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finishing up acute inflammation (with my nifty new keyboard :))
then moving into chronic inflammation.

Abscess vs cellulitis: 

abscess is a localized collection of pus in tissue.
Pus is formed during acute inflammatory rxn produced by pyogenic 
organisms which release chemotactic proteins which draw in large numbers 
of neutrophils.
neutrophils die in about 48 hrs, causing tissue breakdown and pus 
formation.

eg, if you puncture the skin and introduce staph. aureus, you can get a 
localized abscess...

how does an abscess heal? what are the sequelae? central part of abscess 
is dead and dying material. that material has to be removed somehow. if 
abscess is near surface of body, can lance abscess and drain all the 
purulent material out of the abscess. 

as abscess progresses, usually a dense wall of fibrin localizes around 
the abscess, localizing the inflammatory rxn. fibroblasts in periphery of 
abscess are activated, further localizing it. so this is really a 
localized, acute, inflammatory rxn. fibroblasts start to lay down 
collagen as well.

cellulitis is the opposite. also called "phlegmon" sometimes. here, rxn 
widely dissects through fascial and tissue planes. the organisms involved 
with this eg streptococcal strains et al, have the ability to liberate 
fibrinolysins, lecithinases, hyaluronidase, etc - and these enzymes break 
down any fibrin wall that may be forming in the area of inflammation. so 
these enzymes prevent the walling off/localization of the infxn.  so a 
cellulitis is a more serious problem than an abscess, in general. eg, 
infxn from bite wound on neck can enter the chest cavity via a cellulitis 
rxn, vs staying localized  from abcess.

ulcer: localized debridation of surface epithelium, caused by underlying 
inflammatory rxn leading to sloughing off of surface epithelium. complete 
loss of surface epithelium occurs. occur in GI tract, urinary tract, 
skin.

ask yourself - how does an ulcer heal? well, in stomach, may be very hard 
for it to heal. surface epi is lost, and submucosa is exposed to low pH 
and food constantly. this isn't conducive to healing at all. the edges of 
the ulcer on the other hand, as the ulcer progresses, the ulcer may go 
deeper into the submucosa and even erode into some big blood vessel 
causing internal hemorrhage, or could perforate through the serosa, and 
cause a chemical peritonitis. but while this is going on, the surface epi 
will keep trying to cover the defect. so you get tremendous hyperplasia 
at the edge of the ulcer, and you see bulging areas around the edge of 
the ulcer. if edges are sharp, it must be recent ulcer. if you start 
seeing distinct bulges (hyperplasia) then you know this has been going on 
for longer.

characterization of inflammatory lesions based on exudate:
types of exudate:
serous: very low protein, few cells - watery serum fluid. eg, when joint 
injury occurs and joint swells, usually has a serous exudate. also 
blister resulting from a burn contains serous exudate.

serosanguinous: similar to serous, but has some red blood cells in it.  
note that in a plain hemorrhagic exudate, there is rupture of blood 
vessel. serosanguinous exudate occurs when RBCs just escape out of gaps 
between endothelial cells. you can't always tell difference between frank 
hemorrhage and "diapedesis of red blood cells" that occurs here just by 
looking.

purulent/suppurative: pus is present, indicating acute infl rxn with lots 
of neutrophils.

fibrinous: there is accumulation of grossly visible fibrin tags on 
surface of organ eg liver, pleura, spleen, whatever. it comes from 
fibrinogen which polymerizes into fibrin. how does body deal with large 
amt of fibrin on an organ surface? think about it.

fibrinopurulent: combination of accumulation of fibrin and lots of pus. 
many bacteria produce this kind of exudate in an acute infl response. 
when fibrin is present, lots of fibrinogen is leaking out of blood 
vessels, remember.

catarrhal: forms along mucous membranes. if you have a catarrhal 
rhinitis, you have a really runny nose. also in GI tract, respiratory 
tract, anywhere you produce alot of mucous.

pseudomembranous: doesn't occur often. usually occurs along mms, oral 
cavity, resp, GI tract. caused usually by some highly necrotizing 
organisms that have potent exotoxins. the exotoxins kill the surface 
layer of the mucosa. underneath it you get an intense acute infl rxn, 
cauing outpouring of lots of plasma and fibrinogen which mats with 
overlying dead mucosa, forming a "false membrane" - think of diptheria, 
right? the overlying surface epi matted together with fibrin, WBC, etc 
form a white/grey or pink fake membrane. corynebacterium which cause 
bacteria cause this problem in the pharynx. if pseudomembrane was 
stripped off, saw intense acute hemorrhagic inflammatory response beneath 
it. in pigs, corynebacterium cause this in GI tract - farmers think pigs 
are defecating their actual GI tracts, but it's really the inside layer 
of the small intestine which has sloughed off.

try to use these terms as necessary in description of your gross 
specimens.

finally before moving into chronic infl rxn, here's how some people 
characterize acute infl rxn by time course:

immediate transient infl rxn happen quickly and then go away - eg, 
immediate hypersensitivity rxn. lasts about 15-20 min.

most inflammatory rxns though, are caused by trauma or bacteria, and are 
immediate and prolonged - immediate part caused by preformed histamine, 
serotonin, and early produced bradykinin, and then prolonged phase is 
caused by leukotrienes and other newly formed mediators.

another type has a delayed onset and prolonged reaction - seen primarily 
in situations where cause of infl rxn is radiation. if you go to the 
beach, and lay there for three hrs, by the time you get home and have a 
few beers, and someone slaps you on the back, you suddenly realize you're 
fried. this is caused by leukotrienes and prostoglandins, mainly. in 
australia they gave people aspirin to cut down on prostoglandin 
production - lo and behold, sunburn severity was reduced. most people 
would rather take pina coladas than aspirin though,and those don't help 
at all.

quick wrapup of acute inflammatory rxn:
don't fall behind. try to keep up. 
there used to be only a pathology final exam, no midterm.  students used 
to come in a couple of days before the exam and beg for help...

CHRONIC inflammatory rxns:
we characterize acute infl rxn as primarily exudative - increased 
vasodilation, vascular permeability, etc.

chronic is one where inflammatory rxn persists over weeks, mos, even 
years. histologically, is characterized by:
continuous low grade tissue destruction in area of rxn
tremendous influx of chronic inflammatory cells - mainly mononuclear eg 
lymphs, monos, and plasma cells. (contrast with PMNS of acute infl rxn). 
these cells accumulate mainly by immigration to the site. they produce 
alot of factors which are in part responsible for continued destruction 
of tissue, and are also responsible for stimulation of fibroblasts such 
that fibroblasts then produce collagen.

what causes chronic inflammation? persistence of virus or bacterium or 
parasite or fungus will tend to induce chronic inflammation. this could 
be due to the invading organisms escaping the immune system attacks, or 
whatever. repeated episodes of acute inflammatory rxns due to otherwise 
innocuous organisms can also cause chronic inflammatory rxn - eg, if you 
have a bout of cystitis every few weeks or every month, ultimately the 
bladder mucosa and wall will respond with a chronic type inflammatory 
response. repeated trauma to one location can cause this as well. 
repeated exposure or chronic low grade exposure to a hepatotoxin (pina 
coladas...) is a good inducer of chronic inflammatory rxn in liver. 
drinking philadelphia water regularly can induce chronic inflammation in 
the kidney (i hope he's joking here). another important category of 
chronic inflammatory rxn inducing substances is autoimmune disease.

think of rheumatoid arthritis: rheumatoid factor, an IgM made against Fc 
portion of Ig, is deposited in joints, activates complement, neutrophils 
come in, release lysosomal enzymes, draws in monocytes - and this rxn 
persists over mos/yrs, so the joint is ultimately destroyed by fibrosis 
and ankylosis as joint surfaces are bound together by excess fibrous 
tissue.

glomerulonephritis secondary to immune complex dz over time eg in cat 
w/FIV - glomeruli are gradually destroyed, you have a chronic 
inflammatory rxn in glomeruli. how do you see this grossly?
well, there are about 4 or 5 things to know - that is, what would you 
expect organ to do when it undergoes chronic infl rxn? bigger or smaller?


will get smaller. BUT in initial stage of chronic infl rxn when monos and 
fibroblasts are proliferating, you may see some swelling. but ultimately, 
organ gets smaller, distorted, and contracted. this is usually not 
uniform/even, but more uneven. so you see anatomical distortion. if liver 
is undergoing chronic infl rxn, you see an unusual shape - liver can 
regenerate, so will see nodules that kinda look like tumors, but whole 
liver will be less than 3% of body wt. so you know it is contracted, and 
you will see this distortion.

why do organs get contracted? fibroplasia is occuring. when fibroblasts 
lay down collagen, some of it gets remodeled, but ultimately it gets 
contracted. fibroblasts have actin and myosin and physically contract, so 
organ gets smaller. also, increased collagen causes organ to become more 
grey - collagen is grey-white. how would that change consistency of 
organ? will be much firmer, and harder. this is again due to increased 
amt of collagen. 

organ gets smaller, contracted, distorted, grey-white, firm...what else?
the function of the organ is markedly impaired. chronic inflammation of 
liver or kidney produces marked functional deterioration of the organ 
system.

really isn't that difficult..should be able to clearly differentiate 
between acute and chronic...

now, it's easier to see these changes on slides...so, here are a few!

SLIDES:

tranquil mountain scene with some animals and stuff.

why in chronic infl rxn do we have continuous destruction of tissue?
activated macrophage leads to continuous tissue injury by liberating 
oxygen metabolites, proteases, collagenase, elastase, etc, neutrophil 
chemotactic factors drawing in more neuts which die and cause more tissue 
destruction themselves, coagulation factors eg vWf, etc, arachadonic acid 
metabolites eg leukotrienes, prostoglandins, and NO as well. these all 
lead to tissue destruction. also they draw in more monocytes to 
perpetuate rxn. 
the macrophages also liberate a lot of growth factors eg PDGF, FGF, TGFb 
which are all fibrogenic cytokines - stimulate fibroblasts to make 
collagen, also angiogenic factors which promote blood vessel growth, and 
also remodelling collagenases.

in addition to mphage, T cells and B cells are involved. TNFa is 
liberated from mphage and T cells and causes fibrosis as well.

stomach with duodenum and pancreas attached - pancreas is normal

stomach with pancreas and duodenum: marked hyperemia of duodenum, green 
discoloration of one segment of duodenum. pancreas large, swollen, 
hyperemic, sharply demarcated yellow/brown zones of tissue scattered 
through pancreas which are zones of necrosis. this is an acute change. 
acute pancreatitis: swelling, hyperemia, focal necrosis, etc. most 
animals die quickly in septic shock from this.

unrecognizable pancreas. large brown/black discolored area with strands 
of firm white tissue seen on section. 

what happens during pancreatitis? what keeps infl rxn going? you keep 
liberating the pancreatic enzymes eg lipase, amylase, etc, right into the 
tissue itself, which leads to chronic infl response. so there is lots of 
necrosis, and some foci of acute infl rxn, but also lots of collagen 
deposition around the pancreas here, and as collagen contracts, pancreas 
undergoes pressure atrophy.

if you have a pancreas almost completely gone from chronic pancreatitis, 
how does this manifest clinically? animal will have fatty, foul smelling 
stools due to lack of lipase. also  if pancreas is totally destroyed, you 
functionally destroy the islet cells as well, so you can see diabetes 
develop.

normal pancreas slide - can see islet and acinar cells and it's all nice 
and normal.

area of chronic inflammation in pancreas: there is loss of normal cell 
architecture - liquefactive or coagulative necrosis killing the 
pancreatic acinar tissue. adjacent to that region is fibrillar, 
strandlike eosinophilic material - collagen. inside that region are large 
ovoid nuclei of activated fibroblasts. also there are chronic 
inflammatory cells present. 

in another spot, there are recognizable acinar cells which are embedded 
in a mass of fibroblastic tissue, and which appear to be undergoing 
pressure atrophy, as they are kind of smaller looking with lots of space 
between them. note the mononuclear cells within the collagen-filled 
region. note also the actively growing blood vessels containing a few red 
cells within the collagen filled region.

chronic infl cell infiltrate: large cells with eccentricly located and 
kinda bean shaped nucleus and lg amt of cytoplasm are macrophages. (do 
not confuse w/plasma cell which is usually darker...)

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someone asked about something over break...
what is the difference between fibrin and collagen?

well, fibrin is always associated with acute inflammatory rxn. it's a 
polymer of fibrinogen. fibrinogen comes out of blood vessels and 
polymerizes. has nothing to do with collagen. a fibroblast doesn't make 
fibrin! fibrinogen is an acute phase protein made in liver. when vascular 
permeability increases, fibrinogen gets out and polymerizes. once the 
fibrin accumulates, it may stimulate fibroplasia.

fibroblasts are stimulated during chronic infl rxn to produce collagen. 
this is usually an attempt to heal. collagen is a totally separate 
substance.

anyway.

liver is another organ where chronic inflammatory rxn produces grossly 
visible changes.

slides:

normal liver.

normal liver.

abnormal liver. background color is more yellow-brown. surface is 
dissected by widely dissecting areas of yellow grey tissue leaving 
discrete islands of liver parenchyma showing through. this white grey 
tissue is all collagen. you can see there is some degree of contraction 
and some elevation of "pancreatic acinar" tissue (???!!!??? he must mean 
hepatic tissue). as the collagen causes pressure atrophy of surrounding 
parenchymal cells, remaining hepatocytes will try to compensate by 
undergoing hyperplasia. so you see nodular hyperplasia as a compensation 
for fibrosis of the liver. total organ size is smaller and organ is 
firmer. ok, he just said he meant liver parenchymal cells are 
proliferating, not pancreatic acinar cells :). pancreas doesn't undergo 
this kind of hyperplasia. only the liver parenchymal cells undergo 
significant hyperplasia.

another abnormal liver. discrete multifocal coarse nodularity of liver 
surface. liver is yellow and contracted. fatty change occurs with chronic 
inflammation as well.

another abnormal liver. normal heart and lung. congested purple kidney. 
normal spleen. liver markedly contracted, distorted, nodular as described 
above. grey white tissue present indicative of fibroplasia/increased 
collagen. this is not a functional liver.

what is the cause of this chronic hepatitis/fibrosis/cirrhosis?

will you be able to tell the cause by looking at it? we're looking at end 
stage of long process. we have no idea if it was caused by chronic 
infection, toxin exposure, etc. often when you look at chronically 
inflamed organ you can't tell what initial inciting cause was.

another abnormal liver: very small, extremely nodular, extreme 
contraction. grey-white discoloration, etc. this organ markedly smaller 
than normal liver, and only a few functional nodules of parenchymal cells 
seem to be present.

how do you recognize this histologically?

normal architecture- central lobular area, hepatic cords, sinusoids, 
kuypfer cells, etc. 

chronic fibrosis - can't recognize it as liver. see fatty changes in 
hepatocytes, lots of eosinophilic background material (collagen) and 
active fibroblasts, total loss of normal architecture, maybe notice a few 
bile ducts or something. how will blood get through this liver? what 
happens when blood can't get through liver? (hepatic encephalopathy?)

another organ that shows chronic infl well is kidney.
normal kidney - nice smooth edge, smooth rounded cortex, good ratio of 
2:1, fat in renal pelvis. subcapsular surface nice mahogany color w/no 
marked indentations, smooth, glistening, etc.

abnormal kidney: surface is distorted, coarsely granular, with multifocal 
yellow-white appearing tissue, and is extremely firm. on section see loss 
of architecture - dilated pelvis - very little medulla visible. this 
kidney is affected by diffuse fibrosis.

histologically, we see loss of normal architecture as well. tremendous 
increase of amt of connective tissue. distension of tubules is quite 
marked, eosinophilic material present. areas of inflammatory cell 
infiltration present.

abnormal urinary tract: large thick wall of bladder. large prostate. one 
kidney contains huge stone which caused marked pressure atrophy of much 
of kidney parenchyma. other kidney has marked reduction in amt of medulla 
and also has a lot of collagen present which is the remnant of the normal 
architecture of the kidney - eg, backpressure into kidney due to chronic 
purulent prostatitis caused atrophy of medulla, leaving behind the 
collagen, which used to be support tissue. cortical region of same kidney 
has newly formed collagen. this kidney has undergone severe 
hydronephrosis. 
bladder mucosa is elevated, large area of necrosis, bladder wall very 
thick with very prominent, hypertrophied, smooth muscle layer. this 
animal had outflow obstruction. nodular elevation of bladder mucosa is 
present . .. remember that mucosa when chronically irritated will undergo 
hyperplasia, and then will undergo metaplasia. when you talk about 
inflammatory rxn in any organ, think of what tissue is normally present, 
eg here mucosa, submucosa, muscle, serosa. how can each constituent 
respond to inflammation? if you thinka bout it, you can come up iwth the 
answers, most likely :). so always do that, and it will help a lot esp 
when you get to neoplasia, etc. always know normal composition of tissue.


chronic cystitis - mucosa of bladder showing prominent, rounded ridges in 
mucosa, and numerous petechia and ecchymotic hemorrhage. hyperplastic 
mucosa with hemorrhage. sectioned surface of kidney is also abnormal. 
more grey white, distorted, contracted, uneven cortex: medulla ratio.

so the liver and kidney and pancreas show progression of acute-->chronic 
infl pretty well. in order to get chronic infl rxn do you always have to 
have grossly visible signs of an acute infl rxn, that led to chronic 
changes?

many times, in organs that have undergone chronic changes, you do NOT see 
any evidence of acute infl rxn. you can have chronic fibrosis without 
ever seeing acute changes grossly. BUT you might see focal areas of PMN 
infiltration histologically. but the upshot is you can have a very low 
grade acute rxn over a period of weeks/mos resulting in chronic changes 
w/o ever seeing acute rxn grossly. like a smoldering fire...

functional changes in organ are always most dramatic.

moving on to lab....

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