Lecture 4 - Inflammation Flashcards by Leah Schmid

What are the proinflammatory things produced by sentinel cells as early response

-IL-1
-IL-6
-TNF-a
-HMGB-1 (DAMP)

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What are the effects of the proinflammatory cytokines/DAMP on the hypothalamus

fever, anorexia, sleepiness, depression

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What are the effects of the proinflammatory cytokines/DAMP on the liver?

increased synthesis of acute-phase proteins, iron sequestration

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Why is iron sequestration important

makes freely available iron unavailable to pathogens

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What are the effects of the proinflammatory cytokines/DAMP on bone marrow

increased WBC production

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What is inflammation

tissue reaction that rapidly delivers mediators of host defense to the sites of infection and tissue damage

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What 3 essential roles does inflammation play in combating infection

deliver additional effector molecules and cells to sites of inefection to augment the killing of invading microbes by the front-line macrophages
provide a physical barrier preventing the spread of infection
promote the repair of injured tissue

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What is the main purpose of inflammation

focus the immune response to the site of infection or injury

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Acute inflammatory response pathway:
1. ______ and other pro-inflammatory mediators are produced by cells in response to _____ and ____
2. These mediators increase the _________ of blood vessels, leading to entry of plasma proteins into the tissues and promote the movement of ____ from blood into tissue.
3. _____ destroy microbes, clear damged cells, promote more ____, and repair

cytokines, microbial products, damged host cells; permeability, leukocytes; leukocytes, inflammation

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What allows fluid, protein, and inflammatory cells to leave blood and enter tissue

vasodilation and increased vascular permeability

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What are the stages of neutrophil adhesion and emigration from blood vessels

rolling, adherance, emigration

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What is rolling mediated by

selectin (by PAMPs and DAMPs)

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What is adherance mediated by

integrin (by PAMPs and DAMPs)

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What does emigration lead to

chemotaxis

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What is an autosomal recessive immunodefinciency in Holstein calves

Bovine Leukocyte Adhesion Deficiency (BLAD)

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What is BLAD characterized by

recurrent bacterial infections
oral ulcerations, gingivitis, periodontis
chronic pneumonia
stunted growth
delayed wound healing
peripheral lymphadenopathy
persisten extreme neutrophilia

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What calves are affected by BLAD

holstein

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When do calves affected by BLAD die

2 and 7 months of age

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Why is BLAD so deadly

calves have large number of intravascular neutrophils that can’t exit blood vessels to reach infection site because there is a point mutation in the integrin gene, neutrophils cannot attach to vascular endothelial cells or emigrate from blood vessels

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What gene is mutated in calves with BLAD

integrin

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Inflammation at the site of infection is initiated by ….

response of macrophages to pathogens

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Characteristics of inflammation

pain, redness, heat, swelling

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Why is there redness during inflammation

increased blood flow to area of injury

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Why is there edema during inflammation

increased extravascular fluid and phagocyte infiltration to the damaged area

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Why is there heat during inflammation

increased blood flow and action of pyrogens

What are pyrogens

fever-inducing agents

Why is there pain during inflammation

local tissue destruction and irritation of sensory nerve receptors

What happens if a whole organ or tissue is involved in inflammation

loss of function

What are the 6 pro-inflammatory mediators

1. cytokines 2. chemokines 3. vasoactive amines 4. vasoactive peptides 5. vasoactive lipids 6. coagulation system

When do sentinel cells synthesize and secrete cytokines

when exposed to infectious agents or their PAMPs

What are the 3 major cytokines

TNF a, IL-1, IL6

Major functions of IL-1

1. promotes inflammation 2. kills cells 3. affects leukocytes 4. affects metabolism 5. affects blood flow 6. affects cell growth

How can proinflammatory cytokines allow more cells to get to infection site

increase expression of adhesion molecules (integrins) on endothelium for cells to bind and exit

What effect do proinflammatory cytokines have on cytokine production and eosinophils

increase TH2 production and degranulates eosinophils

What cells do proinflammatory cytokines enhance the growth of

fibroblasts, keratinocytes, vascular smooth muscles

How do profinflammatory cytokines promote inflammation

enhanced collagen synthesis, fibroblast activity, chrondrocyte activity

4 major functions of TNF a

1. promotes inflammation 2. enhances fibroblast growth, collagen syn., bone resorption 3. toxic effects 4. activates cells

What happens when proinflammatory cytokines are produced in low quantities

local inflammation, which includes macrophage activation, endothelium activation, complement activation

What happens when proinflammatory cytokines are produced in moderate quantities

local and systemic effects, including fever, lethargy, loss of appetite from effects on hypothalamus, production of acute-phase proteins from actions on the liver, and neutrophilia resulting from action on the bone marrow

What happens when proinflammatory cytokines are produced in high quantities?

systemic vasodilation, increased vascular permeability. This leads to a drop in blood pressure and low cardiac output, vascular injury, thrombosis and disseminated intravascular coagulopathy (DIC), pulmonary edema, air spaces fill with fluid, and leads to acute respiratory distress syndrome (ARDS)

When can septic shock occur in cows

cows with gram-negative bacterial mastitis because endotoxin produces high quantities of proinflammatory cytokines

Proinflammatory cytokines are necessary in low quanities and ______ in high quantities

LETHAL

What are chemokines a family of

50 small chemotactic cytokines

What do chemokines coordinate the migration of?

cells and dictate the course of many inflammatory and immune responses

What are chemokines produced by

sentinel cells including macrophages and mast cells

What is the function of IL-8

chemokine that is produced by macrophages or mast cells that attract and activate neutrophils

What is CXCL2

chemokine that is secreted by macrophages and attracts neutrophils

Where do vasoactive molecules derived from

inactive precursors in plasma, macrophages, mast cells, neutrophils, basophils, platelets, or damaged tissue cells

3 major types of vasoactive molecules

1. vasoactive amines 2. vasoactive peptides 3. vasoactive lipids

What is the most important vasoactive molecule (amine) released by mast cells

histamine

What happens when histamine binds to its receptors on endothelial cells

stimulates them to produce nitric oxide, potent vasodilator

What does histamine stimulate the production of

nitric oxide- potent vasodilator

What does histamine cause

blood vessel leakage, leading to fluid escape into tissues and local edema

What does histamine upregulate

TLR expression on sentinel cells

What is serotonin chemically

5-hydroxytryptamine (5HT)

What is serotonin a derivative of

tryptophan

What effect does serotonin have

vasoconstriction that results in rise in BP (vasodilator in cattle)

What are the 2 vasoactive amines

histamine and serotonin

What are vasoactive peptides producted by

proteolysis of inactive precursors

What are the C5a and C3a (vasoactive peptides) considered

anaphylotoxins

What do C5a and C3a promote

histamine release from mast cells

C5a is a potent attractant for what?

neutrophils and monocytes

Mast cell granules contain proteases called .....

kallikreins

What do kallikreins do

act on kininogens to generate kinins

What is the most important kinin

Bradykinin

What are the 4 roles of kinins

1. increase vascular permeability 2. stimulate neutrophils 3. trigger pain receptors 4. have antimicrobial properties

When is the coagulation system activated

when fluid leaks from blood vessels

What is the main clotting enzyme, which is generated after the coagulation system activates

thrombin

What does thrombin do

act on fibrinogen in tissues and plasma to form insoluble fibrin

What happens to fibrin after its formed

deposited in the inflamed tissue forming a physical barrier to the spread of infection

What do system is also activated with the coagulation system

fibrinolytic system

What does the fibrinolyitc system do

destroys fibrin and releases peptide fragments that attract neutrophils