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".

Maybe this is okay, since some of the mediators (notably TNF-alpha) are the same as in true longstanding systemic inflammation. 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. More on "obesity as a cause of [internist's] inflammation": Nature 444: 860, 2006.

* 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 Uterine cervix ERF/KCUMB

Chronic inflammatory cells around a nerve twig David Barber MD -- KCUMB

Chronic inflammation WebPath Photo

Lymphocytes and fibrosis Rheumatoid arthritis 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 Two good eos in the center ERF/KCUMB

Eosinophil in stomach among 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 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 ERF/KCUMB

Granuloma Exhibit Yale Rosen MD Nicest granulomas on the web

TB of the liver Great granulomas Pittsburgh Pathology Cases Granulomas, low magnification This was TB. WebPath Photo

Granulomas, low magnification WebPath Photo Granuloma Coccidioides 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 WebPath Photo

Foreign body giant cell Around a tiny vegetable fiber WebPath Photo

Foreign body giant cell Around a suture WebPath Photo

Foreign body granulomas Around talc 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 Granulomas and caseation -- trust me WebPath Photo

Caseating granuloma WebPath Photo

Caseating granuloma WebPath Photo

Lots of little granulomas WebPath Photo

Asteroid bodies Lung pathology series; follow the arrows Dr. Warnock's Collection

TB granuloma Classic 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 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 Peptic esophagitis ulcers WebPath Photo

Chronic Peptic Ulcer Australian Pathology Museum High-tech gross photos

Stomach ulcer WebPath Photo

Tube pressure ulcers Larynx 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 Colon WebPath Photo

Pseudomembranous colitis Tom 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 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.

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

Granulation tissue Healing heart attack WebPath Photo

Granulation tissue Wall of abscess WebPath Photo

Granulation tissue Wall of abscess WebPath Photo

Granulation tissue High magnification WebPath Photo

Inflamed Fibrin Meshwork Polys, red cells, dense and loose fibrin David Barber MD -- KCUMB

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. Human Pathology Digital Image Gallery

Granulation tissue 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 m