Inflammation Flashcards
4 causes of inflammation
Pathogenic organisms
Poisons/toxins
Mechanical/thermal injury
Immune reactions and hypersensitivities
Cardinal signs of inflammation
Rubor (redness)
Calor (heat)
Dolor (pain)
Tumor (swelling)
Loss of function (function laesa)
Steps of vascular response to inflammation
- Vasodilation
- Increased vascular permeability
- Change in rate of blood flow
- WBC margination, rolling, adhesion
- Transmigration
- Emigration of WBCs
With mild injury, what do you expect to become more permeable
Post-capillary venules
With Moderate to severe injury, what becomes more permeable
Capillaries to small venules
With very severe injury - what becomes more permeable
Arterioles, capillaries, venules
Why does blood stasis occur (3)
1) Increased viscosity: blood loses plasma (increased vascular permeability) and there is accumulation of larger WBCs and protein to inflammatory site
2) Histamine: swelling of endothelial cells results in mechanical resistance
3) Passive congestion and stasis of lymph flow
Why does leukocyte margination, rolling and adhesion occur
1) Slowed blood flow means leukocytes move to peripheral Plasmatic Zone
2) They roll along endothelium
3) They adhere to Cell Adhesion Molecules (upregulated by inflammation)
How does transmigration occur
WBCs insert pseudopodia into junctions between cells to squeeze through
How does emigration occur
Along chemical gradient (chemotaxis)
What are some chemotaxins
Soluble bacterial products
Complement proteins (C5a)
Lipoxgenase pathway products
Platelet activating factor
Chemokines
Interleukins
Properties of neutrophils at site of infection
Amoeboid movement
Strong phagocytic activity
Ability to digest particulate matter
Release granules to kill microbes and tumors
Form Neutrophil Extracellular Traps - nets that ensnare bacteria
What are primary and secondary granules in neutrophils
Primary: proteins and enzymes that break down and kill bacteria
Secondary: contain toxic oxygen compounds and lactoferrin that bind iron
Whats an important role of neutrophils in sepsis
Formation of neutrophil extracellular traps in blood vessels to trap bacteria
Migration of neutrophils stimulates the release of what? What does this cause?
Colony stimulating factor
CSF stimulates granulopoesis and release of neuts from bone marrow
What’s left shift
Presence of banded neutrophils in blood
Regenerative left sift
Mature and bands are increased
Degenerative left shift
Matures normal or decreased. Bands increased
What does a degenerative left shift mean in most species
Poor prognosis :(
What does a degenerative left shift mean in cows
Common - they dont have large neutrophil reserves in bone marrow!
Should you expect to find a lot of eosinophils in blood
No - they only spend 30 min in blood before moving to tissues, where they spend 12 days
Functions of eosinophils
Cytotoxicity of parasites and fungi
Augmentation of inflammatory reaction during immediate hypersensitivity reaction
Phagocytic activity (more limited than neutrophils)
Eosinophilia is common in…..
Parasitic infections
Allergic conditions
What is eotaxin
IL-5 - mast cell tumors and lymphomas release it, evoking eosinophilia
Important enzymes of eosinophils
Perioxidase
Phosphotase
Idiopathic eosinophilic lesions of animals
1) Feline eosinophilic granuloma complex
2) Equine collagenolytic granulomes
3) Eosinophilic myositis in dogs, cows, sheep
Feline eosinophilic granuloma complexes
Eosinophilic plaque: pruritic lesion in skin of cats. Usually abdomen, inner thigh. Round/ovoid, ooze serum
- Can see eosinophils microscopically
Eosinophilic granuloma: linear granuloma on thighs. Pink to yellow elevated area
— Microscopically look like granulomas
Eosinophilic ulcers (rat ulcer): oral cavity, ulcerated
Location of eosinophilic granulomas in dogs
Usually in oral cavity and lips
Location of equine collagenolytic granulomas
Saddle area
Eosinophilic myositis in dogs
Affects masticatory muscles – attack their myosin
Eosinophilic myositis in ruminants
Affects skeletal and cardiac muscle – sudden death!
Believed to be due to allergy to muscle
Where are mast cells found
Organs rich in connective tissue at environment-host junction (skin, GI, respiratory tract)
Where are basophils found
Mainly in blood, and then emigrate to sites of inflammation
Which live longer in tissues: mast cells or basophils
Mast cells (1-3 months vs 3 days)
Mast cells and basophils have high affinity for which antibody
IgE
T/F - mast cells are phagocytic
No- mast cells and basophils are not
Are mast cells and basophils mobile?
Not really
What do mast cells and basophils contain
Histamine Serotonin Heparin Eotaxin (IL-5) Chemokines
Are lymphocytes acute or chronic
Chronic
Which WBCs constitute majority in peripheral blood
Lymphocytes
How long do lymphocytes live
Several months
Do lymphocytes respond to free antigens
No - must be presented to T-cell with MHC
CD4+ T cells are
Helper
CD 8+ T cells are
Cytotoxic
Types of B cells
Memory
Plasma
How long does transformation to plasma cell take? How long does it live for?
4-5 days
Lives for 12 hours
Which cell represents 15% of lymphocytes
NK cells
Do naive NK cells express T-cell receptors
No
Can NK cells form memory
Yes
How do NK cells kill other cells
Secrete granules containing potent cytoxic molecules (perforin, granzyme)
Functions of blood monocytes (4)
1) Phagocytosis
2) Antigen presentation –> initiate cell-mediate immunity
3) Produce pro-inflammatory substances that kill and remove dead tissue
4) Iron sequestration (less for bacteria)
Which ‘system’ do macrophages engage in
Reticuloendothelial system —> they live in certain organs
Mechanism of phagocytosis
- Makes contact with particle
- Psuedopodia sent out around particle
- Psuedopodia fuse so that particle lays in vacuole
- Phagosome fuses with lysosomes that contain oxygen radicals and other toxins
- Intracellular killing
- Exocytosis, antigen presentation
What type of macrophage might you seen in Johne’s disease
(Chronic inflammation)
Giant multinucleated cells
Where do lipid mediators come from
Cell membranes
Pathways from which lipid mediators are produced
Arachidonic Acid Pathway
Platelet Activating Factor Pathway
What do COX-1 and COX-2 produce
COX-1 and COX -2 produce prostaglandins
COX-1 (alone) produces thromboxane
Which COX is only in inflammation
COX-2
Which COX has good effects, like cytoprotection of mucosal cells
COX-1
Why do NSAIDs run the risk of causing ulcers
Because they also inhibit good effects of COX-1 (mucosal protection)
What are three enzymes from Arachidonic acid pathway
COX-1
COX-2
5-Lipoxygenase
What does 5-lipoxygenase do
Produces leukotrienes
What C/S do prostaglandins cause
Fever Pain Vasodilation Increased permeability Leukocyte adhesion/chemotaxis
What does thromboxane cause (2)
Vasoconstriction
Platelet aggregation
What do leukotrienes cause
1) Smooth muscle contraciton
2) Vasodilation
3) Neutrophil adhesion and chemotaxis
4) Mucous secretion
5) More potent than histamine, less rapid response
What does platelet activating factor do
Potent increase in permeability (1000x potent than histamine and leukotrienes)
Also: chemotaxis, activation and adhesion, platelet activation, mediator release from WBCs
What do vasoactive amines do
Immediate, short lived responses in inflammation
- Vasodilation
- Increased permeability
- Smooth muscle contraction
What are the most prevalent vasoactive amines
Histamine
Serotonin
What does nitric oxide do
Vasodilation
(can also react with oxygen-derived radicals to form nitrogen-derived radicals that are both antimicrobial and damaging to tissue)
What is nitric oxide produced by
Endothelial cells
Macrophages
Main cytokines
IL-1
TNF-a
INF-gamma
IL-10
What does IL-1 do
Fever, neutrophilia
Activates:
- Endothelial cells
- Membrane phospholipase A2
Stimulates acute phase proteins
What does TNF-a do
Shock
Activates:
- Neutrophils
- Endothelial cells
Stimulates production of other cytokines
What does INF-gamma do
Shifts to chronic inflammation
Activates macrophages and lymphocytes
What does IL-10 do
Immune system suppression
Which cytokines are acute
IL-1
TNF-alpha
Which cytokines are chronic
INF-gamma
Which cytokines are immunosuppressive
IL-10
What are the chemokines
1) IL-8
2) Eotaxin
3) CCL1, CCL2, CCL17, CCL22
4) MCP-1, CCL2
What do lysosomal enzymes do
Break down pathogens
But also cause damage to host
What is Classical Path activated by
IgG and IgM antigen attack complexes
What is Lectin Path activated by
Sugar residues
What is Alternative Path activated by
Bacterial surface structures (ie LPS)
Whats the end result of all three complement pathways
Membrane Attack Complex – punctures foreign cells
What is a very important mediator of complement
C3
What does C3 produce when its cleaved
1) C3a - anaphylatoxin (constricts smooth muscle and acts on mast cells to produce histamine)
2) C3b - opsonin (enhances macrophage and neutrophil phagocytosis)
What does C5 produce
C5a and C5b
They are powerful chemotactic agents for neutrophils and (kinda) macrophages. Also increase vasodilation, mast cell activity and interleukin production
Your dog is deficient in C5 proteins. Will this be an issue?
Major issue as it is used in all three complement pathways
Your dog is deficient in C2 proteins. Will this be an issue
Yes, but you can still use Alternative pathway
Your cat is decicient in C4 proteins. Is this bad?
Yes, but you can still use Alternative pathway
Which proteins does Classical Path use
C1, C4, C2, C3, C5
Which protiens does Lectin path use
C4, C2, C3, C5
Which proteins does Alternative path use
C3 C5
Intrinsic clotting cascade triggered by
Damage to vessel
Extrinsic clotting cascade triggered by
Damage to tissue
Which factor starts intrinsic path
XII
Which factor starts extrinsic path
VII and Tissue Factor
Which factor is first step of Common Path
X
What is final common pathway
Prothrombin –> Thrombin
Fibrinogen —> Fibrin
What happens in fibrinolytic system
Plasminogen –> Plasmin which lyses fibrin into FDPs
Also cleaves C3 of complement cascade, generating C3b and C3a
Can also generate Bradykinin
What is Kinin System activated by
Coagulation Factor XII (Hagemen Factor), microbes, and proteases
What does kinin system do and what is most known kinin
Releases Kinins that activate pain, vasodilation, increase permeability, chemotaxis
(BRADYKININ!)
Can factors from clotting, complement and kinin system activate each other
Yes!
What does Plasmin come from and what can it activate
From fibrinolytic system
Can activate both Complement and Kinin system
What does factor XII come from and what can it activate
Its step 1 of intrinsic pathway but also initiates Kinin System
Examples of Vasoactive Amines
Histamine
Serotonin
