Lecture 25 and 26 Inflammation (Stahelin) Flashcards
how do vascular changes at the site of inflammation lead to the classical local signs of acute inflammation?
Acute inflammation is fight off the infection and repair the injury quickly
Vascular changes can lead to signs of inflammation because when injury occurs we will see tight junctions become damaged and loosen. With that we will see an increase in vasodilation thus decreasing fluid velocity. When we decrease the velocity and increase viscosity we see an increase in leukocytes settling along the inner surface of the blood vessels (magrination). slowing down the bloodflow allows the leukocytes more time to bind to the side of injury. These changes lead to local signs like heat, swelling, pain, loss of function, and redness
What are the two major components of inflammation?
The major roles of inflammation are to eliminate the infection and to repair damage that has been done by the infection.
two major components of inflammation are
What are the five mechanisms underlying increased vascular permeability during acute inflammation?
Increasing vascular permeability means that things can pass from the bloodstream to the tissue more easily and this can happen due to a multitude of things resulting in damage to the endothelial cells.
The loss in tight junction leads to intracellulargaps which increase fluid leakage.
Transcytosis which is the increase of fluid flow throught the endothelial cells
Leukocyte dependant endothelial cells can be damaged or killed due to the release of toxic mediators by leukocytes
Leakage of new blood vessels that form at the site of injury (these blood vessels form because they are trying to heal the area of injury)
Understand the events that occur during white blood cell migration. Pay particular attention to the adhesion molecules and enzymes that play a role in this process.
On the outside of a leukocyte, there is the integrin protein and Sialyl-lewis X-modified glycoprotein. Without infection, the leukocytes move throughout the bloodstream and exhibit rolling adhesion. This binding is low affinity so the leukocytes do not bind for long.
During injury, there’s vasodilation that leads to a slower movement of blood. Also with injury, there is a new expression of selectin (P and E) that are at the endothelial surface of the site of injury. These tell the leukocytes to come and bind. This binding (Known as firm adhesion between Integrins and ICAM-1) keeps the leukocytes in one place and allows for the binding of CD31 to the leukocyte which allows the cell to move through the endothelial tight junctions into the site of injury
Understand the mechanisms of phagocytosis and degranulation. Know the definition of opsonin and understand the roles that opsonins play in phagocytosis and degranulation.
Phagocytosis (3 steps)
1. recognition and attachment
- When a microbe binds to a phagocyte receptor and initiated engulfment
2. engulfment
-membrane moves inword forming a bubble around the microbe
this bubble now around the microbe is known as a phagasome and this Phagasome has a key signaling mechanism throught enzyme that can create free radicals that will cause damage many things including DNA synthesis, cell membrane, Protein degradation (NADPH oxidase)
- The phagosome protects our body from these free radicals due to the damage they can cause in the body (listed above)
-The phagasome then fuses with the lysosome that has has enzymes to distroy proteins with its high ph
- When these two fuse we create the phagolysosome which increases the amount of ROS and NO (comes from amino acid arginine)
3. Killing and degradation
- the microbe now in the phagolysosome will be degraded by the enzymes present and cause for the breakdown of it.
- Degranulation occurs when the phagosome with the microbe fuses with the lysosome present in the leukocyte
Opsonins are - Proteins that will coat microbes so that the leukocyte can come in and bind the opsonin and invade and engulf the microbe
IgG, C3 breakdown products and carbohydrate binding lectins can bind to the microbial cell wall sugar groups and serve as important opsonins that will trigger engulfment
Understand the two general classes of local mediators and plasma mediators and the major role of some mediators (nitric oxide, TNF, IL1, ROS).
In the liver, there are plasma-derived mediators
In the cells, there are cell-derived mediators
-Macrophages and Neutrophils produce ROS which works to kill microbes
-Leukocytes and macrophages produce Nitric oxide which works to kill microbes and relax vascular smooth muscle
-lymphocytes, endothelial cells, and macrophages produce cytokines like TNF and IL1 activate local endothelial
- Histamine, serotonin, leukotrienes, PAF, Kinins, prostaglandins all increase vascular permeability
Understand the metabolism of arachidonic acid in inflammation and the molecular targets of the listed drugs.
phospholipases will convert phospholipids to arachidonic acid. This phospholipase is inhibited by steroid drugs. Steroids tend to be used when inflammation is very bad.
Cyclooxygenase will convert arachidonic acid into PGG2. Cyclooxygenase can be blocked by COX-1 and COX-2 inhibitors like aspirin and other NSAIDs
( Aspirin, ibuprofen, and Naproxen all can inhibit COS 1 and 2) (Celebrex and Vioxx inhibit COX 2 specifically)
Understand the four major effects of TNF/IL-1.
- Endothelial effects
- increasing leukocyte adherence, increasing cytokine production, increasing PGI2 synthesis, increasing procoagulant activity, increasing anticoagulant activity - Fibroblast effects
- increase collagenase which thus increases collagen synthesis, increases protease, increases PGE synthesis, with all of this increasing proliferation - Systemic effects
- causes fever, increase sleep, loss of appetite, increase acute phase proteins, and hemodynamic effects neutrophilia (think about all the common cold symptoms you get when sick) - Leukocyte effects
- increases cytokine secretion
Understand the outcomes of acute inflammation.
there are many different outcomes for acute inflammation.
best case is that we see the inflammation and injury return to normal function after the replacement of injured cells.
We can also see with healing a pus formation (abscess) start to form that will eventually lead to fibrosis and thus a loss of cell function.
We can also go from acute damage to fibrosis where we will again see the loss of function in the injured area
We can also see the progression of the injury that will lead to chronic inflammation and eventually lead to fibrosis as well
Understand the relationship and differences between acute and chronic inflammation.
Acute inflammation: is an immediate adaptive response, characterized by heat, pain, edema, redness, and loss of function
Chronic inflammation: is inflammation of prolonged duration (weeks to months to years) (viral infections tend to lead to chronic inflammation)
One of the major differences between acute and chronic inflammation is that in acute inflammation we will see the infiltration of neutrophils into the injured sites. Whereas chronic inflammation has infiltration of macrophages, lymphocytes, and plasma cells
(A doctor could take a sample and under a microscope see which cells are present. If neutrophils were present we would know that the inflammation is in acute phase)
Why anti-PD-1 and anti-CTLA-4 antibodies may be useful for chronic HBC infection?
When someone has HBV infection they are now carriers and can transmit it to others and can also vertically transmit it (mother to baby)
CTLA-4 and PD-1 receptors inhibit immune response in the body.
These antibodies can block the activity of T cells in order to increase the immune response in patients with HBV
