5 - Innate 3: Inflammation Flashcards
what is acute mastitis?
sudden dysfunction/inflammation of the mammary gland by bacteria, accompanied by swelling, heat, and obvious pain and discomfort for the cow. The halmark diagnostic feature of acute mastitis is the presence of leukocytes in the milk
what is the economic importance of bovine mastitis?
lower milk production
what is the farm-side test to test for bovine mastitis?
California Mastitis test. higher levels of agglutination means more inflammation
what are the five steps of acute inflammation?
- delivery of leukocytes and plasma proteins to the site of injury (vasodilation, vascular permeability, chemotaxis of leukocytes)
- elimination of agent (effector processes)
- trigger acquired immunity
- initiate tissue repair
- systemic responses (fever, leukocytosis)
what are the cardinal signs of acute inflammation?
redness (rubor), heat (calor), swelling (tumor), pain (dolor), and loss of function (functio laesa)
the most common initiator of acute inflammation is:
sentinel cell detection of microbial or parasitic products within host tissues
Name a few triggers of inflammation:
trauma, physical and chemical injury, foreign bodies, inappropriate products of adaptive immunity
many of the triggers of inflammation release ___
DAMPs, which, although endogenously derived, can lead to activation of macrophages
activation of macrophages with PAMPs and DAMPs is indicative of:
infection and tissue injury
PAMPs and DAMPs activate inflammasomes within macrophages, leading to the release of:
interleukins (proinflammatory cytokines) and lipid mediators
give 4 examples of mediators for local vascular changes:
- histamine, serotonin (mast cells)
- nitric oxide
- prostaglandins and leukotrienes
- Cytokines and Chemokines
These mediators change the vascular permeability and expand the capillary beds to slow down the blood velocity for leukocytes to have more opportunity to stop the pathogen
Histamine is released from the granules of Mast Cells adjacient to blood vessels. This release is induced by:
-trauma/cold/heat
- immune reactions (IgE)
- C3a, C5a
- histamine releasing proteins from leukocytes
- neuropeptidies (substanceP)
- cytokines (IL1, IL8)
histamine binds to __ receptors on endothelial cells and causes ____
1) H1 receptors
2) dilation of arterioles and increased permeability of venules
nitric oxide (NO) is released from endothelial cells and macrophages. it induces:
relaxation of vascular smooth muscle, leading to vasodilation and increased vascular permeability
in the short term, NO is proinflammatory, as it leads to vasodilation. in the long term, it reduces leukocyte recruitment, and therefore plays an _____ role
anti-inflammatory
Leukotrienes and Prostaglandins are both local vascular mediators. How do they differ in their mechanism of action?
Both increase vascular permeability. Leukotrienes stimulate smooth muscle contraction and neutrophil chemotaxis, and prostaglandins induce vasodilation and hyperalgesia
How do NSAIDS stimulate an antiinflammatory response?
NSAIDs prevent arachidonic acid from converting into prostaglandins by inhibiting the enzymes (COX1 and 2) that catalyze the reaction.
NOTE: prostaglandins are local vascular mediators that stimulate an inflammatory response
What are NSAIDs?
Non-steroidal anti-inflammatory drugs. They are cox 1/2 inhibitors that serve local anti-inflammatory and analgesic effects, as well as serving a central anti-pyretic effect
Cytokines and chemokines (IL-1B, IL-6, TNF-a, IL-8) serve as inflammatory mediators by:
activating leukocytes and endothelial cells, causing systemic reactions. Chemokines in particular activate chemotaxis
what are 4 consequences of vasodilation?
- increased blood to area
- expansion of capillary beds
- decreased velocity of flow
- increased permeability (fluid loss)
what are the three predominant mediators of vasodilation in the inflammatory response?
- Histamine
- Nitric oxide
- prostaglandins
what are four consequences of increased vascular permeability?
- larger gaps between endothelial cells (due to trauma and endothelial contraction)
- active transport of plasma through endothelial cells (transcytosis)
- high protein fluid accumulates within the tissues, causing edema
- edema further activates endothelial cells to produce more inflammatory mediators
increased vascular permeability is primary mediated by what three molecules?
Histamine
Leukotrienes
Prostaglandins
what does vasodilation and increased permeability (fluid loss) result in?
Local stasis of blood flow (AKA decreased blood velocity)
what are the four phases of leukocyte recruitment (extravasation)?
- leukocyte margination (tethering) and rolling
- firm endothelial adhesion (pavementing)
- diapedesis (transmigration)
- migration in intersitital tissues (chemotaxis)
describe margination and rolling of leukocytes
leukocytes transiently adhere to the endothelium, allowing close interaction between them and the endothelial wall. Rolling in the presence of chemokines activates high-affinity integrins on the leukocyte that allow them to adhere
what is bovine leukocyte adhesion deficiency?
in holstein cattle, an autosomal recessive disorder impairs an integrin gene (B2-integrin), which prevents adhesion of leukocytes to the endothelium. this renders them unable to extravasate, and cattle with this disorder tend to die premature deaths due to recurrent bacterial infections due to their impaired immune response.
describe firm adhesion (pavementing) of leukocytes
chemokines and rolling activate leukocytes activate the integrins on the leukocytes to bind to the endothelium through specialized endothelial receptors at the site of infection. Then the leukocytes spread out along the endothelial surface, hence the term “pavementing”
Describe Diapedesis
This occurs primarily in the venules. leukocytes transmigrate through the endothelial wall into the extracellular matrix. This is possible because the basement membrane of the endothelium is compromised by leukocyte secretion of collagenases.
where does diapedesis primarily occur?
the venules
after transmigration (diapedesis), what allows the leukocytes to adhere to the extracellular matrix?
B1-integrins (CD44), found on the leukocytes themselves
Describe chemotaxis
the recruitment of leukocytes to a specific site of insult via the establishment of a chemical gradient of chemoattractants.
give two examples of exogenous chemoattractants used in chemotaxis
Bacterial proteionogenic amino acids (N-formyl-methionine, leucine, phenylalanine, fMLP)
Bacterial lipids
give two examples of endogenous chemoattractants used in chemotaxis
C3a, C5a (complement)
Leukotrienes
IL-8 (chemokine)
how do neutrophils detect a chemotactic gradient and move in the right direction?
Using receptors for chemoattractants
dispersed on its plasma membrane,
the neutrophil extends its pseudopod in
the region of the greatest chemotactic receptor
activation and then pulls the rest of itself
toward the stimulus.
what are a common secondary responder to acute inflammation?
Monocytes, that mature into macrophages after they extravasate to the site of infection
rank the following leukocytes in the order in which they appear during inflammation:
neutrophils, B cells, phagocytes, cytotoxic T cells, helper T cells
- Neutrophils (0-4 days)
- phagocytes (0- week 6)
- Helper T cells (day 4 - week 6)
- Cytotoxic T cells (day 7 - week 6)
- B cells (week 3 - week 6)
what is pus?
necrotic neutrophils and other cells
what is leukocyte is primarily recruited during inflammation caused by parasitic infection?
Parasites elicit eosinophil-dominated inflammatory responses through the recruitment of eosinophils via CCL11 (a, eotaxin)
acute inflammation of the intestinal mucosa of a horse with strongyle infection should show what type of inflammatory response?
eosinophil-dominated
There are at least 11 systemic effects of acute inflammation. Name as many as you can (or at least be able to recognize them on a multiple choice test lol)
- anorexia
- altered sleep patterns
- lethargy
- cachexia
- shock
- fever
- leukocytosis
- metabolic acidosis
- alterations to acute phase proteins
- decreased vascular resistance (systemic vasodilation)
- increased heart rate
the majority of systemic effects of acute inflammation are mediated by the systemic release of:
TNF-a, IL-1, and IL-6 (proinflammatory cytokines) from the activated leukocytes at the site of infection
what is the effect on the bone marrow during systemic acute inflammation?
leukocytosis
what is the effect on the hypothalamus during systemic acute inflammation?
increased prostaglandin release leading to fever, as well as increased ACTH release stimulating further production of corticosteroids which in turn stimulate production of acute phase proteins from the liver
(sorry i know this is confusing, theres a good diagram of this in the slide deck)
what is the effect on the liver during systemic acute inflammation?
increased production of acute-phase proteins
what are the three main organs affected by acute inflammation?
bone marrow (leukocytosis)
hypothalamus (fever)
liver (production of acute phase proteins)
describe leukocytosis
An increased number of leukocytes (primarily neutrophils) circulating in the blood. This is because IL-1 and TNF accelerate the release of stored neutrophils in the bone marrow.
prolonged infection induces production of ______ and the release of __________
- Colony stimulating factors (CSFs)
- Immature (band) neutrophils
what does “left shift” neutrophilia indicate?
neutrophils are immature when they are released from the bone marrow. This is the most common change in blood profile during acute inflammation
Acute phase proteins (APPs) are produced by the liver. Give some examples of APPs whose serum levels INCREASE during inflammation (positive APPs)
C-reactive protein (CRP)
Serum amyloid A (SAA)
Haptoglobin
AGP
Ceruloplasmin
fibrinogen
Acute phase proteins are produced by the liver. give some examples of APPs whose serum levels DECREASE during inflammation (negative APPs)
albumin
transferrin
what are two clinical signs vets use to assess acute inflammation?
Neutrophilia (leukocytosis)
Levels of APP in blood serum
what is the pathogenesis of fever?
pyrogens (TNF-a, IL-1, IL-6, LPS) stimulate the anterior hypothalamus to produce prostaglandins (PGE2), which act on thermoregulatory neurons that control the body’s temperature set point. The set point is increased, which promotes metabolic and behavioural changes that increase heat production and minimize heat loss
during fever, what are three things that increase heat production?
catecholamines
thyroxine
shivering
during fever, what are four things that minimize heat loss?
vasoconstriction
piloerection
postural changes
behavioural changes
what are some proposed functions of fever?
induction of heat shock proteins, enhancing leukocyte response
increased leukocyte response
enhanced phagocytosis
increased T cell proliferation
increased motility and activation of some leukocytes
inhibition of some microbes
enhanced interferon-stimulated responses
induction of Fe-sequestering proteins
Is the resolution of inflammation an active or passive process?
active
failure to actively terminate acute inflammation leads to:
chronic inflammation and tissue destruction
what are the four mechanisms of inflammation resolution?
- short half-life of inflammatory mediators
- production and release of anti-inflammatory cytokines and molecules
- apoptosis of proinflammatory cells
- desensitization of prostaglandin receptors
how quickly after the start of an inflammatory response does the coordinated program of termination occur? (in other words, when does the resolution of acute inflammation begin)
within hours of starting an inflammatory response
what do we call an inflammatory response that lasts months/years/indefinitely due to never resolving the cause of the acute inflammation?
chronic inflammation
during chronic inflammation, the long term production of TNFa, IL-1 and IL-6 promotes:
tissue damage
what are three examples of continual microbial invasion that can induce chronic inflammation?
gum disease
unhealed wounds
fungal and mycobacterial infections that arent resolved
what is fibrosis?
scar-like tissue seen in cases of chronic viral infections, autoimmune diseases, and alcoholic liver diseases. It is caused by excessive fibrous connective tissue (fibroblasts) seen with cell necrosis
what are granulomas?
Granulomas are organized aggregates of macrophages, often with characteristic morphological changes, and other immune cells. they form in response to persistent infection or foreign materials that individual macrophages cannot eradicate/destroy
what is the pathogenesis of mastitis?
infectious bacteria ascends into the mammary gland via the streak canal, where the bacteria then proliferate. PAMPs and sentinel cells do their thing, and acute inflammation occurs. later, the systemic effects of acute inflammation also occur
how do we diagnose mastitis?
- sudden onset, typical clinical signs
- aspect milk, CMT/cell count
- blood: left shift neutrophilia, haptoglobin, SAA
how do we treat mastitis?
intragland antibiotics and herd prevention
