00:01
So the general overall picture
that you need to keep in your mind
when we're talking about injury
in non-regenerating tissues,
or when there's a lot of damage,
is if we're gonna have scarring,
we're gonna have fibrosis.
00:12
So the first panel
there we see ourselves,
we see an area of injury
where cells have died.
00:18
And we have lost
some degree of matrix
around that area,
or some blood vessels.
00:23
Okay.
00:24
We then recruit in neutrophils first
and then macrophages
so that we get the
tissue breakdown
and set the stage for the
subsequent healing responses.
00:33
In these tissues
that cannot regenerate,
we get angiogenesis,
we get granulation tissue.
00:37
So we're seeing the sprouting
from those vessels
into the area of injury.
00:42
Being recruited
those new vessels
by the macrophages
that are in there.
00:48
And then on that provisional matrix
on those railroad tracks,
we bring in fibroblasts
that proliferate, migrate,
and lay down new matrix.
00:57
So we get ECM
extracellular matrix deposition.
01:01
And it's a combination
of increased synthesis,
and decreased degradation
because we are inhibiting
matrix metalloproteinases.
01:09
In a minute, we're also going to see
the next stage
where that scar changes,
it's not just always
going to be that big lump
of fibrosis in the middle,
it's going to remodel.
01:19
But this paradigm
is extremely stereotypical.
01:24
And it happens in any tissue that
cannot completely regenerate.
01:30
And it's going to be kind of
a major underlying process
that will occur
in a lot of pathologies.
01:36
So we will revisit this
in other guises.
01:38
But this is a very stereotypical
response in any healing injury.
01:44
Okay, so, in
non-regenerating tissues,
the principal
mediators in scarring,
first of all,
we have the tissue breakdown
and macrophage activation, and
that's through interferon gamma.
01:57
We get neutrophils,
we get macrophages,
we get licensable enzymes,
we get reactive oxygen species.
02:03
And then we get angiogenesis,
driven by basic FGF, and VEGF,
all the activities of
by those two factors.
02:11
and more,
but those two factors, mainly.
02:13
Fibroblasts need to migrate,
and proliferate.
02:16
This is going to be
growth factors,
epidermal growth factor,
interleukin-1 and TNF.
02:22
They're going to deposit matrix
through increased
synthesis of matrix
and decreased degradation
and that's driven by TGF-beta.
02:31
And then we're gonna have
inhibition of cellular activation,
we're gonna put a brake
on the entire process.
02:37
And again, really importantly,
that's TGF beta.
02:41
So on this one slide,
we've kind of summarized
the important factors
that you need to kind of
keep in mind.