Section 1
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what is the role of NO in inflammation?
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Mar 1, 2020
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Section 1
(50 cards)
what is the role of NO in inflammation?
1. smooth muscle cells: ∙ starts signaling cascade ➙ decreased sensitivity of myosin/ca induced contraction ➙ muscle relaxation/vasodilation 2. antagonist for platelet aggregation/adhesion + leukocyte adhesion ∙ inhibits cellular component of the inflammatory response/controls inflammatory responses 3. macrophages and PMNs ∙ form ROS intermediates ➙ kill microbes
where and when are inflammatory mediators produced?
∙ produced by liver ∙ end product of group of serine proteases ∙ circulate in plasma as zymogens: activated in a stepwise manner by previously activated enzyme ∙ sequestered in ECM
what are three functions of the complement cascades?
1. inflammation ∙ C3a + C5a: stimulate histamine release from mast cells ➙ inc vascular permeability ➙ vasodilation ∙ annaphylatoxins: similar effects similar to mast cell mediators involved in anaphylaxis ∙ C5: chemotactic agent ∙ C5a: can activate lioooxgenase pathway ➙ more inflammatory mediators 2. phagocytosis ∙ C3b: (an opsonin)promotes phagocytosis by neutrophils and macrophages when bound to microbe's cell wall 3. cell lysis ∙ deposition of membrane attack complex on offending cell wall ➙ permeable to water/ions ➙ cell lysis/death
complement cascade overview
20+ proteins, numbered C1-C9 etc ∙ innate and adaptive immune defense ∙ cascade that occurs as cleavage products are generated: inc vascular permeability, chemotaxis, opsonization effects mediated role in inflammation
how are cell derived mediators typically sequestered?
intracellular granules de novo in response to stimulus
properties of inflammatory mediators: 3. cascading effect
one mediator can stimulate release/activation of other mediators ∙ secondary mediators: can have same (promoting mediator) or opposing/different activities of primary mediator ➙ amplifies counteracts activity of primary mediator
what are early & late mediators of endothelial cell activation
early activators: in cells + plasma ∙ histamine ∙ bradykinin ∙ PAF ∙ thrombin late activators: sustain the response ∙ IL1beta ∙ TNFalpha ∙ IFN gamma other mediators ∙ complement factors, bacterial products, hypoxia, viruses
how do anti-inflammatory drugs work via inhibiting eicosanoid synthesis?
aspirin/other NSAIDS = cyclooxgenase inhibitors = inhibits prostaglandin synthesis corticosteroids: broad spectrum inhibitors ∙ reduce txn of genes encoding COX-2, PLA2, proinflamatory cytokines (IL-1, TNF) and iNOS fish oil supplements: favor production of anti-inflammatory lipid mediators (resolvins and protectins)
what are the cardinal signs of inflammation?
redness (rubor) + warmth (calor) ∙ vasodilation = increased blood flow ∙ mediated by relaxation of arteriolar smooth muscles (histamine, prostaglandins, bradykinin) swelling (tumor) ∙ leakage of fluid from post capillary venules into interstitial ∙ mediated by histamine (endothelial cell contraction and tissue, vessel damage pain (dolor) ∙ bradykinin and PGE2 sensitive nerve endings fever ∙ pyrogens (LPS) cause IL1 and TNFalpha release from macrophages, inc cyclooxgenase activity in hypothalamus ∙ increased PGE2 raises temp set point
how are prostaglandins synthesized?
cyclooxygenase pathway produced by: mast cells, macrophages, endothelial cells, other cell types
what are 3 most clinically relevent leukotrines?
1. 5HETE: produced in neutrophils (PMN), potent chemotactic factor for PMN 2. LTB4: PMN chemotaxis and activation ∙ leads to aggre/adhesion in venules at site of injury ∙ generates ROS needed for PMNs to kill microbes/release lysosomal enzyme 3. LTC4, LTD4, LTE4: induce bronchoconstriction (asthma), vasoconstriction, increase vascular permeability in venues ∙ effect in venules is more potent than histamine's
function vs mediator reveiw table
what are some functional changes in activated endothelial cells and what does it leads to?
synthesis of factors that control... 1. vasodilation (PGI2, NO, EDHF) and vasoconstriction (endothelins, angiotensin) on smooth musce 2. pro + anti thrombotic factors 3. ECM components 4. chemokines leads to... 1. contraction of myosin: histamine, bradykinin, leukotrienes... earlier 2. retraction of cytoskeletal elements: IL1, INFgamma, TNFalpha...later ∙ forms intercellular gaps = increased vascular permeability = fluid and cells leave circulation
vascular events in inflammation
why are C3a and C5a important?
generated by several different reactions ∙ immunologic rxns with antibodies and classical complement pathway ∙ activation of alternative compliment and lectin pathways ∙ agents not directly related to immune responses (plasmin, kallikrein, etc)
cell derived inflammatory mediators
kinin system overview
kinins: vasoactive peptides derived from plasma proteins (kininogens) by activity of proteases (kallireins) bradykinin: 1. binds to GCPR B1 and B2 ∙ B1: expression induced by cytokines IL-1, TNF-alpha, IFN-gamma ∙ B2: constitutively on 2. GCPR activates endothelial cells ➙ NO and prostaglandins 3. inc vascular permeability, vasodilation, smooth muscle contraction (lung= cough, uterus), mediates pain
what is plasma?
colorless fluid part of the blood where rbc/wbc/platelets are suspended ∙ mostly water + electrolytes, enzymes, clotting factors, proteins ∙ vs serum: serum is plasma w/o clotting factors (no fibrinogen)
Histamine (vasoactive amines) description
∙ causes dilation of arterioles ∙ increase permeability of venules by binding histamine receptors on endothelial cells ∙ stored in cells = first mediators released ∙ from primarily mast cells, (also basophils and platelets)...mast cells near vessels of tissue section (Black dots) PICTURE FROM LECTURE
clotting/coagulation system overview
products from the activation of FXII to XIIa can be used to also activate = positive loop feedback
how are leukotrines produced?
lipoxygenase pathway produced by: leukocytes
what is not affected by NSAIDS?
lipoxygenase ∙ lipoxygenase inhibitors diminish leukotriene production ➙ work well to tx asthma (bronchoconstriction in lungs from leukotrienes)
vascular permeability overview
slide 8
what are some stimuli for cell derived mediators? why is this important?
microbial products necrotic tissue other inflammatory events ensures that inflammatory response is only initiated when needed
what does inflammation do to the clotting/coagulation pathway?
inflammation enhances number of clotting factors ∙ make endothelial surfaces pro-thrombogenic + inhibit some anti-coagulation pathways ➙ promote clotting ∙ presence of clotting system components = derived inflammatory mediators ➙ recruit leukocytes/support events in inflammation works in coordination ∙ tx strategies for systematic inflammatory diseases: use anticoagulant to help ongoing inflammatory response
regulation of bradykinin
bradykinin rapidly inactivated by kininase= action of bradykinin is short lived ∙ any remaining kinin in plasma is inactivated in lungs by angiotensin converting enzyme (ACE) tx high blood pressure: ace inhibitors ➙ high levels of bradykinin ➙ inc vascular permeability and swelling ➙ risk of angioedema/chronic cough (bronchioconstriction, mediated by high levels of bradykinin)
are lipid mediators of inflammation stored in cells?
NOPE synthesized and released in response to the binding of other mediators ➙ generated only when needed
plasma derived inflammatory mediators
what are the main cell derived mediators?
arachidonic acid (AA) metabolites: prostaglandins, leukotrines, lipoxin platelet-activating factor (PAF) nitric oxide (NO) vasoactive amines: histamine and serotonin cytokines and chemokines
fibrinolytic system
∙ downstream from clotting cascade plasmin ∙ primary function: lyse fibrin blood clots ∙ during inflammation: cleave C3, generate fibrin split products ➙ cleave fibrin ➙ increase vascular permeability
what are 3 properties of plasma inflammatory mediators?
1. tightly controlled 2. short lived 3. cascading effect
cell-derived lipid mediators table
CROSS REFERENCE WITH OTHER TABLE FROM LECTURE
what are 6 properties of cell-derived inflammatory mediators?
1. typically sequestered in intracellular granules ➙ rapidly released by exocytosis (histamine in mast cells) or rapidly synthesized de novo in response to a stimulus (prostaglandins) 2. only released in response to certain stimuli: microbial products, necrotic cells, proteins in kinin/complement/coag systems ∙ response only wehn needed 3. major cell types: platelets, neutrophils, monocytes/macrophages, mast cells, some msenchymal cell types (endothel, smooth musc, fibroblasts) 4. one mediator can stimulate release of other mediators 5. vary in cell selectivity: ∙ can have specific or wide range of target types ∙ can have opposite effects on different cell types 6. short lived: quickly decay/inactivated/scavenged/inhibited
what is platelet activating factor derived from and what is its mechanism of action?
derived: from membrane phospholipids of PMNs, monocytes, activated endothelial cells, platelets, basophils ∙ short lived ∙ binds to specific GCPR PAFR: expressed on platelets, endothelial cells, and leukocytes
properties of inflammatory mediators: 1. tightly controlled
active mediators are produced only in a response to stimulus such as microbes or material from necrotic cells (initiating mediators) ∙ ensures inflammation is only triggered when needed and that the reaction is specific (signaling pathways/receptors
NO summary quick facts
1. free radical, gas, diffuses across membranes 2. 2 synthetic pathways (NOS-dependent = normoxia = inflammation) 3. bactericidal, SM relaxation/vasodilation, can negatively regulate inflammatory cells
what causes histamine to be released from mast cell granules (degranulation via exocytosis)?
PICTURE
complement cascade pathways
cx step: proteolytic cleavage of C3 ∙ classical pathway: triggered by fixation of C1 to antibody (IgG or IgM) bound to antigen ∙ alternative pathway: triggered by microbial surface molecules (LPS, endotoxin, etc) in absence of antibody ∙ lectin pathway: plasma mannose-binding lectin (MBL) binds carbs on microbes + directly activates another complement molecules (C1) ‣ each pathway can form C3 convertase ➙ cleaves C3 into C3a and C3b C3a: released C3b: binds to cell or microbial surfaces ➙ complement is activated ➙ further activate alternative in feed forward ➙ forms C5 convertase ➙ cleaves C5 C5a: released C5b: attaches to cell surface ➙ binds to late complement components (C6-C9) ➙ forms membrane attack complex (MAC)
what are the functions of platelet activating factor?
enhances platelet aggregation activates leukocytes ∙ leukocyte emigration ∙ synthesis of ROS, lipid mediators, cytokines (TNFalpha and IL6) activates endothelial cells ∙ inc vascular permeability ∙ vasodilation via NOS
which NSAID is the most potent in controlling inflammation and why?
corticosteroids ∙ reduces PLA2 expression which can down regulate the entire AA synthesis system ∙ can reduce txn of pro-inflammatory cytokines and iNOS
vasodilation overview picture
slide 12
cell-derived non-lipid mediators table
which four systems in the inflammatory response does Factor XIIA (activated hagman factor) initiate?
1. kinin system ➙ vasoactive peptides (bradykinin) 2. clotting system ➙ thrombin ➙ inflammatory properties 3. fibrinolytic system ➙ produces plasmin, degrades fibrin 4. complement system ➙ produces anaphylatoxins + other mediators
properties of inflammatory mediators: 2. short lived
quick decay, enzymatically inactivated, scavanged, inhibites ∙ ensures systems of checks and balances ∙ built in control mechanism
what are 5 clinically important prostaglandins and their actions?
1. PGI2: vasodilation 2. thromboxane (TxA2): vasoconstriction, platelet agg, bronchioconstriction 3. PGE2: vasodilation, inc vascular permeability, pain, fever 4. PGD2: major prostaglandin of mast cells, bronchoconstriction, vasodilation, inc vascular permeability, recruitment of eosinophils 5. PGF2alpha: uterine SM contraction/giving birth, bronchoconstirction
what are the 3 tissue distributions of NOS?
1. neuronal: no role in inflammation 2. inducible: induced in phagocytic cells/macrophages 3. endothelial: vasodilation (diffuses across PM of endothelial and SM cells)
arachidonic acid (AA) metabolites pathway
lipoxins pathway
lipoxygenase pathway potent inhibitors of inflammation ∙ transcellular synthesis ∙ inhibit leukocyte recruitment and cellular components of inflammation ∙ endogenous regulators of leukotrienes
what are the 4 plasma inflammatory mediator systems?
1. complement cascade 2. kinin cascade 3. fibrinolytic system 4. clotting/coagulation cascade
which are the most important plasma derived inflammatory mediators and what do the do?
bradykinin, C3a, C5a, thrombin ∙ bradykinin, C3a, C5a: increases vascular permeability + vasodilation, smooth muscle contraction (bradykinin) ∙ C5a: mediates cheomitaxis and thrombin's effect on endothelial cells factor XII activation: common to all pathways and give rise to serum mediators of inflammation
Section 2
(50 cards)
edema and congestion
what are clinical features of lymphedema?
∙ unilateral, upper or lower limbs ∙ made worse by prolonged dependency/gravity ∙ physical exam: inc diameter of lung, pitting, weep fluid, sensory/ROM problems ∙ inc risk for infection
what are the mechanisms/steps that leads to leukocyte transmigration following leukocyte and endothelial cell activation?
1. margination ∙ vasodilation slows blood flow in postcapillary venules ➙ cells marginate from center of flow to periphery of vessel 2. rolling *important ∙ selectin "speed bumps" upregulated on endothelial cells ∙ p-selectin: mediated by histamine ∙ e-selectin: induced by tnf and il1 (later) ∙ interaction results in rolling of leukocytes on vessel wall 3. adhesion: *important ∙ cellular adhesion molecules (ICAM, VCAM) are upregulated on endothelial cell by TNF and IL1 (late regulators) ∙ integrins upregulated on leukocytes by C5a and LTB4 ∙ CAMs-Integrin X = firm adhesion of leukocytes to endothelial cell 4. transmigration & chemotaxis ∙ leukocytes transmigrate across endothelial cell of postcapillary venules toward chemical attractants (chemotaxis) ∙ neutrophils: attacked by bacterial products IL8, C5a, LTB4 5. phagocytosis ∙ leukocytes consume pathogens/necrotic tissue: enhanced by opsonins (IGG, C3b) ∙ leukocytes extend psedopods, form phagosomes, merge with lysosomes, form phagolysosomes = engulf organism 6. destruction of phagocytosed material ∙ most effective = o2 dependent killing ∙ also HOCl (bleach) 7. resolution ∙ neutrophils undergo apoptosis within 24 hrs of stimulus *Cross reference with pictures from lecture
what is a granuloma?
microscopic aggregation of macrophages ➙transformed into epithelium-like cells ➙ surrounded by a collar of mononuclear leukocytes, lymphocytes, occasional plasma cells ∙ cant tell where one cell ends and one begins
endothelial cell activators
thrombin histamine bradykinin LPS (bacterial product) C3a LTC4, LTD4, LTE4 TNFalpha IL1Beta IFNgamma leukocyte binding
pseudomembranous inflammation
acute inflammatory exudate (volcanic eruption of mushrooms) forming grey/yellow/plaque adhesions on endothelial surface of colon and pharynx ∙ mucosal surface containing membranes with neutrophils, macrophages, necrotic debris, organisms, fibrin
what does serous inflammation consist of?
clear fluid (transudate), few to no cells
what are hallmark features of chronic inflammation?
∙ lymphocytes and macrophages ∙ fibrosis!!!
what are hallmark features of acute inflammation?
∙ small vessel dilation ∙ extravascular accumulation of leukocytes ∙ extravascular accumulation of fluid (edema/swelling)
edema due to increased hydrostatic pressure
backup/stasis of venous blood in circulation impaired venous return ∙ hepatic cirrhosis ∙ pulmonary edema due to CHF venous obstruction ∙ lower limb inactivity (gravity) ∙ thrombosis ∙ mass
suppurative inflammation histology
acute bronchopneumonia air sacs filled with purulent material/PMNs
etiologies of lymphedema
primary: ∙ congenital, hereditary secondary: ∙ infection and inflammation = CHANGES K bc increased endothelial permeability ∙ obstruction/fibrosis: trauma, surgery, tumors (plug vessels impeding lymph flow), radiation therapy ∙ surgical dissection (lymphadenectomy): same side as breast cancer
serous inflammation histology
venous congestion
∙ often accompanies/may precede edema ∙ increases organ weight and size ∙ pump failure, clogged pipes increasing hydrostatic pressure
what does suppurative/purulent inflammation contain?
PMN, cell debris, fibrin, maybe organisms = cloudy exudate, pus
what are some clinical presentations of left side of heart pump congestion?
respiratory difficulties pulmonary edema short of breath/dyspnea
which organs are impacted with congestion due to pump failure on the right side of the heart?
congestion of liver, spleen, lower limbs
edema due to impaired lymph drainage
lymphedema amount of edema in interstitial tissue >>> ability of the lymphatic system to drain it ∙ takes up extra fluid that does not move into the venous side of microcirculation
what does an x-ray look like with someone who has left side heart pump congestion?
white splotches = pulmonary edema
the left side of the heart congestions = _______ congestion
pulmonary
what are some clinical presentations of right side of heart pump failure congestion?
pitting edema of legs blue skin/cyanosis disruption in jugular vein enlarged spleen and liver
movement of fluid across arteriole/capillary/venule
hydrostatic pressure: moves fluid out of arterioles and cap and into interstitium oncotic pressure: fluid in at venules on other side of the microcirculation ∙ oncotic pressure is directly proportional to protein concentration of the plasma cross reference slide 3 for normal values of each
what's the difference in histology of leukocyte nuclei?
neutrophils = nuclei have multiple lobes (Polymorphonuclear cell) macrophages, lymphocytes = mononuclear cell
acute inflammation: neutrophils/PMNs
main cell of acute inflammatory response type of granulocytes multilobated nucleus
congestion due to obstruction (Clogged pipes)
localized obstruction (often venous) water levels rising behind a dam ∙ "blue leg" vs other leg normal ∙ venous stasis: defective valves in large veins of lower limb ➙ high venous pressures ➙ venous insufficiency ➙ skin changes/infection
transudate vs excudate cell damage?
transudate: fluid leakage due to increased hydrostatic pressure or decreased osmotic pressure ∙ fluidy-serum ∙ not many cells/leukocytes/proteins ∙ clearer ∙ no endothelial cell damage ∙ blister, bee sting, chf, edema exudate: increased permeability ∙ cloudy, milky, etc ∙ cell/protein rich ∙ may or may not be due to endothelial damage prulent: pus fibrin rich sanguineous: bloody pus slide 17
fluid dynamics of endothelial gap formation/cell injury
increased permeability constant (k) results in endothelial cell activation by various mediators or direct damage
what happens to the venous bp with pulmonary edema?
it is elevated
morphologic patterns of inflammation
what are effects of vasodilation and increased permeability?
increased permeability ➙ increased cell concentration/less fluid ➙ hemoconcentration ➙ slows blood flow ➙ leukocyte movement/come in contact with endothelial surface ∙ mainly in post-cap venule slide 25
ulcers
necrotic and eroded appearing area of epithelial surface with underlying acute and chronic inflammation ∙ trauma, toxins, ischemia
edema due to decreased oncotic pressure
increased protein (albumin) loss ∙ nephrotic syndrome: proteinuria (protein is loss due to kidney dysfunction) ∙ protein-losing gastroenteropathy: plasma proteins lost via gi tract decreased protein (albumin) synthesis ∙ hepatic cirrhosis: liver damage impairing the ability of liver cells to synthesize albumin/plasma proteins *can also inc hydrostatic protein ∙ malnutrition excess IV fluid resuscitation
suppurative is cell _____ and protein _____
cell rich, protein rich
what are some differences between acute and chronic inflammation?
activated endothelial cell changes
∙ release of stored p-selectin and vwf ∙ increased cell adhesion molecule synthesis and expression: vcam, icam, e-selectin ∙ matrix metalloproteinases (MMPs) ∙ inc IL-8R ∙ inc permeability: contraction of myosin and rearrangements of cytoskeletal elements ∙ increase syntehsis and release of NO, PGI2, tissue factor
what does excess fluid accumulation in the extravascular tissue/interstitum result from?
increased vascular permeability (k) increased hydrostatic pressure decreased oncotic pressure obstruction of lymphatic vessels (Qlymph)
what is the difference between hyperemia and congestion?
hyperemia: increased blood flow into organ/tissue due to arteriole dialation ∙ active process ∙ red ∙ assoc with exercise and inflammation congestion: reduced blood outflow from an organ/tissue ∙ passive process ∙ blue ∙ systemic (cardiac) or focal (isolated venous obstruction)
mediators of vasodilation/increased vascular permeability review table
slide 13
after _____ amount of days does leukocyte infiltration happens/changes?
1 day: edema 2 days: neutrophils 3 days: monocytes, macrophages
what occurs with chronic left side of heart pump congestion?
RBC ruptures = iron = stains with prussian blue
what does the liver look like for right side heart pump congestion?
nutmeg liver, sinusoids liver
what cells define a granuloma?
multi-nucleated giant cells
fibrinous inflammation is cell ____ and protein _____
cell poor, protein rich
what are etiologies of chronic inflammation?
persistent infections: can't kill (TB), unresolved acute inflammation, viral/parasitic infections hypersensitivity immune rxs: allergy, asthma exogenous/endogenous toxic agents: silica, cholesterol
fibrinous inflammation histology
"butter on bread" eosinophilic meshwork with only few cells on the surface
what is something that someone with left side of heart pump congestion cannot do? why?
cannot lie flat due to fluid overload
what are the most common etiologies for acute inflammation?
bacteria and cell death
what is the infiltrative pattern of chronic inflammation?
macrophages: big nucleus lymphocytes: dec cytoplasm plasma cells: big lymphocytes eosinophils: red granules (raspberries with sunglasses)
what are the different types of granulomatous inflammation?
∙ noncaseating = necrosis ∙ caseating = TB
what are morphologic types of acute inflammation?
serous fluid fibrinous purulent/suppurative/pus pseudomembranous ulcers
Section 3
(42 cards)