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dr weber again.
today we're going to go over the pathology homework which ARGH I FORGOT 
ABOUT!!

1. an abcess in the dermis - how will it heal? first thing that has to 
happen - 2 cm abcess is big. often, an abcess caused by pyogenic 
organisms will have neutrophils come in, killing all organisms, leaving 
behind a sterile abcess - no bacteria left, but pus still present. so the 
inflammatory rxn won't be perpetuated since no viable organisms. if 
abcess isn't lanced or ruptured, you could then wall off the whole thing, 
encasing it in a wall of fibrous CT. the pus in there will inspissate - 
get thicker and thicker - and then may mineralize and remain as 
mineralized focus in dermis gradually getting smaller, parts being 
removed by mphages, but ultimately just sitting there not bothering 
anyone. most of the time does not happen this way. for the most part, 
abcesses keep on causing more and more tissue destruction, so needs to be 
lanced and drained. pus is removed, and you have acute infl cell 
infiltrate continuing at the edges where there are viable tissue, and 
eventually there will be healing via repair and regeneration. there will 
be fibrous CT filling in the defect.
what makes healing process stop? there are a number of things to 
consider. as granulation tissue matures, there is several things 
occuring. gradually cellularity decreases, amt of edema and mphages 
decreases, and great decrease in the # of factors produced which 
stimulate the infl response/healing.
things like high concentrations of TFGb, heparin, IFNa, and PGE2 are 
products that when liberated from cells actually INHIBIT fibroblast 
growth, so these too are involved in inhibiting the healing. one reason 
why granulation tissue ttops and you get less and less fibroplasia, is 
that the inciting agent is gone, and you have fewer and fewer WBC, 
mphage, around, fewer blood vessels and edema, and stimulating factors 
are largely absent. also as granulation tissue matures, there is more 
cell:cell contact as tissue gets denser. cells in close association 
produce connexins allowing molecules to go from one cell to another. we 
don't know all the molecules that can go across. in the surface 
epithelium, between keratinocytes and melanocytes, about 5k to 1 m is the 
normal ratio. if that ratio is upset, eg if you get a melanoma, there are 
more melanocytes in relation to keratinocytes, one must consider that the 
contact inhibition which occurs when cells are close to one another is 
another factor which allows /causes tissue to stop proliferating (WHAT?)

what is exuberant granulation tissue aka "proud flesh" ?
eg on horse leg, you see overgrowth of granulation tissue, growing above 
the surface epithelium. why doesn't it stop when it reaches the surface? 
probably due to constant trauma, reinfection of the area, etc. so there 
is constant stimulation of the healing process. you'd have to cut off and 
cauterize the surface tissue, put pressure bandage on it, and hopefully 
get the granulation tissue that is deeper to mature, and keep it clean so 
surface epi can get across.

also what is a keloid? a keloid is excessive formation of a scar in 
otherwise relatively non-remarkable wounds. the scar is far in excess of 
what one would expect in that area based on the amount of tissue 
destruction that has occured. some people here may get keloids. even a 
small scratch causes a prominent scar to develop, we think because as 
collagen matures and as a wound matures into fibrous CT, normally a 
constant turnover of collagen occurs, partially based on production of 
metalloproteinases. these mps are enzymes which break down collagen and 
are produced by a variety of cells in tissue and are important for 
collagen remodelling. if you don't have a good balance between the mps 
and the factors stimulating fibroblast growth, you may have excess 
collagen deposition. less activation of mps, less breakdown of collagen. 
this is genetically determined and results in production of more scar 
tissue. the mps are made by mphages, fibroblasts, etc. they have to be 
activated in the healing area, and are activated by plasmin, hypochlorite 
(from phagolysosome) - otherwise they aren't active. ok, well, why 
doesn't all the collagen dissolve? There are inhibiting factors. mp 
inhibitors regulate the amt of active mp functioning in an area of wound 
healing. so the remodelling of tissue is dramatic. it is an interplay 
between factors stimulating fibroblast growth and collagen deposition and 
the mps which break down the collagen.

what about the actual tensile strength of the collagen that is formed? if 
you look at a graph of the strength of collagen during wound healing, 
during first five days, there is a breakdown of collagen - neuts and 
mphages are releasing lysosomal enzymes including elastases and 
collagenases, adn they break down collagen. as wound healing then begins, 
you get an increase in strength. the tensile strength never returns to 
100% - at best, you get 80-85%. so the area of wound healing, is always 
the weakest part in the link. a sutured wound, btw, as soon as you get 
done w/surgery, what is the tensile strength of the incision? it's about 
60% of normal.  but once you take the sutures out, it takes about 3 mos 
to get to 85% and never really returns to normal at all.

remember, once collagen is formed, it never totally disappears. it may be 
markedly reduced but it wont' totally go away.

looking at chart - probably on right hand side where it says scarring, 
fibrous CT, basement membrane destroyed, is where this fits in.

2. cow has nail puncture reticulum/pericardial sac, resulting in 
fibrinous exudate in pericardial sac. describe sequelae.

drew diagram of epicardial surface and pericardium and pericardial space. 
normally, there's just a small amt of serous fluid in the space, produced 
by the serosal lining cells. but now, there is a lot of fibrinopurulent 
exudate in there. 
Dana says:
it acts as an irritant in the sac. next, neutrophils come in and 
phagocytose this exudate. granulation tissue is formed. either exudate is 
removed and all is ok, or you end up with adhesions if this isn't 
resolved w/in 4 days.
Doc weber says:
is resolution possible? let's put it this way. if there were no nail in 
there, but instead a viral infxn had caused the pericarditis, a little 
bit of exudate which could be removed w/in 3-4 days by neuts and mphages, 
could be totally resolved leaving no evidence of this episode. resolution 
is possible, provided the exudate isn't too extensive to be removed in 
3-4 days. this is critical because it takes about 3-4 days to trigger 
fibroblasts. once you trigger the fibroblasts, they will lay down ground 
substance and collagen, which is not good in this scenario. so, in this 
situation, there's a nail in there and a lot of exudate, so it will take 
more than 3-4 days to remove exudate, so we're going to have fibroplasia 
to some degree. when you have fibrin present, whenever you have a fibrin 
clot, it had to come from the blood vessels - a severe acute inflammatory 
rxn caused increased vascular permeability - so there is also a lot of 
neutrophils, plasma, proteins - including fibrinogen which now 
polymerized into fibrin - and also including fibronectin, which coats 
everything around it. the fibronectin lining all this fibrin in here is a 
perfect scaffold for fibroblasts to grow on. the fibroblasts come from 
the surface of the epicardium. that's where the acute inflammatory rxn is 
taking place. so there is an outgrowth of fibroblasts along the 
fibronectin coated fibrin fibers. while they are growing, there is 
constant removal of the fibrinopurulent exudate by mphages and neuts, but 
the fibroblasts are making collagen. so the collagen is replacing the 
fibrin. so eventually you have strands of collagen connecting the 
pericardial sac to the epicardial surface. these are called fibrous 
adhesions. originally, we called them "fibrinous" adhesions - made of 
fibrin. but now, they are made of collagen and are termed "fibrous" - got 
it? realize that fibrinous adhesions are easily broken down, aren't as 
strong as fibrous adhesions. a fibrinous adhesion is indicative of recent 
injury. over time, fibrinous adhesions are replaced by the fibrous 
adhesions. so, one or two months down the road, you have these fibrous 
adhesions, and you can't break them down. the whole pericardial space is 
now full of a couple cm worth of collagen. this can start to remodel. as 
it matures, it will start to contract, get denser. but here this is very 
bad. you get a constrictive pericarditis - which means an old progressive 
lesion which prevents the heart from expanding properly because it is 
encased by a wall of fibrous CT. so  in terms of working out what can 
happen here, ask yourself what is the degree of inflammatory rxn, how 
much exudate is present, can it be removed w/in 3-4 days? if it can, you 
can get resolution. if not there can be problems later on. grossly, this 
isn't going to look like true granulation tissue because there is less 
new growth of blood vessels. when we talked about wound healing the other 
day, we had a blood and fibrin clot and we grew new blood vessels - we 
had damaged a very vascular tissue. here, the epicardial surface isn't as 
vascular, and we aren't getting a lot of growth of new blood vessels. 
keep that in mind, in terms of not being so puzzled when you see 
constrictive pericarditis that looks like a grey, shaggy mass. you don't 
see prominent vasculature in this situation. but the basic process is the 
same.

if you came across this clinical scenario at a late stage, what do you 
do?
well, people do rumenotomy, remove nail, put cow on abx, will heal - if 
you do it early enough. but, if cow already has constrictive 
pericarditis, it can NEVER get better. collagen doesn't ever get removed, 
only remodelled. this damage is permanent. if you see the animal after 4 
days but before constriction occurs, could try doing thoracotomy and 
adding fibrinolysins and other enzymes into the pericardial sac, but is 
unlikely you'd get a chance to do that.

what about the nail? at this point, it's only important if it isn't well 
walled off - area around it would get pyogranulomatous rxn - but if not - 
would have continuous infiltration of bacteria stimulating new 
inflammation. if it is well walled off, it's not a big factor here.

note: a number of people have asked "what is hemorrhage"
dr weber says it is when a number of red blood cells are outside of blood 
vessels. can occur two ways. one is by rhexis of blood vessels - 
disruption of the blood vessel. there is another way - often called 
diapedesis, which means "walking through" but RBCs don't have motility to 
"walk" - but with increased vascular permeability, increased pressure in 
the vessel can push RBCs through the gaps in the endothelial lining into 
the extravascular space. this is also hemorrhage.

is everyone happy with the pericarditis and what happens? understand that 
fibrin does NOT chemically convert into collagen. someone always says 
that on an exam and it is NOT TRUE. fibrin is removed by inflammatory 
cells and is replaced by collagen from fibroblasts. will get a reward if 
everyone gets this right on the exam.

3. kidney - cow ingests nephrotoxin resulting in destruction of 10-20% 
renal epi cells. how is it repaired, what is end result?

your nephron has the glomerulus, the tubule - lined by epithelial cells 
on a basement membrane. these are stable epithelial cells. now, we've 
wiped out 15-20% of these cells due to this nephrotoxin. is that a large 
number? well, not really. it's not insignificant, but there are still a 
lot of viable epithelial cells in the tubules. so, what happens is, as 
long as the basement membrane is not destroyed, and here it is not - the 
remaining epi cells, at least a portion of them, are triggered into 
mitosis, to repopulate the gaps in the tubular epithelium. you will get 
complete resolution. so a one time toxic insult wiiping out 15-20% of 
renal tubular epi can totally resolve. necrotic cells will slough off and 
can be seen as casts in the urine. they are replaced by newly generated 
cells.

"tissue with stable or labile cells" is what we're dealing with here. 
since framework is intact, we can get regeneration and total resolution.

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4. next case - also kidney. an infarct in the renal cortex of the kidney. 
two mos later, what do you see?

infarct usually due to thrombus at corticomedullary jction, eg 
thromboembolus from vegetative endocarditis, etc. this causes ischemic or 
coagulation necrosis (same thing) so a  whole wedge shaped area of the 
cortex dies. how does this repair, what is the end result?

Lisa says:
in the center of the infarct, the tubules/glomeruli are dead. may get 
some revascularization around the periphery, but necrotic zone is filled 
in with fibrous CT. in a week, the tubules that didn't totally die may be 
trying to regenerate, but if totally destroyed, also will be replaced by 
fibrous CT. the remaining healthy nephrons may hypertrophy

Doc weber says:
inflammatory rxn must occur in zone between dead and viable tissue. this 
will be acute inflammation occuring - increased vascular permeability, 
dilation of bvs, exudation of neutrophils, gradually macrophages come in, 
etc. whole mass of dead tissue needs to be removed by phagocytic cells. 
meanwhile, granulation tissue from edges is growing in. so gradually, 
whole dead area is removed and replaced by fibrous CT. fibroblasts, 
collagen, etc. as this restructures, what does it look like in 3 mos? 
well, collagen undergoes restructuring aka organization. when infarct 
"organizes" it heals and gets restructured. it's dense fibrous CT, 
contracted, depressed, and firm. how much regeneration can you get of 
tubules or glomeruli in this zone here? well, glomeruli can't regenerate 
at all in any case. any tubules in this zone of total coagulation 
necrosis will also be totally replaced by fibrous CT. there is NO 
regeneration occuring here in this zone. the tubules that were here no 
longer have a scaffold, a basement membrane, all stem cells died, and 
even if a few were there, no normal architecture left to grow along. 
with a 2 cm infarct, not enough stimulus to cause hypertrophy of 
remaining nephrons. this goes next to the previous one on the chart =- 
the framework is destroyed, basement membrane is interrupted, and fibrous 
CT replaces dead tissue.

red infarct vs white infarct is a description of amt of hemorrhage in 
area of infarct. if infarct is white, area is totally blanched due to cut 
off blood supply. although, you don't really know for sure, 'cause could 
be white due to influx of WBCs. a red infarct indicates a lot of 
hemorrhage or diapedesis of RBCs into the area and so it looks red. these 
are really just descriptive terms. they are both infarcts. you can't 
really have a "partial infarction" - when you have an infarct, tissue 
dies.

5. 1-3% of liver parenchymal cells destroyed by a toxin. what damage 
occurs, how is it repaired?

student says: hepatocyte is stable, so can regenerate. since single 
episode, won't see hhyperplastic nodules. the damage is minimal. probably 
not a lot of collagen deposition.

doc says: this is really an insignificant event. the liver cells will be 
removed by mphages and or kuypfer cells so fast that fibroblasts aren't 
activated. you get complete resolution with no clinical signs of a 
problem. no icterus, etc. this is a "no significant necrosis of cells, 
exudate resolved by 4 days, complete restitution of normal tissue" case.

what if it were 5% of liver cells destroyed repeatedly every couple of 
weeks for a year. then what would happen? end result?

after a year or two you'd see a contracted, fibrotic, cirrhotic liver. 
this situation causes chronic inflammatory rxn with contraction, 
distortion, change of color to grey-white, reduction of total organ size, 
compensatory hyperplasia in nodules. may see development of icterus, 
ascites, etc.

if a liver has undergone fibrosis and scarring, can it ever repair to 
normal? well, no. as discussed, collagen can't be removed. BUT if you can 
remove the toxic insult, you can arrest the fibrosis, and maintain 
acceptable liver function due to remarkable regenerative capacity of the 
liver. as long as the regeneration takes place such that bile ducts and 
vascularity are not totally impaired, you can have acceptable liver 
function.

what about pressure atrophy? you get a more and more shrunken,more and 
more nodular liver. the remaining hepatocytes try to compensate. the 
liver starts looking more and more like a tumor, but is reduced in size. 


you can arrest the inflammatory response, but cna't REVERSE it. that's 
the real crux of chronic inflammatory response.

6. pretty simple. probably also falls into left side. dog gets bacterial 
bronchopneumonia - mild amt of purulent exudate in alveoli in part of 
lung, tx w/abx, resolved w/in one week. what are clinical findings  in a 
month? 

effie says:
if a common bacteria not inducing granulomatous inflammation, could get 
complete resolution. if a mycobacterium for example, could get focal 
nodules remaining - granulomas. areas would be walled off areas of 
caseous necrosis +/- mineralization.

doc weber says effie was too detailed :)
bacterial bronchopneumonia doesn't usually involvve mycobacteria or 
fungi. normally it means infxn w/pyogenic organism, which causes an acute 
infl rxn and purulent or fibrinopurulent exudate. here, we txd animal 
aggressively with abx and animal was better in a week. result here is 
since there was no significant destruction of lung tissue, and 
infiltrating neuts and mphages were able to remove exudate w/in 4 days, 
you got total resolution. later, no evidence of the pneumonia is present.


now, if you don't tx dog for a whole week, then start tx, it's too late 
for total resolution. you've built up a week's worth of exudate and 
you've destroyed a fair amount of alveolar septae, and this dead tissue 
and exudate has by now a fibroblast infiltrate and collagen beginning to 
be deposited. so these lungs will end up with some fibrosis. remember - 
once tissue is replaced with collagen, that's it. alveoli can't regrow or 
regenerate, either. 

if it were a TB infxn, yes, would get granulomas.

is the inside of the lung considered a lumen? in a way, but probably 
better thought of as a tissue with tremendous spongelike cavitations 
normally filled with air. trachea is a lumen. but lung is just more like 
aerated tissue, alveolar septae, etc.

but if you inhale a foreign body, will you develop a granuloma?
well, when you inhale things, you wonder how big is it, how far down does 
it get? if you inhale a corn cob, it won't get far. if you inhale 
particulate matter it may get down into alveoli. many times, small 
particles you inhale are actually caught in mucus in bronchioles. but 
very fine dust and plant fibers and asbestos get down into the alveoli. 
depends on size and number what kind of rxn if any you may get.

re: our homework:
amt of collagen formed really depends on amt of injury in tissue, extent 
of inflammatory rxn, etc.

tissue with permanent cells, scarring, fibrotic tissue - brain or 
myocardial muscle. when heart undergoes ischemic necrosis, this is the 
only way to repair.

re: regenerative capicity of tissues...
know that brain, heart do not regenerate.
know that liver does
know that renal tubular epi cells can, glomeruli cannot
know skeletal muscle does not regenerate
know smooth muscle of blood vessels can regenerate.
most parenchymal organs eg liver, pancreas - are stable, can regenerate 
somewhat, but except for liver have limited regenerative capacity
labile cells are mostly surface epithelium - in bladder, resp tract, 
skin, etc.

in what types of granulomas would immune system play significant role? in 
granulomas stimulated by something antigenic eg proteinacous. bacteria, 
parasites, fungi, etc will cause immune type granulomas. but a sterile 
metal fragment, sterile wood splinter, sterile gauze, plant fiber - not 
antigenic. so why does a granuloma form, if immune system isnt involved? 
well, macrophages can't phagocytose the sterile foreign body, but they do 
get activated trying to phagocytose it, and they release factors 
triggering the granulomatous response. also lymphocytes are stimulated as 
well by these factors. but this is not an immunologically specific 
reaction. there is stimulation of components of the immune system, but 
nonspecifically.

caseous necrosis in a granuloma is pretty much specific to 
mycobacterially induced granulomas.

back to question one: the wood splinter is contaminated with pyogenic 
bacteria. an abscess implies presence of pyogenic organisms (pus forming 
organisms) eg staph, strep. on the other hand, if you take a different 
organism, eg weird strain of streptococci - may produce enzymes eg 
hyaluronidase, lecithinase, etc - which break down fibrin. so you get a 
very dissecting inflammatory response, a cellulitis. so the infecting 
organism can determine the type of response.

what happens to parasite? will act like an antigenic foreign body. will 
cause a granuloma.

in lab today - efficiently go over some slides we haven't gone through 
yet. after that, we can go...

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