PATHOLOGY LABORATORY II - INFLAMMATION AND REPAIR
Questions and Answers
SLIDE 3: COLON, ACUTE PERITONITIS
1. What is edema? What does it look like grossly and histologically?
Edema is excess fluid in the interstitial space or body cavities. Grossly, there can be an excess amount of fluid in the pleural cavities (pleural effusions), pericardial cavity (pericardial effusion), or peritoneal cavity (ascites). Other forms of edema include accumulation of fluid in the interstitial space of an injured site (local edema) of the lower extremities (lower extremity edema) or throughout the body (anasarca). The cause of the edema may be a circulation disturbance resulting in a transudate or inflammation resulting in an exudate. Protein rich edema fluid appears as amorphous eosinophilic material expanding the interstitial space. Generally, the term edema, particularly in reference to inflammation, is used for extracellular edema. However, it should be recalled that cell swelling producing intracellular edema also can occur with various forms in cell injury.
2. Edema may be a transudate or an exudate. What is the difference? How does an exudate develop or what produces the exudate?
An exudate is an inflammatory extravascular fluid with a high protein concentration, cellular debris, and specific gravity above 1.020. A transudate is extracellular fluid of low protein content and specific gravity of less than 1.012. A transudate occurs with an intact endothelium, and a mild net outward flux of fluid. This is the typical picture of edema occurring with congestive heart failure or some other circulatory disturbance. In contrast, an exudate results from a significant increase in permeability of the endothelium of blood vessels leading to an outpouring of protein rich fluid.
3. Why does inflammation develop? What is typically meant by the term acute inflammation. Does this slide fit? What is the sequence of events that occur in acute inflammation that lead to the histologic picture in this side?
Inflammation is a local response to injury. Acute inflammation is that phase of inflammatory response characterized by local edema, hyperemia (active congestion) and polymorphonuclear leukocytosis. This slide is a good example of a type of acute inflammation. The sequence of events is injury to the tissue. This is followed by direct neural stimulation and release of cellular constituents which act as chemical mediators. Next hemodynamic changes occur. These are changes in blood flow and caliber of vessels. There is transient arteriolar constriction (neurogenic), followed by dilatation. This occurs at the precapillary splinters. The result is hyperemia. Permeability changes then follow. These are most pronounced in venular endothelium allowing escape of plasma protein from the blood causing edema. The increased tissue turgor leads to stasis of blood flow. In this particular case, there has been massive outpouring of blood proteins due to marked leakage of the vessels. Outside the vascular space, there has been an activation of the coagulation cascade leading to precipitation of fibrin. The final step is exudation of leukocytes particularly polymorphonuclear leukocytes. This slide therefore shows foci of both fibrinous inflammation and fibrinopurulent inflammation. The purulent component results from the extravascular accumulation of neutrophils.
4. What are the specific types of exudates of acute inflammation and what are the differences?
The various types of exudates are:
1. Serous - thin fluid, relatively low in protein.
2. Fibrinous - rich in fibrin or fibrinoid.
3. Suppurative (pus) - neutrophils and debris.
4. Hemorrhagic - occurs when vessels rupture.
How do the neutrophils get into the tissue? What is the function of the neutrophils?
Initially, there is margination and pavementing of the neutrophils along the surface of the endothelium. This is mediated by various cytokines and adhesion molecules. Next the neutrophils undergo emigration through the endothelial functions of the microvasculature into the interstitial space. The process is driven by chemotaxis which is the unidirectional migration of white blood cells toward chemical attractants released by the damaged tissue. Aggregation of leukocytes then occurs and results in the accumulation of white blood cells at the site of injury. Accumulated white blood cells including neutrophils and macrophages, then become activated and undertake phagocytosis of the damaged tissue constituents.
5. This slide is an example of what type of exudate or acute inflammation?
Fibrinopurulent inflammation
6. How did the neutrophils get into the tissue? What is the function of the neutrophils?
After margination, rolling, pavementing, they are bound to adhesion molecules, and transmigrate through the vascular wall. Upon completion of transmigration, chemotactic agents interact with leukocyte receptors, and chemotaxis progresses until the leukocyte arrives to the site of the insult.
7. What is an abscess?
An abscess is an well demarcated cavity filled with pus. Pus is the end result of suppurative inflammation and consists of a liquefying mass of necrotic tissue debris and degenerating neutrophils.
8. What are the classic signs of inflammation and do you think they were present in this case?
This case undoubted showed the classic signs of inflammation which are:
a) Rubor (redness): result of tissue hyperemia.
b) Calor (warmth): result of tissue hyperemia.
c) Tumor (swelling): result of tissue edema.
d) Dolor (pain): result of tissue turgor, plus action of liberated intracellular amines, enzymes, potassium and blood kinins.
e) Functio laesa (dysfunction): due to all of the above.
9. What are the major categories of mediators of the inflammatory response and important mediators in each category?
The important mediators are:
a) Vasoactive amines, including histamines and serotonin;
b) Plasma proteases consisting of three interrelated systems: the kinin system, the complement system, and the clotting system;
c) Arachidonic acid metabolites, namely prostaglandins and leukotrines;
d) Products of neutrophils including cationic proteins, acid proteases and neutral proteases;
e) Products of monocytes and macrophage including enzymes, lymphokines, monokines, and cytokines;
f) Oxygen derived free radicals;
g) Platelet activating factor.
10. What are the systemic effects this patient probably experienced?
Fever is induced by mediators, primarily interleukin-1 and TNF, produced by macrophages and other cell types, as well as prostaglandins, acting on centers in the brain, including hypothalamus. In addition the patient likely had leukocytosis with an increased number of polymorphonuclear leukocytes mostly neutrophils.
SLIDE 12: SKIN DECUBITUS ULCER
1. Would you think this is an example of primary union (healing by first intention) or secondary union. What is the difference?
The presence of chronic ulceration and extensive granulation tissue would indicate that this lesion is attempting to heal by secondary union. Primary union occurs in a clean wound where the edges have been approximated fairly rapidly. In contrast, secondary union occurs when there is extensive tissue lost creating large defects or abscesses. Healing by secondary union leads to much more scarring than primary union.
2. What factors modify inflammatory-reparative responses? Which ones are likely to be affecting healing of this patient's decubitus ulcer?
Age is generally not a factor. However, nutritional state is. Severe protein depletion impairs wound healing. Hormones, particularly hydrocortisone, inhibit the inflammatory reaction and impair would healing. Local factors are also important. Blood supply is important because vascularized tissue is more resistent to infection and more capable of supporting the reparative phase. Immobilization is especially important in the healing of bone. Secondary infection, particularly associated with foreign bodies, retards the healing process. The latter is the most important single cause of delayed healing. In our case, the patient probably had poor nutrition coupled with poor blood supply due to pressure on the vessels. In addition, the lesion probably was chronically infected.
3. What is the difference between an inflammatory reaction and granulation tissue? How does granulation tissue and fibrosis or a scar differ? Can you find examples of both in the slide?
An inflammatory reaction is the humoral and cellular response to injury. Granulation tissue is the initial stage of healing and repair. Granulation tissue is composed of a loose connective tissue rich in vascular channels and containing fibroblast and macrophages. Fibrous tissue is composed of much denser collagen which is much less vascular. Scar results from the maturation of granulation tissue. This slide shows predominantly granulation tissue. However, focal areas of fibrosis may be present.
4. What is an ulcer, an abscess, a cellulitis, pseudomembrane formation, catarrhal inflammation?
An ulcer is a surface defect. An abscess is a well demarcated cavity filled with pus. Cellulitis is diffused spread of inflammation through solid tissue. Pseudomembrane formation is a fibrin and debris of mucous membrane. Catarrhal inflammation is the production of excess mucin by inflamed mucous membrane.
5. What are the possible end results of the acute inflammation?
This depends on the caused of the inflammation, the effectiveness of the inflammation, and the tissue involved. If the noxious stimulus is promptly destroyed, the exudate may be resolved leading to restitution of normal structure (mild heat injury) or the exudate may undergo organization leading to scarring (fibrinopurulent pericarditis, peritonitis). If the stimulus is not promptly destroyed and there is involvement of tissue with stable or labile cells and the framework is intact, there may be regeneration and restitution of normal structure (lobar pneumonia), but if the framework is destroyed, scarring will result (bacterial abscess). If the tissue involved is one of permanent cells, there will be scarring (myocardial infarct).
SLIDE 19: LUNG, CASEOUS GRANULOMAS IN PRIMARY TUBERCULOSIS
1. Is granulomatous inflammation a type of acute or chronic inflammation?
Granulomatous inflammation is a special type of chronic inflammation. Two factors appear to determine the form of granulomatous inflammation. These are: 1) the presence of indigestible organisms or particles and 2) the presence of cell mediated immunity to the inciting agents.
2. Are all granulomas caseous? What are examples of when caseous necrosis develops?
Granulomas are small collections of inflammatory cells composed of modified macrophages called epithelioid cells surrounded by a rim of lymphocytes. Now all granulomas have associated caseous necrosis. An example of non-caseous granulomas occurs in a condition known as sarcoidosis. Other conditions are associated with caseating granulomas. These include tuberculosis and deep fungal infections.
3. What types of cells are present in the granuloma?
Modified macrophages called epithelioid cells are predominant, they may be surrounded by a rim of lymphocytes. Granulomas often contain multinucleated giant cells either of the Langerhan's or foreign body types. The giant cells are formed by the fusion of individual macrophages.
4. What are diseases which cause granulomatous responses?
Tuberculosis, leprosy, schistosomiasis, deep fungal infections, sarcoidosis, cat-scratch fever, and syphilis.
5. Why does caseous necrosis occur?
Caseous necrosis results from the effects of hydrolytic enzymes and other substances released from the macrophages and other inflammatory cells in response to the persistence of organisms. Cell mediated immunity plays a key role in this.
6. Granulomas may develop a peripheral fibrous reaction. This is what method of defense? What are other methods of defense against infectious agents?
The fibrous reaction is attempt to wall off or seal off the infection. Another method of defense is phagocytosis of the offending organisms by macrophages or neutrophils.
SLIDE 56: HEART, VIRAL MYOCARDITIS
1. The mononuclear, especially lymphocytic, response in an acute inflammatory episode indicates what type of etiology?
The presence of a predominate lymphocytic response in an acute inflammatory process is usually indicative of a viral infection.
2. This slide represents an example of an acute inflammatory response that is not composed of neutrophils. What are other types of acute inflammatory responses that are not neutrophilic?
Another example is serous inflammation in which there is an outpouring of proteinaceous fluid without white blood cells. Another example is fibrinous inflammation in which there is an outpouring of even more protein-rich fluid leading to fibrin precipitation, again without much in the way of neurophilic emigration.
SLIDE 58: HEART, HEALED MYOCARDIAL INFARCT
1. What do the pink fibrous bands with abundant collagen represent, fibrosis or granulation tissue?
These are foci of fibrosis. The tissue much denser than granulation tissue and is not rich in capillaries or fibroblasts which is characteristic of granulation tissue.
2. What steps were involved in the formation of the scar?
Coagulation necrosis of the myocardium followed by acute inflammation with outpouring of fluid and exudation of neutrophils. This was followed by an influx of macrophages with phagocytosis of the dead myocardium. The next phase involved an ingrowth of endothelium forming vascular channels and an influx of fibroblasts. This resulted in progressive replacement of the dead myocardium by granulation tissue. Maturation of the granulation tissue with progressive laying down of collagen by the fibroblast lead to the formation of the scar.
3. Why did the heart heal by scar rather than regeneration? Clue: Myocardial cells have what type of regenerative capacity? Name types of cells which are labile, stable, and permanent. What is meant by the terms?
The heart healed by scar formation rather than regeneration because myocardial cells are permanent cells which lack the ability to undergo mitotic division. These should be contrasted with labile cells which are cells which regularly undergo mitotic division. An example of labile cells would be the epithelial cells in the crypts of the gastrointestinal mucosa. Stabile cells are cells which ordinarily are quiescence but can be stimulated to undergo mitosis. A good example would be hepatocytes involved in liver regeneration. Another example of a permanent cell type is the neuron of the nervous system.
4. What type of response do the large myocytes represent? What may have caused the response?
The large myocytes have undergone hypertrophy. They are cells which have survived the infarct and have undergone adaptation change in an attempt to take over the workload from the lost myocytes in the infarct.
SLIDE 59: HEART, ACUTE MYOCARDIAL INFARCT
1. What type of acute inflammatory exudate is on the pericardial surface? Where did the inflammatory exudate come from or what produced it? How does it differ from a serous effusion? A suppurative or purulent effusion?
The type of acute inflammatory exudate on the pericardial surface is composed predominately of fibrin. The fibrin was derived from the exudation of blood proteins from inflamed, leaky blood vessels in the epicardium. There was an activation of coagulation leading to precipitation of fibrin on the pericardium surface. This resulted from the inflammatory reaction present in the region of the infarct triggered by the dead muscle. The fibrinous exudate differs from a serous effusion because, in a serous effusion, there is an outpouring of fluid without activation of coagulation or precipitation of fibrin. A suppurative or purulent effusion is characterized by exudation of large numbers of neutrophils in addition to the presence of fibrin.
2. What are the histologic features of acute inflammation present within the myocardium? Since neutrophils are present does it mean the heart is infected with bacteria? If not what are the neutrophils responding to?
The acute inflammation within the myocardium is characterized by interstitial edema and exudation of white blood cells predominately neutrophils. These neutrophils are scattered throughout the interstitium in close apposition to the necrotic myocytes. The neutrophils are not, however, present in large masses typical of abscesses which form in response to various bacteria. The neutrophils have accumulated in the infarct as a result of release of chemotactic factors from the necrotic myocardium.
3. If the patient had not died what would have happened to exudate on the pericardial surface? If the effusion had been a serous exudate what would the result of healing most likely been?
The fibrinous exudate on the pericardial surface likely would have undergone organization and conversion to fibrous tissue. Frequently this process will lead to fibrous adhesions between the epicardial surface and the opposing surface of the parietal pericardium. In contrast, a serous effusion likely would heal by resolution leaving no residua.
4. If the patient had lived, what would the result have been in the myocardium?
The acutely inflamed necrotic myocardium would have been converted to granulation tissue and then a scar.