To remember the four causes of cell injury, think of how the injury tipped (or

TIPD) the scale of homeostasis:

T: Toxin or other lethal (cytotoxic) substance
I: Infection
P: Physical insult or injury
D: Deficit, or lack of water, oxygen, or nutrients.

Necrosis: the 4 types

"Life Can Get Complicated":
Liquifactive
Coagulation
Gangrene
Caseous
· 'Life' used since necrosis is 'death'.

Gout: factors that can precipitate an attack of acute gouty

arthritis
DARK:
Diuretics
Alcohol
Renal disease
Kicked (trauma)
· And, the attack occurs most often at night [thus "dark"].
Real Clinicians Don't Take Five
The five cardinal signs for inflammation:
Rubor, Calor, Dolor, Tumor, Function Loss

Blood disorders: commoner sex

HE (male) gets:
HEmophilia (X-linked)
HEinz bodies (G6PD deficiency, causing HEmolytic anemia: X-linked)
HEmochromatosis (male predominance)
HEart attacks (male predominance)
HEnoch-Schonlein purpura (male predominance)
SHE (female) gets:
SHEehan's syndrome
Mnemonic acronym for agents of disease = “double MINT”
Malformation (genetics, teratogens, etc)
Miscellaneous (metabolic, aging, hypoxia, etc)
Infectious (viruses, bacteria, fungi, etc)
Immune (immune mediated, hypersensitivity, autoimmune, etc)
Nutritional (protein-caloric intake, vitamins, minerals, etc)
Neoplastic (epithelial, mesenchymal, etc)
Trauma (mechanical, temperature, radiation, etc)
Toxicity (inorangic, chemicals / drugs, plant toxins, etc)

FATTY CHANGE ("fatty metamorphosis", "fatty degeneration", "steatosis"):

accumulation of excess neutral fat in vacuoles within non-adipocytes

If there's one big fat vacuole, it's "macrovesicular". If there's many little
fat vacuoles, it's "microvesicular".
Fatty change of injured cells occurs classically in the liver and the
heart.

There are at least six mechanisms by which the liver cell

accumulates fat during disease, any or all of which may be
operating in a given situation.

1. Too much free fat coming to the liver

2. Too much fatty acid synthesis by the liver

3. Impaired fatty acid oxidation by the liver

4. Excess esterification of fatty acid to triglycerides by the

liver

5. Too little apoprotein synthesis by the liver

6. Failure of lipoprotein secretion by the liver.

At first the fat accumulates in the rough endoplasmic reticulum,

but soon fat globules occur that are not membrane-bound.

You will care for many patients with fatty liver.

It is now clear that, as the world gets fatter, the

commonest cause of fatty liver in non-drinkers is non-
alcoholic steatohepatitis ("NASH", runs with "the
metabolic syndrome"). Much, much more about this later.

Fatty liver develops during heavy drinking, and all six

mechanisms are known to contribute here.

As you'd expect (why?), liver hypoxia from any cause will

produce mild fatty change. Also note that both ischemia
and toxic injury are worst in the centers of the lobules,
since this is where the oxygen supply is poorest (why?)

If the fat is periportal, think of malnutrition / total

parenteral nutrition / AIDS wasting.

* Among the viruses, only hepatitis C produces much

fatty change. Nobody knows why.

Other causes of heavy-duty fatty liver include kwashiorkor

(why?), Reye's syndrome, poisoning by phosphorus,
carbon tetrachloride, * outdated tetracycline, pregnancy
(rare and mysterious), * the bad kind of galactosemia,
and * following ileal bypass for weight reduction.
 Fatty change in the heart is seen in two classic situations, both
fortunately rare today:

(1) It most often reflects poor oxygenation (i.e., chronic severe

anemia). It is distributed away from the vessels, and produces a
"tiger-stripe" or "thrush-breast" heart.

(2) The heart damaged by diphtheria exotoxin is uniformly flabby

and often fatty. (The old idea that diphtheria toxin block fatty acid
burning by inhibiting the carnitine shuttle has been replaced by
the finding that the protein is a nonspecific and very potent
inhibitor of protein synthesis.).

Notice that the injured, fat-laden cell may not be permanently

damaged or killed. And remember cells can and do die without
undergoing fatty changes.

Accumulation of fat in phagocytic cells is a common theme in

pathology. The fat is usually made up largely of cholesterol esters.

You'll see this in brain necrosis and in xanthomas

(hyperlipidemia, "strawberry gallbladder", idiopathic).

Atherosclerosis, still the #1 disease in our country, results when

phagocytic cells in the intimal layers of large arteries become
engorged with cholesterol and its esters. The phagocytes
themselves tend to die off and leave the cholesterol to
crystallize.

You can recognize cholesterol (esters) in tissue sections

by the "needle-shaped" clear spaces left behind when it is
removed in processing. (* Cholesterol crystals are really
flat rectangles in cross section).

{11051} early atherosclerosis ("fatty streaks", all of you have these already)
{11648} early atherosclerosis, gross (natural-color and "oil red O stain")

LEARN FIRST

Acute inflammation is a stereotyped response to recent or ongoing

injury. Although the process is complex, the principal features are
dilatation and leaking of vessels, and involvement of circulating
neutrophils.

You can recognize neutrophils in tissue sections by their segmented

nuclei. Pus is neutrophils plus liquefaction necrosis . Usually, the
neutrophils themselves caused most of the necrosis.

Chronic inflammation ("late-phase inflammation") is a response to

prolonged problems, orchestrated by T-helper lymphocytes. It may
 feature recruitment and activation of T- and B-lymphocytes,
macrophages, eosinophils, and/or fibroblasts. Again, the process is
complex. You will recognize lymphocytes in tissue section by their
small, "blue button" nuclei.

Granulomas are seen in certain chronic inflammation situations. They

are clusters of macrophages that have stuck tightly together, typically
to wall something off. Such macrophages are called epithelioid cells.
You will recognize granulomas in tissue sections by their characteristic
appearance, or the presence of giant cells.

Fibrin is fibrinogen released from damaged vessels, and activated by

the clotting cascades when blood meets tissue juices. Fibrin forms the
meshwork that controls bleeding, and then becomes the framework for
fibroblasts and angioblasts that will form the scar. Until the new scar is
complete, the whole meshwork of immature scar is called granulation
tissue. When the scar has matured, it contracts.

INTRODUCTION

War is the metaphor for inflammation. Both are necessary

evils. Both are more-or-less stereotyped responses to
outside threats. There are specialized troops (white cells),
including suicide-commandos (neutrophils), long-term siege
armies (granulomas), and many others. There are supply
routes (vessels), communications and intelligence
(mediators), and a huge array of lethal weapons
(inflammatory enzymes). In war as in inflammation, there will
be damage to both the enemy and to friendly forces, and
there will very likely be severe damage to the battlefield itself.
Despite idealistic rhetoric about "the laws of war", when the
fighting starts, there is really only one law for the soldiers:
"Kill your enemy." Like it or not, if you want peace, you must
be prepared to fight under certain conditions. Like it or not, if
you want to be healthy, your body must be able to mount an
inflammatory response. Force will always rule our world. Our
best hope is that this will be the force of good laws. And the
best for which we can hope from the inflammatory response
is that, for most of our lives, it will do us more good than
harm.

Probably your own death will be caused by your last inflammatory

response.

"Big Robbins" defines inflammation as "the reaction of vascularized living

tissue to local injury". Inflammation is the name given to the more-or-less
stereotyped ways our tissues respond to noxious stimuli, with blood vessels
and white blood cells as its twin centerpieces and a host of proteins as actors.
Inflammation "destroys, dilutes, or walls off the injurious agent" and sets in
motion the limited powers of the body to heal itself. Inflammation and repair
can and do themselves damage the body.

Strictly speaking, "immunity" is all the things the body does in defense against
invaders (growing skin, making neutrophils, etc., etc.) As used today, the
unmodified word immunity refers to the activities of B ("humoral immunity")
and T ("cellular immunity") lymphocytes.

Beginning medical students have a tendency to equate "inflammation" and

infection, at least unconsciously. This is plain wrong. Several infectious
diseases feature no inflammation (Creutzfeldt-Jacob disease, yellow fever,
and many of the opportunistic infections in AIDS are only three examples.)
Noxious, non-infectious things that produce inflammation include trauma,
radiation injury, various poisons, chemical or thermal burns, tissue necrosis
itself (except apoptosis), and any of the four major types of immunologic
injury. (You'll learn about all of these soon enough.) A sunburn or a red
scratch are inflammation, just like mosquito bites, pimples, plague and
leprosy .

Obviously, there are differences among inflammatory reactions. Acute

inflammation is almost completely stereotyped -- over minutes to a few days,
blood vessels widen and disgorge protein, and neutrophils leave the
bloodstream and rampage through surrounding tissues. Chronic inflammation
is more variable, with variable participation by lymphocytes, plasma cells,
macrophages, and healing cells (fibroblasts and angioblasts).

Whole body inflammation, formerly a popular term used especially by

surgeons for the patients who they could not save, is going out of
fashion in favor of multiple organ failure.

Whatever you call it, in super-sick people, various cytokines

increase tremendously in the bloodstream; this situation
interacts with ischemia, free radical production, and leakage of
heatshock proteins from cells to create a vicious downward
cycle into irreversible shock. See JAMA 271: 226, 1994; Surg.
Clin. N.A. 80: 885, 2000; Crit. Care Med. 28: 537, 2000; Crit.
Care Med. 29(7S): S-99, 2001.

As pathologists, we recognize "multliple organ failure" clinically

by a striking drop in the absolute lymphocyte count caused by
apoptosis of these cells; lymphoid depletion is seen at autopsy
(J. Imm. 174: 3765, 2005).

"Subacute inflammation" does not describe a distinct pattern.

We suggest that you first try to understand inflammation at the light

microscopic level. You are already acquainted with fibrinogen and fibrin. Only
when you have a clear picture of acute inflammation, chronic inflammation,
and wound repair should you go back and learn the host of molecular
mediators that derive from cells and plasma. All those mediators: J. Allerg.
Clin. Imm. 103: S-378, 1999; or if you really want to go deep, J. Allerg. Clin.
Imm. 106: 817, 2000. Still deeper: The genes / proteins that modulate the
inflammatory response: Nature 420: 846, 2002. Dozens are known, each has
an associated clinical syndrome in patients bearing mutations, and each is a
potential target for therapy.

The suffix that indicates inflammation is "-itis" (the plural is "-itides".

Philologists: "-osis" means "full of".)

* The public recognizes inflammation, and the words "inflame" and

"inflammatory" have found their way into journalism and law.

Terms for abnormal accumulations of fluid: A transudate is protein-poor salt

water squeezed through blood vessels by hydrostatic pressure, i.e., it has
specific gravity of extracellular fluid, 1.010 or thereabouts. An exudate is an
abnormal, protein-rich fluid that has leaked out of inflamed vessels.

A body fluid (either an exudate or an area of liquefaction necrosis ) containing

neutrophilic leukocytes and necrotic debris is pus. The preferred adjective to
describe things with lots of pus is purulent. To produce pus is to suppurate.
Pus that literally fills an important body cavity is called an empyema. (This is
most common in the pleural cavities.) If you've got a lot of pus, you need it
drained by a surgeon.

* Of course, it was Virchow who first demystified pus, showing that it

was white cells and necrosis.
Pus Purulent meningitis
Suppurative pericarditis
WebPath Photo WebPath Photo
Purulent peritonitis

WebPath Photo

Pus requires no description, but it is worth mentioning at this

point that is not always the same color or thickness.

Pus always has a yellow-green tinge because of

myeloperoxidase.

Classic yellow pus (as in a staphylococcal boil) also

includes some lipid from necrotic tissue, hence the
stronger yellow color.

Without necrosis (as in a streptococcal phlegmon), pus

is more yellow-gray.

Pseudomonas bacteria make a pigment that imparts a

blue-green fluorescent sheen to pus.

Clostridia produce extensive hydrolysis of tissue, and the

discharge from a clostridial wound contains free lipid and
 other small molecules that impart a "dirty dish-water"
look.

When the arteriolar constriction phase is over, the arterioles dilate and
stay dilated as long as acute inflammation continues. This produces
the redness and (since heart's blood is warmer than exposed body
parts) the sensation of heat. The slightly increased pressure that this
causes in the capillaries may produce some transudation of fluid into
the tissue spaces, but this cannot be a huge effect (if it were, blushing
would cause impressive edema).

Hyperemia is a generic term for extra blood in an organ due to

dilation of the arterioles. More about this soon.

Soon after injury, the small vessels (mostly the venules 20-60 microns)
become permeable to some or all plasma proteins. This increases the
osmotic ("oncotic") pressure of the interstitial fluid, water is drawn out
of the vessels, and inflammatory edema ("swelling") results.

As protein leaks out into the interstitial spaces, the local

concentration of cells in the blood increases. Red cells pack
small vessels ("red cell stasis"), neutrophils stick to endothelium,
and the viscous blood flows more slowly ("stasis"). The water
that follows the protein out of the vessels contributes to edema.
Much of this fluid will return to the circulation only via the
lymphatics.

The physicochemical changes that cause the increased

permeability to protein are only partly understood. The key
seems to be opening gaps in the intercellular junctions
("endothelial cell contraction"). Another factor seems to be loss
of various polyanions from the basement membrane
surrounding the endothelial cells. Of course, if the vessels are
damaged by the first injury, or by the neutrophils, or are
themselves regenerating, they will leak.

The worse the injury, the larger the protein molecules that can
pass through the vessel walls. In the worst injuries (and, of
course, if the vessel is severed), fibrinogen escapes into the
tissue fluids, and under these circumstances is certain to be
transformed to fibrin (by your clotting cascade, of course).

Of course, the fibrin controls bleeding and provides a

mechanical barrier. If needed, it will also serve as the
framework while the new scar tissue will be laid down.
Students often confuse fibrin and collagen. "The
difference between fibrin and collagen is the difference
between a scab and a scar."
 NOTE: When unqualified, the word fibrous means
"composed of type I collagen". Fibrinous always means
"composed of fibrin".

Once acute inflammation has begun, there are four possible outcomes:

1. Complete resolution, i.e., there has been no damage to the

connective tissue framework or non-recoverable cells of any part
of the body.

2. Healing by scarring (see below)

3. Abscess formation. Pus in a confined space is called an

"abscess". As proteases continue to work on the fluid itself, the
osmotic pressure within the abscess becomes greater and
greater, causing it to swell ("ripen" -- ever had a pimple?) While
the body might succeed in walling it off, usually you still have to
drain pus.

4. Progression to chronic inflammation (see below). This

happens when, and only when, the neutrophils and their fast-
acting molecular allies cannot remove the noxious agent.

MONONUCLEAR PHAGOCYTES

This is a generic term for blood monocytes and the cells to which they
give rise. They are important in acute inflammation, as well as being a
key element in chronic inflammation. Much of what you have just
learned about neutrophils is equally applicable to monocytes.

{26440} monocyte in smear; most monocytes you see will not have such good
vacuoles
{26442} monocyte in smear

Like neutrophils, monocytes bear Fc and C3b receptors on their

surfaces, in order to recognize opsonized materials for phagocytosis,
and they will also engulf other kinds of particles. In addition to their
famous role as scavengers, these cells ("all derived from the circulating
blood monocyte") perform a host of other functions. Lone mononuclear
phagocytes in the tissues are macrophages ("histiocytes", "dirt-bags",
etc.), and may be fixed or mobile (but never so speedy as neutrophils).

Certain factors (notably gamma interferon from T-cells) make

macrophages angry ("activated"), increasing their ability to kill
any organisms they have devoured, and sometimes causing the
macrophages themselves to adhere to form "granulomas" (see
below). Other factors (notably transforming growth factor β, also
called "activin") de-activate them. Macrophages themselves
generate a host of biological molecules.
 * Macrophages that harbor many intracellular pathogens take on the
appearance of "foam cells", just as if they had eaten lots of free fat.
We'll see these in leprosy , leishmaniasis , rhinoscleroma,
malakoplakia, and xanthogranulomatous pyelonephritis.

ACUTE INFLAMMATORY MEDIATORS

You will find yourself overwhelmed if you try to learn all the effects of
the chemical mediators of inflammation. This section includes items
that are worth knowing for medical undergraduates.

Vasoactive amines include histamine and serotonin, the classic

mediators of immediate vascular permeability.

Histamine is immediately available from our mast cells.

(Serotonin is found in rat mast cells.) These amines are
released by trauma, cold, binding of antigen to the IgE on the
mast cell surface, C3a and C5a, interleukin-1, and a host of
histamine releasing factors from other white cells.

Histamine and serotonin are also released form our platelets

("the platelet release reaction").

Pharmacologists and clinicians: H1 receptors mediate the

effects of histamine in inflammation.

The complement system is a group of 20 or so plasma proteins that are

activated in cascades by the classic or alternate pathways (don't worry
about the details now, just remember that the alternate pathway
bypasses C4) or individually. Antigen-antibody complexes, dead tissue,
and even plasmin activate ("fix") complement. Perennial test-bank
items:

C3a and C5a ("the anaphylatoxins") increase vascular

permeability, at least in part by releasing histamine from mast
cells. C5a also liberates various chemotactic and noxious
factors (notably arachidonic acid metabolites) from neutrophils
and macrophages.

C3b is the great opsonin of the complement system.

C5b-9 is the membrane attack complex, which punches holes in

membranes of both friend and foe.

The kinin system is another group of proteins, which ultimately produce

the nonapeptide bradykinin.

Bradykinin increases vascular permeability, dilates blood

vessels, contracts non-vascular smooth muscle, and causes
pain. (Remember the last -- bee venom is largely bradykinin.)
 * Kallikrein, another factor in the system, is chemotactic for
neutrophils, and both activates and is activated by factor XII.
Don't worry about the pathways of activation for these
substances.

The clotting system is a third system of proteins that you know. For
now, just remember that activating the intrinsic pathway at its origin
(factor XII) is one way to activate the kinin system, and that plasmin
activates C3.

* Discussions of these cascades often make clotting factor XII

("Hageman factor") seem utterly central to the body's defenses.
However, the real Mr. Hageman, who lacked the factor named
for him, seemed none the worse for his deficiency -- he only
learned late in life that his blood would not clot in a glass tube.

Prostaglandins: products of the cyclooxygenase pathway of

arachidonic acid metabolism. (Review: The pathways in "Big Robbins",
including the names of enzymes, are USMLE I pathology favorites.)
Worth remembering:

Thromboxane A2 (TXA2), from platelets, aggregates platelets,

constricts blood vessels. Great for hemostasis.

* Thromboxane probably causes the cough due to the

popular ACE-inhibitor antihypertensives (Lancet 350: 3,
1997). Stay tuned for picotamide, the thromboxane
inhibitor, which may someday come into use for various
vascular diseases.

Prostacyclin (PGI2), from the vessel wall, prevents platelet

aggregation, dilates vessels. Great for whenever hemostasis is
unnecessary.

Prostaglandin E (PGE) is also a potent vasodilator (probably the

most important one), greatly potentiates the ability of bradykinin
to cause pain, and seems to be the local mediator of fever
production for the hypothalamus. Both PGE and prostacyclin
potentiate permeability-increasing and chemotactic mediators.

Other prostaglandins exert a host of effects.

Aspirin, the non-steroidal anti-inflammatory drugs, and

glucocorticoids inhibit cyclooxygenase, preventing the formation
of the whole family.

Leukotrienes: products of the lipooxygenase pathway of arachidonic

acid metabolism. They are produced by all of the inflammatory cells
except lymphocytes. Formerly called SRS or slow-reacting
substance(s). Review: J. Imm. 174: 589, 2005. Worth remembering:
 Leukotrienes C4 and its products D4, and E4 increase vascular
permeability and constrict smooth muscle, and leukotriene B4
makes polys adhere to endothelium and is a potent chemotactic
agent.

Diets rich in omega-3 fatty acids prevent production of

leukotrienes (and, to a lesser extent, prostaglandins).
Leukotriene receptor antagonists may someday be a part of the
regular drugs used by clinicians; so may inhibitors of leukotriene
synthesis (Arth. Rheum. 39: 515, 1996).

Term: prostaglandins and leukotrienes are examples of

autocoids, i.e., short-range, locally-active hormones.

Lysosomal constituents:

We have already seen that neutrophils release the contents of

their granules during inflammation. For now, remember these
neutrophils proteins:

 From specific granules: collagenase, alkaline

phosphatase
 From azurophil granules: elastase, myeloperoxidase, acid
hydrolases, * even α1-antitrypsin, Am. J. Path. 139: 623,
1991
 From both kinds of granules: Lysozyme

Remember that monocytes produce acid hydrolases,

collagenase, and elastase. Eosinophil specific granules contain
several cationic proteins that seem to help fight the larger
parasites.

Regardless of their sources, the proteases and free radicals

released from inflammatory cells are can and do harm the
body's own tissues. For reviews, see Hum. Path. 16: 973, 1985;
NEJM 320: 365, 1989; Neth. J. Med. 36: 89, 1990. Havoc
wrought by free radicals: J. Royal Coll. Phys. 23: 221, 1989;
specifically by neutrophil free radicals: Am. J. Path. 139: 1009,
1991.

The inflammatory response is often excessive. This is

why, for example, it's probably best to put cold, rather
than heat, on athletic and other minor injuries throughout
the time they're healing. (* Tip from my best D.O. sports
medicine consultant.)

The body has several proteins (notably α1-antitrypsin inhibitor,

also known as "α1-protease inhibitor") to prevent them from
ruining our own tissues while we are still young. Remember that
 H2O2 and free radicals are also released from neutrophils and
macrophages.

Platelet activating factor, a small molecule, is generated on

demand by various cells. Its various contributions to
inflammation are only now being worked out (activates
neutrophils and platelets, constricts smooth muscle, recruits and
degranulates eosinophils), but the total effect is massive (Nature
374: 501, 1995). It is important because a new class of anti-PAF
agents is under investigation.

Nitric oxide: Dilates vessels locally (very fast), helps kill bacteria
over the following several days, and has goodness-knows-how-
many other effects: update J. Phys. Pharm. 54: 469, 2003.

Cytokines are polypeptide mediators made by lymphocytes

("lymphokines") and macrophages ("monokines"). Long familiar from
immunology, it is now clear that they modulate the acute inflammatory
response as well. Don't worry about the details in "Big Robbins".

The monokines interleukin-1 and tumor necrosis factor α

("cachectin" or "TNF-α") are key actors in the acute phase
reaction, part of "just being sick" with an inflammatory illness.

During the acute phase reaction, there is somnolence,

poor appetite, increased production and early release of
neutrophils, and altered rates of hepatic synthesis of most
of the major plasma proteins (albumin and transferrin go
down; α1-antitrypsin inhibitor, serum amyloid-associated
protein, the complement components, fibrinogen,
haptoglobin, and the atavistic (?) C-reactuve protein go
up.)

* The serum chemistry changes of the acute phase

reaction can be induced by the physical and
psychological distress of military school hazing: Am. J.
Clin. Nut. 53: 126, 1991. Interestingly, this preceded
today's excitement over "low-grade systemic
inflammation" as a big coronary risk factor, just like
"stress" used to be (remember?)

* CD16, the marker for the acute phase reaction: Am. J.

Clin. Path. 107: 187, 1997.

* Interleukin 6 is up and down by the end of the first day

after uncomplicated surgery. C-reactive protein is up and
down by two days. Fibrinogen rises more slowly and is
back down by 8 days or so.
The change in levels of plasma proteins is responsible for the
increased red cell sedimentation rate, described by Hippocrates
and still used to monitor the course of inflammation.

C-reactive protein, long used in the clinical lab as a

"marker for inflammation somewhere in the body", is now
a subject of much interest.
* An elevated level is supposed to be an
independent risk for coronary artery
atherosclerosis (Circulation 100: 96, 1999); today
the effect is clearly real and at least somewhat
independent of other risk factors (Circulation
109(S1): II-2, 2004). Your instructor still suspects
that plaque grunge makes C-reactive protein, and
that this has a lot to do with the phenomenon. This
finds support in Mayo's discovery that CRP levels
correlate independently with big plaques and
especially "mobile debris" (i.e., plaque grunge
exposed to the flowing blood: Arch. Int. Med. 164:
1781, 2004), and the International Pathology
Registry's discovery that high C-reactive protein
correlates most strongly with necrotic debris ready
to burst out (J. Am. Coll. Card. 47(S8): C13-8,
2006). Now people are writing about the protein as
a major mediator of atherosclerosis itself (Am. J.
Med. 117: 499, 2004), and the meaning of the
word "inflammation" is changing as a result.

During the past decade, there has been a

tremendous amount written about atherosclerosis
and obesity as "inflammatory diseases", based
almost entirely on the altered chemistry with
elevated serum "inflammatory biomarkers". Even
depression is now discussed as if it were a
systemic inflammatory disease (Am. J. Card. 96:
1016, 2005). Of course, exercise produces "a
short-term inflammatory response", while being
physically fit produces "a long-term anti-
inflammatory effect".

Whether or not this use of the term "inflammation"

comes into common practice, I think it's proper to
point out that this is not the historical meaning of
the term "inflammation", and does not yet seem to
be mainstream among pathologists. Without any
disrespect, I'd suggest calling it "internist's
inflammation", because the morphology is
completely invisible to old-fashioned pathologists
like me. Perhaps someone can think of a better
term -- the term "so-called low grade systemic
 inflammation" is used in Rheumatology 45: 944,
2006.

Forgive my skepticism... I'm still a little surprised

by articles such as "In obesity an inflammatory
illness?" (BJOG 113: 1141, 2006 -- "markers of
inflammation" are "moderately increased" in the
blood of overweight people, and there are
macrophages in fat like in every other tissue.)

* The lymphokine lymphotoxin ("tumor necrosis factor β") has

not received much attention in the past decade.

The systemic inflammatory response syndrome ("total-body

inflammation") represents toxicity from excessive production of the
cytokines and/or other white-cell products.

Venous return to the heart (i.e., venous responsivity) is

compromised, perhaps myocardial function is depressed, etc.,
etc., etc., etc., etc.

When it is caused by bacterial infection of the bloodstream, it's

called sepsis.

* Deltibant ("Bradycor"), an anti-bradykinin antagonist, was once

promoted as improving survival in sepsis (JAMA 482: 277, 1997
-- didn't come into use) and for post-traumatic neuroprotection
(J. Neurotrauma 16: 431, 1999 -- again, doesn't seem to have
come into use.)

* Future clinicians wanting criteria: Make the call of SIRS when

you have two of more of these and no other obvious explanation
(Muscle Nerve 32: 140, 2005):

 body core temperature over 38.0 C or under 36.0 C

 pulse greater than 90 beats per minute
 tachypnea, i.e., respiratory rate over 20/min or PaCO2
less than 32 torr
 white cells over 12,000 or under 4000 or more than 10%
immature neutrophils (bands)

CHRONIC INFLAMMATION

The hallmark of chronic inflammation is infiltration of tissue with

mononuclear inflammatory cells ("mononuclear cells", "round cells",
i.e., monocytes, lymphocytes, and/or plasma cells). Generally, good
tissue has been (and is being) destroyed, and there will be some
evidence of healing (scarring, fibroblast proliferation, angioblast
proliferation).
{10973} lymphocytes and plasma cells in chronic inflammation
{10061} mostly lymphocytes;
{25397} autoimmune adrenalitis; low power photo; many lymphocytes in the
adrenal gland
{26430} small lymphocyte; notice that it is slightly larger than the red cells
{26433} lymphocyte
{26436} lymphocytes, one resting, one a little bit turned-on (more cytoplasm,
more euchromatin)
{26412} plasma cell in a smear, top; eccentrically-located clockface nucleus,
abundant basophilic cytoplasm, golgi pale spot

Chronic inflammation Chronic inflammatory cells

Uterine cervix around a nerve twig
ERF/KCUMB David Barber MD -- KCUMB

Chronic inflammation Lymphocytes and fibrosis

Rheumatoid arthritis
WebPath Photo WebPath Photo
Mixed acute and chronic inflammation
Neutrophils and lymphocytes
WebPath Photo

In clinically significant disease, we believe that the tissue macrophages

are almost all recruited directly from the bloodstream monocytes.
Plasma cells produce antibodies against the persistent antigen or the
altered tissue components. Lymphocytes are likely to be present even
where there is no involvement of the immune system.

Plasma cells appear in chronic inflammation as a result of T-helper

cells activating B-lymphocytes. Interleukin 1 causes the B-cells to
divide. The transformation into plasma cells is mediated (at least in
part) by interleukin 4.

If IgE or worms are involved, you will probably see eosinophils. Their
granules contains several alkaline ("basic") proteins that are noxious to
worms.

The damage in chronic allergic sinusitis seems to be mediated

by deposition of eosinophil basic protein onto the epithelium due
to its entrapment in the mucus (J. Allerg. Clin. Imm. 116: 362,
2005).

The eosinophil proteins are now targets for specific therapies: J.

Allerg. Clin. Imm. 113: 3, 2004).

{14708} eosinophil in smear

Eosinophils and lymphocytes Eosinophil in stomach

Two good eos in the center among parietal cells
ERF/KCUMB ERF/KCUMB
 Eosinophils in tissue

KU Collection

* Review of the harm mediated by chronic inflammation: J. Allerg. Clin.

Imm. 98: S-291, 1996.

Granulomatous inflammation is a special kind of chronic inflammation

that occurs in the presence of indigestible material and/or cell-mediated
immunity ("type IV hypersensitivity"; more about this in a few days).
Ignore the definitions offered in textbooks. A granuloma is an abnormal
structure built from at least two activated macrophages adhering to one
another. Such macrophages are (confusingly) called epithelioid cells.
Granulomas serve to wall off stuff (splinters, the caseous debris of TB
, etc., etc.)

Epithelioid cells of a granuloma

Purple rice krispies on a frayed pink tablecloth
WebPath Photo

In the absence of a very large foreign body, a granuloma will

almost always contain at least a few T-lymphocytes (though this
is not absolutely mandatory).

The cells in a granuloma are activated by gamma-interferon

(and/or α-TNF or whatever).

However, not all activated macrophages stick together.

The current best candidate for "granuloma glue" is
osteopontin (Proc. Nat. Acad. Sci. 94: 6456, 1997;
Science 287: 860, 2000; update Am. J. Path. 164: 567,
2004).

Whatever makes them the way they are, granulomas vanish as

soon as the disease is effectively treated.
 You must learn to recognize granulomas. Epithelioid cells have
abundant pink cytoplasm, indistinct borders, and elongated,
euchromatin-rich, reticulated nuclei oriented helter-skelter. My
favorite gestalt: blue rice-crispies (nuclei) scattered on a frayed,
pink tablecloth (cytoplasm).

{17629} granulomas in the lung

Granuloma
Crohn's disease Granuloma Exhibit
ERF/KCUMB Yale Rosen MD
Nicest granulomas on the web
TB of the liver
Granulomas, low magnification
Great granulomas
Pittsburgh Pathology Cases
WebPath Photo

Granuloma
Granulomas, low magnification
Coccidioides
This was TB.
WebPath Photo
WebPath Photo

Granulomas can (but need not) contain syncytial giant cells

(polykaryons). These fused clusters of epithelioid cells take a
week to form. For our purposes, there are two kinds. Langhans
giant cells have their nuclei arranged in a horseshoe around the
edge, and foreign body giant cells, with nuclei dispersed more or
less evenly. The distinction is of no known significance.

Langhans giant cells Foreign body giant cell

WebPath Photo Around a tiny vegetable fiber
WebPath Photo
Foreign body giant cell Foreign body granulomas
Around a suture Around talc
WebPath Photo WebPath Photo

{17628} epithelioid giant cell

 The giant cells of granulomas occasionally contained altered
cytoskeletal components in the shapes of stars, or asteroid
bodies. They are pretty, but of no known significance. Or you
may see laminated calcified nuggets, called Schaumann bodies
(* "conchoid bodies"), also of no known significance.

{25626} asteroid bodies in giant cells

{21428} granuloma with good asteroid body; this was a reaction to a jailhouse
tattoo

Tuberculosis Caseating granuloma

Granulomas and caseation -- trust me WebPath Photo
WebPath Photo
Lots of little granulomas
Caseating granuloma
WebPath Photo
WebPath Photo
Asteroid bodies TB granuloma
Lung pathology series; follow the arrows Classic drawing
Dr. Warnock's Collection Adami & McCrae, 1914

The classic granulomatous diseases include tuberculosis ,

tuberculoid leprosy , foreign body reactions (* including the
reactions to everything from sutures to schistosome eggs ), the
deep fungal infections, berylliosis, and the mysterious disease
"sarcoidosis".

The newly-described entity "immune restoration

syndrome" is seen in AIDS patients who go on highly-
active anti-retroviral therapy. Why might this produce
granulomas?

* "Big Robbins" lists syphilis (the granulomas, if any, are

small and loose) and silicosis (the granulomas, if any, are
very fibrous).

{10958} tuberculosis, good caseous granuloma

{10964} tuberculosis, good caseous granuloma
{10106} sarcoid granuloma
{49350} silicone granuloma from ruptured breast implant
(microscopy would be needed for confirmation)

TB granuloma
Good caseous necrosis
WebPath Photo

* Future pathologists: Here is a reasonably complete catalogue

of the granulomatous diseases.

Granulomas with suppuration (i.e., with pus in their

centers; "stellate microabscesses") are typical of those
 bacterial diseases with a propensity to involve lymph
nodes. These are lymphogranuloma venereum , cat
scratch fever, brucellosis, plague , tularemia , glanders-
melioidosis, listeria, campylobacter, and yersinia
infection. In the central midwest, don't forget
blastomycosis .

{23386} lymphogranuloma venereum

Granulomas with caseation are typical of certain fungal

infections (histoplasmosis , blastomycosis, and
coccidioidomycosis , as above) and of mycobacterial
("fungus-like bacteria") infections (basically TB ; also
remember BCG bacillus, and "atypical mycobacteria").

Granulomas with foreign bodies: aspirated food,

schistosome eggs , toxocara, silicone injections,
splinters, sutures, windshield fragments, chalazions,
ruptured epidermoid cysts, sea urchin spines, mucus
plugs in cystic fibrosis, nitrogen bubbles ("pneumatosis";
"tissue emphysema"), amyloidomas, dead aspergillus
fungi, dead filaria, ingrown hairs, talc in the lungs,
metastatic calcification bits, uric acid crystals (in
longstanding gout, of course; these are "tophi"),
sclerosing lipogranuloma of the penis (J. Urol. 133: 1046,
1985, a fun article), insect bites, "actinic elastolytic
granuloma of Mieschler" (a foreign body reaction to your
own elastic fibers), etc., etc.

Ruptured silicone breast implants produce

aggregates of foamy macrophages (like
macrophages loaded with lipid or mucin) but not
good granulomas (Am. J. Clin. Path. 107: 236,
1997).

Other solid granulomas invite subclassification as

immunologic diseases:

Straightforward immune problems: The organic

pneumoconioses, berylliosis, zirconium disease
(the infamous "armpit sarcoidosis", from zirconium-
based deodorants), positive skin tests

More arcane immune problems: Wegener's

granulomatosis (and its variants Churg-Strauss
and lethal midline granuloma)

Immunologic reactions to tumors: Lennert's

lymphoma, seminoma (both are often rich in
granulomas); lymph nodes draining other cancers
 Mysterious immune problems: sarcoidosis, Crohn's
disease, primary biliary cirrhosis, bronchocentric
granulomatosis

Neutrophil deficiency syndromes: notably "chronic

granulomatous disease"

Toxoplasmosis and Q-fever (curious little

granulomas) and cutaneous leishmaniasis
("foamy granulomas", present if immune response
is good). Baboon amoebas (don't worry about
them just now: Lancet 362: 220, 2004), and CNS
amoebas in the immunocompromised

HIV encephalitis presents groups of giant cells, the

result of macrophages recognizing HIV protein on
each others' surfaces

Scarring means laying-down of dense (type I) collagen in chronic

inflammation and/or wound healing (see below; brain makes its scars
out of glial filaments instead). Usually, when there is chronic
inflammation of any time, some dense collagenous scar gets laid down.

Right now, transforming growth factor β gets most of the credit

(blame) for causing fibrosis in chronic inflammation. Interleukin
1, from macrophages, is also a potent activator of fibroblasts.
This probably accounts for part of the scarring in chronic
inflammatory diseases.

An ulcer (* "ulceration", for those who prefer nouns made from verbs
made from nouns) forms when necrosis has involved a body surface
and a portion of it is sloughed. Further, there must be necrosis of both
the epithelium and at least some of the underlying connective tissue.

If there is necrosis only of the epithelium, without any necrosis of

the underlying connective tissue, we call it an erosion.
Esophageal erosion
Very severe reflux
ERF/KCUMB
Chronic Peptic Ulcer
Australian Pathology Museum
High-tech gross photos
Peptic esophagitis ulcers

WebPath Photo
Stomach ulcer Tube pressure ulcers
Larynx
WebPath Photo WebPath Photo

Inflamed Fibrin Meshwork

Ulcer crater
David Barber MD -- KCUMB
 Note that any definition of an ulcer must exclude paper cuts (i.e.,
breaks in surfaces without necrosis) and unroofed friction
blisters (i.e., loss of epithelium without loss of connective tissue.)

Ulcers are discussed here by "Big Robbins" because they are

always inflamed.

We've seen pictures of ulcers when we discussed necrosis.

Please note that the familiar, banal decubitus ulcer of pressure
points results from ischemic necrosis. (Do you understand
how?)

A little-known fact is that decubiti of the colonic and rectal

mucosa from fecal impaction are common, and can be
the portal of entry for bacteria. These are called
"stercoral" or "stercoraceous" ulcers, and they can easily
kill a person.

{10461} duodenal ulcer (stomach is at top)

{10471} stomach ulcer (esophagus at right, duodenum at left)
{53543} stomach ulcer (a section has already been taken by the pathologist)
{10811} stomach ulcer, side view of a section through the crater; see how the
ulcer has penetrated through the muscularis propria and only scar prevents
perforation)
{11651} bad foot ulcer
{15560} bleeding stomach ulcer (arrow marks bleeding site)
{48177} diabetic ulcer

A pseudomembrane results when the upper portion of a mucosal

surface undergoes necrosis, freeing fibrinogen from vessels that then
clots along the surface. A pseudomembrane is actually a very large,
very shallow ulcer. The best pseudomembranes include secretory
product from the underlying glands as well.

When you see a striking pseudomembrane, think of diphtheria

(in the upper airway) or antibiotic-induced pseudomembranous
colitis (in the lower gut).

{10529} pseudomembranous enterocolitis

Pseudomembranous colitis
Great photos
Pittsburgh Pathology Cases

Pseudomembrane Pseudomembranous colitis

Colon Tom Demark's Site
WebPath Photo

NOTE: Very confusing to students is sloppy use of the term "chronic

inflammation" for scarring left over from acute inflammation that
 resolved long ago. "Chronic pyelonephritis", "chronic pancreatitis", and
"chronic pericarditis" are generally misnomers.

Ignore old-fashioned discussions of "serous", "fibrinous",

"hemorrhagic", "suppurative" and "purulent" inflammation.
Remember that really severe inflammation will allow fibrinogen
out of the vessels. Catarrh is an archaic word for an exudate, or
for heavy secretion from an inflamed mucous membrane.

* In the future, look for much more about mediators in inflammation

produced by epithelium and fibroblasts, especially as causes of
"idiopathic" diseases in which chronic inflammation figures prominently.

REGENERATION

Trauma Image Bank

Trauma.org
Regeneration Great site, but the image bank is presently
From Chile down!
In Spanish

Inflammation is said to resolve when no structural cells have been lost

after the inflammatory process is complete and phagocytosis has
cleaned up the area. When the tissue has been damaged during the
inflammatory process or in other ways, but the body itself is still alive,
the tissue will either regenerate or be repaired by fibrous tissue. If none
of the latter is required, the word "resolution" is also appropriate. If any
repair by fibrous tissue occurs, there will be a scar. (Depending on the
site, scar tissue may be called "cicatrix", "fibrosis", "adhesions",
"gliosis", "fibroplasia", etc., etc.)

We rank cells according to their ability to regenerate:

Labile cells ("continuous replicators") are constantly replenishing

their neighbors that have died or been shed. Examples include
the epithelium of skin, mucous membranes, oviducts, ducts;
urothelium; endometrium; seminiferous tubules; bone marrow;
lymphoid tissue.

Probably these cells would "like to" proliferate all the time,
but are stopped by "contact inhibition" by their neighbors.
More about this arcane subject when we talk about
cancer....

Epidermis can regenerate from the skin adnexal

structures (hair follicles, sebaceous glands, sweat
glands), enabling full removal of epidermis as for a skin
graft.
 Stable cells ("discontinuous replicators") can proliferate rapidly
in response to need, especially when required to replace lost
neighbors. These include all glandular parenchymal cells, as
well as fibroblasts, endothelial cells (cuboidal, and called
"angioblasts", when they are healing), smooth muscle cells,
osteoblasts, and chondroblasts.

Cartilage and tendon heal very poorly, since nothing will

restore their specialized structure. Smooth muscle cells
regenerate poorly. Otherwise, provided a scaffolding of
fibrous tissue is available (i.e., the collagen framework in
an area has not been totally wrecked), a few of these
cells can regenerate the organ.

* The pop notion that normal chondrocytes never

undergo cell division is clearly false. Old folks'
chondrocytes have much shorter telomeres and
other evidence of cell line senescence, and this
probably has a lot to do with "old-age arthritis" (J.
Bone Joint Surg. 85-A (S2): 106, 2003).

The champion healer is the liver. For one thing, it's almost
impossible to destroy its connective tissue framework in
the short-term.

Permanent cells ("non-replicators") cannot undergo mitosis or

be replenished after birth. These cells include glia, neurons, and
cardiac (non-failing heart) and (maybe) skeletal muscle cells.
(Plasma cells and other mature products of marrow are post-
mitotic too, but can be replenished. Nerve cell processes have
some ability to regenerate, and there are reserve cells that can
replace a lost portion of a skeletal muscle fiber.)

* In animals models, neurons can reappear from stem cell

progenitors (even in response to SSRI's -- see Science
301: 757, 2003).

* The regenerative ability of the myocardial cell: Lancet

363: 1306, 2004. Maybe someday this will be clinically
useful.

Obviously, cells will not regenerate if there is inadequate blood

supply, inadequate nutrition, or complete destruction of their
connective tissue framework.

* Someone will tell you, "The more specialized the tissue, the less its
powers of regeneration." This isn't true. Liver regenerates, and belly
button doesn't.

Repair Organization / Granulation Tissue

 From Chile From Chile
In Spanish In Spanish
Healing by Secondary Intention
From Chile
In Spanish
Regenerating skeletal muscle
Tom Demark's Site

REPAIR BY CONNECTIVE TISSUE

* They jest at [joke about] scars that never
felt a wound.
-- Shakespeare's
Romeo

* And the world will be better for this, that

one man scorned and covered with scars
still strove with his last ounce of courage to
reach the unreachable stars.

-- Cervantes's Don
Quixote ("Man of La
Mancha")

* The history of a soldier's wound beguiles

the pain of it.
<>
-- Sterne's Tristram
Shandy

You already know the "law of epithelium" -- it will not tolerate a free
edge. In other words, an epithelial cell without a neighbor will divide to
replace it. This is a fast process, and re-epithelialization happens as
long as there is any "free edge" nearby.

A few hours after injury, there is already evidence of connective tissue

repair. Fibroblasts become active and begin to proliferate, and buds
("angioblasts") sprout from the damaged capillaries. Of course, the
cells will show lots of euchromatin, large nucleoli, and abundant
basophilic cytoplasm. Typically, both kinds of cells invade the fibrin
meshwork created during the injury and inflammatory response.

The fibroblasts produce ground substance, fibronectin, and type III

collagen; later they will produce type I collagen for the mature scar.

The young vessels are leaky, so healing wounds are edematous both
grossly and microscopically. The fibroblasts lay down collagen and
proteoglycans ("ground substance"), and some acquire contractile
elements as in smooth muscle ("myofibroblasts"). Of course, there are
plenty of macrophages (to keep the new tissue clean) and mast cells.
The new tissue is called granulation tissue ("immature scar", etc.), and
the fibrin meshwork is said to be undergoing organization. You've seen
 granulation tissue -- it was moist, red, jelly-like stuff under the scab that
you picked off too soon.

Granulation tissue
Student Doc's Soccer Injury
Young capillaries
Fibrin
KU Collection

Granulation tissue Granulation tissue

Healing heart attack
WebPath Photo
Granulation tissue
Wall of abscess
WebPath Photo
Inflamed Fibrin Meshwork
Polys, red cells, dense and loose fibrin
David Barber MD -- KCUMB
Wall of abscess
WebPath Photo
Granulation tissue
High magnification
WebPath Photo
Epithelium growing down the
track of a colon perforation
One of my cases.

* You may run into granulation tissue that doesn't mature; depending
on its location, you may call it an "inflammatory pseudotumor", or
whatever.

If everything goes well, eventually there is sufficient collagen to fill the

gap (type I replaces the type III originally laid down in the granulation
tissue), most of the capillaries are reabsorbed, the fibroblasts revert to
a resting mode, and finally the myofibroblasts contract.

Especially where there has only been chronic inflammation, you can
also see dense collagen production, which of course also counts as
scar tissue. This is done by fibroblasts on the instructions of
macrophages.

{12707} granulation tissue

{17606} granulation tissue in healing ulcer
{17607} granulation tissue in healing ulcer
{17608} granulation tissue
{17609} granulation tissue
{17610} granulation tissue in healing ulcer
{17611} granulation tissue in healing ulcer

Scar Tissue
Text and photomicrographs. Nice. Granulation tissue
Human Pathology Digital Image Gallery Becoming dense scar
WebPath Photo

HEALING BY PRIMARY INTENTION

A well-approximated surgical wound is the ideal situation for wound

healing. Since the edges are close together and held tight by sutures
and fibrin, and there is little necrosis and hopefully no infection, the
healing is by primary union or first intention.

Timetable for "the best possible wound" (i.e., a clean, protected one
with edges apposed, in a well-nourished patient with good blood
vessels):

minutes: Fibrinogen from the severed vessels is activated via

one or the other arms of the clotting cascade, forms a
meshwork, and stops the bleeding. The meshwork also contains
platelets.

24 hours: Polys have entered the fibrin meshwork. Epithelial

cells are regenerating from the edges of the wound surface, etc.

3 days: The fibrin meshwork is extensively invaded by

macrophages. Granulation tissue is appearing at the edges of
the incisions. A thin layer of epithelial cells now covers the
wound surface.

5 days: Granulation tissue fills the entire wound, and there is

abundant collagen.

2 weeks: Fibroblasts continue to multiply, and collagen

continues to accumulate.

4 weeks: The overlying epidermis is now normal, though it will

not re-grow adnexal structures. Capillary involution and scar
contraction is well underway, and the red scar is turning white.
The wound is still growing stronger, though it will never have the
tensile strength of uninjured tissue (sorry).

{08210} skin scar, nicely healed

HEALING BY SECONDARY INTENTION

Most wounds do not conform to the above ideal. There is a larger fibrin
meshwork (a scab, rich in red cells -- now brown because of
 methemoglobin), more inflammation, possibly infection, more
granulation tissue, and more spectacular wound contraction (up to 90-
95% of the original surface area.)

When epidermis grows underneath some of the fibrin meshwork, the

edges of the scab loosen. When re-epithelialization is complete, the
scab falls off.

As surface epithelium grows into crevices (i.e., down suture tracks,

etc.), it excites excessive fibroblastic activity. This is why there's more
scarring where the sutures were.

Scarring by secondary intention always produces some deformity.

When the scar contracts TOO well, as after a burn, messy

surgery, or fibrosis-producing disease, the result may be a
crippling contracture. You'll see plenty of these.

The weave of collagen in the final scar (primary or secondary

intention) is never the same as in the surrounding connective
tissue.

Sometimes the granulation tissue undergoes striking

proliferation beyond the wound margins. This is called exuberant
granulations by physicians and "proud flesh" by the public.
(You'll excise it.)

More intractable are keloids, (literally "crab claws") disfiguring

scars with excessive collagen production, seen primarily in
darkly-pigmented people.

* Purists: Keloids send little processes into the

surrounding connective tissue, like the serrations on a
crab's claw. If these are absent, an exuberant scar is
merely called "hypertrophic". A keloid is likely to grow
over time. A hypertrophic scar is likely to regress over
time. Both can show glassy fibers.

Treating keloids usually involves re-excision and injection

of the surgical bed with glucocorticoid and/or
administration of surface radiation. Newer remedies that
show promise are tamoxifen (changes the milieu of
fibroblast growth factors) and 5-fluorouracil.

{12805} "keloids", gross

{12807} "keloid", elbow
{24487} keloid, after a burn
{40368} "keloid", ear lobe
{25527} keloid, histology
{26432} keloid, histology
{26438} keloid, histology ("glassy fibers")

Keloids Keloid
Text and photomicrographs. Nice. Prize photograph
Human Pathology Digital Image Gallery Institute of Medical Illustrators

Even worse than ugly surface scars are acquired deformities of

the cardiac valves, and scars that compress or plug the lumens
of hollow organs.

If a scar is subjected to continual strain, the wound will stretch.

Incisional hernias are the best examples of this phenomenon.

Other mishaps may occur.

Pigment in a wound is likely to stay in the macrophages.

Hemosiderin may persist for years in a scar, especially if the
person already has a high total-body iron burden.

Fragments of epidermis trapped in a healed wound may grow

into spheres "with the skin-side inside" -- the familiar "epidermal
inclusion cysts" ("sebaceous cysts", etc.)

Attempts by severed sensory nerves to grow back into wounded

tissue may produce painful "traumatic neuromas".

NOTE: The wall of an abscess is, of course, granulation tissue. * You

may hear the revolting word "pyogenic membrane" applied to the wall
of an abscess.

WHAT MAKES WOUND HEALING HAPPEN?

As for inflammation, growth factors for wound healing are continually

being discovered. "Big Robbins" lists the seven growth factors that
seem to direct the production of granulation tissue. You should
recognize platelet-derived growth factor as a key to fibroblast activation
and fibrogenesis, and recognize the names of the others ("epidermal
growth factor", "fibroblast growth factor", "transforming growth factors α
and β", interleukin 1, and TNF/cachectin.) Angiogenesis is obviously
central to wound healing, but the molecules are still getting discovered.

* VEGF must be of major importance, confirmed by several

papers and the fact that bevacizumab / Avastin interferes badly
with healing when given after colon cancer surgery (no surprise;
Br. J. Surg. 93: 1456, 2006). PDGF-D seems to be required for
good smooth muscle growth once VEGF has incuded
endothelial cells to sprout into the healing wound (Blood 104:
3198, 2004). Endoglin: Circulation 114: 2288, 2006. More J.
 Clin. Inv. 117: 1249, 2007; Am. J. Path. 166: 303, 2005. Watch
this research for substances that may speed healing, especially
of diabetic ulcers.

Fibrin itself seems to attract inflammatory cells, fibroblasts, and

angioblasts. Contact inhibition and crowding seem to put the brakes on
the process. Material in "Big Robbins" on cell-cell and cell-matrix
interactions are still experimental. Now is a good time to read up on
"integrins" in your biochemistry book; such medicines as natalizumab
(α4 integrin antagonist that has been found to be useful in Crohn's
disease and multiple sclerosis) will probably come into use soon.

FACTORS MODIFYING INFLAMMATION AND REPAIR

Despite conventional wisdom, age is not known to exert much effect on

inflammation or wound healing.

Adequate nutrition is needed for good wound healing. Protein is

needed for collagen synthesis, and vitamin C for hydroxylation of the
proline and lysine in collagen. Several enzymes required for wound
healing are zinc-based. Some surgeons supplement some or all of
these nutrients for their post-operative patients.

Inadequate blood supply greatly interferes with both inflammation and

healing.

Wound infection interferes with timely wound healing. Foreign bodies

(dirt, sutures, others) in a wound are a tremendous aid to bacteria in
causing infections, as the bugs can cling to the surfaces and thus
escape phagocytosis.

We do not know exactly how glucocorticoids interfere with wound

healing, but the effect is potent. (For starters, they inhibit the migration
of fibroblasts into fibrin meshworks.)

Future surgical clerks: Here are some names for surgical operations!

-tomy: The surgeon cut something.

-ectomy: The surgeon cut something out.

-ostomy: The surgeon cut something to make a mouth. If one

organ is named, the mouth opened to the outside of the patient.
If two organs are named, the mouth connected two organs.

-plasty: The surgeon changed the shape of an organ.

-pexy: The surgeon moved the organ to the right place.

-rraphy: The surgeon sewed something up.

 -desis: The surgeon made two things stick to one another.

RULES OF THUMB:

In infections by the common bacteria (staphylococci , streptococci ,

gram-negative rods or cocci), the predominant cell in the inflammatory
infiltrate is the neutrophil.

In viral infections and autoimmune diseases, the predominant cell in

the inflammatory infiltrate is the lymphocyte.

There might be some neutrophils early-on in the process.

Whooping cough produces a spectacular increase in circulating

lymphocytes.

In the spirochetal diseases (syphilis and Lyme disease ), the

predominant cell in the inflammatory infiltrate is the plasma cell along
with plasmacytoid lymphocytes.

In typhoid fever, tuberculosis, and fungal infections (except some

hyphal forms and candidiasis ), the predominant cell in the
inflammatory infiltrate is the monocyte / macrophage / histiocyte /
epithelioid cell.

* As above, in lymphogranuloma venereum , cat scratch fever,

brucellosis, plague , tularemia , glanders-melioidosis, and
yersinia infection, there will be a plentiful mix of neutrophils and
epithelioid histiocytes.

In infections caused by metazoan parasites (i.e., worms), and in

Hodgkin's disease, and in many nonspecific inflammations in the gut, a
predominant cell in the inflammatory infiltrate is the eosinophil.

But depending on the agent and the host, there may not be any
inflammatory reaction!

Viral lung infection

Lymphocytes
WebPath Photo

TYPES OF PAIN

If you have missed this so far in your medical education, learn it now.

In questioning people about their pain, you ask:

o location (where is it worst?)

o duration (how long has it been present?)
o quality (see below)
 o onset (sudden or gradual, how long)
o radiation (where does the pain radiate to?)
o what makes it worse (eating, position, etc.)
o what makes it better (eating, position, etc.)

Aching pain: Probably periosteum, tooth, dura, or some circuit inside

your own brain is involved

Burning pain: Either (1) the integrity of a mucosal surface has been
breached, or (2) the nerve or its immediate environment has been
damaged.

* Burning pain and sensitivity from injured nerves may result

from depletion of substance P; "causalgia" (now "complex
regional pain syndrome") from nerve injury, thermal burns,
sunburns, leprosy , epidermal necrolysis, capsaicin, ergot all
feature it; this is a "hot" topic right now, and a mainstay of
treatment is application of cold; see Lancet 345: 160, 1995.

Crampy pain (gas, labor, kidney stones): A hollow organ is being

distended

Stabbing ("lancinating") (pleuritis, pericarditis, peritonitis): If you haven't

really been stabbed, then one of your serosal membranes is hurting.

* Almost everybody has experienced the "stitch", a brief,

sudden, stabbing pain that occurs with each of several
successive inspirations. This is probably due to a fold in the
pleura. (Relieve it with the deepest possible inspiration.)

Not really any of these: ischemia, common inflammation (everything

from beesting to plague )

Buttercup: You mock my pain.

Westley: Life is pain, Highness. Anyone who says differently is
selling something.
-- The Princess Bride
CELL INJURY

Note: MC= most common; MCC= most common cause;

S/S= signs & symptoms; N=normal; I=increase; D= decrease

Oxygen (O2) Related Terms

1. O2 Content

A. Definition: Total amount of Oxygen O2 carried in Blood.

B. Formula:

O2 Content = 1.34 (Hb) x SatO2 + PaO2

Hb= Hemoglobin; SaO2= O2 Saturation; and PaO2= amount of O2 dissolved in

plasma

C. Amount of Hb in RBCs is the most important factor for carrying O2 in the

blood.

2. PaO2

A. Def: Amount of O2 dissolved in the plasma of arterial blood; a=arterial

• It is not the O2 attached to Hb in RBCs (SaO2)
• Decrease in PaO2 is called Hypoxemia (normal: 75-105mmHg)

B. PaO2 depends on:

• O2% in inspired air (21%)
• with high elevation while O2% is still 21%↓Atmospheric Pressure:
• Matched Ventilation/Perfusion in the lungs
• Normal diffusion of O2 through the Alveolar-Capillary interface.

C. Decreased Alveolar PO2 (PAO2) always leads to Hypoxemia

D. Hypoxemia always leads to less O2 carried by the Hb in RBCs (SaO2)
E. PO2 at the tissue level:
• PO2 is the driving force for diffusion of O2 from capillaries into the tissue
• Capillary PO2 must be higher than tissue PO2 for diffusion to occur
• In hypoxemia, the amount of Oxygen diffused into tissue is decreased

3. SaO2
A. Def: %O2 attached to the 4 Heme groups in Hb within RBCs (N: 94-96%)

B. SaO2 is dependent on:

- PaO2
- Valence of Heme Iron: Must be Ferrous (+2) to bind O2
- If oxidized to ferric (+3), it cannot bind O2: +3 Iron is called Methemoglobin

C. Measurement of SaO2:
- Measured non-invasively with a pulse oximeter
- In Arterial Blood Gases (ABG), it is usually calculated from the measured PaO2

SaO2 correlates with cyanosis of↓D. Decreased Skin/Mucous membranes:

SaO2&lt;80% produces visible CYANOSIS.

4. ALVEOLAR – ARTERIAL (A-a) Gradient-difference between calculated PAO2 and

measured PaO2.

A. Normally, the (A-a) is less than &lt; 10mmHg; > 30mmHg is medically
significant

B. Problems with lung ventilation, perfusion, diffusion, and right to left shunting in
the hearts always increase the gradient.

IMPORTANCE OF OXYGEN:

1. Oxygen is an electron acceptor in the oxidative pathway

A. If Oxygenation is inadequate; then the oxidative pathway cannot pump
protons into the intermembranous space in the mitochondria.

B. No protons in the intermembranous space means that none can reenter proton
pores in the inner mitochondrial membrane for the synthesis of ATP.

2. Anaerobic glycolysis is the only other source for ATP that does not require the
oxidative pathway- produces 2 ATP.

HYPOXIC CELL INJURY

(Inadequate Oxygenation of tissue with decreased synthesis of ATP)

1. ISCHEMIA
A. Def: Decreased arterial blood flow to tissue

B. Normal PaO2 and SaO2

C. Causes; Occlusion of an artery (eg. Coronary artery atherosclerosis), MCC:
**decreased cardiac output (e.g. left sided heart failure) **oxygen content is
normal

2. HYPOXEMIA: decrease in PaO2

A. Respiratory Acidosis: I PACO2 (CO2 retention) always decreases in alveolar
PO2, PaO2 and SaO2

D PAO2 D PaO2 D SaO2

B. Ventilation Defect:
Massive Atelectasis (collapse of the respiratory unit in the lungs)
1. Def: Impaired O2 delivery to the alveoli for gas exchange with decrease in
PaO2 and SaO2
Ex: Respiratory Distress Syndrome (RDS) with decreased synthesis of surfactant
and subsequent collapse of alveoli; Adult respiratory distress syndrome.

2. Mx: Leads to intrapulmonary shunting of blood: perfusion of alveoli occurs

without O2 exchange. Giving 100% O2 does not significantly increase PaO2

PaO2,↓Hb, ↔3. D O2 Content: SaO2↓

D PaO2 D SaO2

C. Perfusion Defect:
e.g.: Pulmonary embolus
1. Def: absent blood flow to alveoli (e.g. pulmonary embolus) with SaO2↓PaO2
and ↓decrease in
Dead Space: alveoli contain O2 but↑2. Increase there is no gas exchange.
3. Since not all the vessels are occluded, giving 100%O2 raises the PaO2 by
allowing more O2 exchange in normally perfused lungs.
4. D O2 Content: N Hb, D PaO2, D SaO2
DPaO2 DSaO2

D. Diffusion Problems:
1. Def: O2 cannot diffuse through the alveolar-capillary interface.
e.g.: Interstitial fibrosis, pulmonary edema
2. Decreases PaO2 and SaO2
D O2 Content: N Hb, D PaO2, D SaO2
3. HEMOGLOBIN (Hb) RELATED ABNORMALITIES:
A. ANEMIA:
D [Hb] decrease Hb concentration
1. DO2 Content: D Hb, N PaO2, N SaO2 (gas exchange is normal)
2. Iron deficiency is MC Anemia

B. METHEMOGLOBINEMIA:
With Iron Fe+3, HEME cannot bind O2
1. D O2 content: N Hb, N PaO2, D SaO2
2. Causes:
- HEME group is oxidized by NITRO/SULFA compounds (drugs with NITRITES or
SULFUR), water, particularly in the mountains or on farms where the water is
often contaminated with Nitrates.
- Deficiency of Methemoglobin Reductase
3. Clinical:
• Cyanotic (not reversed by O2)
• Blood is chocolate colored from increased deoxyHb
• Giving 100% Oxygen O2 does not correct the cyanosis
4. Left shifts the ODC
5. Treatment (Rx):
- IV Methylene Blue (activates Methemoglobin reductase) is the gold standard for
Rx.
- Ascorbic acid: reducing agent that is used as ancillary therapy (reduces Ferric
Fe+3 to ferrous Fe+2)

C. CARBON MONOXIDE CO POISONING:

1. Def: CO has high affinity for the HEME group in RBCs, hence lowering the SaO2
without affecting the Hb or the PaO2.
CO competes with O2 for binding sites on HEME Iron.
2. D O2 Content: N Hb, N PaO2, D SaO2
3. CO poisoning also:
• Left shifts the O2 dissociation curve (ODC) [or O2 Bind Curve OBC]
• Inhibits Cytochrome Oxidase in the Oxidative Pathway (electron transport chain
(ETC)
4. Causes of CO poisoning:
• Car exhaust
• Space heaters
• Smoke inhalation in fires
• Wood stoves
5. Rx:
• 100% O2, which displaces CO from the HEME group
6. S/S:
• Headache first symptom
→• Cherry red color on skin Carboxyhemoglobin (masks cyanosis)
7. Chronic Effect:
• Necrosis of Globus pallidus leading to Parkinson-like findings

D. FACTORS LEFT-SHIFTING OBC:

High affinity of Hb for O2
Left shifted ODC causes tissue hypoxia: I affinity for O2 (does not release O2 into
blood)
i.e. :
• D 2,3-biphosphoglycerate (BPG)
• Alkalosis
• CO
• Methemoglobin (MetHb)
• Fetal Hb (Hb F)
• Hypothermia

E. CLINICAL CORRELATION:
Right shifted OBC (decreased affinity of Hb for O2)
1) I (increase) 2,3 DPG
2) Fever
3) Acidosis
4) High Altitude: Respiratory alkalosis increases the rate of glycolysis, hence
increasing conversion of 1,3 BPG into 2,3 BPG, which offsets the effect of
Respiratory alkalosis in left-shifting the OBC.

4. PROBLEMS WITH OXIDATIVE PATHWAY IN MITOCHONDRIA

Inner mitochondrial membrane pathway transfers electrons to O2 and creates
energy to pump protons into the intermembranous space for production of ATP
Carbon Monoxide CO and Cyanide CN:
• CO and Cyanide CN inhibit Cytochrome Oxidase in the ETC
• Blocks Oxidative pathway in the Mitochondria even though O2 may be present
as an electron acceptor.
• Protons are no longer entering the No ATP is synthesized.◊intermembranous
space
Cyanide Poisoning: Systemic asphyxiant
• Poisoning is common in the setting of combustion of polyurethane products
during residential fires
• Accidental poisoning
• S/S:
- Bitter almond smell to breath
• Rx of Cyanide Poisoning:
- Nitrites: amyl MetHb competes with Cytochrome◊ create Methemoglobin◊and
sodium nitrite oxidase for cyanide.
- Thiosulfate: combines with Cyanide from nontoxic Thiocyanate.◊
Cyanmethemoglobin
5. UNCOUPLED OXIDATIVE PHOSPHORYLATION IN MITOCHONDRIA
A. Mitochondrial poisons render the entire ATP synthesis):↓inner mitochondrial
mb permeable and carry protons with them ( poisons include:
• Dinitrophenol
• Pentachlorphenol (used to treat wood to prevent insect invasion)
• Thermogenin (natural uncoupling agent in newborn )↑brown fat that keeps
internal temperature up
• Alcohol and Salicylates also damage the mitochondrial and produce a similar
result, but they are not uncoupling agents.
• Rate of chemical reactions increases to produce more potential for
hyperthermia.◊NADH and NADPH
6. ARTERIOVENOUS SHUNTING
Direct communication of arterial system with venous system (microcirculation is
bypassed): AV fistula from trauma.

Effects of a Decrease in cellular ATP

1. Cell must utilize anaerobic glycolysis to generate ATP
A. In tissue hypoxia, Phosphofructokinase (PFK), the rate limiting reaction in
Glycolysis, is activated by:
• Low citrate: most important factor
• Increase in Adenosine Monophosphate (AMP)
B. Net gain of 2ATP and no gain in NADPH:
• NADH is converted into NAD+ when pyruvate is converted into lactate
• NAD+ is used to produce 2 more ATP
C. Decrease in Intracellular pH from Lactate production:
• Denatures cellular enzymes and other proteins (called coagulation necrosis)
Anion↑• Produces an increased Gap metabolic acidosis.

2. Impaired Na+/K+ ATPase Pump

A. Na+ and water enter the cell producing cellular swelling: first histologic sign of
tissue hypoxia.
B. This is a Reversible change if O2 is restored.

3. Ribosomes fall off rough the Endoplasmic Reticulum- Decreased protein

synthesis

Causes of Irreversible Cell Injury due to tissue hypoxia

1. Disruption of the cell membrane:
• Most important factor
• Lipid Peroxidation by Free Radicals FR: reversed by Vit E
2. Damage to Mitochondria
3. Calcium in Irreversible Cell Injury:
• Accumulates in the Cytosol: Ca++ ATPase Pump disrupted
• Activates Enzymes:
- Cell Mb Phospholipase (enhances Lipid Peroxidation)
- Enzymes in the nucleus (produces Nuclear Pyknosis)
• Enters mitochondria: produces electron dense deposits and destroys
mitochondria
• Contribuyes to coagulation necrosis along with the intracellular buildup of lactic
acid.

Summary of sequence in Hypoxic Cell Injury

1. Hypoxia: decrease Oxidative Phosphorilation in mitochondria leading to a
decrease ATP
2. decrease ATP leads to:
• Increase Anaerobic glycolysis: decrease intracellular pH from lactic acid,
decrease glycogen
• Dysfunction of Na+/K+ ATPase Pump: Reversible cellular swelling
• Ribosomes detach from RER: decrease protein synthesis, fatty change->
3. Irreversible Cell Membrane Injury:
• Intracellular release of Lysosomal enzymes damages membrane
• Endogenous influx of Ca++ into cytosol) with release of↑activation of
phospholipases ( toxic lipid products.
• Cytoskeletal alterations: activation of proteases by Ca++
4. Irreversible Nuclear changes:
• Activation of nuclear enzymes by Ca++
• Nuclear Pyknosis and lysis
5. Irreversible mitochondrial dysfunction:
• Entry of Ca++ into mitochondria with activation of phospholipases causing
destruction of inner and outer mb
• Ca++ produces large densities

ENZYME MARKERS CELL DEATH

Hepatitisץ Transaminases
ץ Creatine Kinase Skeletal/cardiac muscle
Cardiac muscleץ CK:MB
• Amylase/Lipase : Acute Pancreatitis
Myocardial Infarction (Troponin)◊• LDH ½ flip

FREE RADICALS:
Unpaired electrons in the outer orbit
1. Examples.-
• Superoxide: O2* generated FR inactivated by Superoxide Dismutase (SOD)
• OH* : generated by ionizing radiation and iron
• Peroxide: Inactivated by catalase and Glutathione (GSH)
• Drugs/Chemicals:
- Acetaminophen (inactivated by GSH)
- CCl4 converted into CCl3-
2. Iron Increases the synthesis of OH*: FRs via the Fenton reaction. FRs are the
Mx of damage in Iron overload diseases: e.g. Hemochromatosis.
3. Lipofuscin accumulates in cells damage by FRs in the normal aging process and
in atrophy: indigestible lipid from lipid peroxidation that gives tissue a brown
appearance.
4. Clinical Examples of FR damage:
A. O2 Dependent myeloperoxidase (MPO) system in neutrophils/Monocytes
B. O2 toxicity due to superoxide FR damage: e.g. Retrolental fibroplasia leading
to blindness in newborns
C. Ionizing Radiation:
• Generates Hydroxyl (OH) FRs in tissue from Radiolysis of water in cells
• Damages DNA with potential for cancer (e.g., Squamous skin cancer)

D. Iron overload conditions

E. Acetaminophen toxicity***: Acetaminophen is converted by the hepatocyte
Cytochrome system into FRs that act on sulfhydril groups in the hepatocyte cell
mbs.
• MCC of Fulminant Hepatic Necrosis due to drugs: See necrosis around central
vein in the liver
• Acetylcysteine/therapy (Mucomyst) replenishes GSH, which neutralizes the drug
FRs
F. CCl4 poisoning in dry cleaning industry: CCl4 converted by Cytochrome Liver
cell necrosis with fatty change.◊system into CCl3 FR

APOPTOSIS:
Individual cell necrosis
1. Def: genetically determined internal programmed series of events leading to
individual cell death.
2. Functions of Apoptosis:
A. Hormone-dependent involution of tissue in adults:
• Involution of lactating cells with withdrawal of Prolactin
• Endometrial cell breakdown after withdrawal of Estrogen/Progesterone in the
menstrual cycle
• Prostatic atrophy after removal of dihydrotestosterone (castration, drug
induced, old age)
• Atrophy of Thyroid with inhibition of TSH
B. Programmed destruction of cells during embryogenesis:
• Loss of mullerian structures in male fetus by mullerian inhibitory factor or
Wolffian structures in female fetus
• Development of lumens in the intestines
C. Involution of the Thymus in an adult
D. Cell death related to injurious agents:
• Viruses (e.g. HBV infected cells)
• Cell cycle specific chemotherapy drugs
• Tissue hypoxia
• Ionizing and UV light radiation
E. Death of tumor cells
F. Pathologic Atrophy of parenchymal obstruction due to duct obstruction:
• Atrophy of pancreatic exocrine cells with duct obstruction by thick secretion in
Cystic Fibrosis
• Atrophy of Parotid gland due to stone in the duct
G. Cytotoxic T cell-induced death of target cells
H. Programmed cell death involved in old age

3. Sequential mechanisms of Apoptosis

A. Signals Initiating Apoptosis:
• Injurious agents: Radiation, free radicals, toxic agents
• Withdrawal of growth factor or hormones
• Receptor-ligand interactions on the plasma mb of cells
• Tumor Necrosis Factor
B. Activation of CASPASES, a group of cysteine-proteases that sets into motion an
enzymatic death programs:
• Endonuclease activation leading to nuclear fragmentation (first steps in actual
cell death)
• Activation of proteases that breakdown the cytoskeleton
• Transglutaminase activation with increased cross-bridging of proteins
C. Mitochondrial Injury
D. Formation of Cytoplasmic blebs that fragment into apoptotic bodies that are
surrounded by cell mb and contain cytoplasm, packed organelles, with or without
nuclear fragments
E. Phagocytosis of Apoptotic bodies by neighboring cells or macrophages which
destroy the bodies in lysosomes.

4. Microscopic appearance:
• Cell separates away from neighboring cells
• Deeply Eosinophilic staining cytoplasm
• Pyknotic nucleus
• No or minimal inflammatory infiltrate

TYPES OF CELL NECROSIS

Necrosis is widespread damage to tissue as opposed to apoptosis, which is
individual cell necrosis.
1. Coagulation Necrosis
A. In Coagulation Necrosis the tissues is dead but vague outlines of what used to
be living tissue can still be identified: e.g. can identify cardiac muscle, but
striations are fading out and nuclei are disappearing
B. Coagulation Necrosis is most often due to thrombosis of a vessel (e.g. artery
or vein) and less commonly due to the effect of heavy metals (e.g., Lead, Arsenic
mercury) on tissue (particularly the proximal tubules of the kidneys)
C. The Gross (visible to the naked eye) manifestation of coagulation Necrosis is
called and Infarction of which there are two types:
• Pale Types of Infarction (Increased density of the tissue prevents RBCs from
diffusing through the Necrotic tissue) e.g.: heart, kidney, liver (least likely to
infarct due to dual portal vein/hepatic artery blood supply), Spleen
• Hemorrhagic Types of Infarction (loose textured tissue allows RBCs to diffuse
through tissue) e.g.: small bowel, Lungs, testicles.
D. Dry gangrene:
• Predominantly coagulation necrosis when there is no infection: e.g. Diabetic
food
Wet Gangrene:
• Is predominantly Liquefactive necrosis (see below) when there is infection.
2. CNS Infarcts
A. Example of Liquefactive not Coagulative necrosis
B. Brain tissue has cells with numerous lysosomes and all the enzymes cannot be
denatured by Lactic Acid, hence there is an autocatalytic effect in the cell.
C. Brain tissue has very little structural integrity (held together by processes from
Astrocytes), therefore the cells breakdown easily and leave a cystic cavity.
3. Liquefactive Necrosis
A. Usually refers to neutrophils-dependent enzymatic destruction of tissue
B. Examples include:
• Abscesses : usually staphylococcus aureus owing to coagulase production
• Cellulitis: usually Group A Streptococcus infections due to Hyaluronidase
• Wet Gangrene: e.g. Gangrenous toe becomes infected with anaerobes and
neutrophils destroy tissue
• Brain Infarct/abscesses
4. Caseous Necrosis
A. Cheese-like material noted on gross exam of tissue: represents lipid material
in granulomas from macrophage destruction of typical/atypical TB and systemic
fungi
B. Other types of Granulomas are non-caseating:
• Crohn’s Disease
• Sarcoidosis
5. Enzymatic Fat Necrosis in Acute Pancreatitis
• Release of Amylase and Lipase from damaged Pancreas
• Fatty Acids combine with calcium to form Chalky White areas in the pancreas
(called Saponification): Calcium deposits can be seen on X-Ray
6. Fibrinoid Necrosis
A. Necrosis of Immunologic Injury with protein material appearing like Fibrin
B. Examples:
• Small Vessel Vasculitis: Henoch-Schonlen purpura
• Rheumatic Heart disease vegetations on Mitral valve
• Immunocomplex glomerulonephritis: e.g. SLE
7. Gummatous Necrosis in Tertiary Syphilis-
Rubbery masses that are very destructive in tissue

FATTY LIVER

1. Alcohol MCC
A. Increased NADH in the metabolism of alcohol causes a build-up of
dihydroxyacetone phosphate (DHAP), an intermediate in Glycolisis: DHAP
produces Glycerol 3-phosphate, the carbohydrate backbone of TG
B. Increased Acetyl CoA in alcohol metabolism is used for fatty acid (FA)
synthesis
2. Kwashiorkor
Fatty liver due to decreased synthesis of Apolipoproteins necessary to coat very
low density lipoprotein (VLDL)
3. Miscellaneous.-
• CO poisoning
• Shock
• Drugs: Tetracycline, Amiodarone
• Reye’s syndrome

HEMOGLOBIN - DERIVED PIGMENTS

1. Bilirubin
A. Unconjugated Type:
Lipid soluble: end product of macrophage metabolism of Hb in phagocytosed
RBCs
e.g.: Rh hemolytic disease of the newborn
B. Conjugated type:
Water soluble: conjugated in the liver; e.g.: Obstructive Jaundice: stone in the
common bile duct.

2. Hemosiderin
B. Storage Iron consists of 2 forms:
• Soluble Ferritin
• Insoluble Ferritin
C. Soluble Ferritin; is the primary Iron storage protein
• All cells in the body contain Ferritin: Liver and Bone Marrow macrophages are
two biggest storage sites.
• Small amount circulates in blood and correlates with Iron stores in macrophages
in the marrow: best screening test for Iron disorders
↓• Serum Ferritin is Increased in Iron overload disease↑decreased in Iron (Fe)
deficiency; and (Hemochromatosis, Hemosiderosis), Anemia of chronic disease,
Sideroblastic Anemia.
• It cannot be visualized by microscopy and does not take up the Prussian Blue
stain for iron.
D. Insoluble hemosiderin is a product of Ferritin degradation:
• Visualized as Golden-yellow granules in the cytosol of cells (e.g. hepatocytes,
marrow macrophage)
• Stains positive with the Prussian Blue Stain
• See above for hemosiderin excess, Hemosiderin stores are absent in iron
deficiency: first finding in Iron deficiency but requires a bone marrow exam to
evaluate its stores.
3. Hematin:
Black pigment derived from acid effect on Hb
Responsible for Black Tarry stools (melena) associated with peptic ulcer disease.

DYSTROPHIC CALCIFICATION
1. Definition.- Calcium deposition in damaged tissue in the presence of a normal
serum calcium/phosphate. (Psammoma bodies-> calcifications occur in
Meningiomas.ex. pap. Ca of thyroid or ovaries.
2. Examples:
• Atherosclerosis plaques
• Enzymatic fat necrosis (visible in plain films)
• Damaged cardiac valves (e.g. bicuspid aortic valve)
• Periventricular calcification in congenital CMV infections (Monckebeigs medial
calcification sclerosis.

METASTATIC CALCIFICATION
1. Def: Increased serum calcium and/or phosphate leading to the deposition of
calcium in normal tissue
2. Examples:
• Nephrocalcinosis, in primary hyperparathyroidism - calcification of tubular
basement membranes
• Calcification of basal ganglia in primary hypoparathyroidism

CONGENITAL SPHEROCYTOSIS
Genetic example of a membrane defect: AD disease with a defect in Spectrin in
the cell Mb results in RBCs with too little membrane (spherocytosis)

EXAMPLES OF UBIQUINATION OF DAMAGED INTERMEDIATE FILAMENTS

1. Mallory Bodies.- Ubiquinated (marked for destruction by Ubiquitin) Keratin
intermediate filaments: microscopic feature of alcoholic hepatitis.
2. Lewy body.- Ubiquinated neurofilaments from degenerated Substantia Nigra
neurons in Parkinson’s disease.
3. Neurofibrillary tangles.- Ubiquinated neurofilaments in the brain in old age/
Alzheimer’s.

CELL TYPES IN TISSUE:

1. Labile cells: Contain Stem Cells with >1.5% of the Stem Cells in the cell cycle
at any one time.
A. Ex:
- Bone Marrow Stem Cells
- Stratum Basalis of Skin
- Intestine- Stem cells at the base of the glands
B. These cells are most affected by radiation and S phase chemotherapy drugs
due to their high rate of mitotic activity.

2. Stable Cells: cells that are usually in the Go (resting) phase of the cell cycle
A. Must be stimulated to enter the G1 phase by:
- Hormones (e.g., Estrogen)
- Growth factors (e.g. epidermal derived growth factor)
- Loss of parenchymal tissue (e.g. removal of liver tissue)
B. &lt;1.5% of the cells are in the cell cycle at any one time
C. Examples:
- Most parenchymal cells in organs; e.g. hepatocytes, renal tubular cells,
endothelial cells.
- Smooth muscle: not striated or cardiac cells
- Astrocytes / other Neuroglial cells
D. Stable cells have the capacity to undergo hypertrophy and / or hyperplasia.
3. Permanent Cells:
A. cells can not enter the cell cycle
B. Ex:
• Skeletal cardiac muscle can only HYPERTROPHY
• Neurons

CELL CYCLE
1. Inactive CDK (Cyclin-dependent Kinase) is activated by Cyclin D (see diagram)
A. Cyclin D is synthesized in the G1 phase of the cell cycle: key phase of the cycle
B. G1 phase is the most variable phase: this would be the phase that explains
either a shorter or longer cell cycle than normal.

cdk= Cyclin-dependent Kinase

Rb (hypophosphorylated form) inhibits cell from going from G1 to S phase
Rb phosphorylated form allows cell to go from G1 to S phase
2n= normal amount of DNA in a cell, 4n is after duplication of the DNA prior to
mitosis.

• Inactivated cdk is activated by cyclin D, which is synthesized in the G1 phase of

the cell cycle.
• The Rb suppressor gene on chromosome 13 produces the Rb protein, which
inhibits the cell from moving from the G1 phase into the S phase.
• When Rb protein is phosphorylated by active cyclin D/cdk complex, the cell
passes into the S phase and finishes the cycle.
• The p53 suppressor gene (‘guardian of the cell”) located on chromosome 17
produces a product that inhibits the active cyclin D/cdk complex, hence
preventing phosphorylation of the Rb protein and keeping the cell in the G1 phase
for repair of DNA defects, or if they are too extensive, time for apoptosis.
• Inactivation of the Rb suppressor gene results in the loss of the inhibitory effect
of the Rb protein in keeping the cell from entering the S phase.
• Furthermore, inactivation of the p53 suppressor gene allows the active cyclin
D/cdk complex to continually Phosphorylate the Rb protein, which allows the cell
to complete enter the S phase and complete cell division.
• Inactivation of either the Rb or p53 suppressor gene leads to unrestricted cell
growth and the potential for cancer Hypertrophy is thought to be a block at the
G2 phase (tubulin synthesis), while hyperplasia is thought to be a problem after
Gm (mitosis) phase such that cell continues to enter the G1 phase and progress
through the cycle again.

2. Rb suppressor gene on chromosome 13 produces the unphosphorilated Rb

protein.
• Rb protein prevents the cell from moving from the G1 phase into the S phase: S
phase functions include chromosome replication and organelle replication.
• Phosphorylation of the Rb protein by the active Cyclin D/cdk complex allows the
cell to pass into the s phase and finish the cycle which includes the G2 phase
(Tubulin synthesized) and the M phase (mitosis).
• Inactivation of the Rb suppressor gene: Loss of the inhibitory effect of the Rb
protein on the cell allows the cells to constantly enter the S phase once they are
phosphorylated.
3. p53 Suppressor Gene functions on Chromosome 17
A. Produces a protein product that inhibits active cyclin D/cdk complex
1. Prevents phosphorylation of the Rb protein and keeps the cell in the G1 phase
2. Allows cell to repair any defects in DNA (“Guardian of the cell”): cells incapable
of repair undergo apoptosis
B. Inactivation of the p53 suppressor gene: active cyclin D/cdk complex
continually phosphorylates Rb proteins and cells continually mitose.
4. Important concept:
• Inactivation of either the Rb or p53 suppressor gene leads to unrestricted cell
growth and the potential for cancer.
• E6 and E7 gene produces in HPV inactivate both of these suppressor genes.

Examples of Growth alterations

1. ATROPHY.- Decrease in cell/tissue mass
A. Characteristics include:
• Less organ weight
• Wrinkled capsular surface
• Less mitochondria
• Increase Lipofuscin in cells
B. examples:
1. muscle in a cast: disuse of muscle leads to atrophy
2. Thyroid gland in someone taking excess thyroid hormone: decrease in TSH
from increase in T4 causes atrophy of thyroid
3. Renal artery atherosclerosis: affected kidney is atrophied, while the
contralateral kidney is hypertrophied (compensatory)
4. Compression atrophy of renal cortex by hydronephrosis
5. Carotid artery atherosclerosis: cerebral atrophy due to apoptosis of neurons
(called “red neurons”) in layers 3,5,6
6. Atrophy of pancreatic ducts and islets cells in cystic fibrosis: thick ductal
secretions obstruct the lumen leading to glandular atrophy and fibrosis (fibrosis
destroys islet cells)
7. Patients on long-term corticosteroids develop atrophy of the zona fasciculate
and reticularis in the adrenal cortex, since ACTH does not stimulate aldosterone
synthesis.
C. Agenesis: anlage (primordial tissue) is absent (e.g. renal agenesis)
D. Aplasia: anlage is present but never develops
E. Hypoplasia: anlage develops incompletely; however, the tissue that is present
is histologically normal.
2. HYPERTROPHY: Increased cell size
A. Cell has passed the S phase but cannot enter the Gm phase: cytosol and
nucleus is larger (4n) since it contains organelles for two cells.
B. Examples include:
- Left ventricle hypertrophy
- Removal of kidney and hypertrophy of remaining kidney
3. HYPERPLASIA: Increase in number of cells
A. Common alteration in hormone excess states
B. Can progress to dysplasia and cancer if left unregulated
C. examples:
1. Hormone excess states:
- Unopposed endometrial hyperplasia◊estrogen
- Prolactine induced lactation
- RBC hyperplasia-hypoxia leads to Erythropoietin stimulation of erythroid Stem
cell.
2. Persistent injury to tissue: e.g. regenerative nodules in cirrhosis
3. Psoriasis: hyperplasia of squamous epithelium
4. Clinical examples of equal hyperplasia/hypertrophy:
- Uterine smooth muscle hyperplasia/hypertrophy in pregnancy
- Iodine deficiency leading to a goiter.
4. METAPLASIA: replacement of one adult cell type by another adult cell type,
which may be squamous (squamous metaplasia) or glandular (glandular
metaplasia)
A. Mucous secreting columnar cells normally undergo squamous metaplasia to
replace Exocervical Epithelium: may progress to squamous dysplasia/cancer if
HPV is present.
B. Schistosoma hematobium eggs in submucosal venous plexus in the bladder
cause mucosal squamous metaplasia, which may progress to dysplasia/cancer.
C. Squamous epithelium in the distal esophagus undergoes glandular metaplasia
(mucous secreting cells/Goblet cells) due to acid injury (gastroesophageal reflux
disease); this is called Barret’s esophagus and may progress into dysplasia and
adenocarcinoma.
D. In chronic atrophic gastritis due to Helicobacter pylori, normal glandular cells
undergo glandular metaplasia with the formation of Goblet cells and Paneth cells,
which are cells that are normally present in the intestinal epithelium; this
intestinal metaplasia is a precursor for gastric adenocarcinoma.
5. DYSPLASIA: Atypical hyperplasia with the potential for evolving into cancer.
A. Dysplasia is a pre-malignant growth alteration
B. In the above examples, note that:
* Squamous metaplasia may progress into Squamous Cancer &
* Glandular metaplasia into Adenocarcinoma.
C. Examples of Dysplasia:
- ACTINIC (solar) KERATOSIS: A UVB light derived dysplasia that is a precursor
for squamous cancer of the skin
- CERVICAL DYSPLASIA: Precursor for cervical squamous cancer (usually related
to HPV 16 or 18 )
- LEUKOPLAKIA in the mouth in smokers and/or alcoholics: dysplasia that may
progress to squamous cancer.
- DYSPLASTIC NEVUS: Atypical nevus that may progress into a malignant
melanoma