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110 Cards in this Set
- Front
- Back
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What is the typical sequence of an inflammatory response? (hint: the 5 R's) |
1. offending agent recognized by host molecules/cells 2.leukocytes recruited from circulation 3.leukocytes/proteins activated to remove offending agent. 4. reaction is regulated and terminated 5. damaged tissue is repaired |
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what is rubor, tumor, calor, dolor, and functio laesa |
redness, swelling, heat, pain, and loss of function. classic signs of inflamation |
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what is the most common and medically important cause of inflammation |
infection |
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what are the common causes of inflammation |
infections, presence of foreign bodies, tissue necrosis, and immune reactions (hpersensitivity) |
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what is a common family of receptors that recognize microbe? what does activation of these receptors induce |
Toll like receptors (TLRs). Activation will trigger production of inflammatory mediators |
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what are the 3 major components of acute inflammation |
1. dilation of small vessels 2. increased permiability of those vessels 3. emegration of leukocytes from circulation to focus of injury and activation at the site of injury |
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what is the escape of fluid, protein and blood cells from vascular system into interstitium called? |
exudation |
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what is an exudate |
extravascular fluid with a high protein concentration and cellular debris |
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what is a transudate |
fluid wth low protein content, little cellular material. |
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what does presence of exudate, transudate imply about the tissue? |
exudate implies increased vascular permeability
transudate implies that there is a osmotic or hydrostatic imbalance but not an increase in permeability |
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what is edema |
excess fluid in serous cavities or interstitial tissue (can be exudate or transudate) |
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what is pus |
an inflammatory exudate rich in dead leukocytes and cellular debris |
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what is the primary mediator of increased VSM dilation in acute inflammation |
histamine |
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what is stasis? How does it develop? |
increased permeability in endothelium concentrates red cells and causes vascular congestion, erythemia and heat associated with acute inflammation |
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what is the most common mechanism of vascular leakage in inflammation? what mediates it? |
contraction of endothelial cells.
it is elicited by histamine, bradykinin, leukotrienes |
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what is a common mechanism of endothelial leakage associated with severe injuries and burns |
direct endothelial injury |
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what is a secondary inflammation of lymph nodes called |
lymphangitis |
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what are the mediators of leukocyte recruitment |
chemokines (adhesion molecules and cytokines) |
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what are the 3 phases of leukocyte recruitment |
1. lumen: margination, rolling, adhesion to endothelium 2.migration through endothelium and vessel wall 3.migration to chemotactic attractant |
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how does the process of margination occur |
slowed blood flow and stasis caused by early inflammatory mediators displaces leukocytes peripherally along epithelium |
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what is the role of E, L, and P selectin in leukocyte adhesion |
the selectins mediate initial rolling reactions that slow down leukocytes (rolling) |
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what activates selectins? |
Tissue macrophages, mast cells and endothelial cells secrete cytokines (TNF, IL-1, chemokines) in response to injury. These cause increased expresion for E-selectin (on endothelium). Histamine and thrombin will induce surface expression of P-selectin on platlets |
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what are the integrins? |
VCAM-1 , ICAM-1 are most common, mediate firm binding of leukocytes to the endothelium at inflammation site |
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what prevents leukocytes from binding to integrins in normal state? |
normally leukocytes express integrins in a low affinity state. chemokines that bind and activate leukocytes during rolling increase expression of integrin ligands |
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what common function do cytokines (chemokines), compliment (c5a), AA metabolites (LTB4) |
they are all active chemotaxic agents |
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what are the intercellular mechanisms of chemotaxis |
chemotactic agents bind to GPCRs and activate second messangers, increase Ca++, and downstream messangers, resulting in extension of filopodia (due to actin polymerization at leading edge) toward stronger gradient |
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what predominates a leukocyte infiltrate in the first 6-24 hours? |
neutrophils |
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what predominantes a leukocyte infilttate from 24-48 hours |
monocyte/macrophages |
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what are 3 fundamental steps in phagocytosis |
1.recognition and attachment 2.engulfment 3.killing/degradation |
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how is killing of microbes accomplished in phagocytosis? |
by reactive oxygen specias and reactive nitrogen species (derived from NO) and lysozymes |
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what does NADPH oxidase do? when is it activated? |
oxidizes NADPH and by doing so reduces Oxygen to superoxide. This is a reactive oxygen free radical.
it is activated by cytokines, TLRs, phagocytic receptors, and other leukocyte activating factors |
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where are oxygen free radicals produced within neutrophils/mphages |
within the lysosome and phagolyosome |
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what is the function of superoxide dismutase, catalase, and glutathione peroxidase? |
these are antioxidant enzymes that protect against the deleterious effects of free radicals that are present in inflammatory reactions |
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what induces the formation of the form of nitrous oxide that is involved in microbial killing? |
cytokines (IFN-gamma)
NO reacts with the superoxide anion to form the free radical ONOO- (peroxynitrate) |
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what are NET's? |
neutrophil extracellular traps
these are fibrillar networks that contain antimicrobial substances to sites of infection and reduce spread of microbes |
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are the mechanisms by which leukocytes damage normal tissue different than the mechanisms they use to attack pathogens? |
no
inflammation often results in damage to tissues caused by reaction itself by the same factors that damage invading organisms and damaged tissue |
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what major role do TGF-B and IL-10 share? |
they are antiinflammatory cytokines that inhibit continuation of the inflammatory reaction |
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what are the most important mediators of acute inflammation |
vasoactive amines lipid products cytokines compliment |
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what major cell types produce mediators of inflamation |
setinal cells such as tissue macrophages, dendritic cells and mast cells |
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are mediators of inflammation long lasting or short lived? why? |
short lived.
you don't want inflammation to linger because of possible tissue damage. once offending agents are removed inflammation needs to stop quickly |
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what is the largest source of histamine for inflammation? what triggers its release? what does it do? |
mast cells
injury, antibody binding, anaphylaxatoxins from compliment system
histamine causes arteriolar dilation and increased permeability of venules
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where are prostaglandins and leukotrienes derived? |
arachadonic acid (AA) |
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what is the function of prostaglandins? |
vasoactivity, some cause vasoconstriction and some cause vasoconstriction. TXA2 promotes platelet aggregation
also they are involved in the pathogenesis of pain and fever |
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what does cyclooxygenase do? |
convert AA to prostaglandin G2 which is a precursor for vasoactive prostaglandins |
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what does 5-lipoxygenase do? |
involved in vascular smooth muscle reactions and also in leukocyte recruitment. LTB4 is potent chemotactic agent for neutrophils, it also activates them
other leukotrienes are involved in bronchospasm and are targeted by some pharmacologic agents (monteluklast) |
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what is the primary function of lipoxins |
inhibition of inflammation |
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what does COX-1 do? |
involved in inflammation and cytoprotection articularly in the GI tract
asprin which is a nonselective cox1/2 inhibitor can reduce clotting by reducing platelet activation |
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what does COX-2 do? |
acts only in inflammation, specific COX2 inhibitors are marked for treatment of inflammatiory disorders |
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what would a lipooxygenase inhibitor reduce levels of? what conditions could this help? |
inhibition of leukotrienes
useful in treatment of asthma |
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how do corticosteroids exert their antiinflammatory effects |
reduce COX-2 transcription and production of IL1 and TNF, as well as iNOS |
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what cells produce cytokines? |
activated lymphocytes, mphages, dendritic cells, also endothelial and epithelial cells |
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what is the role of TNF and IL-1 |
TNF and IL-1 recruit lymphocytes by promoting adhesion to endothelium and migration through vessels.
They activate endothelium by increasing P/E-selectin expression
They also activate fibroblasts and induce the fever |
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what is the systemic acute phase response |
induced by IL1 and TNF and the hallmark sign is fever
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antagonists of what cytokine have been remarkably effective in the treatment of chronic inflammatory diseases? |
TNF |
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what is the primary function of chemokines |
chemoattractants for certain types of leukocytes |
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what is the compliment system and what is its primary function? |
collection of soluble protein and membrane receptors. primary function is in host defense against microbes and in inflammatory reactions |
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what is the most abundant component of the compliment system? |
C3 |
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what is the classic pathway of compliment activation |
C3 cleavage triggered by binding of C1 to antibody that has combined with an antigen |
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what is the alternative pathway of compliment activation |
C3 cleavage triggered directly by a microbial product in absence of antibody |
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what is the lectin pathway of compliment activation? |
plasma lectin binds to carbohydrates on microbes and activates C1 |
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what effects does C3a induce, C3b? |
C3a and C5a are associated with inflammatory responses and histamine release. They are referred to as anaphalyxins and cause increase vasodilation/permeability. C5a is alsoc chemotactic and an activator of lipoxygenase (leukotriene production) |
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what are the effects of C3b? |
C3b activates the C5 and then acts as an opsonin for phagocytosis |
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what is the effect of the downstream compliment components (C6-9) |
formation of the Membrane attack complex which makes bacteria cells particularly neisseria osmotically unstable |
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What are the main functions of C1-INH, DAF, and CD59 |
C1 INH blocks activation of C1, deficit can cause hereditary angioedema
DAF prevents formation of C3 covertase
CD59 prevants formation of the MAC |
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What is PAF |
platelet activating factor
causes vaso/bronchoconstriction as well as increased venular permeability |
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what is the effect of bradykinin |
increased vascular permeability, smooth muscle contraction, dilation of blood vessels and pain
similar to histamine |
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dilation of small vessels, leukocyte accumulation, and fluid in extravascular tissues are hallmarks of what process? |
acute inflammation |
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what is serous inflammation? |
marked by exudation of cell-poor fluid, often resulting in edema and effusion. Seen when plasma protein count is lower or when there is reduced blood flow.
An example is a skin blister |
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what is fibrinous inflammation |
fibronious exudate occurs due to increased vascular leakage or large procoagulant stimulus. often reorganized to fibrous scar tissue |
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what is the hallmark of purulent inflammation and abcess |
pus, which is an exudate consisting of liquified debris of necrosis and leukocytes, particularly neutrophils |
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how does an ulcer form? |
inflammatory tissue is sloughed off and a local excavation remains.
example is a peptic ulcer |
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what are the 3 possible outcomes for an acute inflammatory reaction |
complete resolution
healing by fibrotic scarring
progression to chronic inflammation |
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what are the 3 primary causes of chronic inflammation |
persistant infections hypersensitivity (autoimmune) diseases prolonged exposure to potentially toxic agents |
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infiltration with mononuclear cells, tissue destruction, and attempts of healing are features of ____________________ |
chronic inflammation |
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what is the dominant cell type in chronic inflammation and how does it contribute? |
macrophages. they contribute by secreting cytokines and growth factors, also activate T cells and participate in phagocytosis |
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where are macrophages derived from during development, and in adult life |
in utero- yolk sack and fetal liver
in adult- bone marrow
monocytes circulate in blood (HL = 1 day) and enter tissues to become macrophages |
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what is the classical pathway of macrophage activation? |
induction of TLRs by bacterial products, by T cell signals (IFN-gamma)
these are M1 macrophages and work towards propagating inflammation and microbicidal and phagocytic processes |
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what is the alternative pathway of macrophage activation? |
induced by cytokines (not IFN-gamma) mostly IL4,IL13. These M2 macrophages inhibit classical pathway and secret TGFB which is helpful for tissue repair, fibrosis, and general anti-inflammatory effects. |
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how to CD4+ lymphocytes promote inflammation |
They secrete cytokines
TH1- IFN gamma, classic pathway for macrophage activation TH2- IL4,5,13, alternative pathway TH17- chemokine secretion |
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what activates eosinophils? |
IgE and parasitic infections
eosinophil granules have major basic protein which damages parasites |
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What type of inflammatory reaction characterized by collections of activated macrophages and T lymphocytes, and sometimes central necrosis? |
granulomatous inflammation |
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which type of inflammation is initiated by a large, relatively inert foreign body? |
foreign body granuloma. giant cells surround the foreign body which can be seen at the center of the granuloma |
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what type of inflammation is caused by difficult to eradicate microbes? |
immune granuloma |
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tuberculosis, leprosy, syphilis, cat-scratch disease, sarcoidosis, and chron disease are all associated with ______________ inflammation |
granulomatous
tuberculosis is the prototypical disease and upon identification of a granuloma must be excluded |
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describe the process of pyrogenesis |
bacterial products (particularly LPS) induce leukocyte release of IL1/TNF which increase AA conversion to prostaglandins (PGE2) which increase the set point temperature
NSAIDS lower fever by inhibiting COX and reducing prostaglandin production |
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CRP, fibrinogen and serum amyloid are well known _______________ proteins |
acute phase proteins
these are stimulated by cytokines and are produced in the liver, act as opsinins for compliment binding |
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fever, increased SAA, leukocytosis, increased pulse and blood pressure are all signs of |
acute phase response to inflammation |
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what is the difference between regeneration and scar formation |
regeneration is restoration of tissue architecture and function while scar formation is fibrous in nature and seen when normal architecture cannot be restored. |
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what are liable tissues? example? |
continuously dividing tissues such as epithelium of GI tract or hematopoetic cells of bone marrow, epithelia of skin.
these cells can readily regenerate as long as stem cell pool is partially reserved |
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what is a stable tissue |
these are quiescent cells that have minimal proliferative potential in the normal function but can regenerate to an extent after injury
ie: liver, kidney, pancreas. although liver has a high regenerative ability |
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permanent tissue |
cells are considered to be terminally differentiated cannot be regenerated, damage to these tissues results in fibrosis
ex: cardiac myocytes, neurons in CNS |
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what stimulates proliferation of damaged liable tissues? |
growth factors and interactions with the ECF |
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what triggers liver regeneration ? what is the process? |
cytokines and polypeptide growth factors.
priming from IL6 (kupffer cells) makes remaining cells competent
then growth factors (HPF,TGF-A) stimulate reentry into the cell cycle |
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what induces angiogenesis, the first step of scar formation? |
VEGF |
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what is granulation tissue |
fibroblast rich tissue which is pink, soft, loose and contains new thin and delicate capillaries. invades sites of inflammation progressively |
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what is remodeling |
maturation and reorganization of CT into a stable fibrous scar. |
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what are the basic steps associated with angiogenesis |
1.vasodilation (NO induced) and increased permeability (VEGF) 2. separation of pericytes and breakdown of BM 3. proliferation of leading tip 4. remodeling into capillary tubes 5. recruitment of periendothelial cells 6. termination of process |
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_______ is the most important cytokine for synthesis and deposition of connective tissue proteins |
TGF-beta
it is actively secreted by granulation tissue cells particularly those in M2 macrophages |
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what family of proteins are responsible for degrading collagens and other ECM components? |
matrix metalloproteases MMPs |
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what does the TGF-B MMP ratio help to control |
tendency for fibrotic buildup or breakdown |
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Effect on tissue repair/scar formation: infection diabetes nutritional status (vitamin C) glucocorticoids increased pressure/torsion poor perfusion nature of injured tissues |
infection- delays healing diabetes- abnormal wound healing nutritional status- vit C deficit inhibits collagen glucocorticoids- weaken scar formation (TGF-B inhibition) |
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Skin wound repair at 24 hours |
neutrophils migrating toward fibrin clot |
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skin wound repair at 24-48 hours |
epithelial cell migration has begun and is actively depositing basement membrane components |
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skin wound repair at 3 days |
macrophages have replaced neutrophils and granulation tissue has invaded the incision space. |
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skin wound repair at 5 days |
neovascularization has peaked , new vessels are leaky and edemous. fibroblast migration driven by chemokines,TNF,PDGF…etc… supplied by the macrophages |
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healing by first intention |
mechanism of skin repair when injury involves only the epithelial layer |
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healing by second intention |
occurs when tissue loss is more extensive ie: abscess, ulceration, infarct
involves a combo of regeneration and scarring |
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what is the percent strength of normal skin of a well formed scar |
roughly 70% |
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what can excessive formation of components of repair process result in |
hypertrophic scars, keloids |
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what can inadequate formation of granulation tissue/scar tissue lead to? |
dishisense
ulceration |
