Pathology
08/28/2008
Chronic Inflammation
Transcriber: Sheila Karst Morris
39:16
I am sure you noticed he skipped around a lot; I’ll do my best to keep things straight. I’m numbering the
slides we have starting with page 12 of the Inflammation & Repair handout, the first slide on the page
being Slide 34. I will note when necessary which slide and page he jumped back to. It will probably be
easier to follow if you number your slides as well.
***First three slides are not in our handout.
Slide – Acute Inflammation
We’re going to continue with the discussion about inflammation. Acute inflammation, you’re primarily
thinking about neutrophils, they’re the first to come out, and then you have macrophages to help with
the process.
Slide – Outcomes of Acute Inflammation
As this goes along you get the process of acute inflammation, you either get resolution, abscess
formation or healing (either scar formation or regeneration of tissue).
Slide – Chronic Inflammation
Today what we’re going to do is take it one step further, if you don’t go right to this resolution/abscess
formation or healing, even if you do, it takes longer than just those first two or three days to get to that
stage. That’s what happens with chronic inflammation; things don’t get cleaned up right away and you
get rid of the mess and everything back to normal, things stick around for a while. What are some
examples? If you have a lot of dead tissue, it may take several months to clean out, an infarct for
instance. If you have TB, where the body can’t phagocytose or can’t kill the organism and get rid of it,
it’s a continual process and it just keeps the process going for a long period of time. That’s why it’s
called chronic; it goes on for a long time.
With chronic inflammation, we have the first, no matter what the insult is (foreign body,
mycobacterium), start out with acute response with neutrophils, macrophages and fluid. Remember
neutrophils only live 2-3 days in tissue, may keep trying to send them, but eventually recognized that we
need to send something more helpful, macrophages. They come out into the tissue, can proliferate,
release substances; they’re the main cell type involved in chronic inflammation.
Slide 34
Macrophages are monocytes in the blood, they come out of the blood stream, once in tissue they’re
macrophages. There are also macrophages/phagocytic cells in various tissues, waiting to do their thing.
Examples: kupffer cells in the liver, pulmonary alveolar macrophages, histiocytes, microglia in the brain,
osteoclasts, spleen and lymph nodes are full of lymphocytes and macrophages, and the langerhans cells
in the epidermis.
Pathology: Chronic Inflammation
Sheila Karst Morris
pg. 2
Slide 35
So this is very similar to what we talked about Tuesday with the neutrophils. The monocytes in
circulation bind, roll, emigrate through the wall and enter tissues. Neutrophils, once out, do their thing
and they die. Tissue macrophages can become activated; they release all of these substances that can
cause tissue injury: toxic free radicals, proteases, neutrophil chemotactic factors, coagulation factor, AA
metabolites and NO. This is a diagram out of the book. All of these things help activated macrophages
deal with process going on.
The other thing with chronic inflammation is a lymphocyte component. Chronic is macrophages and
lymphocytes. Those are the two primary players. In this case, it’s an example of activated tlymphocytes; you can also activate b-lymphocytes to make Ab and whatnot.
Slide 36
Lymphocytes, if they’re b-lymphocytes they get activated and can become plasma cells. You have Ab
specific to whatever caused the chronic inflammation. Eosinophils, IgE mediated, primarily in parasitic
infections. Anytime you see a bunch of eosinophils, you must think of an allergic reaction or parasites.
Mast cells are sort of eosinophil type cells in tissues.
Slide 37
You have some sort of stimulus, either an injury, infectious agent, and you have these cells come out
and we call this “chronic inflammation” and we usually call it “granulomatous inflammation”, because
when the cells are out there for a while they form a granulomatous reaction and tend to form
granulomas. I’ll show pictures and describe those.
Chronic inflammation is usually lymphocytes and macrophages, coming out and when you have an
inflammatory reaction that’s chronic, you would call it a granulomatous type of inflammation.
Granulation tissue is different; terminology needs to be kept straight. Granulomatous inflammation is
accumulation of activated macrophages, once they’re out in tissue for a while they’re called epitheloid
because they start taking on a more epithelial appearance, rather than the round appearance expected.
When they form focal aggregates of macrophages and lymphocytes, in a ball/clump, then it’s called a
granuloma.
Slide 38
Unlike neutrophils, macrophages are recruited out into the tissue, once into tissue can actually divide.
If they just sit there dividing for a while, you get a clump of them, called a granuloma. A clump of
macrophages that have been dividing will form a nice little pocket of macrophages. The other things
that can happen are that not only are they dividing to form this clump of tissue, also some of these
cytokines produced by the macrophages and other inflammatory pathways actually immobilize them, so
Pathology: Chronic Inflammation
Sheila Karst Morris
pg. 3
even if they decide to “cut and run” because there’s a bacteria, they can’t because they’re frozen there.
They have to stay there, that’s why you see focal accumulations, which we call a granuloma.
***Pictures from Labs
What’s the classic type of granulation tissue? This is a section of lung; see a focal area of lung tissue.
Last week, we saw caseous necrosis, this is sort of late-stage caseous necrosis, where a lot of the
caseous stuff has gotten a lot of fibrous tissue in it. Within this focal area of chronic inflammation, going
on for probably years, you get what are called granulomas. These little clumps are granulomas.
Inside these granulomas, the center part is caseous because it’s dead material. Outside are multinucleated giant cells, the little blue dots are lymphocytes and macrophages. Giant cells are bunches of
macrophages that have fused together to form one big giant cell. You can also get a macrophage where
the cell will go to divide and the nuclei divide but the cytoplasm won’t divide. That also forms giant
cells. Either by fusion of macrophages or proliferation without dividing. All of the other nuclei around
are lymphocytes and other macrophages.
From another case of TB, see less necrosis. See multinucleated giant cells of various sizes and ages. All
these cells are t-lymphocytes, b-lymphocytes and macrophages. That’s a TB granuloma; it’s called a
granulomatous inflammatory reaction. There are a few plasma cells around the outside.
Why do you get chronic inflammation and granulomas with TB? The TB organism has components that
the macrophages can’t kill, so they come in, try to kill it, can’t, eventually give up and die. Then another
macrophage tries, eventually dies, that’s why the central areas in the granulomas have a lot of dead
material in the center. The caseous material in the center is a bunch of dead macrophages that have
tried to phagocytose the mycobacterial organism but can’t. It’s resistant, they end up dying, and leave
their broken up bodies in the center of the granuloma.
Another example of this is with foreign bodies. Why would you have a chronic infection/process, why
can’t the body clean this out? This is a lab example of a drug dealer who got shot, looking at his lungs.
He was shooting up drugs; often IV drugs have talcum powder in them to cut the drug. Talcum powder
gives you granulomas, (hard to see in this case, took just a lobe of the lung which got smashed). You can
see little nodules; under the microscope you see a blood vessel full of blood, and a big granuloma
around the outside. There are multinucleated giant cells, fibrous tissue, funky pale areas which when
polarized see as birefringent crystals in there. That’s talcum powder. It gets stuck in capillaries of lungs
(and other places in body), macrophages try to phagocytose the crystals, and again they are not able to
break it down. They end up dying because they can’t digest it; dead bodies accumulate as more
macrophages come in. You get a chronic inflammatory reaction around the foreign body.
The body reacts to something with an acute inflammatory reaction, if that doesn’t do it, it turns into a
chronic reaction or in some cases (foreign body & mycobacterium), you actually start out with a chronic
inflammatory reaction. With chronic, it will either stay there and smolder, or if it does heal it heals by
scarring or regeneration.
Pathology: Chronic Inflammation
Sheila Karst Morris
pg. 4
***Slide not in handout - Outcomes of Acute Inflammation
How does the body heal? Acute reaction first, then chronic reaction with macrophages. If they’re
successful in cleaning up the mess, remove dead material and foreign material, as they are killing they’re
also releasing growth factors that stimulate the healing process. It’s all sort of one continuum; acute,
chronic and healing process all in a temporal relationship.
Slide 41 (Page 14)
How does the body heal? What determines it is what type of cell is involved. If a cell is able to
proliferate, still has the capability, depending upon the situation the tissue can regenerate. If you can
make more cells you repopulate the area and regenerate tissue. If the cell cycle is such that they are in
permanent cell stage (cardiac myocytes & neurons), if killed the only thing you can do is form a scar.
You can’t regenerate that tissue.
***Figure from Book
What decides whether you form a scar or regenerate? First is type of cell affected, if the cell is able to
regenerate you can still go two ways. You either form a scar or resolve the damage to the point where
the tissue is completely normal. In the diagram, it shows nicely that if you have injury just to individual
cells, surrounding cells will proliferate and replace it, tissue keeps going on after injury. On the other
hand if you really screw up the tissue, basically you damage the infrastructure (BM, blood vessels,
fibrous CT) even though cells may still proliferate, once they proliferate they don’t know where to go,
they form a clump. In cirrhosis of the liver, you get damage to the parenchyma and to liver cells, BM
and everything else. The liver cells that do proliferate don’t know where to go, and don’t hook up
correctly. You repair that with just scar tissue and a clump of cells not hooked up right.
Slide 44 (Page 15)
The best way to demonstrate this is acute tubular necrosis. If you think about tubules in kidneys, it’s a
tube lined by epithelial cells. If you get hit by a car, go into shock and your heart stops, you don’t have
blood going to body organs for a certain amount of time. If you reach the point of irreversible injury in
kidney cells, they die and fall off, and eventually you will pee them out. They degenerate and leave with
urine.
If someone comes along and does CPR, heart starts beating, and you survive, what you end up with is a
tubule with an intact BM. Blood vessels are still there, fibrous tissue surrounding, so cells adjacent to
area of cell death can proliferate and they can form a new layer inside the tube. Two weeks after the
wreck you can’t pee because of the swelling, you’ll be on renal dialysis. After two weeks, the cells
proliferate and reline the tubules, and you can go home and kidney is totally normal. This is called
resolution. Supporting structures all in tact, can proliferate new cells, form an almost perfect new
tubule.
The other side of it, like the liver we discussed, if you wipe out the whole thing, an infarct and not only
are the epithelial lining cells killed but also have breakdown of BM, blood vessels, and fibrous tissue, you
Pathology: Chronic Inflammation
Sheila Karst Morris
pg. 5
end up with a break in the renal tubule. The cells adjacent can still divide, but they don’t know where to
go. There’s no scaffolding there for them to line up on. You end up with repair of the injury, but it
doesn’t work right because it’s not hooked up correctly. There’s a bunch of factors involved with
whether the injury will be reversible or non-reversible. It depends upon the cell type and the character
of the damage caused in the first place.
Resolution means it goes back to normal function. Repair means you aren’t dead, it repaired itself, but
it’s not working correctly. Often besides not working correctly you get a lot of fibrous connective tissues
associated, a scar.
Slide 47 (Page 16)
How do you form a scar? During healing, if you do have damage to the BM and area, the way you heal is
by causing proliferation of new blood vessels, and proliferation of fibroblasts. Fibroblasts in granulation
tissue can also transform into myofibroblast, it has actin filaments in it (the filament in SM that that
make them contract). Not only are they making collagen with their RER, but they can also contract. You
need wound contraction to pull it all back together.
Slide 40 (Page 14)
The process that occurs is acute inflammation, chronic inflammation, overlapping with this is
granulation tissue (starts early and ends up by trying to form fibrous CT), then after it goes on you begin
to lay down collagen, which forms bands and entire wound contracts form myofibroblasts. Wound
contraction between 10-30 days, it’s a long period of time.
Slide 48 (Page 16)
This is a histologic section of granulation tissue. These are all blood vessels in here because you need
blood in there to help it heal. The other cells, bigger red cells, are fibroblasts and myofibroblasts. The
smaller are lymphocytes and macrophages; remember it’s a continuum from chronic inflammation into
healing.
Remember to keep it straight. There’s granulomatous inflammation, granulomas and granulation tissue,
which is the healing process. You have fibroblasts, blood vessels trying to lay down collagen and form a
scar. It’s different from granulomatous inflammation. To make it really confusing, there’s an overlap
where you have granulomatous inflammation and granulation tissue starting at the same time.
Slide 49
Here it is a month later (15-20 days) more collagen, less cells. This is getting closer to forming scar
tissue. There are also some blood vessels, fewer the later you go. You get a lot of blood vessels at first
to get lots of blood in there, as it begins to mature, the blood vessels sort of squeeze down, get fewer
and fewer.
Slide 42 (Page 14)
Pathology: Chronic Inflammation
Sheila Karst Morris
pg. 6
This is a diagram out of your book to show you that if the BM is intact you get resolution, if you break it
you end up with scar tissue. Underneath the BM in the underlying tissue you have blood vessels and the
different components of the various glycoproteins, collagens, and all that make up the extracellular
matrix. When you see these tissues, although they look like a bunch of cells, there are a lot of complex
interactions going on between the cells, signaling between them.
Slide 45 (Page 15)
Once you get from granulation tissue to beginning laying down collagen, that’s the process called
“wound healing”. We look at it as two separate pathways. Same process, but depending upon what
you start with, it goes two different tracks.
Wound healing called by “primary union”, or “first intention”, classic example is a clean surgical wound.
A scalpel cut on skin, watch it heal. Get a suture, or band-aid to pull edges of wound together. The
wound healing by “second intention” or “secondary union” is like if you fall off a mountain bike and
have a big gash on your arm, half the tissue stuck on the tree you hit. You have a big blob of empty
space that has to fill in and heal.
Slide 46
So here’s the example, on the left is healing by first intention. The incision goes all the way through the
skin, through dermis, into fat tissue. A single nice slice. There’s still fluid in there because of acute
inflammation, release of clotting factor causes a thrombus. Since it’s a clean fresh wound you have
neutrophils. On the right is the mountain bike accident. It’s not quite as deep (could be) but there’s a
big hole where the edges won’t come together, you have to let it granulate it. This is within the first 24
hours.
From 3-7 days go to chronic inflammation, get macrophages, and then start developing granulation
tissue. The granulation tissue is made of new capillaries, and fibroblasts (some of which convert to
myofibroblasts). Because that lesion was so close together, it doesn’t take much to fill in the hole. In a
very short period of time most of the lesion is already filled in with granulation tissue. The large wound
will take a lot longer to fill in, but it’s the same process. Macrophages, fibroblasts and new blood
vessels.
Weeks to months later, you have a fibrous union- back together. The collagen is not mature, starts out
as immature and develops more crosslinking. As more crosslinking occurs the wound gets stronger. In a
month, the strength is only about 10% what it used to be before the cut. It takes a while to develop the
linking to give it strength.
With the second intention, same sort of thing, a bigger area/scar, hasn’t quite filled in yet, it takes
several months before the collagen turns to mature collagen with better strength.
Slide 50 (Page 17)
Pathology: Chronic Inflammation
Sheila Karst Morris
pg. 7
So what are some things that prevent wound healing? One is if inadequate granulation tissue and
healing. The one we see more often, that’s more profound, is excessive scar formation.
Examples: slide 52: hypertrophic scar – instead of healing smooth it heals too much, you get a bump
there. It’s not causing major problems. The other is slide 53: keloid. Instead of healing back to normal
level, it heals so much it produces way too much scar tissue. This shows a young boy with severe burns.
This is “hyperhealing”.
Slide 51
Things that will delay wound healing: poor vascular supply, vitamin C and zinc deficiency, low protein.
Infections, if the wound’s infected get all of the inflammation going on. Tissue necrosis or foreign
material and excessive movement, (keep playing with it).
Slide 54 (Page 18)
Talk about the strength of the collagen: it starts out as tropocollagen, eventually goes through
crosslinking: lysine oxidation which is the step requiring vitamin C, people with scurvy have loose
collagen.
Slide 55
Over a period of time the type III collagen, the initial collagen in beginning would healing is replaced by
type I collagen that within 3 or more months gives 70-80% of original tensile strength.
Slide 56
Just to summarize, have an injury, if persistent damage or a lot of initial damage get fibrosis and scar
tissue. Less serious damage, (no BM damage) get regeneration and resolution or if underlying tissue
damage get healing with scar tissue formation.