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) substanceI: InfectionP: Physical insult or injuryD: Deficit, or lack of water, oxygen, or nutrients.

Necrosis: the 4 types"Life Can Get Complicated":LiquifactiveCoagulationGangreneCaseous· 'Life' used since necrosis is 'death'.

Gout: factors that can precipitate an attack of acute gouty arthritisDARK:DiureticsAlcoholRenal diseaseKicked (trauma)· And, the attack occurs most often at night [thus "dark"].

Real Clinicians Don't Take FiveThe five cardinal signs for inflammation:Rubor, Calor, Dolor, Tumor, Function Loss

Blood disorders: commoner sexHE (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.

PusSuppurative pericarditis

WebPath Photo

Purulent meningitis

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 inflammationUterine cervixERF/KCUMB

Chronic inflammatory cellsaround a nerve twig

David Barber MD -- KCUMB

Chronic inflammation

WebPath Photo

Lymphocytes and fibrosisRheumatoid arthritis

WebPath Photo Mixed acute and chronic inflammation

Neutrophils and lymphocytesWebPath 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 lymphocytesTwo good eos in the center

ERF/KCUMB

Eosinophil in stomachamong parietal cells

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 granulomaPurple 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

GranulomaCrohn's disease

ERF/KCUMB

Granuloma Exhibit Yale Rosen MD

Nicest granulomas on the web

TB of the liverGreat granulomas

Pittsburgh Pathology Cases

Granulomas, low magnificationThis was TB.

WebPath Photo

Granulomas, low magnification

WebPath Photo Granuloma

CoccidioidesWebPath 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 cellsWebPath Photo

Foreign body giant cellAround a tiny vegetable fiber

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Foreign body giant cellAround a suture WebPath Photo

Foreign body granulomasAround talc

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{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

TuberculosisGranulomas and caseation -- trust me

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Caseating granulomaWebPath Photo

Caseating granulomaWebPath Photo

Lots of little granulomas

WebPath Photo Asteroid bodies

Lung pathology series; follow the arrows

Dr. Warnock's Collection

TB granulomaClassic drawing

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 granulomaGood 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 erosionVery severe reflux

ERF/KCUMB

Peptic esophagitis ulcers

WebPath Photo

Chronic Peptic UlcerAustralian Pathology Museum

High-tech gross photos

Stomach ulcer

WebPath Photo

Tube pressure ulcersLarynx

WebPath Photo

Inflamed Fibrin MeshworkUlcer 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 colitisGreat photos

Pittsburgh Pathology Cases

PseudomembraneColon

WebPath Photo

Pseudomembranous colitisTom Demark's Site

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

Regeneration From Chile In Spanish

Trauma Image Bank

Trauma.org Great site, but the

image bank is presently down!

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 From Chile In Spanish

Organization / Granulation Tissue

From Chile In Spanish

Healing by Secondary

Intention From Chile In Spanish

Regenerating skeletal muscleTom 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.

Student Doc's Soccer InjuryFibrin

Granulation tissueYoung capillaries

KU Collection

Granulation tissueHealing heart attack

WebPath Photo

Granulation tissueWall of abscessWebPath Photo

Granulation tissueWall of abscessWebPath Photo

Granulation tissueHigh magnification

WebPath Photo Inflamed Fibrin Meshwork

Polys, red cells, dense and loose fibrinDavid Barber MD -- KCUMB

Epithelium growing down thetrack 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 TissueText and photomicrographs. Nice.

Human Pathology Digital Image Gallery

Granulation tissueBecoming 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")

KeloidsText and photomicrographs. Nice.

Human Pathology Digital Image Gallery

KeloidPrize photograph

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 infectionLymphocytes

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 BrideCELL 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 HypoxemiaD. 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. SaO2A. 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 ofD. 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 pathwayA. 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 SaO2C. 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 PaO2A. 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 SaO2Ex: 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 embolus1. Def: absent blood flow to alveoli (e.g. pulmonary embolus) with SaO2PaO2 and decrease in Dead Space: alveoli contain O2 but2. 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 SaO2DPaO2 DSaO2

D. Diffusion Problems:1. Def: O2 cannot diffuse through the alveolar-capillary interface. e.g.: Interstitial fibrosis, pulmonary edema2. Decreases PaO2 and SaO2 D O2 Content: N Hb, D PaO2, D SaO2

3. HEMOGLOBIN (Hb) RELATED ABNORMALITIES:A. ANEMIA: D [Hb] decrease Hb concentration1. 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 O21. D O2 content: N Hb, N PaO2, D SaO22. 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 Reductase3. Clinical: • Cyanotic (not reversed by O2) • Blood is chocolate colored from increased deoxyHb• Giving 100% Oxygen O2 does not correct the cyanosis4. Left shifts the ODC5. 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 SaO23. 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 stoves5. Rx: • 100% O2, which displaces CO from the HEME group6. 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 O2Left 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 DPG2) Fever3) Acidosis4) 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 MITOCHONDRIAInner 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 spaceCyanide 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 Methemoglobinand sodium nitrite oxidase for cyanide.- Thiosulfate: combines with Cyanide from nontoxic Thiocyanate.Cyanmethemoglobin5. UNCOUPLED OXIDATIVE PHOSPHORYLATION IN MITOCHONDRIAA. 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 NADPH6. ARTERIOVENOUS SHUNTINGDirect communication of arterial system with venous system (microcirculation is bypassed): AV fistula from trauma.

Effects of a Decrease in cellular ATP1. Cell must utilize anaerobic glycolysis to generate ATPA. 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 PumpA. 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 hypoxia1. Disruption of the cell membrane:• Most important factor• Lipid Peroxidation by Free Radicals FR: reversed by Vit E2. Damage to Mitochondria3. 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 Injury1. Hypoxia: decrease Oxidative Phosphorilation in mitochondria leading to a decrease ATP2. 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 ofactivation 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 lysis5. 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 Hepatitis• Transaminases • Creatine Kinase Skeletal/cardiac muscle Cardiac muscle• CK:MB • Amylase/Lipase : Acute Pancreatitis Myocardial Infarction (Troponin)• LDH ½ flip

FREE RADICALS: Unpaired electrons in the outer orbit1. 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/MonocytesB. O2 toxicity due to superoxide FR damage: e.g. Retrolental fibroplasia leading to blindness in newbornsC. 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 conditionsE. 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 FRsF. CCl4 poisoning in dry cleaning industry: CCl4 converted by Cytochrome Liver cell necrosis with fatty change.system into CCl3 FR

APOPTOSIS: Individual cell necrosis1. 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 TSHB. 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 intestinesC. Involution of the Thymus in an adultD. Cell death related to injurious agents:• Viruses (e.g. HBV infected cells)• Cell cycle specific chemotherapy drugs• Tissue hypoxia• Ionizing and UV light radiationE. Death of tumor cellsF. 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 ductG. Cytotoxic T cell-induced death of target cellsH. Programmed cell death involved in old age

3. Sequential mechanisms of ApoptosisA. 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 FactorB. 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 proteinsC. Mitochondrial InjuryD. Formation of Cytoplasmic blebs that fragment into apoptotic bodies that are surrounded by cell mb and contain cytoplasm, packed organelles, with or without nuclear fragmentsE. 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 NECROSISNecrosis is widespread damage to tissue as opposed to apoptosis, which is individual cell necrosis.1. Coagulation NecrosisA. 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 disappearingB. 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 foodWet Gangrene: • Is predominantly Liquefactive necrosis (see below) when there is infection.2. CNS InfarctsA. Example of Liquefactive not Coagulative necrosisB. 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 NecrosisA. Usually refers to neutrophils-dependent enzymatic destruction of tissueB. 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/abscesses4. Caseous NecrosisA. Cheese-like material noted on gross exam of tissue: represents lipid material in granulomas from macrophage destruction of typical/atypical TB and systemic fungiB. Other types of Granulomas are non-caseating: • Crohn’s Disease• Sarcoidosis5. 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-Ray6. Fibrinoid NecrosisA. Necrosis of Immunologic Injury with protein material appearing like FibrinB. Examples: • Small Vessel Vasculitis: Henoch-Schonlen purpura• Rheumatic Heart disease vegetations on Mitral valve• Immunocomplex glomerulonephritis: e.g. SLE7. Gummatous Necrosis in Tertiary Syphilis- Rubbery masses that are very destructive in tissue

FATTY LIVER

1. Alcohol MCCA. 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 TGB. Increased Acetyl CoA in alcohol metabolism is used for fatty acid (FA) synthesis2. KwashiorkorFatty 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 PIGMENTS1. BilirubinA. Unconjugated Type:Lipid soluble: end product of macrophage metabolism of Hb in phagocytosed RBCse.g.: Rh hemolytic disease of the newbornB. Conjugated type: Water soluble: conjugated in the liver; e.g.: Obstructive Jaundice: stone in the common bile duct.

2. HemosiderinB. Storage Iron consists of 2 forms:• Soluble Ferritin• Insoluble FerritinC. 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 diseasedecreased 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 HbResponsible for Black Tarry stools (melena) associated with peptic ulcer disease.

DYSTROPHIC CALCIFICATION1. 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 CALCIFICATION1. Def: Increased serum calcium and/or phosphate leading to the deposition of calcium in normal tissue2. Examples: • Nephrocalcinosis, in primary hyperparathyroidism - calcification of tubular basement membranes • Calcification of basal ganglia in primary hypoparathyroidism

CONGENITAL SPHEROCYTOSISGenetic 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 FILAMENTS1. 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 glandsB. 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 cycleA. 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 timeC. Examples: - Most parenchymal cells in organs; e.g. hepatocytes, renal tubular cells, endothelial cells.- Smooth muscle: not striated or cardiac cells- Astrocytes / other Neuroglial cellsD. Stable cells have the capacity to undergo hypertrophy and / or hyperplasia.3. Permanent Cells: A. cells can not enter the cell cycleB. Ex: • Skeletal cardiac muscle can only HYPERTROPHY• Neurons

CELL CYCLE1. 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 cycleB. 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 KinaseRb (hypophosphorylated form) inhibits cell from going from G1 to S phaseRb phosphorylated form allows cell to go from G1 to S phase2n= 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 17A. Produces a protein product that inhibits active cyclin D/cdk complex1. Prevents phosphorylation of the Rb protein and keeps the cell in the G1 phase2. Allows cell to repair any defects in DNA (“Guardian of the cell”): cells incapable of repair undergo apoptosisB. 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 alterations1. ATROPHY.- Decrease in cell/tissue massA. Characteristics include: • Less organ weight• Wrinkled capsular surface• Less mitochondria• Increase Lipofuscin in cellsB. examples:1. muscle in a cast: disuse of muscle leads to atrophy2. Thyroid gland in someone taking excess thyroid hormone: decrease in TSH from increase in T4 causes atrophy of thyroid3. Renal artery atherosclerosis: affected kidney is atrophied, while the contralateral kidney is hypertrophied (compensatory)4. Compression atrophy of renal cortex by hydronephrosis5. Carotid artery atherosclerosis: cerebral atrophy due to apoptosis of neurons (called “red neurons”) in layers 3,5,66. 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 developsE. Hypoplasia: anlage develops incompletely; however, the tissue that is present is histologically normal.2. HYPERTROPHY: Increased cell sizeA. 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 kidney3. HYPERPLASIA: Increase in number of cellsA. Common alteration in hormone excess statesB. Can progress to dysplasia and cancer if left unregulatedC. examples: 1. Hormone excess states: - Unopposed endometrial hyperplasiaestrogen - 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 alterationB. 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