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CMOD Week 2 > Inflammation 2 > Flashcards

Inflammation 2 Flashcards

1
Q

What are the two ways in which cell-derived mediators of acute inflammation are made?

A

they are preformed in granules or synthesized in response to a stimulus

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2
Q

How do cell-derived mediators of acute inflammation work?

A

most mediators act by binding to specific receptors on different target cells

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3
Q

T or F. The actions of most mediators are loosely regulated and long-lived.

A

F. They are tightly regulated and short-lived

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4
Q

What are two examples of preformed mediators in secretory granules?

A

1) Histamine
2) Serotonin

termed ‘vasoactive’ amines

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5
Q

What cells make histamine?

A

mast cells next to vessels and circulating basophils and platelets

In humans, histamine causes arteriolar dilation and rapidly increases vascular permeability by inducing venular endothelial contraction and formation of interendothelial gaps. Soon after its release, histamine is inactivated by histaminase.

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6
Q

What cells make serotonin?

A

platelets. It induces vasoconstriction during clotting.

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7
Q

What are some examples of newly synthesized mediators?

A

prostaglandins, leukotrienes, platelet-activating factor, ROS, NO, cytokines

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8
Q

New synthesized mediators of acute inflammation are mainly made by which kids of cells?

A

leukocytes. These AA (arachidonic acid)-derived mediators act locally at the site of generation and then decay sponta- neously or are enzymatically destroyed.

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9
Q

One of the first events in acute inflammation is vasodilation of blood vessels to allow leukocyte diapedesis. Which cell-derived mediators aid in causing this to occur?

A

Histamine (increases permeabiltiy and causes dilation) and Serotonin (released during platelet aggregation)

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10
Q

Study Arachidonic Acid pathway

A

Study Arachidonic Acid pathway.

AA is released from these phospholipids through the action of cellular phospholipases that have been activated by mechanical, chemical, or physical stimuli, or by inflamma- tory mediators such as C5a.

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11
Q

Which arachidonic acid metabolites cause Vasodilation?

A 
Prostaglandins PGI2 (prostacyclin),
PGE1 , PGE2 , PGD2

Endothelial cells, on the other hand, lack throm- boxane synthase but contain prostacyclin synthase, which is responsible for the formation of PGI2, a vasodilator and a potent inhibitor of platelet aggregation.

PGD2 is the major metabolite of the cyclooxygenase pathway in mast cells; along with PGE2 and PGF2α (which are more widely distributed), it causes vasodilation and potentiates edema formation.

The prostaglandins also contribute to the pain and fever that accompany inflammation; PGE2 augments pain sensitivity to a variety of other stimuli and interacts with cytokines to cause fever.

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12
Q

Which arachidonic acid metabolites cause Vasoconstriction?

A

Thromboxane A2 ,
leukotrienes C4 ,D4 , E4

platelets contain the enzyme thromboxane synthase, and hence TXA2, a potent platelet-aggregating agent and vasocon- strictor, is the major prostaglandin produced in these cells.

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13
Q

Which leukotriene metabolites cause Increased vascular permeability?

A

Leukotrienes C4, D4, E4 (produced mainly in mast cells and cause bronchoconstriction and increased vascular permeability.

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14
Q

Which arachidonic acid metabolites cause Chemotaxis, leukocyte recruitment/adhesion?

A

Leukotriene B4 , HETE

Once leukocytes enter tissues, they gradually change their major lipoxygenase-derived AA products from leukotrienes to anti-inflammatory mediators called lipoxins, which inhibit neutrophil chemotaxis and adhesion to endothelium and thus serve as endogenous antagonists of leukotrienes.

Platelets alone cannot synthesize lipoxins A4 and B4 (LXA4 and LXB4), but they can form these media- tors from an intermediate derived from adjacent neutro- phils, by a transcellular biosynthetic pathway.

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15
Q

Platelet-Activating Factor is derived from what?

A

phospholipids (like AA).

Originally named for its ability to aggregate platelets and cause their degranulation, platelet-activating factor (PAF) is another phospholipid-derived mediator with a broad spectrum of inflammatory effects.

it is generated from the membrane phospholipids of neutrophils, monocytes, basophils, endo- thelial cells, and platelets (and other cells) by the action of phospholipase A2.

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16
Q

How does PAF work?

A

PAF acts directly on target cells through the effects of a specific G protein–coupled receptor

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17
Q

What does PAF cause?

A
  • Stimulates platelets to aggregate and causes their degranulation
  • Bronchoconstriction (potent)
  • is 100 to 1000 times more potent than histamine in inducing vasodilation and increased vascular permeability.
  • can elicit many of the reactions of inflammation, including enhanced leukocyte adhesion, chemotaxis, leukocyte degranulation, and the respiratory burst.
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18
Q

What are the major cytokines in acute inflammation?

A

TNF-alpha (tumor necrosis factor), IL-1 (does some chronic too), IL-6, and a group of chemoattractant cytokines called chemokines.

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19
Q

What are the major cytokines in Chronic inflammation?

A

include interferon-γ (IFN-γ) and IL-12

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20
Q

TNF-alpha and IL-1 are mostly produced by which cells?

A

ACTIVATED macrophages (some mast cells and endothelial cells)

As mentioned earlier, IL-1 is also the cytokine induced by activation of the inflammasome.

these stimulate adhesion expression on endothelial surfaces

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21
Q

T or F. TNF-alpha decreases thrombogenicity

A

F. it increases the risk of having a clot

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22
Q

IL-1 activates which cells?

A

fibroblasts resulting in increased proliferation and production of ECM. Thus involved in chronic inflammation

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23
Q

Why do people that are acutely ill have an increased erythrocyte sedimentation rate?

A

IL-6 causes production of fibrinogen in the liver that causes red cells to ‘stack’

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24
Q

What is an example of a negative acute-phase reactant (i.e. levels drops in acute illness)?

A

albumin

25
Q

What PATHOGENIC effects can TNF-a have on the heart and endothelial cells?

A

thrombos formation risk

26
Q

What PATHOGENIC effects can TNF-a AND IL-1 have on skeletal muscle?

A

they are both involved in insulin resistance

27
Q

Plasma protein derived inflammation mediators mainly come from which organ?

A

the liver

28
Q

Review coagulation pathway

A

Review coagulation pathway

29
Q

Deficiency in C1INH leads to what disease?

A

HANE, hereditary angioneuotic edema, in which excessive production of kinins secondary to complement activation results in edema of multiple tissues including the larynx

30
Q

Paroxysmal nocturnal hemoglobinuria is caused by what?

A

Genetic defect in the pigA gene resulting in lack of anchoring lipid of DAF and CD59 which results complement mediated lysis of red cells

Pee blood at night due to pH increase due to slower breathing

31
Q

What causes hemolytic uremic syndrome?

A

deficiency in Factor H leading to kidney disease, as well as spontaneous vascular permeability in macular degeneration of the eye

or caused by Sheika toxin

32
Q

Chronic inflammation is characterized by:

A
  • Infiltration with mononuclear cells
  • Tissue destruction
  • Repair, angiogenesis and fibrosis

Caused by:

  • Persistent infections by microbes that are difficult to eradicate. These include Mycobacterium tuberculosis, Treponema pallidum (causative agent of Syphillis)
  • Immune-mediated inflammatory diseases (hypersensitivity diseases).
  • Prolonged exposure to potentially toxic agents
33
Q

What is the main cell in chronic inflammation?

A

macrophages. Under the influence of adhesion molecules and chemokines, they migrate to a site of injury within 24 to 48 hours after the onset of acute

When monocytes reach the extravascular tissue, they undergo transformation into macrophages, which are somewhat larger and have a longer lifespan and a greater capacity for phagocytosis than do blood monocytes.

34
Q

What is the lifetime of a macrophage?

A

~1 day

35
Q

What are the two ways in which macrophages can be activated and what are each used for?

A

1) classic- is induced by microbial products such as endotoxin, by T cell–derived signals, importantly the cytokine IFN-γ. lassically activated macrophages produce lysosomal enzymes, NO, and ROS, all of which enhance their ability to kill ingested organisms, and secrete cytokines that stimulate inflammation. These macrophages are important in host defense against ingested microbes and in many chronic inflammatory reactions.
2) alternative- induced by cytokines other than IFN-γ, such as IL-4 and IL-13, produced by T lymphocytes and other cells, including mast cells and eosinophils. Alternatively activated macrophages are not actively microbicidal; instead, their principal role is in tissue repair. They secrete growth factors that promote angiogenesis, activate fibroblasts and stimulate collagen synthesis. It may be that in response to most injurious stimuli, macrophages are initially activated by the clas- sical pathway, designed to destroy the offending agents, and this is followed by alternative activation, which ini- tiates tissue repair.

36
Q

What would classically activate macrophages?

A

IFN-gamma from T cells and microbes

37
Q

What do classically activated macrophages produce?

A

1) ROS, NO, lysozymes- kill pathogens

2) Il-2, IL-12, IL-23, chemokines- cause inflammation

38
Q

What would alternatively activate macrophages?

A

IL-13 and IL-4

39
Q

What do alternatively activated macrophages produce?

A

1) TFG-beta- tissue repair, fibrosis

2) IL-10- anti-inflammatory effects

40
Q

Macrophages have several critical roles in host defense and the inflammatory response:

A
  • ingest and eliminate microbes and dead tissues. (classical)
  • initiate the process of tissue repair. (alternative)
  • secrete mediators of inflammation (classical)
  • display antigens to T lymphocytes and respond to signals from T cells, essential for cell-mediated immune responses.

After the initiating stimulus is eliminated and the inflam- matory reaction abates, macrophages eventually die or wander off into lymphatics. In chronic inflammatory sites, however, macrophage accumulation persists, because of continued recruitment from the blood and local prolifera- tion. IFN-γ can also induce macrophages to fuse into large, multinucleate giant cells.

41
Q

T or F. Lymphocytes are mobilized in the setting of any specific immune stimulus (infections) as well as non–immune-mediated inflammation (trauma)

A

T. Also, autoimmune and other chronic inflammatory diseases

By virtue of cytokine secretion, CD4+ T lymphocytes promote inflammation and influence the nature of the inflammatory reac- tion.

42
Q

TH1 cells produce the cytokine ___, which activates macrophages in the classical pathway.

A

IFN-γ

43
Q

TH2 cells secrete IL-4, IL-5, and IL-13, which do what?

A

recruit and activate eosinophils and are responsible for the alternative pathway of macrophage activation.

44
Q

How do Cox inhibitors work?

A

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, inhibit cyclooxygenase activity, thereby blocking all prostaglandin synthesis (hence their efficacy in treating pain and fever). There are two forms of the cyclooxygenase enzyme, COX-1 and COX-2. COX-1 is produced in response to inflamma- tory stimuli and also is constitutively expressed in most tissues, where it stimulates the production of prostaglan- dins that serve a homeostatic function (e.g., fluid and electrolyte balance in the kidneys, cytoprotection in the gastrointestinal tract). By contrast, COX-2 is induced by inflammatory stimuli but it is absent from most normal tissues. Therefore, COX-2 inhibitors have been developed with the expectation that they will inhibit harmful inflam- mation but will not block the protective effects of constitutively produced prostaglandins. These distinctions between the roles of the two cyclooxygenases are not absolute, however.

45
Q

Why would COX-2 inhibitors cause risk for cardiovascular clotting

A

Furthermore, COX-2 inhibitors may increase the risk for cardiovascular and cerebrovascular events, possi- bly because they impair endothelial cell production of prostacyclin (PGI2), an inhibitor of platelet aggregation, but leave intact the COX-1–mediated production by platelets of TXA2, a mediator of platelet aggregation.

46
Q

What do glucocorticoids do?

A

Glucocorticoids, which are powerful anti-inflammatory agents, act in part by inhibiting the activity of phospholipase A2 and thus the release of AA from membrane lipids.

47
Q

What is Hageman factor?

A

(also known as factor XII of the intrinsic coagulation cascade) is a protein synthesized by the liver that circulates in an inactive form until it encounters collagen, basement membrane, or activated platelets (e.g., at a site of endothelial injury).

48
Q

Activated Hageman factor (factor XIIa) initiates four systems that may contribute to the inflammatory response:

A

(1) the kinin system, producing vasoactive kinins;
(2) the clotting system, inducing the activation of thrombin, fibrinopeptides, and factor X, all with inflammatory properties;
(3) the fibrinolytic system, producing plasmin and inactivating thrombin; and
(4) the complement system, producing the anaphylatoxins C3a and C5a

49
Q

Main points of the Kinin system.

A

Kinin system activation leads ultimately to the formation of bradykinin from its circulating precursor, high-molecular-weight kininogen (HMWK).

Like histamine, bradykinin causes increased vascular permeability, arteriolar dilation, and bronchial smooth muscle contraction. It also causes pain when injected into the skin. The actions of bradykinin are short-lived because it is rapidly degraded by kininases present in plasma and tissues.

50
Q

What intermediate in the kinin cascade with chemotactic activity is also a potent activator of Hageman factor?

A

kallikrein

51
Q

What happens in the clotting system?

A

the proteolytic cascade leads to activation of thrombin, which then cleaves circulating soluble fibrinogen to generate an insoluble fibrin clot. Factor Xa, an intermediate in the clotting cascade, causes increased vascular permeability and leukocyte emigration. Thrombin participates in inflammation by binding to protease-activated receptors that are expressed on platelets, endothelial cells, and many other cell types. Binding of thrombin to these receptors on endothelial cells leads to their activation and enhanced leukocyte adhesion.

In addition, thrombin generates fibrinopeptides (during fibrinogen cleavage) that increase vascular permeability and are chemotactic for leukocytes.

52
Q

How is the clotting system connected to the complement system?

A

Thrombin also cleaves C5 to generate C5a, thus linking coagulation with complement activation.

53
Q

T or F. As a rule, whenever clotting is initiated (e.g., by activated Hageman factor), the fibrinolytic system is also acti- vated concurrently

A

T. This mechanism serves to limit clotting by cleaving fibrin, thereby solubilizing the fibrin clot

54
Q

What molecules cleave plasminogen?

A

Plasminogen activator and Kallikrein. The resulting product, plasmin, is a multifunctional protease that cleaves fibrin and is therefore important in lysing clots.

55
Q

What do fibrin degradation products do?

A

increase vascular permeability

56
Q

How is the fibrinolytic pathway connected to the complement pathway?

A

plasmin cleaves the C3 complement protein, resulting in production of C3a and vasodilation and increased vas- cular permeability. Plasmin can also activate Hageman factor, thereby amplifying the entire set of responses.

57
Q

What is a main point about the functioning of mast cells?

A

When these antigens are subse- quently encountered, the IgE-coated mast cells are trig- gered to release histamines and AA metabolites that elicit the early vascular changes of acute inflammation. IgE- armed mast cells are central players in allergic reactions, including anaphylactic shock

58
Q

Granulomas can form under what three settings?

A
  • With persistent T-cell responses to certain microbes (such as Mycobacterium tuberculosis, T. pallidum, or fungi), in which T cell–derived cytokines are responsible for chronic macrophage activation. Tuberculosis is the proto- type of a granulomatous disease caused by infection and should always be excluded as the cause when granulomas are identified.
  • Granulomas may also develop in some immune- mediated inflammatory diseases, notably Crohn disease, which is one type of inflammatory bowel disease and an important cause of granulomatous inflammation in the United States.
  • They are also seen in a disease of unknown etiology called sarcoidosis, and they develop in response to rela- tively inert foreign bodies (e.g., suture or splinter), forming so-called foreign body granulomas.
59
Q

How is Fever produced?

A

Fever is produced in response to substances called pyrogens that act by stimulating pros- taglandin synthesis in the vascular and perivascular cells of the hypothalamus in response to IL-1 and TNF-a secretion

Bacterial products, such as lipopolysaccharide (LPS) (called exogenous pyrogens), stimulate leukocytes to release cytokines such as IL-1 and TNF (called endogenous pyrogens), which increase the levels of cyclooxygenases that convert AA into prostaglandins. In the hypothalamus the prostaglandins, especially PGE2, stimulate the production of neurotransmitters, which function to reset the temperature set point at a higher level. NSAIDs, including aspirin, reduce fever by inhibiting cyclooxygenase and thus blocking prosta- glandin synthesis. Although fever was recognized as a sign of infection hundreds of years ago, it is still not clear what the purpose of this reaction may be. An elevated body temperature has been shown to help amphibians ward off microbial infections, and it is assumed that fever does the same for mammals, although the mechanism is unknown

CMOD Week 2 (10 decks)

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