Lecture 4 - Inflammation Flashcards
What are the proinflammatory things produced by sentinel cells as early response
-IL-1
-IL-6
-TNF-a
-HMGB-1 (DAMP)
What are the effects of the proinflammatory cytokines/DAMP on the hypothalamus
fever, anorexia, sleepiness, depression
What are the effects of the proinflammatory cytokines/DAMP on the liver?
increased synthesis of acute-phase proteins, iron sequestration
Why is iron sequestration important
makes freely available iron unavailable to pathogens
What are the effects of the proinflammatory cytokines/DAMP on bone marrow
increased WBC production
What is inflammation
tissue reaction that rapidly delivers mediators of host defense to the sites of infection and tissue damage
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
What is the main purpose of inflammation
focus the immune response to the site of infection or injury
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
What allows fluid, protein, and inflammatory cells to leave blood and enter tissue
vasodilation and increased vascular permeability
What are the stages of neutrophil adhesion and emigration from blood vessels
rolling, adherance, emigration
What is rolling mediated by
selectin (by PAMPs and DAMPs)
What is adherance mediated by
integrin (by PAMPs and DAMPs)
What does emigration lead to
chemotaxis
What is an autosomal recessive immunodefinciency in Holstein calves
Bovine Leukocyte Adhesion Deficiency (BLAD)
What is BLAD characterized by
- recurrent bacterial infections
- oral ulcerations, gingivitis, periodontis
- chronic pneumonia
- stunted growth
- delayed wound healing
- peripheral lymphadenopathy
- persisten extreme neutrophilia
What calves are affected by BLAD
holstein
When do calves affected by BLAD die
2 and 7 months of age
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
What gene is mutated in calves with BLAD
integrin
Inflammation at the site of infection is initiated by ….
response of macrophages to pathogens
Characteristics of inflammation
pain, redness, heat, swelling
Why is there redness during inflammation
increased blood flow to area of injury
Why is there edema during inflammation
increased extravascular fluid and phagocyte infiltration to the damaged area
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
- cytokines
- chemokines
- vasoactive amines
- vasoactive peptides
- vasoactive lipids
- 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
- promotes inflammation
- kills cells
- affects leukocytes
- affects metabolism
- affects blood flow
- 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
- promotes inflammation
- enhances fibroblast growth, collagen syn., bone resorption
- toxic effects
- 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
- vasoactive amines
- vasoactive peptides
- 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
- increase vascular permeability
- stimulate neutrophils
- trigger pain receptors
- 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
