SFP: Inflammation I Flashcards
What are some examples of harmful effects of chronic inflammation?
Rheumatoid arthritis, anaphylactic reaction, pericarditis
Describe the general order of events in inflammation
-Stimulus occurs
-Plasma and connective tissue cells evoke soluble chemical mediators
-Soluble mediators elicit vascular and cellular response aimed at recruiting macrophages to remove the stimulus of injury
Differentiate between acute and chronic inflammation.
Acute inflammation: occurs over minutes to days, primarily involves neutrophilic leukocytes, and the tissue change is flooding of fluid and proteins (exudate)
Chronic inflammation: lasts days to years, primarily involves lymphocytes and macrophages, and the tissue change is vascular proliferation and scarring
Exudate formation is an indicator of…
acute inflammation
List the cardinal signs of inflammation and describe the events that cause each.
vascular changes in caliber and permeability cause heat, redness, and swelling
cellular events like leukocyte recruitment and activation causes loss of function and pain
What are the three steps in the triple response
-Dull red line
-Red halo
-Wheal
what are the three major changes that occur in terms of caliber and flow
- Transient vasoconstriction, arteriolar dilation, and finally stasis
what causes the redness and warmth associated with inflammation?
increased RBC’s due to arteriolar dilation
describe stasis
volume loss due to fluid leaving the vascularature and entering the interstitial space makes blood more viscous. this slows the flow of blood and allows for leukocytes to settle and marginate.
What is the difference between transudate and exudate?
Exudate has protein and transudate does not
what two mechanisms are associated with increased vascular permeability
hydrostatic pressure changes and mechanisms impacting endothelial integrity
Describe how hydrostatic mechanisms cause edema
arterial hydrostatic pressure is increased due to increased blood volume, and osmotic pressure decreases in the vascular department. This results in more fluid leaving the capillary bed than fluid re-entering. This causes local swelling AKA edema.
What part of the vessel is considered the most “leaky”
Venules
endothelial contraction and retraction primarily impacts which part of the vascularature
venules
What are endothelial gaps
The loss of tight junctions between endothelial cells can make them leaky
Describe endothelial contraction
vasoactive mediators like histamine cause a transient response that results in receptor mediated phosphorylation of junction associated proteins in the venules. this creates gaps that make the endothelium more permeable.
describe endothelial retraction
cytokines like TNF and IL-1 4-6 hours post injury causes a reorganization of cytoskeletal proteins. This typically occurs for about 24 hours and targets primary venules and capillaries. this restores the endothelium and prevents excessive leakage of fluid
burns and infections lead to what kind of cell death
necrosis
thermal injury, bacterial toxins, and sunburn lead to what kind of cell death
apoptosis
What does VEGF stimulate?
Fusion of pinocytotic vesicles to form channels for transcytosis through the endothelial cell. It also stimulates endothelial cell mitosis in the process, and the new vessels they form have leaky junctions, this increases fluid leakage unto the interstitial space
what is angiogenesis
the formation of new vessels; immature vessels have immature junctions and thus leakage can occur
What is considered the most important event in acute inflammation?
The movement of leukocytes out if the vessels and into the extra vascular space.
What is laminar flow?
In normal conditions, the smallest elements of blood are found in the central axial column and leukocytes are pushed to the periphery
What is a major function of stasis
Prolongs interaction between leukocyte and endothelial cells
Describe the steps in extravasation of leukocytes and the factors that facilitate the
movement.
-Margination: white blood cells interact with endothelial cells due to stasis
-Rolling: transient contact as the blood slows due to upregulation of selectins/binding between selectins and receptors. Leukocyte has L selectin and endothelial cells have E and P selectins
-Adhesion: cytokines increase affinity for ICAM and VCAM, stabilizing the contact between leukocytes and endothelium
-Transmigration through the wall
what receptors facilitate rolling?
L- selectins and sialyl-lewis on neutrophils. E and P selectins on endothelium
what receptors facilitate adhesion?
ICAM and VCAM on endothelium and integrins on leukocytes
describe the upregulation of endothelial selectins
during inflammation, P selectin translocates from Weibel-palade bodies and E selectins are synthesized in response to IL-1 and TNF
what receptors facilitate diapedesis
PECAM
Where is L-selectin, E selectin, P selectin, and Sialyl-lewis X GP found?
L selectin and sialyl lewis X are on the leukocyte, and E/P selectin are on the endothelium
What is chemotaxis?
Chemicals that bind to receptors on neutrophils to activate them and provide them mobility to move toward the site of injury. They act via G protein coupled receptors
What are two big examples of chemotactic agents?
C3a and C5a
what is a major opsonizing agent?
C3b
how do chemotactic agents act?
via GPCRs
What are some functions of PKC
Lysosomal degranulation/secretion and oxidative burst
What are some functions of activated phospholipase A2
In the presence of elevated calcium, it can metabolize membranes to produce amino acids
Describe the formation of pseudopods that aids leukocyte adhesion
G protein coupled receptors activate phospholipase C and activate IP3 and DAG. The calcium released by IP3 allows for cytoskeletal reorganizing required for pseudopod formation.
Describe the steps of phagocytosis and the specific mechanisms by which microbes are killed and degraded.
-Recognition and attachment: opsonin’s coat the microbe. Leukocyte receptors allow these to bind which in turn allows for recognition
-Engulfment and phagolysosome formation pseudopods form and the phagosome fuses with the lysosome
-Killing and degradation: NADPH oxidase, myeloperoxidase (forms hypochlorous acid), lysosomal acid hydrolases, major basic protein, defensin.
name the genetic defects that lead to leukocyte dysfunction
defect in LAD1, LAD2, and NADPH oxidase
describe how a defect in LAD1 leads to leukocyte dysfunction
mutation in beta subunit of the integrin that makes them unable to bind to their adhesion molecule. This means cells cannot make contact with endothelial cells for long enough to be able to leave the vessel. This results in lots of infections for the individual
describe how a defect in LAD2 can lead to leukocyte dysfunction
defective fucose metabolism leads to no sialyl-lewid X. this impacts the rolling, which impacts adhesion and ability of cells to leave the vessel
describe chronic granulomatous disease
an NADPH oxidase deficiency that impact the ability to produce superoxide. this makes patients susceptible to recurrent bacterial injection as they can’t break stuff down.
what type of inflammation is this?
acute
what type of inflammation is this?c
chronic
