclooxygenases: prostoglandins & thromboxanes Lipoxygenases: leukotrienes & lipoxins
Serve as short-range signaling agents
What is the first conversion of the arachidonic acid pathway? What can inhibit it?
Membrane bound phospholipids to arachidonic acid through phospholipase
Corticosteroids can inhibit
From arachidonic acid what two pathways arise? What can inhibits
Cyclooxygenase pathway (COX 1 and COX2) (NSAIDS can inhibit)
Lipoxygenase Pathway (lipoxygenase)
Describe the function of COX 1 and COX 2. How can NSAIDS inhibit COX 1 and COX2?
Cox-1: constituitive, prostaglandins protect stomach from acids, produced in inflammation
Cox-2: produced in inflammation
Most NSAIDS are non-specific COX- 1/COX-2 inhibitors
What are produced from the cyclooxygenase pathway?
Prostaglandins: vasodilation, inhibit platelets aggregation, pain (PGE2), fever (PGE2)
Thromboxanes: vasoconstriction, platelet aggregation
What is produced from the lipoxygenase pathway?
Leukotrienes: Bronchospasm, increase vascular permeability, increase leukocyte chemotaxis
Lipoxins: inhibit inflammation, decrease leukocyte chemotaxis
Describe platelet activating factor (chemical mediator of inflammation).
Derived from phospholipid
Produced by neutrophils, monocytes, basophils, endothelial cells, and platelets by the action of phospholipase A
Acts directly on target cells through the effects of a specific G protein-coupled receptors
Function: Bronchoconstriction, Vasodilation, Increased vascular permeability, Elicit enhanced leukocyte adhesion, chemotaxis, leukocyte degranulation
Describe cytokines.
Modulate function of other cell types
Bind to specific receptors on target cells
Transient response, regulated with Endo and exogenous signals
Major cytokines in acute inflammation are TNF, IL-1, IL-6 • Chronic inflammation: interferon-γ (IFN-γ), IL-17 and IL-12
Describe plasma proteases. (Chemical mediators of inflammation)
3 interrelated plasma-derived mediators that play a key role in inflammatory responses
1. Complement system
2. Kinin system
3. Clotting factor system
Principal mediators in vasodilation.
Histamine
Prostaglandins
Principal mediators in increased vascular permeability
Histamine and serotonin
C3a and C5a
Leukotrienes C4, D4, E4
Principal mediators in chemotaxis, leukocyte recruitment, and activation.
TNF, IL-1
chemokines
C3a, C5a
Leukotriene B4
Principal mediators in fever.
IL-1, TNF
Prostaglandins
Principal mediators in pain.
Prostaglandins
Bradykinin
Principal mediators in tissue damage.
Lysosomal enzymes of leukocytes
Reactive oxygen species
What is the function of bradykinin in the complement system?
Increased vascular permeability, arteriolar dilation, and bronchial smooth muscle contraction, pain
What is the function of factor 12 (Hageman factor) in the complement cascade?
Clotting system- leads to thrombin formation and clotting
Kinin system- leads to formation of bradykinin and activates fibrinolytic system
Increases inflammation
Define chronic inflammation.
Inflammation of prolonged duration (weeks to years), continuing inflammation, tissue injury, attempts at healing occur simultaneously
What kind of setting cause chronic inflammation?
Persistent infection (TB or syphilis)
Immunity mediated inflammatory response (rheumatoid arthritis)
Prolonged exposure to potentially toxic agent (cholesterol crystals)
May develop with acute inflammation (sever persistent irritation)
What are the characteristics of chronic inflammation?
Tissue infiltration by mononuclear cells
• macrophages, lymphocytes, plasma cells
Tissue destruction
• largely induced by products of the inflammatory cells
Attempts at repair
• Increased connective tissue (fibrosis)
• Angiogenesis
What pathology does chronic inflammation contribute to?
Alzheimer’s
Pulmonary
Atherosclerosis
Rheumatoid arthritis
Tuberculosis
Cancer
Neurodengenerative
Diabetes
Describe macrophages? What response are they dominant in? Where is the location of the mononuclear phagocytic system?
Derived from peripheral blood monocytes
Transform into phag cell in extravascular space
Dominant in chronic inflammation
Mononuclear phagocyte system:
Normally scattered in connective tissue
Liver (Kupffer cells)
Spleen and lymph nodes (Sinus histiocytes)
CNS (microglial cells)
Lungs (alveolar macrophages)
What is the function of macrophages? How are they induced to form multinucleate giant cell?
Ingest and eliminate microbes and dead tissues
Initiate the process of tissue repair
Secrete mediators of inflammation
Display antigens to T lymphocytes and respond to signals from T cells
IFN-y can induce macrophages to fuse into large giant cell
Describe the mechanism by classically activated macrophage M1 functions.
Activated by IFN-1 (microbe)
ROS, NO, lysosomal enzymes cause microbicidal actions:
Phagocytosis and killing of bacteria and fungi
IL-1, 12, 23 and chemokines: activate inflammation
Describe the mechanism by which alternatively activated macrophage (M2) functions.
Stimulated by IL-13, 14
Growth factors, TGF-b: tissue repair, fibrosis
IL-10, TGF-b: anti-inflammatory effects
Describe the function of lymphocytes in chronic inflammation.
Major drivers of inflammation in many autoimmune and chronic inflammatory diseases
CD4+ T cells
–TH1 cells produce the cytokine IFN-γ, which activates
macrophages in the classical pathway.
–TH2 cells secrete IL-4, IL-5, and IL-13, which recruit and activate eosinophils and are responsible for the alternative pathway of macrophage activation.
–TH17 cells secrete IL-17 and other cytokines that induce the secretion of chemokines responsible for recruiting neutrophils and monocytes into the reaction.
B lymphocytes- May develop into plasma cells in tissues
E scribe the function of mast cells in chronic inflammation.
Found in CT
Express receptors that bind Fc portion of IgE
Participate in acute and chronic inflammation
Describe the function of eosinophils in chronic inflammation.
Found in parasitic infection and allergic reaction mediated by IgE
Granules contains major basic protein: toxic to parasite and mammalian epithelial cells
What is granulomatous inflammation?
Collections of activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis
What is a granuloma?
Formation is a cellular attempt to contain an offending agent that is difficult to eradicate
Focal collections of macrophages (epithelioid macrophages) surrounded by a collar of mononuclear leukocytes, principally lymphocytes & occasionally plasma cells
Giant Cell- Multinucleate cells made by fusion of macrophages, can be also be found in the granuloma
What are two types of granuloma?
Foreign body granuloma
• foreign body in the absence of T cell–mediated immune responses
– suture, talc, thorn, fibers etc
Immune granuloma
• Caused by a variety of agents that are capable of inducing
a persistent T cell–mediated immune response
– certain microbes, Self antigen eg. Crohn’s disease, unknown etiology, eg. Sarcoidosis, Wegener’s granulomatosis
Compare a caseating granuloma vs a non caseating granuloma.
Caseating: central caseous necrosis, lungs, response to infection
Non-caseating: no central necrosis, response to foreign material, sarcoidosis, or Crohn’s disease
What are the system is effects of inflammation also known as? What are the most important mediators?
Known as “acute-phase” reaction
TNF, IL-1, and IL-6 are the most important mediators of the acute-phase reaction.
What are the systemic effects of inflammation?
Fever, elevated plasma levels of acute-phase proteins, leukocytosis, increased heart rate and blood pressure, chills, cachexia, severe bacterial infection (sepsis, shock)
Describe the mechanisms of a fever.
In the hypothalamus the prostaglandins, especially PGE2, stimulate the production of neurotransmitters, which function to reset the temperature set point at a higher level
Describe the mechanism of elevated plasma levels of acute phase proteins.
C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA) protein
Stimulated by IL-6 (for CRP and fibrinogen) and IL-1 or TNF (for SAA)
Describe the mechanism of leukocytosis.
Cytokines stimulate production of leukocytes from precursors in the bone marrow
What is cachexia?
Loss of weight, muscle atrophy, fatigue, weakness, and significant loss of appetite
Describe the effects of severe bacterial infection (sepsis).
Disseminated intravascular coagulation
Hypotension
Metabolic disturbances including acidosis
What are the diagnostic tests for inflammation?
ESR, CRP, SAA, Leukocyte count
Describe the Erythrocyte sedimentation rate test (ESR).
Finer in Ogden bind to erythrocytes and causes increase in ESR
Measures distance RBC fall in one hr
HIGH ESR: RBS settles quickly to bottom: nonspecific inflammation
Different for men and women
Age is a factor
Describe the CRP test for inflammation.
CRP (acute phase protein, bind to phosphocholine on surface of dead or dying cells, activate complement system)
What is SAA? (Diagnostic test for inflammation)
Serum amyloid A (acute phase protein, recruitment of immune cells to inflammatory site)
What leukocytes are counted when testing for inflammation?
neutrophilia, eosinophilia, lymphocytosis
What may be concluded when we see cells in the AC of the eye? Flare?
Cells- immune cells in AC
Flare- proteins leaked form inflamed blood vessels
