Exam 1: Dr. Kaplan Inflammation: Mechanisms 1 Flashcards
What are the roles of inflammation?
Deliver additional effector molecules and cells to infection site
Augment the killing of microorganisms
Induce local blood clotting to provide a physical barrier to spread of infection
Promote repair of injured tissue
What are the signs of inflammation?
Rubor (redness) Tumor (swelling) Calor (heat) Dolor (pain) Functio Laesa (loss of function)
What is acute inflammation often like?
Self-limiting
What is the onset of actue inflammation like?
Quick
What is the resolution of inflammation like?
Often quick
What does acute inflammation predominantly involve?
The innate immune system
What is tissue injury like with acute inflammation?
Mild
How apparent are local and systemic signs of acute inflammation?
Obvious
When can chronic inflammation occur?
If the pathogen is adapted to resist antimicrobial mechanisms
What are the processes of chronic inflammation like?
Diverse, dependent on the pathogen
What is the onset of chronic inflammation like?
Can be days to years
What does chronic inflammation often involve?
Adaptive immune response
What are signs of chronic inflammation like?
Subtle or absent, but tissue injury can be severe
When does adaptive immunity begin?
When T cells come into play
What is the most common initiator of acute inflammation?
Sentinel cell detection of PAMPs
What are the typical sentinel cells in tissues?
Macrophages
Once activated, what do macrophages synthesize and release?
Cytokines and chemokines
What are some examples of cytokines?
IL-1β
IL-6
TNF-α
What do cytokines do?
Signal other inflammatory cells or blood vessels in the area
What is an example of chemokines?
CXCL8
What do chemokines do?
Recruit other inflammatory cells to the area
What is the most common trigger of inflammation?
Microbial infections
What other tissue insults can initiate inflammation?
Trauma
Physical or chemical injury
Foreign bodies
Inappropriate products of adaptive immunity
What does sterile inflammation often result in?
Release of endogenously produced DAMPs, which activate macrophages
What are examples of sterile inflammation?
Liver ischemia/reperfusion following surgery or acute myocardial infarction
What is an inflammasome?
Multi-subunit complex of proteins that cleave IL-1β and IL-18
What does an inflammasome typically conatin?
Sensor protein
Adaptor protein
Enzyme that cleaves IL-1β and IL-18 from their pro form to their active form
In addition to cytokines and chemokines, what are inflammatory processes regulated by?
Eicosonoids
What are eicosonoids?
Fatty acid derivatives
What are 2 kinds of eicosonoids?
Leukotrienes
Prostaglandins
What are eicosonoids synthesized from?
Membranes following liberation of arachidonic acid from diacylglycerols or phospholipids
What are prostaglandins synthesized from?
Arachidonic acid by cyclooxygenase enzymes
What are the different cyclooxygenase enzymes?
COX-1 and COX-2
How is COX-2 induced? COX-1?
Induced in inflammation
It is constitutive
What does PGE2 do?
Vascular permeability and vasodilation
What are leukotrienes synthesized from?
Arachidonic acid by lipoxygenase
What does LTB4 do?
Chemoattractant for neutrophils
What do LTB4 and LTD4 do?
Vascular permeability
What are examples anti-inflammatories and anti-pyretics?
Meloxicam
Phenylbutazone
Carprofen
What is meloxicam selective for?
Slight selectivity for COX-2
What is phenylbutazone used in?
Horses
What is carprofen selective for?
COX-2
What do anti-pyretics do?
Help with fever
What kind of vascular changes can cause inflammation?
Vasodilation
Increased blood flow
Increased vascular permeability
Expression of cell-adhesion molecules on vascular endothelium
What does vasodilation occur through?
The action of inflammatory mediators on arteriole and postcapillary venule smooth muscle
In vasodilation, what does the decreased tone to smooth muscle do?
Widens the lumen of the vessels
What does the widening of the vessels in vasodilation do?
Slows blood flow in the area
What is vasodilation mediated by?
Histamine and 5-HT (serotonin; mast cells), PGE2 (macrophages and mast cells), and nitric oxide (endothelium)
What does vasodilation contribute to? How?
Both rubor and calor by increasing blood volume
What do PAMPs, DAMPs, macrophages, mast cells, inflammatory mediators, and inflammatory molecules act on? What does it do?
Acts on blood vessel to make it bigger
What does increased vascular permeability occur through?
The action of inflammatory mediators on endothelial cells
What does increased vascular permeability form?
An exudate that moves from vasculature to affected interstitial tissue
What does increased vascular permeability contribute to?
Blood flow stasis
What does endothelial cell contraction during increased vascular permeability cause?
Gaps in the tight junctions between endothelial cells
What are other mechanisms for increased permeability?
Transcytosis
Direct damage to enothelial cell layer
What is transcytosis?
Active transport of fluid and macromolecules across the endothelial cell cytoplasm through vesicles
Another way to form pores for cells and mediators to get through
What is the first cell to respond when there is an infection?
Neutrophils; however, macrophages are the resident cell so they are there initially and then release something to attract the neutrophils
What are the 4 stages of leukocyte extravasation?
Tethering and rolling
Firm adhesion and crawling
Transmigration
Chemotaxis through tissue
What is tethering?
IL-1 and TNF-α activate endothelial cells to express adhesion molecules to which neutrophils can bind
What does E-selectin bind to?
Sialylated Lewis-X modified glycoprotein
What does P-selectin bind to?
Platelet selectin glycoprotein ligand 1
What are the interactions like during tethering?
Low affinity but many interactions increases the strength of binding neutrophils and endothelial cells
What are integrin interactions like?
Initially low affinity, but switch to high affinity
What does ICAM-1 bind to?
LFA-1
What will the high affinity interaction during firm adhesion do?
It will stop the neutrophil from rolling
What is transmigration?
Movement of leukocytes from lumen of blood vessel through the vessel wall and into interstitium
Where does transmigration usually occur?
In thin-walled postcapillary venules, but neutrophils still have to penetrate the endothelial barrier and underlying basement membrane
Where do neutrophils typically transmigrate?
Through small gaps between endothelial cells and digest basement membrane with collagenase
Once out of the vasculature, what do neutrophils do?
Respond to chemical gradients to move to the site of infection
What are endogenous products produced by?
Innate cells
Where do exogenous microbial products diffused from?
The site of infection
What do neutrophils do once in the tissue?
Adopt an amoeboid-like morphology with a leading pseudopod
What do receptors for chemoattractants on the pseudopod bind? What does it do?
The liagand and moves the rest of the cell toward the stimulus
What happens as the neutrophil moves toward infection?
It becomes activated in response to cytokines or other pro-inflammatory mediators making it more efficient at its primary functions
What are macrophages called in the liver?
Kupffer cells
What are macrophages called in the lung?
Alveolar macrophages
What are macrophages called in the CNS?
Microglial cells
What are macrophages called in the spleen?
Splenic macrophages
What does the type of cellular response depend on?
Pathogen
Types of adhesion molecules that are expressed
What will neutrophils be recruited in response to?
CXCL8
What will eosinophils be recruited in response to?
CCL11
What will monocytes differentiate into once in the tissue?
Macrophages and further migrate toward the insult
What are functions of macrophages?
Moderately proficient at killing
Phagocytose and break down debris
Clean up dead neutrophils, debris and dead microbes
What are examples of systemic effects of inflammation? (9)
Loss of appetite Altered sleep patterns Lethargy Muscle wasting Hemodynamic changes Fever Leukocytosis Metabolic acidosis Alterations in acute phase proteins
What are examples of cytokines?
TNF-α
IL-1
IL-6
What do cytokines do?
Rapidly disseminate throughout the body
Function to conserve energy and mobilize proteins
What does TNF-α cause?
Loss of apepetite
Altered sleep patterns
Lethargy
Cachexia
What can TNF-α and IL-1 stimulate?
Hypothalamus to produce PGE2
What does the release of PGE2 in anterior hypothalamus do?
Acts on thermoregulatory neurons to cause fever
What are the targets of inflammatory mediators that change the response from acute to systemic?
Bone marrow
Brain
Liver
What is PGE2 a main player in?
Fever and vascular permeability
Know the different proposed functions of fever
Know the different proposed functions of fever
What is leukocytosis?
Increased number of leukocytes circulating in the blood
What is leukocytosis known as in response to acute systemic inflammation?
Neutrophilia
What does neutrophilia cause?
Increased release of neutrophils from bone marrow
What does neutrophilia allow for?
More neutrophils to extravasate and contribute to immune defense at site of infection
What will a prolonged release of neutrophils from bone marrow do?
Deplete its store of mature cells prompting increased neutrophil production, but less mature neutrophils
Causes a left shift
What does a severe left shift in neutrophil maturation cause?
Acute inflammatory response
What can acute systemic inflammation do?
Alter the serum acute phase proteins profile
What does positive serum APP profile do?
Increase with inflammation
What does negative serum APP profile do?
Decrease with inflammation
Why are APPs used as diagnostic indicators of inflammation?
Because they can be induced so quickly and with high magnitude
What does an opsonin do?
Helps macrophages phagocytose
What are the positive APPs?
C-reactive protein Serum amyloid A Haptoglobin Alpha-1-acid glycoprotein Ceruloplasmin Hepcidin Fibrinogen
What are the negative APPs?
Albumin
Transferrin
What do APPs do?
Act as opsonins and activate complement
What is C-reactive protein a major APP in?
Dogs and pigs
What is serum amyloid A and major APP in?
Dogs
Cats
Cattle
Pigs
What is haptoglobin a major APP in? Moderate?
Pigs, cattle, sheep
Dogs, cats
What is alpha-1-acid glycoprotein a major APP in? Moderate?
Cats
Dogs
What is ceruloplasmin a moderate APP in? Minor?
Dogs
Cattle
What is fibrinogen important in?
Horses and cattle
