Acute inflammation, very transiently you are going to go into
fight or flight mode. The sympathetic response kicks in.
And your blood vessels are vasoconstricting. This is not what
you want for acute inflammation. This is not the state
that you wish your blood vessels to be in so then you can
facilitate the transmigration of neutrophil from the blood
vessel into the interstitium. So therefore what is it. What
component or chemical or peptide is then responsible for overcoming
the initial vasoconstriction. Obviously histamine. Neurogenic is
the response, vasoconstriction. Very transient. And shortly
thereafter, you will have vasodilation of the arteriole and the
major component that results in such a vasodilation
we talked about is histamine. Responsible for your swelling, the
tumor. The redness, the rubor. The calor, the heat.
Remember also that bradykinin then causes your pain and that's
called your dolor. And your fifth and final cardinal sign
with inflammation. Imagine if you've sprained your ankle. If you
sprained your ankle then at some point you expect there to be
inflammation don't you. And if you have inflammation taking place
do you think that you might feel pain. Or even sensations
have been lost. That's because of inflammation there might be
compression of your nerves, or compromise of proper impulses,
neuronal impulses, resulting in functio laesa, loss of function.
What then happens when you have vasodilation? Well, I want you to go
anatomically in the blood veessel from the capillary out towards
your venule. Are you there? This will be the major site
of how you can get your neutrophil permeable through your blood
vessel into the interstitium. This of course also
histamine will be responsible for. What then happens here? Well once
you have the vasodilation taking place initially, that type
of fluid which is escaping into the interstitium is your transudate,
initial. This is due to increased hydrostatic pressure.
This is only fluid initially, can you picture it. Fluid is now
escaping from your blood vessel into the interstitium
due to vasodilation and as a result of a increased hydrostatic
pressure. What then happens? Well eventually neutrophil gets out
and let's say that this neutrophil is targetting a bacteria in the
interstitium. If the neutrophil is targetting a bacteria in the
interstitium and it undergoes the process of phagocytosis. You are
going to now fill up the interstitium with lots of protein.
So therefore as a rule of thumb inflammation ultimately the type
of edemea that you are going to find will be exudate,
protein rich. Initially it will be protein poor. Blood flow movement
into the interstitial space along with you have tons of protein.
The neutrophil is then going to marginate. What does that mean to
you? It means that now, instead of being in a normal laminar flow,
you are then going to get out into the margin. And when it does,
well this is a good thing. Now what ends up happening is
loss of axial stream due to rouleaux formation perhaps. By that
we mean, often times with acute inflammation due to the
margination that is taking place, remember please. Your focus
here with acute inflammation is going to be the neutrophil, right.
You move from the circulating pool into the marginating pool.
Obviously all blood flow has been affected in acute inflammation.
So therefore you can expect loss of axial stream and
maybe perhaps a development of stacking of the RBC's
Let's get into the specifics of acute inflammation. Things that you
want to know. So here is my neutrophil that you are trying to get
out into the interstitium. The first thing that has to happen as
I told you is that the neutrophil has to come out into the margin.
This is margination. Initially, when the neutrophil comes out in
the margin, it does not stop immediately. So therefore,
this loose affinity of the neutrophil to the endothelium is an
interaction called rolling. The major cytokines that you want
to know that mediates rolling will be IL-1 and TNF.
Pay attention to that. What is it that has a loose affinity.
Can you picture the endothelium for me. And the neutrophil with
the leucocyte. Loose affinity. Has loose affinity, it's going to
roll. Because it's marginating, it's marginating. Think of a plane
crashing. I know that it seems rather morbid but it helps.
A plane crashes but when it does it's going to slide. That's what
the neutrophil is doing. It's sliding on the margin. Are we clear.
That's selectin. In Immunology remember those selectins that
are on the endothelial cell. E-selectin, P-selectin. Good.
This will then bind on to what on your neutrophil? Good,
sialyl Lewis X. Remember that. Sialyl Lewis X.
If you are not familiar with that or if you are not good with
this right now, it might be good idea for you to skip over to
Immunology and get a real good handling for acute inflammation at
least and come back here to pathology with me. At some point,
the plane is crashing, we talked about rolling, and eventually the
plane stops. This is called adhesion. The neutrophil is now adherent
to whom? Where are you? Where is the neutrophil? Adherent to the
wall of your blood vessel. In the meantime tell me about the state
of my blood vessel right now. Vasodilated due to histamine, right.
So you have that rubor, calor, tumor so on and so forth.
What is responsible for actual adhesion? The mediators here would
be, well C5a and LTB4. It's a complement and leukotriene B4.
We'll talk more about C5a/Leukotriene B4 won't we. Of course we
will. We'll talk about this as part of your chemotactic complex,
chemotactic factors. Okay so, in the meantime, we have adhesion
of the neutrophil to the endothelial cell. What are these
called as a family? Integrins, integrins. You must memorise CD11,
CD18. You must. Why? Once again, in Immunology, we talked about
a particular disease called leucocyte adhesion deficiency. Leucocyte
adhesion deficiency. There are two major types, there are more.
But there is one and two that you definitely want to pay attention
to. And of those two, you pay attention to one. Focus more on one.
So, leucocyte adhesion deficiency type 1. This was an adhesion
deficiency that took place congenitally that particular
mutation there is a loss of CD11, CD18. Memorise that. First LAD
type 1, there is a loss of CD11, CD18. So therefore
you don't have adhesion. How is your young child going to present?
There is going to be ulcers maybe around the mucosa or mucosa
around the genital region which don't heal. Just keep this in mind,
that there might be delayed separation of the umbilical cord.
Okay. Delayed separation umbilical cord. All pointing you towards
your LAD and especially CD11, CD18 deficiency, LAD type 1.
What do this bind to on the endothelial cell? These are then called
your ICAM and VCAM. So we have your cellular adhesion molecules.
So we have a couple of mediators here as well. Group them all
together interleukin-1/TNF will play a role. As will C5a/LTB4.
If that discussion of cortisone catecholamine was inhibition of
activation of adhesion. Our next topic would be activation of adhesion.
So what have you done now. Do you understand the language becomes
important. If it's activation of adhesion molecules that means
that neutrophils are going to marginate or demarginate please? It
will marginate. You're moving your circulating pool
into the marginating pool. Examples; endotoxins, sepsis. You are
going to decrease in neutrophils. Remember once again,
when you do a CBC, what are you measuring? The circulating
pool or the marginating pool? Good, the circulating pool.
So if you marginate, you've taken the neutrophil out of the
circulating pool you've put it into the margin.
Because you've activated what? The adhesion molecules. That has to
be clear. Because you've done that, laboratory wise it's going to
show you neutropenia. And leucocyte adhesion deficiency is
what you are paying attention to, specifically type 1.
And I have asked you to please memorise CD11, CD18 deficiency
resulting in such a state and this newborn is then may or
may have a history of delayed separation of the umbilical cord. And
if the child becomes injured, and so there is an ulcer that may
develop in the genital region or in the mucosal region that it has a
hard time. The ulcer will not heal properly. Welcome to LAD type 1
and just to make sure that you are clear from Immuno that if it's
leucocyte adhesion type 2nd, then it's a deficiency of
sialyl Lewis X. But your focus should be upon LAD type 1. In this
step of acute inflammation, we'll take a look at transmigration.
Let me set up the picture first. We have a tubule here. This
tubule is a blood vessel. Inside the blood vessel we have those
blue cells that you are seing that line the blood vessel. Those are
called endothelial cells. Inside the blood vessel you see that gray cell.
Our focus should be on the specific leucocyte called your
neutrophil obviously with segmentation. If it's transmigration
remember that the blood vessels now undergone vasodilation due
to the help of your histamine. You can then expect there to be
rubor, redness; and your tumor your swelling; and calor, we talked
about heat emission. The first step is when the neutrophil is then
loosely binding to the endothelial side and this step is called rolling.
And the specific markers or the binding is through your selectins.
E-selectin, P-selectin, L-selectin and sialyl Lewis X will be
playing roles with selectin sometimes referred to as being your
addressins. Eventually, the neutrophil slow down, it will stop. You
have your adhesion. And with adhesion we're referring to our
integrin. And I told you that you needed to know about what may
then happen when there is a mutation of CD11, CD18
resulting in LAD type 1. Next, our step is this. You'll notice
please that the neutrophil on the very end of the tube on the right
is making it's way through the endothelial cell. You see that.
It literally going to then shoot out what's called this feet
diapedesis. It's shooting out this feet so that it can pull the
neutrophil through your blood vessel. This is transmigration.
Once you get the neutrophil down into your interstitium what's going
to happen next is the fact that neutrophil through chemotaxis
is going to then approach your bacteria. Now at this point, is
when we call this exudate and majority of inflammation
and the time that it spends in the type of fluid meaning to say
transudate or exudate, would be exudate. The chemotactic factors
as you remember from Immuno would be C5a/LTB4. Remember, the
neutrophils come out of interstitium, brave new world,
Ah, I don't know where to go, help me. So you have your chemotactic
factors. This is the GPS for the neutrophil. It tells the
neutrophil where to go. Chemicals that help you with taxing. Okay.
So now you approached the bacteria. You also have interleukin-8
and remember in microbiology you've talked about (inaudible)
right. Meaning to say bacterial product which will attract
the neutrophil towards it. That's crazy. It's almost like saying
Here, come here, kill me. Right. Whatever. Our body uses it
to our advantage. So what do you think the next step will be.
You have chemotaxis, neutrophil come to the bacteria,
now we're going to have phagocytosis.