Inflammation Flashcards
Cyclooxygenase produces
PGI2, TxA2, PGD2, PGE2 (pain and fever)
What does PGI2 do? Where is it mostly made?
potent vasoconstrictor and inhibits platelet aggregation, and potentiates membrane permeability and chemotactic; endothelial cells
What does TxA2 (Thromoboxane) do? Where is mostly expressed?
potent platelet aggregator and vasoconstrictor, bronchoconstriction; platelets
What does PGD2 do?
major PG of mast cell, bronchoconstriction, vasodilation, increase vascular permeability and recuritment of eosinophils
What does PGF2alpha do?
uterine smooth muscle contraction, bronchoconstriction, intiates parturition (labor)
What does PGE2 do?
Vasodilation, increase vaso permeability, pain and fever
What cells synthesize PG? what are they involved in?
mast cell, macrophage, enothelial cells; systemic inflammation
What is LTB4 for?
PMN chemotaxis and activation of PMN: so aggregation and adhesion, ad also generate reactive oxygen species
What us LTC4, LTD4, AND LTE4 for?
induce bronchoconstriction and vasoconstriction, increase vascular permeability in venules–more potent than histamine.
What is 5-HETE for and what produces it?
Chemotactic factor for PMNs and produced in PMNs
What is lipoxin production an example of?
As leukocytes and platelets need to make it together: trancellular biosythesis
What does lipoxin do?
inhibits leukocytes recruitment, neutrphil chemotaxisand adhesion to cell wall
What is endogenous negative regulators of Leukotriene?
Lipoxins
What inhibits PG synthesis?
Aspirin and NSAIDs
What do lipoxygenase inhibitors do?
diminish LT production–treats Asthma
What does corticosteroids do?
reduce transcription of COX-2, PLA2, and proinflam cytokines such as IL-1 and TNF
What favors the production of anti-inflammatory lipid mediators? (resolvins and protectins)
fish oil
Where is PAF derived from?
PM of neutrophils, monocytes, activated endothelial cells and basophils, and platelets
Where does PAF bind?
Bind to G-protein coupled receptor (PAFR) which is always expressed in endothelial cells, platelets, and leukocytes
What does PAF do?
Enchance platelet aggregation and degranulation, activates leukocytes–promoting adherence as well as ROS, lipid mediators and TNF-a and IL-6, motility, chemotaxis, invasion; also endothelial cells increase vasocular permeability and vasodilation–and stimulates production of eicosanoids and cytokines from platelets and other cells.
What do lipid mediators do? where are they stored?
Only potentiate the inflam response and they are not stored and only released in response to bradykinin and cytokines–which stimulate PKA2
What produces NO?
Endothelial cells, macrophages and some neurons
How is NO produced?
L-arginine, oxygen, NADPH by Nitric Oxide synthase
Types of NO
Neuronal, Inducible and endothliel
Neuronal NO (nNOS):
made in neurons, no role in inflam
Inducible NO(iNOS)
made by macrophage, PMN, endothelial cells when stimulated with IL-1, TNF and Interfeuron Gamma and bacterial endotoxin
Role of NO in phagocytic cells during inflam
Kill microbes through Free radical form
Endothelial NOS
made primarily in endothelial
Functions of NO
1) relaxes smooth muscles: dilation through cGMP
2) inhibits inflammation by reducing platelet agg. and inhibiting mast cell -induced inflam and leukocyte recruitment
3) antomicrobial: kills microbes through free radical in macro and neut.
What does histamine do?
increase vasopermiability, vasodilation, bronchoconstriction, eosinophils chemotaxis
What induces histamine production?
Leukocytes: Il-1 and Il-8
Physical: trauma, cold and heat
Allergy: IgE binding
Complement: anaphylatoxins (C3a and C5a)
Cell source of histamine?
Mostly mast cells, basophils and platelets
Plasma derived inflamm mediators
Synth in liver, end product of serine proteases, zymogen are activated in step wise manner, circulating in matrix of tissues
What do complement products do?
increase vasopermeability, chemotaxis, opsonization
How is classical complement pathway triggered?
fixing C1 to IgG or IgM bound to antigen
How is lectin complement pathway triggered?
plasma mannose binding protein binds to carbs on microbes and activates another complement molecule
How is alternate complement pathway triggered?
microbial surface molecules such as LPS, endotoxin in the absence of antibody
For which cell is C5a a chemotactic agent for?
monocytes, eosinophils, basophils, neutrophils
What pathway can C5a activate?
Lipoxygenase pathway in AA metabolism in neut and monocytes–release more mediators, and thrombins effect on endothelial cells
What do C5a and C3a do?
They are anaphylatoxins–stimulate mast cell to release histamine–increase vaso permeability and vasodilation
How does C3b work?
Coats microbes and Neut. and macro have CR1 which binds with C3b and phagocytoze the microbe
What does C5b do?
Make membrane attack complex with C6-9 on microbes, make the membrane permeable to water and ions–cell death and lysis
What are kinins?
Vasoactive peptides from plasma kininogen when cleaved by kallikrens
What does bradykinin do?
Increase vasopermeability, vasodilation, smooth muscle contraction (bronchi and uterus) and mediates pain
Which receptor does bradykinin bind to?
B1 and b2 G-coupled receptors in various cells
How is B1 receptor expression induced?
binding of cytokines: IL-1, TNF-a, IFN gamma
What does bradykinin binding with B1 and B2 receptor do?
endothelial cells activated and produce nO and prostaglandin synthesis which increases vasopermeability, vasodilation and constriction of non vascular smooth muscles in uterus and bronchi
What are the side effects if ACEi is taken for hypertension?
As bradykinin is not broken down, Edema due to vasopermeability and vasodilation, and persistant cough due to bronchoconstriction
What releases plasminogen activator?
endothelial cells, leukocytes, and other cells
What can plasmin do?
Primarily cleave fibrin, cleave C3 and generate fibrin split product that results from cleavage if fibrin–increase vascular permeability, activate XII to XIIa
What can presence of thrombin do to endothelial cells?
promote inflammation by inducing exp. of CAMs, cytokines, chemokines, prostaglandins, NO and platelet activating factor–these recruit leukocytes and support other events in inflam.
How does C-reactive protein affect macrophages?
activates synthesis of cytokines, and binds to Fc and acts as an opsonin.
How does C-reactive protein activate complement pathway?
Through classical and alternative pathway
How does C-reactive protein recognize altered self and foregin materials?
binding to cell walls of bacteria and fungi, damaged or dead cell
What can C-reactive protein level indicate? where is it produced?
non-specific marker of inflam; liver
Where is Serum amyloid A produced and what is it associated with?
Liver and with high density lipoprotein
How does SAA activate cells?
toll-like receptor binding
How does SAA effect neutrophils and mast cell?
Chemotactic agent
Which disease is SAA involved in?
Amyloid A-type amyloidosis and chronic inflam
What does mannose-binding lecti (MBL) do?
binds to mannose on bacteria and acts as an opsonin and activate complement via lectin binding pathway; crucial in resolution of infection
What does a-2-macroglobulin do?
inhibits proteases involved in coagulation and fibrinolysis
What are some protein that reduces Fe for bacteria?
Haptoglobin (binds Hb), ferritin (binds Fe), Hepcidin ( prevents Fe release from ferritin in macro and intestine) and Ceruloplasmin (oxidizes iron); some of them associated with anemia
What do a-1 anti-trypsin and a1chymotrypsin do?
downregulate inflammation
What does erythrocyte sedimentation rate show?
nonspecific test that measures presence of inflamm and acute phase response, tendency of blood to settle when there is more plasma fibrin, Ig. RBC have Rouleaux form, when value over 20mm/hr–inflammation
What are coagulation proteins involved in acute phase response?
prothrombin, vWF, fibrinigen, FVIII, plasminogen
Three phases of fever?
Initial: shivering, chills, rigors
Plateau phase: core body temp = set point
Defervecence: when body temp> set point
patient feels warm–> sweating
Positive aspect of fever?
enhance immune response and increase cell death to prevent viral replication
Negative aspect of fever?
Decrease cardiac output, decrease blood flow to brain (seizure and damage CNS), acidosis (increase repiratpru rate and o2 consumption and increase metabolic rate.
Which PG leads to sleepiness?
PGD2
What does Il-1 and TNF-a do in fever?
malaise and decrease appetite and sleepiness
When does neutrophils increase in peripheral tissues?
bacterial infection
When does Lymphocyte increase in peripheral tissues?
viral infection
When does esoinophils increase in peripheral tissues?
parasite infection, asthma, hay fever, autoimmune process
When does leukopenia happen?
Viral infection, rickettsia, protozoa, TB and cancer
Normal range of WBC? Neutrophils make up what percentage of WBC? Bands are precursur to what cells?
5,000-10,000, 57-63%, neutrophils–refer to bandemia when there are a lot of it
bacterial infections primarily in skin and mucosal surfaces, omphalitis and delayed separation of umbilical chord; absence of pus formation at site of infection, gingaivits and periodontits, leukocytosis and neutrophils predominate
Leukocyte Adhesion deficiency I
Mode of transmission of LADI and what it is defective in?
Aut recessive, integrins of Leukocyte
Lab for LAD1
Neutrophils, but lack CD18 ells and mut analysis
Treatment of LAD1
antibiotics and BMT (severe LAD1)
What is defective in LADII?
specific golgi GDP-fucose transporter that leads to absence in fucosyl moieties and absence of selectin ligan on leukocyte surface–defective rolling
What is defective in LADIII?
Integrin activation
What mut leads to Chronic granulomatous disease
NADPH Oxidase–so lack of respiratory bursts as no ROS
How is CGD diagnosed?
Neutrophils function test
CGD common sites of infection?
skin, lung, lymph nodes, and liver and patients have normal response to viral infection
Which bacterial infection is common in CGD
catalse producing staphylococcus aureus and aspergillus (with minimal fever and lower leukocytosis)
How to diagnose CGD effectively?
Tissue biopsy: look for granulomata in CGD
Oxidative bursts test: Nitroblue tetrazolium test (NBT)
Treatment of CGD?
antibiotics and antifungal prophylaxis, INF-gamma or bone marrow transplant
Sx: 70% x-linked, fungal and bacterial infection, granuloma formation, defects in phagocytes NADPH oxidase?
CGD
Fluid encountered in pleural or pericardial effusions, erythematous vesicles and autoimmune or viral in etiology, yellowish, no mononuclear cell and little protein
Serous inflam–transudate
Where does serous fluid accumulate?
Between epidemris and dermis
Irrefular surface with fibrinous inflammation in heart or abdominal lining; meshwork of fibers
fibrinous inflammation
Days of infiltration of leukocytes:
Hours: edema, 1 day: neutrophils and Day 2: monocytes and macrophages
Where can you see suppurative inflammation:
acute bronchopneumonia (exudate) amd typically bacterial and has neutrophils (streptoccoci pyogenes, pneumoniae, e coli and meningitidis, and gonorrhoeae).
Cellulitis: acute inflammation of skin
bacterial: staphylococcus and streptococcus, secondary to trauma or surgery, travels along between dermis and subcut
Sx: fever, headache, nausea, vomiting, neck stiff, photophobia, and confusion
Purulent leptomeningitis
Charactertistics lab finding of Purulent leptomeningitis
increase in pressure, increase in proyein WBC, and decrease glucose vs serum, (and bacteria and PMNs)
Pulmonary abscess?
walled off with fibrin wall, etiology is bacterial (staph and strep) and some fungi
Location of pseudomembranous inflammation? Exudate involved?
colon and pharynx, yes, mushroom shaped , yellowish-gray, plaque like
Where is ulcer common and what happens?
skin, GI and urinary bladder, and eroding epithelial cells due to trauma, toxins and ischemia
Common etiologies of chronic inflammation?
persistent inflammation, hypersenstive immune response, exogenous (silica) and endogenous (cholestrol) toxic agents
Features of chronic inflam?
collection of chronic inflam cells (lympp ad macro) and parenchymal destruction –organ function loss
Viral infection–almost always involve chronic inflam
Types of chronic inflam?
Inflitritive; thyroid and prostate
Granulomatous
Noncaseating Granulomatous etiology
Foregin body, fungus, parasite and immune and most common
caseating Granulomatous etiology
TB and Bartonella henselae, seen in chest on radiographs
necrotizing Granulomatous etiology
fungus and immune
Granulomatous image looks like
multinucleated cells and peripheral nuclei
example of non caseating granulomas
sarcoidosis, autoimmune disorders
