Robbins Chapter 2 - Inflammation Flashcards
What are the five cardinal signs of inflammation?
Rubor = redness Tumor = swelling Calor = heat Dolor = pain functio laesa = loss of function
Describe exudate
Exudate is an acidic fluid which is high in protein content, cell debris, and has a high specific gravity. It is the result of vasodilation and increased vascular permeability.
Note: may become purulent when it contains a lot of neutrophils
Describe transudate
Transudate is an alkaline fluid with low specific gravity, low protein content, and no cellular debris. It is the result of increased hydrostatic pressure in the capillaries.
What is the immediate transient response?
immediate changes in vascular permeability due to the actions of NO and histamine.
What is the delayed proloonged response?
Same response as immediate but occurs later and lasts longer
What is the immediate prolonged response?
An immediate response of the vascular membrane, but remains for longer duration due to damage to endothelial cells
What do serous, sanguinous, purulent, and chylous mean in describing an effusion? What is an effusion?
Serous = yellow/clear fluid Sanguinous = blood Purulent = pus chylous = milky, white
An effusion is the occurence of edema with in a potential or pre-existing space.
What are the chemical mediators which cause contraction of endothelial cells?
Histamine, bradykinin, leukotrienes (LTC4, D4, E4), and substance P
What process are vesiculovacuolar organelles involved in? What factor mediates this process?
Transcytosis - movement of fluid and proteins through the endothelium occurs through a channel of connected vesiculovacuolar organelles.
Mediated by the expression of VEGF.
Describe the changes seen in the lymphatic system in response to inflammation.
Lymph flow will increase in the inflammatory response due to edema. Vessel proliferation is also mediated by VEGF and VEGFR-3.
Describe the process of leukocyte recruitment from the vessel lumen to the interstitium of the injured tissue.
The immediate response of histamine and NO cause slowing of blood flow resulting in margination of the leukocytes, specifically neutrophils. Leukocytes are stimulated by local factors to express selectins to initiate rolling adhesion. Leukocytes will come to a complete stop through the expression of integrins. Diapedesis results via PECAM-1. Chemotaxis occurs along the ECM through the expression of endogenous and exogenous mediators.
Describe L-, E-, and P-selectins. What stimulates their expression?
L-selectin is expressed by leukocytes and binds to GlyCam-1 and CD34. It is responsible for homing of leukocytes to lymphatic tissues.
E-selectin is expressed by endothelial cells and binds to sialyl-lewis x-modified proteins.
P-selectin is expressed by platelets, in addition to endothelial cells, and also binds an x-modified protein.
E-and L-selectin expression is stimulated by TNF and IL-1.
P-selectin is stored in weibel-palade bodies, the redistribution of which is caused by histamine, thrombin, and PAF.
What are two clinically significant signs of adhesion molecule deficiency?
Recurrent bacterial infections along side lack of purulent lesions.
Describe the expression and binding of integrins.
Integrins are expressed by leukocytes in response to the expression of TNF and IL-1. VLA-4 and LFA-1 bind to VCAM-1 and ICAM-1, respectively, on the endothelium.
Describe diapedesis in reference to location and mechanism
Typically occurs in the post-capillary venules. Mediated by the molecules PECAM-1 (CD34) and CD99. After traversing the endothelium collegenases are secreted to allow movement through the basement membrane.
Describe chemotaxis of leukocytes in the interstitium
Leukocytes adhere to the ECM through the action of integrins and CD44.
Exogenous (f-met) and endogenous (cytokines, complement, and eicosanoids) mediators bind GPCRs on the cell.
Receptor binding causes increase in calcium and the polymerization of actin at the leading edge of the cell. At the tail edge myosin filaments localize. Leukocytes move through the extension of filopodia.
What are the specific exceptions (3) discussed in class to the normal pattern of leukocyte infiltration?
Pseudomonas - infiltrate is continuously dominated by neutrophils
Viral Infections - dominated by lymphocytes
Hypersensitivity reactions - dominated by eosinophils
What do TLR’s recognize and how do they transduce their signals? What is the general result of signal transduction?
TLRs recognize bacterial LPS and proteoglycans, and viral dsRNA
Transmit their signal through Tyrosine kinase-associated receptors.
End result is the production of microbicidal agents and cytokines by activated leukocytes
What do GPCRs recognize and how do they transduce a signal? What is the end result of receptor binding?
GPCRs will bind f-met, chemokines, PAF, leukotrienes, prostaglandins, and C5a
Transmit signal through activation of g-proteins
Causes cell migration and production of microbicidal agents by neutrophils and macrophages.
Describe the action of opsonins and how they are detected (3).
Opsonins coat the surface of microbes to signal phagocytosis.
IgG bound to a microbe can also bind to the FCγRI on phagocytes.
C3b binds microbes and the C1R on phagocytes
Mannan-binding lectin will also stimulate opsonization.
What is the major macrophage-activating cytokine and what cells produce it?
IFN-γ
Produced by NK cells and Antigen-activated T lymphocytes
What are the three ways a phagocytic cell binds to an object targeted for phagocytosis?
Mannose receptor - binds to mannose and fucose residues of glycoproteins and glycolipids.
Note: Host cells have sialic acid and are not recognized.
Scavenger receptor - binds microbes and modified LDL particles
Osponin receptors
What enzyme is responsible for the production of superoxide anion and where does this production occur in the cell?
Multicomponent (phagocyte) oxidase is responsible for rhe produciton of superoxide anion in the lysosome.
Describe the H2O2-MPO-halide system
Hydrogen peroxide is formed from the dismutation of superoxide anions. MPO is found in azurophilic granules of neutrophils. MPO can create hydroxyl radicals or hypochlorite in the presence of halides.
Note: hypochlorite is the most potent antimicrobial ROS
What is a byproduct of the production of NO and superoxide
NOS produces NO which can react with superoxide anions to form peroxynitrite
Describe the etiology, pathogenesis, and manifestations of Chediak-Higashi Syndrome.
Due to a mutation in the LYST gene lysosomal trafficking is dysfunctional leading to the inability of phagosomes to fuse with lysosomes.
Albinism results from abnormalities in melanocytes.
Recurrent infections due to giant granules in lymphocytes.
Nerve defects
Dense bodies in platelets causing bleeding disorders.
What is the etiology and pathogenesis of chronic granulomatous disease?
Mutation or dysfunction of phagocyte oxidase leads to a macrophage rich reaction due to the inability of neutrophils to remove the offending agent. Granuloma will follow.
What are the active methods of terminating inflammation (4)?
Switch of AA metobalites to lipoxin instead of leukotrienes
Production of anti-inflammatory lipid mediators resolvin and protectin
Release of TGF-β and IL-10
Nervous inhibition of TNF production by macrophages
Note: resolvin and protectin production is thought to be stimualted by the intake of fish oil
What are the two types of mediators of inflammation?
Cell mediators and plasma proteins. Cell mediators are either preformed or produced in response to stimuli. Plasma proteins are synthesized by the liver and found in the circulation as a precursor.
What are vasoactive amines, give 2 examples?
These are preformed mediators of inflammation and include histamine and serotonin.
Describe the sources of histamine, stimuli for its release, and its physiologic effects.
Released by basophils, platelets, and mast cells.
Stimuli - traumatic injury, antibodies, complement anaphylatoxins, substance P, and cytokines (IL-1 and -8).
Causes dilation of arterioles, constriction of large arteries, and increased permeability of venules
Note: Histamine is the principle mediator of the immune response
Describe the sources of serotonin, stimuli for its release, and its physiologic effects.
Released by platelets and neuroendocrine cells.
Stimulus = platelet aggregation
Causes increased vascular permeability
Describe eicosanoids and give 3 examples
Eicosanoids are mediators of inflammation synthesized de novo from arachidonic acid. Includes prostaglandins, leukotrienes, and lipoxins.
What are the enzymes required for the mobilization of AA and production of the various eicosanoids?
AA is liberated from the plasma membrane by phospholipase A2. Cyclooxygenase manufactures prostaglandins while lipoxygenase manufactures leukotrienes and lipoxins.
Note: steroids inhibit all production of eicosanoids by inhibiting phospholipase A2
Describe the two isoforms of COX?
COX-1 is constitutively expressed while COX-2 is inducibly expressed
What cell types produce prostaglandins (3)? What are the important prostaglandins (5)?
Mast cells, macrophages, and endothelial cells
TxA2, PGE2, PGD2, PGF2, and PGI2
Where is thromboxane produced and what are it’s effects (2)?
TxA2 is produced in platelets. Released to cause aggregation of platelets and vasoconstriction.
Where is prostacyclin produced and what are its actions (3)?
Produced in the vascular endothelium. Inhibts aggregation of platelets, causes increased vascular permeability, and vasodilates.
What are the effects of PGD2 (3)?
attracts neutrophils, vasodilates, and mediates pain/fever
What are the effects of PGE2 (2)?
causes pain and vasodilates
What are the effects of PGF2 (1)?
Vasodilates
What cells produce leukotrienes? What are the most relevant leukotrienes (4)? What are the actions of these molecules (4)?
Leukocytes are responsible for the production of leukotrienes.
LTB4 - chemotaxis of neutrophils
LTC4, D4, and E4- mediate vasodilation, bronchospasm, and increased vascular permeability
What are lipoxins and describe their synthesis
Lipoxins inhibit inflammation. Require intermediates to be produced by leukocytes. Synthesis is finished by platelets.
How can arterial thrombosis occur with selective COX-2 inhibitors?
This decreases the production of PGI2 which is responsible for the inhibition of platelet activation. Also allows the unrestricted production of TxA2 by COX-1, inducing platelet aggregation.
What are the sources (3) of PAF and its actions (5)?
Produced by platelets, endothelial cells, and leukocytes.
Causes platelet aggregation, vasonconstriction, and bronchoconstriction.
Note: at low concentrations it causes increased vascular permeability and vasodilation
What are the sources (3) and actions (4) of NO?
NO is produced by macrophages, endothelial cells, and some neurons.
The actions of NOS are to increase vasodilation, but limit the cellular components of inflammation: inhibit platelet aggregation, inhibit mast cells, inhibit leukocyte recruitment.
What enzymes produce NO?
NO synthetase is responsible for the production of NOS. There is nNOS, eNOS, and iNOS. iNOS is activated by TNF and IL-1 in response to injury.
What structure is involved in the production of IL-1 and what is its mechanism of action?
The inflammosome of macrophages will activate proteases to cleave the inactive precursor of IL-1 so it can be secreted.
Describe the etiology of inherited autoinflammatory syndroes, the manifestaations, and give an example.
Mutations of the proteases which cleave IL-1 lead to their constitutive activation producing fever and other systemic inflammatory sympotoms. An example of this is Mediterranean fever.
Name and describe the three pathways by which proteolysis of C3 occurs.
Classical pathway - C1 combines with an antigen-antibody complex
Alternative pathway - recognition of microbial surface molecules by complement system
lectin Pathway - mannose-binding lectins cause activation of C1
What are the funcitons of C3 and C5 convertase?
C3 convertase will cleave C3 into C3a, which diffuses and acts as an anaphylatoxin, and C3b, which binds to the microbe to opsonize and participate in C5 convertase.
C5 convertase cleaves C5 into C5a and C5b. C5b leads to the formation of the membrane attack comlex via C6, 7, 8, and 9.
What are two functions of C5a?
Acts as a chemoattractant for leukocytes and an activator of LOX
What are the four systems activated by Hageman Factor (XII)?
complement, kinin, clotting, and fibrinolytic system
Describe the clotting system from Factor XII to fibrin
Factor XII activates the clotting cascade, a product of which is thrombin. Thrombin is a protease that causes the polymerization of fibrinogen to form a plug.
Thrombin can also bind to protease-activated receptor-1 (PAR-1) on platelets –> mobilization of P-selectin, COX-2, cytokines, PAF, and NO
Describe the Kinin cascade from Factor XII to bradykinin.
Activated factor XII will cleave prekallikrein into kallikrein. Kallikrein can activate Factor XII and cleave high molecular weight kininogen (HMWK) into bradykinin.
Note: Kalikrein can also convert C5 to C5a
What are the actions (3) of bradykinin and how is it terminated (2)?
Bradykinin elicits pain, vasodilation, and increased vascular permeability.
Terminated quickly through kininase or by ACE in the lungs.
Describe the fibrinolytic system from factor XII to fibrin-split products.
Activation of factor XII causes the cleavage of prekallikrein to form active kallikrein. Kallikrein converts plasminogen into plasmin. Plasmin is able to cleave fibrin polyers creating fibrin-split products.
Note: Plasmin can also convert C3 to C3a
What is the action of fibrin-split products?
They can increase permeability of endothelium
Describe Fibrinous Inflammation and negative outcome of it
This is the shaggy appearance of tissues due to the ability of fibrinogen to pass through the endothelial barrier and accumulate in tissues. This exudate is removed by macrophages and fibrinolysis. If it is not completely removed fibroblasts will mediate scarring. This can occur in the pericardial sace leading to obliteration of the pericardial space.
How would purulent inflammation present on a microscope slide?
Zone of neutrophils surrounding necrotic lymphocytes with dilated vessels at the periphery.
What are tertiary lymphoid organs?
Accumulations of APCs, lymphocytes, and plasma cells in an area of chronic inflammation
What is the chemotactic element and granule component specifically associated with eosinophils?
Eotaxin and major basic protein, respectively.
Describe the formation and two types of giant cells.
Giant cells form from the aggregation of epithelioid macrophages.
The langhans giant cell has nuclei arranged peripherally
The foreign body giant cell has nuclei organized haphazardly.
What are the systemic effects (3) of inflammation mediated by TNF?
Fever through the actions of pyrogens on prostaglandin synthesis in the hypothalamus. Increased blood pressure and decreased swelling. Production of acute-phase proteins.
What are the acute phase proteins, when are they produced, and what are their actions (3)?
C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA)
Produced by hepatocytes in response to IL-1 and IL-6.
SAA and CRP will opsonize microbes
All can assist in the phagocytic clearing of necrotic nuclei by binding chromatin
SAA replaces apoplipoprotein A to increase targeting of HDLs to macrophages
Describe the disease process of sepsis and its manifestations (4).
Increased amount of circulating LPS lead to large amount of TNF and IL-1 in the circulation. This results in widespread vasodilation, disseminated intravascular coagulation, hypoglycemia, and acute respiratory distress syndrome.
