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Welcome.
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We're gonna charge right into the
early stages of acute inflammation.
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And before even neutrophils arrive,
there are changes in
vascular permeability,
and vascular flow into the tissue.
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That's going to set the stage
for a lot of subsequent things.
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But it's important that we
understand the vascular changes
that are happening.
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So we have an acute inflammation,
three components, three components.
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First one here
is the vascular response.
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And that's what this particular
topic discussion is about.
00:34
We will then transition
to the cellular response,
and how the cells
the neutrophils get in.
00:42
And then we will finally get into
the effector cascades,
the mediators
that gets secreted.
00:47
But for now we're going to focus on
the vascular response.
00:49
And this is going to be part of
the three of the cardinal features
of inflammation.
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This is going to be the calor,
the increased warmth;
the rubor,
the increased redness;
and the tumor,
the increased swelling.
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Keep in mind,
as we go through all of this,
there are lots and lots of details,
tons of details.
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Do not get too bogged down
in the details.
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Why am I even showing them
to you then?
Well, one, they're really important
therapeutic targets.
01:21
And there are many things
that you do
for your own treatment when
you sprain an ankle or something
that are now therapeutic targets
because we understand those details.
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But it's also, they're just
intrinsically interesting.
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So, but see the big picture,
really see and feel the force.
01:43
And don't get too bogged down in
whether Darth Vader is your father.
01:48
All right. First up,
the vascular response.
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So this is going to increase
blood flow,
it's going to be
increased permeability,
and it's going to mediate
inflammatory cell recruitment.
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Okay, so that's why we have
the initial vascular response.
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And this happens incredibly quickly.
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If I were to bang my hand,
right now,
within a couple seconds,
I would be getting to see
the edema.
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And in a couple more minutes,
it might get red.
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And it might even get
a little bit painful. All right.
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So this vasodilation,
why does it happen?
Well, I mean, why is it
important that it happens?
It increases the blood flow
into the tissue
and allows us to deliver cells
and mediators into the tissue.
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So, I'm showing you
on the right hand side,
this happens to be a preparation
from a rabbit ear.
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The central blue stripe
is elastic cartilage.
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The glands that you can see
top and bottom
are little sebaceous glands
that are associated with the
rabbit hair.
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And we're going to in a minute,
add an inflammatory stimulus
that will cause
the vascular changes,
and you'll see how dramatic
it can be.
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So that's why the picture
is there.
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The vascular changes
besides vasodilation,
increased size of the vessel
going into the tissue,
to increase blood flow.
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There is also
increased permeability.
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This happens predominantly
at the level not of the arterioles,
the permeability,
or at the capillaries,
but rather the
post-capillary venules.
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So the veins that are on the
other side of the capillary bed,
and that's where the permeability
is going to occur.
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By having this
increased permeability,
we're losing fluid into
the extravascular space,
that slows the blood flow, right?
Because all of that extra water
is gone.
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So the blood flow slows,
and that allows cells
that were previously
zipping along...
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white blood cells
that are previously zipping along
in the middle of the bloodstream
to tumble out and start rolling
over the surface of the endothelium.
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So that increased permeability is
going to be important for recruiting
inflammatory cells,
but it's also going to allow the
deposition of circulating mediators.
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Okay.
03:59
And here's what happened
to this poor rabbit ear.
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So the the dark blue pink stripe
at the bottom
this is a slightly different
magnification.
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So we can get all on
the same screen,
that blue little purple stripe,
that's that same thickness of
elastic cartilage in the rabbit ear.
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And on one side, we have
rubbed inflammatory stimulus,
we have had increased
vascular permeability,
and increased vasodilation.
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You see some big
blood vessels there
that weren't
previously apparent,
and that is the
early vascular response.
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So this would be red,
it would be hot, and
it would be a edematus.
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So, we'd have rubor, calor,
and tumor.
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And I'm sure the poor rabbit
had some pain too.
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I'm sorry about that.
04:40
I didn't do it.
04:41
Okay. So in the vascular bed,
how is this happening?
How are we getting
increased blood flow
in the vascular bed?
And it happens at the level
of the arteriole
coming into the capillaries.
04:53
So we just drawn
kind of a schematic here
of an arteriole and
then a capillary bed
and then a post-capillary venule.
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At the bottom, you see the arrow,
the red arrow going up,
that's hydrostatic pressure.
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So that's how much force
is exerted,
because of the pressure
within the vessel,
the blood pressure,
and the green arrow going in
reflects the
colloid osmotic pressure.
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So that's the effects of albumin
and other proteins
in the bloodstream,
and to push in,
or to suck in water.
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So we have hydrostatic pressure
pushing water out,
and we have colloid osmotic pressure
bringing water back in.
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And at the arteriole or side,
the pressure winds.
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So you have a net flow of fluid
water for the most part,
but some electrolyte
into the extravascular space.
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In the capillary bed,
it's balanced.
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And then on the other side,
that's very low pressure.
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We now have the colloid forces,
colloid pressure,
greater than the
hydrostatic pressure,
and we have a net inflow
of water.
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So across a capillary bed,
we have a balance.
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And in most tissues,
you don't have any excess edema.
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That changes in the
inflammatory settings.
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So that's just setting the stage.
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So now, if we increase
arteriolar diameter,
now, by increasing kind of flow
into the tissue,
we have a net flow on the front end
that's much greater,
because we've increased the dilation
and the amount of blood that's
getting in there and pressure.
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And we haven't changed
the colloid pressure at all.
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So we have a net flow of fluid out
because of that dilation.
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And then in the capillary bed,
in fact,
all those vessels
are also dilated,
so there's increased
hydrostatic pressure
across the capillary bed.
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And it even continues into
the post capillary venules.
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So that poor
colloid osmotic pressure
is not able to balance that
and we have a net flow
of water and electrolyte
out into the tissues.
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That's happening just because
of increased hydrostatic pressure,
squeezing the water across.
06:59
So how is this
proximal dilation
of the smooth muscle arterioles
happening?
It's happening through
a couple different mediators.
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One is histamine.
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So remember, the mast cells?
The poor cell that doesn't get
any credit?
Well, in fact, one of the things
that releases when it's triggered,
is histamine.
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And that histamine will cause
relaxation of the smooth muscle
in that proximal arteriole
allowing increased blood flow.
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So that happens through mast cell
degranulation.
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It also happens through
nitric oxide.
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So nitric oxide is synthesized by
endothelium and inflammatory cells.
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So other cells that are part
of the equation,
and that will also cause
vasodilation.
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And there are some other mediators
but histamine and nitric oxide
are probably the most important
ones for you to remember.
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That causes smooth muscle
relaxation,
increasing blood flow
into a capillary bed.
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It also happens
that some of the mediators
produced by inflammatory cells
also drive this process.
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So beyond the nitric oxide,
beyond the histamine,
we have something called
eicosanoids.
08:02
And we will come back to this.
We will belabor this point a bit
because the eicosanoids
are very important.
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They come in several
different flavors,
prostaglandins and leukotrienes.
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But they also cause relaxation of
the smooth muscle in the arteriole
allowing increased inflow.
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And those eicosanoids.
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They're made by
inflammatory cells,
but they're made by
every other cell in the mix,
including smooth muscle cell,
including the mast cell,
including macrophages,
including endothelial cells.
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So those are important
inflammatory mediators.
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And we'll pay attention to those
because we have good drugs
that block the activation
of eicosanoids.
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Believe me,
we'll come back to this.