Inflammation 2 Flashcards
Sequence of leukocyte events
1.Margination, rolling, adhesion
2.Transmigration across endothelium (also called diapedesis)
3.Migration in interstitial tissues toward chemotactic stimulus (chemotaxis)
4.Phagocytosis and synthesis of biochemical mediators
Neutrophil margination
-vasodilation results in slower flow of blood which allows the neutrophils to move to the edges
-edema and stasis
Neutrophil rolling
-binding of proteins on endothelium and the neutrophils
>done by selectins. Slows the neutrophils and rolls them along the endothelium
Neutrophil Adhesion
-getting the neutrophils to stop and have firm adhesion is conducted by integrins (beta1 and beta2)
Leukocyte adhesion deficiencies
-Cattle, dogs (irish setters) and people with Leukocyte adhesion disorders that lack the expression of beta 2 integrins
>means neutrophils can slow down, but never stop and can’t get into site of infection. Therefore neutrophils high in circulation but low numbers in sites of infection
-animals typically die within a few days/weeks
BLAD
-cattle leukocyte adhesion deficiency
-develop severe gingivitis, tooth loss, oral ulcers, enteric ulcers, cutaneous ulcers, diarrhea, pneumonia (**note all things that are interacting with the outside environment)
Leukocyte types depending on time
-Early inflammation: neutrophils because there is many of them, they respond rapidly to cytokines, and they adhere strongly to adhesion molecules. But they have a short lifespan once they leave the circulatory system
-Late inflammation: neutrophils are replaced by monocytes (long life)
Viral infections
-lymphocytes predominant
Hypersensitivity reactions
-eosinophils predominant
Chemotaxis
-directed movement of cells toward a chemical attractant. They will move toward the higher amount/gradient
Hydrocephalis
-congenital or acquired
>congenital if the skull is dome shaped because no way for the skull to change afterwards
-enlarged ventricle, very large brain and dome shaped skull
-excess fluid in the brain
Leukocyte induced injury
-Eg. pus filled kidney
>leukocytes release lysosomal substances into extracellular space= Frustrated phagocytosis
Frustrated phagocytosis
-blob attached to something and neutrophils are unable to properly engulf
-when it can’t fully surround, the neutrophils will “barf” everything out (lysozymes) and destroy surrounding tissues by accident
Smoke induced frustrated phagocytosis
-Smoking results in antigens that result in neutrophils releasing elastase through frustrated phagocytosis which breaks down elastin in the alveoli, resulting in smoke induced pulmonary emphysema
Heave line in horse
-Horse is working heard to breath
-results from chronic inflammatory response to lung
Neutrophils release Reactive oxygen species
-results in damage to surrounding structures
Neutrophils are indiscriminate about what they target
**reason why you would want to minimize immune response
-occurs through NETs, reactive oxygen species, lysozymes
Mandible of Cow
-pylogranulomas inflammation in jaw resulting in lumpy jaw, chronic legion
>morphologic diagnosis: abscesses or bone growth
Chemical mediators of inflammation
-high number of them that all interact
-short lived because they can become inactivated by enzymes, scavenged, of inhibited by other proteins
-either come premade within cells or secreted in inflammatory cells, or within the liver
Plasma derived mediators
-complement
-kinins
-coagulation proteins
Cell derived mediators
-always present sequested in granules of cells= histamines
-sythesized within cells (not always present)= NO, cytokines, chemokines, Arachidonic acid metabolites
Complement pathway functions
-induces inflammation, phagocytosis, and MAC: lysis of microbes
C5a, C3a Complement
-inflammatory pathway
-induces endothelial breakage
-also activate enzymes that tend to inhibit complement
Complement components inadvertently attached to vessel walls
-can also see immune reactions and damage to vessels/tissues
Fibrin pathway
-When fibrinogen activates and becomes fibrin, at the same time there will be activation of pathways which results in activation of plasminogen and formation of plasmin which helps break down fibrin
**Good because don’t want excess fibrin formation and having everything stuck together
What cells make inflammatory mediators?
1.platelets
2.neutrophils
3.monocytes/macrophages
4. mast cells
5.mesenchymal cells (connective tissue cells such as osteoblasts, fibroblasts, etc.)
Histamine
-among the first mediators to be released during inflammation by mast cell degranulation due to physical injury, immune reactions, anaphylatoxins, cytokines
Histamine effects
-causes dilation of arterioles and increases vascular permeability of venules
-redness, heat, swelling
Arachidonic acid metabolites
-produced by platelets, endothelial cells and leukocytes via remodeling of plasma membranes
-involved in almost all steps of acute inflammation
Anti-inflammatory steroids
-inhibit phospholipases which prevent arachidonic acid
COX inhibitors and aspirin
-inhibit cyclooxygenase which inhibits prostaglandin production
-prevents clotting
Chemotaxis
-linked to arachidonic acid
-when inhibited by steroids, less movement of cells
Renal medullary infarction
-associated with vet intervention from animals being given NSAIDs because it results in less vasodilation and poor blood flow
Cytokines
-produced by many cell types that modulate functions of other cells
-Eg. Tumor necrosis factor & interleukin-1
Tumor necrosis factor and interleukin-1
-react at local level and systemic level
>change set points or modulate inflammation levels
>liver to make more acute phase proteins
>increase set point temp of hypothalamus
>increase leukocytes production in bone marrow
-can have good or bad impact (eg. Can induce thrombus formation, decrease CO)
Chemokines
-family of small cytokines that act as chemoattractants for leukocytes
NO
-vasodilator relaxing vascular smooth muscle
-NO free radicals are toxic to microbial and mammalian cells
-reduce platelet aggregation and adhesion
Acute phase response
-an adaptive component of innate defense and consists of numerous predetermined and orchestrated local and systemic reactions to the acute phase stimuli
>mediated by IL-1, TNF, IL-6
Clinical or pathological changes associated with acute phase response
-fever (triggered by things like changes in cell wall of bacteria)
-anorexia
-somnolence
-tremors, shivering
-acute phase proteins
-leukocytosis
Fever
-most common sign off acute phase response
-PGE2 in vascular and perivascular cells of the hypothalamus which stimulates the production of NTs which reset the temperature set point
-can allow growth in terms of fungus or can prevent growth of bacteria
Acute phase proteins
-produced by liver
-increases plasma concentration 25%
-there are positive or negative acute phase proteins
>Positive: anti-inflammatory
>negative: maintenance of homeostasis
Fibrinogen and acute phase response
-increase in fibrinogen concentration measured in ruminant and horses which determine where animal is with its acute phase protein response
Leukocytosis
-increased number of leukocytes in blood
-common with bacterial infection
-increased release of cells from bone marrow (younger WBCs)= left shift
-prolonged infection induced proliferation of precursors in the bone marrow
Three choices with inflammation
1.damage is neutralized, and animal goes back to normal health
2.damge neutralized, but enough damage occurs that healing occurs through fibrosis and scarring
3.Chronic inflammation
IL-8
-chemokine
-attracts neutrophils
Macrophage inflammatory protein
-chemokine
-attracts everything except neutrophils
Eotaxin
-chemokine
-attracts eosinophils
