Tobias Chapter 1: Inflammatory Response

Front 1

What are the cardinal macroscopic signs of acute inflammation

Back 1

Rubor (redness / erythema), calor (heat), dolor (pain), tumor (swelling / edema), loss of function

Front 2

What are the major responses in acute inflammation

Back 2

- Vasodilation (after an initial vasoconstriction to achieve hemostasis) with lymphatic proliferation
- Increased vascular permeability and loss of serum protein -> edema
- Vascular stasis (congestion) -> increased WBC margination
- Leukocyte extravsation

Front 3

What are the steps of WBC extravasation

Back 3

Blood stasis -> rolling of WBC on endothelial wall / margination -> weak endothelial adhesion via selectins -> integrin activation by chemokines -> WBC adhesion -> diapedesis through interendothelial junction -> chemokine gradiant to site of injury

Front 4

What is the first migratory cell to arrive at and take a role in acute inflammation

Back 4

Neutrophils. Local killing and degradation of bacterial macromolecules via phagocytosis and release of superoxide radicals and produce several pro-inflammatory cytokines.

Front 5

What are the major pro-inflammatory cytokines created by neutrophils

Back 5

IL-1a, IL-b, IL-6, and TNF-a.

Front 6

What is the role of macrophages in acute inflammation

Back 6

Early recognition of inflammatory stimuli; early source of pro-inflammatory cytokines; clean up of necrotic pmns; Release of anti-inflammatory mediators; debridement (phagocytosis, dissolution of ECM); stimulate fibroblasts later on

Front 7

What are the major pro-inflammatory cytokines created by macrophages

Back 7

Pro-inflammatory cytokines (IL- b, IL-6 and TNF-a), PGs and GFs (PDGF, TGF-a)

Front 8

Is Interleukin-10 pro or anti-inflammatory

Back 8

Anti-inflammatory
Depresses production pro-inflammatory cytokines and chemokines including TNF-A, IL-1, IL-6 & Il-8, by inhibiting translocation of nuclear factor kB (NF-kB) and promoting degradation of mRNA.

Front 9

How long does it take for neutrophils to be replaced by macrophages at a site of inflammation

Back 9

24-48 hours.. Macrophages phagocytose apoptotic neutrophils in tissue.

Front 10

What function do lymphocytes play in inflammation

Back 10

Mostly acquired immunity but also early protective inflammatory responses (cell med immunity).
Helper (CD 4+) & cytotoxic (CD8 +) T cells major components cell-med imm. CD4+-> Th-1 &Th-2.

Front 11

What are the different functions of Th-1 and Th-2 cells

Back 11

Under influence IFN-g & IL-2, T-cells -> Th-1 cells with characteristic cytokine profile (IFN-g and IL-2). IFN-g -> production of IG-G (IGg)2a by B-cells.
Th-2 function in helminthic infections and allergic reactions. Th-2 produce IL-2, IL-5, Il-10, IL-13. Overall this causes suppression of innate macrophage function, an increase in IgG1 and IgE production and eosinophil activation.

Front 12

What function do Mast cells have in inflammation

Back 12

Ubiquitously distributed in all organs and degranulate in response to physical trauma, complement factors, microbial products or neuropeptides. Overall, degranulation enhances the local inflammatory response.

Front 13

What is the difference between pathogen associated molecular pathogens (PAMPS) and danger associated molecular pathogens (DAMPS)

Back 13

PAMPS: highly conserved microbial molecules, recognized as foreign by the host. Includes LPS, lipotechoic acid, peptidoglycan and microbial oligonucleoetodes.
DAMPS: endogenous molecules such as fibrinogen, which alert the body to cellular damage initiated by infectious or non-infectious agents.
Both PAMPS and DAMPS signal the immune system by interacting with cell surface receptors
See Figure 1-2, Page 4.

Front 14

What are toll-like receptors

Back 14

Transmembrane proteins that initiate intracellular signaling cascades to activate nuclear factor-kB and result in altered gene transcription. Bind to ligands on PAMPs and DAMPs

Front 15

What are tachykinins

Back 15

Neuropeptides released from peripheral neurons after stimulation or trauma of sensory neurons. E.g. substance P

Front 16

Name the two major vasoactive amines in inflammation.

Back 16

Histamine -> mast cells

Serotonin -> mast cells, basophils, neuroendocrine cells

Front 17

What are cytokines

Back 17

Diverse group small soluble proteins that act as intercellular messengers during physiologic processes.
Pro-inflammatory cytokines (e.g. TNF-a, IL-1b, IL-6 ) increase innate immune response
Anti-inflammatory cytokines (e.g. IL-10, IL-1ra) attenuate the responses.

Front 18

What is the role of Tumor Necrosis Factor-a (TNF-a) in inflammation

Back 18

1st pro-inflammatory mediator - Initiates production of pro-inflammatory cytokines (i.e. IL-6), reactive O2 intermediates, chemotaxins & endothelial adhesion molecules -> invasion of cells at site of inflammation
Also activates NK cells, proliferation of cytotoxic T-cells and T-cell apoptosis

Front 19

What is the role of interleukin-1 (IL-1) in early inflammation

Back 19

One of the 1st pro-inflammatory mediators -- Initiates cellular signaling pathways. Similar to TNF-a

Front 20

What is the role of IL-6 in inflammation

Back 20

Initiation of hepatic synthesis of APPs and influences the proliferation of lymphocytes.
Also has a compensatory down-regulation effect
Increases in plasma proportionately with duration and severity of the condition. = can be used as prognostic and diagnostic indicator

Front 21

What are chemokines

Back 21

Chemotactic cytokines responsible for attraction of cells across concentration gradient.
Peak shortly after TNF-a and IL-1, along with IL-6.
CXC and CC chemotaxins most involved in pro-inflammatory response to trauma of infection.
CXCL8 (aka IL-8) attracts neutrophils and promotes production of other inflammatory mediators.

Front 22

What is the role of IL-10 in inflammation

Back 22

Produced primarily by CD4+ and Th-2 cells, monocytes and B-cells.
Depresses production of TNF-a, IL-1, IL-6 & Il-8, by inhibiting translocation of nuclear factor kB (NF-kB) and promoting degradation of mRNA.
Down regulates Th-1 cytokines, promotes shedding of TNF receptors into systemic circulation and inhibits Ag presentation by macrophages and dendritic cells.

Front 23

What are Eicosanoids

Back 23

Lipid mediators that are rapidly created from membrane phospholipids and exert effects locally.
Their precursor is the fatty acid, arachadonic acid (AA).

Front 24

How do glucocorticoids suppress inflammation

Back 24

*Decrease phospholipase A2 expression required for release of AA.
*Upregulate genes encoding anti-inflammatory proteins that inhibit AA release from PL.

Front 25

What function do PGs play in inflammation

Back 25

*Chemotaxins for leukocytes
*Induce vasodilation
*Contribute to the pathogenesis of pain and fever.
*Produced in COX pathways, where AA metabolism is catalyzed by COX-1 (constitutively expressed) and COX-2 (induced: trauma, growth factors, pro-inflammatory cytokines, other mediators).

Front 26

What is thought about selective COX inhibition

Back 26

Inhibition of COX-1 causes gastric ulceration and should be spared
inhibition of COX-2 alone may increase risk of cardiovascular and cerebellar vascular event -> no evidence yet of this in dogs so COX-2 selective agents are still a good option

Front 27

Leukotrienes are produced in the LOX pathway prostaglandins are produced in the COX pathway-true or false

Back 27

True, COX inhibitors are used to reduce the production of the PGs.

Front 28

What function do leukotrienes play in inflammation

Back 28

Pro-inflammatory mediators of leukocyte trafficking and blood flow. Secreted by leukocytes; peptidoleukotrienes provoke vasoconstriction, bronchoconstriction, and increased venule permeability.
e.g. LTB4 potent chemotactic agent and activator of neutrophils, potentiating extravasation, degranulation and production of free radicals.

Front 29

What are pro resolution eicosanoids

Back 29

They halt neutrophil infiltration, activate macrophage phagocytosis, increase clearance of phagocytes, and stimulate expression of molecules involved in antimicrobial defense
lipoxins -> increased by aspirin; attenuate the effect of leukotrienes
resolvins and protectins -> derived from Omega – 3 fatty acids and promote resolution of inflammation

Front 30

Where is platelet activating factor produced

Back 30

It is produced by numerous cells and stimulated by multiple inflammatory mediators

Front 31

There are many effects of platelet activating factor. Name three

Back 31

*Stimulation of arachidonic acid release and increase of eicosanoid production

*direct pro-inflammatory effects on neutrophils: enhanced neutrophil adhesiveness, enhance neutrophil motility, primes neutrophils for degranulation.

*Aggregate and degranulate platelets.

*Degranulation and production of reactive oxygen species by eosinophils

*increased vascular permeability.

*Bronchoconstriction.

*Pulmonary vasoconstriction

Front 32

What are the effects of reactive oxygen species

Back 32

*Antibacterial defense (used in phagocytic oxidative burst), *intracellular signaling (induction of pro-inflammatory cytokine synthesis)

*pathologic tissue damage (reperfusion injury, pancreatitis, surgical trauma, abdominal adhesions)

Front 33

Is Nitric Oxide (NO) anti-inflammatory or pro-inflammatory

Back 33

BOTH. Depends on concentration and mode of production. Produced by Nitric Oxide synthase.
constitutive = protective
Basal levels protective anti-inflammatory effect on GIT, constitutive NO suppresses action of NF-kB, a transcription factor necessary for the expression of inducible NO synthase.
Constitutive + out-of-control inducible = damaging
High levels damaging effects on local tissues, perpetuate inflammatory cycle due to reactive nitrogen species (RNS) derived from NO

Front 34

What is the primary physiologic function of NO

Back 34

Regulation of vascular tone & immune defense
Produces vasodilation by diffusing into smooth muscle cells and indirectly initiating intracellular signaling events, leading to smooth muscle relaxation.
See Figure 1-4 Pg 10.

Front 35

What function does CO play in inflammation

Back 35

Anti-inflammatory (impairs production, differentiation and activation of inflammatory cells, cytoprotective).

Front 36

What are negative acute phase proteins (APP)

Back 36

Proteins active in regulating hemostasis (albumin); decrease by at least 25% during inflammatory response

Front 37

What are positive acute phase proteins

Back 37

Role is to enhance protective host responses by minimizing tissue damage and enhancing repair processes.
Increase in plasma concentration by at least 25% during an inflammatory response.
Increase within hours and peak within 24-48 hours and, elevated as long as inflammatory stimulus
maybe useful as diagnostic or prognostic markers
e.g. C-reactive protein, Serum Amyloid A, Serum Amyloid P, Complement Proteins, coagulation factors

Front 38

What are the three routes of complement activation

Back 38

*Classical – Immune complexes
*Lectin – Lectin proteins + pathogen surface carbohydrates
*Alternative – Contact with foreign microbes
*Result of each is a membrane attack complex -> cell lysis

Front 39

Whatare the parameters of systemic inflammatory response syndrome (SIRS) in humans?What does it indicate? Is this the same in dogs?

Back 39

–Aberrations in body temperature, heart rate, blood pressure, respiration, whiteblood cell counts. – Diagnosis of sepsis when accompanied by nidus of infection. – Not really – too much variation in physiologic normalsragmenti`BC9

Front 40

What is MODS

Back 40

Progressive dysfunction ≥ 2 organ systems not involved in initial insult; probably secondary to major self-destructive information
increasing incidence due to protracted patient survival

Front 41

What organ is believed to be the mediator driving MODS in the dog

Back 41

GIT; reperfusion-mediated oxidative injury to gut epithelium = major source of mediators driving dysfunction of distant organs.