GENERAL MORPHOLOGY OF INFLAMMATION. EXUDATIVE INFLAMMATION. PROLIFERATIVE INFLAMMATION: NONSPECIFIC AND SPECIFIC. MORPHOLOGY OF GRANULOMA.
Inflammation is defined as the local response of living tissues to injury caused by any agent. It is body defense reaction in order to eliminate or limit the spread injurious agent.
Causes. The agents causing inflammation may be follows:
1. Physical agents (heat, cold, radiation, mechanical injury).
2. Toxic chemical agents (organic and inorganic poisons).
3. Microbiological agents (bacteria, viruses, parasites, fungi).
4. Immunological agents (cell-mediated, immune complex and antigen-antibody reactions).
Clinico-morphological signs of inflammation. There are 5 main clinico-morphological signs of inflammation: rubor (redness); tumor (swelling); calor (heat), dolor (pain) and functio laesa (loss of function).
The word “inflammation” means burning. This nomenclature has its origin in old times but now we know that burning is only one of the signs of inflammation. The condition develops on the histion. T’pes of inflammation
There are 3 phases in inflammation: alteration, exudation and proliferation. The first phase is alteration, degeneration and necrosis of the cells, tissue. The second phase is exudation, formation of exudate. There are several stages in exudation: a) micro- circulation reaction with disturbance of blood rheology, b) increased vascular permeability, c) exudation of main blood components, d) emigration of blood cells, e) phagocytosis, f) formation of exudation and g) development of inflammatory infiltration.
According to prevailing one of these phases, inflammation is classified into 2 groups. We distinguish exudative and proliferative inflammations.
Depending upon the defense capacity of the host and duration of the response, inflammation can be classified as acute and chronic.
Exudative inflammation usually develops as acute inflammation, proliferative inflammation develops as chronic one.
Acute inflammation is of short duration and represents the early body reaction and is usually followed by repair.
Chronic inflammation is of longer duration and occurs either after the causative agent of acute inflammation persists for a long time, or the stimulus is such that it induces chronic inflammation from the beginning. Cells involved in inflammation Neutrophils (also known as polymorphonuclear neutrophils), are the predominant cells in acute inflammation as well as in abscess formation, connective tissue proliferation, and empyema. They are the white blood cells (WBCs) most responsible for the leukocytosis that occurs in response to an inflammatory or infectious crisis.
Neutrophils are granular leukocytes with a polymorphonucleus and fine cytoplasmic granules that stain readily with neutral dyes. In the inflammatory response, neutrophils are the first cells to arrive at the injured area. The major activity of neutrophils is phagocytosis of invading bacterial cells, with subsequent destruction of the cells through the release of lysosomal enzymes.
Eosinophils (eosinophilic granulocytes) have a characteristic bilobate nucleus and cytoplasmic granules that stain orange with Romanovsky’s stain and red-orange with eosin. The granules contain hydrolytic enzymes (e.g., histaminase, which inactivates histamine; arylsulfatase B, which inactivates S kS-A). The granules also contain a poorly understood major basic protein. Although they also can be found in peripheral blood, a number of the body’s eosinophils exist in hypersensitivity sites within the tissues, where they can abort hypersensitivity reactions. Eosinophils are increased in the peripheral blood in the presence in the allergy and parasitic infestation. Eosinophils are readily chemotactic upon the Bronchopneumonia (hemorrhagic release of eosinophil chemotactic factor (ECF) from IgE-sensitized mast cells—an occurrence in anaphylaxis. Eosinophils are also phagocytic, although phagocytosis is a minor function.
Basophils (basophilic granulocytes) contain granules that stain blue with Wright’s stain. The granules contain histamine, heparin, and slow-reacting substance of anaphylaxis. Basophils are involved in type I immediate, or immunoglobulin E (IgE)mediated hypersensitivity reactions. When an IgE specific antigen enters the body, basophils stimulate the formation of IgB, which binds to the surface of the antigen. The basophilic granules then release histamine and other vasoactive substances to produce anaphylactic reactions in susceptible persons. Basophils also play a role in type IV (i.e., delayed) hypersensitivity reactions, such as contact dermatitis.
Macrophages. The mononuclear phagocyte system (also known as the monocyte-macrophage system and reticuloendothelial system) is an extensive network of macrophages that exists throughout the body. Pulmonary alveolar macrophages, Pleural and peritoneal macrophages, Kupffer cells of the liver, Histiocytes of mesenchymal and connective tissue, Mesangial cells of the kidney. Both fixed and mobile macrophages in the lymph nodes, spleen, and bone marrow. Macrophages in the body tissues develop from monocytes that have left the peripheral blood. The monocytes originally derive from bone marrow precursors. Monocytes in the bone marrow and the peripheral blood can be converted rapidly into additional macrophages wheeeded.
Macrophages dispose of noxious matter within tissues, for example, microorganisms and necrotic tissue or other debris. Macrophages also appear to serve in tumor cell killing. In phagocytosis, the cytoplasmic membrane extends around particles and engulfs them, forming an intracellular vacuole. In microcytosis, the cell membrane engulfs extracellular fluid along with the particles. The lysosomes of macrophages contain degradative substances similar to those ieutrophils. Macrophages have surface receptors for the Fc segment of the immunoglobulin U (IgG) molecule and for complement component C3b. These aid the macrophage in phagocytosis of opsonized microorganisms.
Macrophages are important components of the immune system. Their involvement begins with the initiation of the immune response, and they interact closely with T-lymphocytes. B-cell activation requires IL-i, which is secreted by macrophages (and some other cells). B-cell activation also requires that antibody on the B-cell surface match its specific antigen. Antigen on the macrophage surface can serve this purpose.
Mast cells resemble basophils in both structure and function. Whereas basophils are present mainly in the peripheral blood and at sites of inflammation, mast cells are connective tissue cells found close to small blood vessels. Mast cells contaiumerous granules that stain metachromatically with basic dyes. Like basophilic granules, mast cell granules release histagune, heparin, and SRS-A during type I reactions. In addition, mast cell granules release. Agents that cause inflammation (e.g., physical factors, drugs, immunoglobulins, complement components C3a and C5a, cationic proteins) may cause histamine release from mast cells.
Lymphocytes and their derivatives are found in the tissues in all types of inflammation, especially after the acute ingress of neutrophils. All lymphocytes are: derived from bone marrow stem cells. Stem cells differentiate into lymphocytes in the primary lymphoid organs (thymus and bone marrow). From these1 locations, some lymphocytes migrate — via the circulation—to secondary lymphoid organs, namely, the spleen, lymph nodes, and lymphoid germinaL centers throughout the body. Lymphocytes are divided into two types —i T-cells and B-cells — which serve different functions (See Immunopathology).
ACUTE INFLAMMATION
Morphological manifestations of inflammation depend upon a number of factors and processes. They ire factors of the organisms and the host, type of exudation, cellular proliferation.
Factors involving the organisms:
1. Type of injury and infection. For example, skin reacts to herpes simplex infection by formation of a vesicle and to streptococcal infection by formation of a boil; lung reacts to pneumococci by occurrence of lobar pneumonia while to tubercle bacilli it reacts by granulomatous inflammation.
2. Virulence. Many species and strains of organisms may have varying virulence e.g. the three strains of C. diphtheriae (gravis, intermedius and mitis) produce the same diphtherial exotoxin but in different amount.
3. Dose. The concentration of organism in small doses produces usually local lesions while a larger dose results in more severe spreading infections.
4. Portal of entry. Some organisms are infective hanly if administered by particular route, e.g. Vibrio ho lerae is not pathogenic if injected subscutaneously but causes cholera if swallowed.
5. Product of organisms. Some organisms produce enzymes that help in spread of infections, e.g. hyaluronidase by Cl., streptokinase by Streptococci, staphylokinase and coagulase by Staphylococci.
Factors involving the host
1. General health of host. For example, starvation, hemorrhagic shock, chronic debilitating diseases like diabetes mellitus, alcoholism, etc. render the host more susceptible to infections.
2. Immune state of host. Immunodeficiency helØs in spread of infections rapidly, e.g. in AIDS.
3. Leukopenia. Patients with low WBC count with neutropenia or agranulocytosis develop spreading infection.
4. Site or type of tissue involved. For example, the lung has loose texture as compared to bone and thus both tissues react differently to acute inflammation.
5. Local host factors. For instance, ischemia, presence of foreign bodies and chemicals cause necrosis and are thus harmful.
Type of exudation. The appearance of escaped plasma determines the morphological type of inflammation. These are:
1. Serous, when the fluid exudate resembles serum or is watery, e.g. pleural effusion in tuberculosis, blister formation in burns.
2. Fibrinous, when the fibrin content of the fluid exudate is high, e.g. in pneumococcal and rheumatic pericarditis.
Two types may be croupous and diphtheria fibrinous inflammation.
3. Purulent or suppurative exudate is formation ot creamy pus as seen in infection with pyogenic bacteria, e.g. abscess, acute appendicitis, phlegmon.
4. Hemorrhagic, when there is vascular damage, ‘g. acute hemorrhagic pneumonia in influenza.
5. Catarrhal, when the surface inflammation of epithelium produces increased secretion ofmucus, e.g. common cold.
Cellular proliferation. Variable cellular proliferalion is seen in different types of inflammations.
1. There is no significant cellular proliferation in acute bacterial infections except in typhoid fever in which there is intestinal lymphoid hyperplasia.
2. Viral infections have the ability to stimulate cellular proliferation, e.g. epidermal cell proliferation in herpes simplex, chickenpox and smallpox.
Necrosis. The extent and type of necrosis in inflammation is variable. In gas gangrene, there is extensive necrosis with discolored and foul smelling tissues. in acute appendicitis, there is necrosis as a result of vascular obstruction. In chronic inflammation such as tuberculosis, there is characteristic caseous necrosis. Morphology of acute inflammation
Inflammation of an organ is usually named by adding the suffix “itis” so its Latiame e.g. appendicitis, hepatitis, cholecystitis, meningitis, etc. A few morphologic varieties of acute inflammation are described below:
1. Catarrhal inflammation. A surface inflammation associated with greatly increased secretion of clear mucus. Later, polymorphs appear (common cold and some forms of colitis).
2. Hemorrhagic inflammation. Where the damage is severe, actual rupture of all blood vessels occurs, with hemorrhage the most striking feature (acute hemorrhagic pneumonia occasionally occurring in fatal cases of influenza).
3. Suppuration. There are several types of suppuration: an abscess, phlegmon, furuncle, carbuncle, cellulitis, bacterial infections of the blood.
When acute bacterial infection is accompanied by intense neutrophilic infiltrate in the inflammed tissue, it results in tissue necrosis. A cavity is formed which is called an abscess and contains purulent exudate or pus and the process of abscess formation is known as suppuration. The bacteria which cause suppuration are called pyogenic. Pus is creamy or opaque in appearance and is composed of numerous dead as well as living neutrophils, some red cells, fragments of tissue debris and fibrin. In old “pus” inacrophages and cholesterol crystals are also present. The wall of abscess is called pyogenic membrane. An abscess may be discharged to the surface due to increased pressure inside or may require drainage by the surgeon. Due to tissue destruction, resolution does not occur but instead healing by fibrous bearing takes place.
Phlegmon is unbounded purulent inflammation in which pus spreads diffusely between different components of tissue owing to fusion and tissue lysis. Phlegmon frequently occurs along the muscular bands, tendons, fascias, vascular-nerves bands and in subcutaneous fat. Two types of phlegmon have been described: sofi and dense.
If purulent exudate appears in the human cavities ‘is called empyema.
Furuncle is an acute inflammation via hair flicles in the dermal tissues.
Carbuncle is seen in untreated diabetics and occurs as a located abscess in the dermis and soft tissues of the neck.
Cellulitis. It is a diffuse inflammation of soft tissues resulting from spreading effects of substances like hyaluronidase released by some bacteria.
Bacterial infections of the blood. This includes the following 3 conditions: bacteremia, septicemia, pycmia.
Bacteremia is defined as presence of small number ol bacteria in the blood which don’t multiply significantly. They are commonly not detected by direct microscopy. Blood culture is done for their detection, e.g. infection with Salmonella typhi, Escherichia colt, Streptococcus viridans.
Septicemia means presence of rapidly multiplying, highly pathogenic bacteria in the blood, e.g. pyogenic cocci, bacilli of plague, etc. Septicemia is generally accompanied by systemic effects like toxemia, multiple small hemorrhage, neutrophilic leucocytosis and disseminated intravascular coagulation (DIC).
Pyemia is the dissemination of small septic thrombi in the blood which cause their effects at the site where they are lodged. This can result in pyemic abscesses or septic infarcts. Pyemic abscesses are multiple small abscesses in various organs such as in cerebral cortex, myocardium, lungs and renal cortex, resulting from very small emboli fragmented from septic thrombus. Microscopy of pyemic abscess shows a central zone of necrosis containing numerous bacteria, surrounded by a zone of suppuration and an outer zone of acute inflammatory cells. Septic infarcts result from lodgment of larger fragments of septic thrombi in the arteries with relatively larger foci of necrosis, suppuration and acute inflammation, e.g. septic infarcts of the lungs, liver, brain, and kidneys from septic thrombi of leg veins or from acute bacterial endocarditis.
4. Serous inflammation. Serous inflammation is marked by the outpouring of a thin fluid that, depending 1pericardial space.
One the size of injury, is derived from either the blood serum or the secretions of mesothelial cells lining the )erltoneal, pleural, and pericardial cavities. The skin blister resulting from a bum or viral infections represents a ‘arge accumulation of serous fluid, either within or immediately beneath the epidermis of the skin.
5. Fibrinous inflammation. With more severe injuries and the resulting greater vascular permeability, larger molecules such as fibrin pass the vascular barrier. A fibrinous exudate develops when the vascular leaks are large enough or there is a pro- coagulant stimulus in the interstitium (e.g., cancer cells). A fibrinous exudate is characteristic of inflammation in body cavities, such as the pericardium and pleura. Microscopically, fibrin appears as an eosinophilic meshwork of threads, or sometimes as an amorphous coagulum. Fibrinous exudates may be removed by fibrinolysis, and other debris by macrophages. This process, called resolution, may restore normal tissue structure, but when the fibrin is not removed it may stimulate the ingrowth of fibroblasts and blood vessels and thus lead to scarring. (‘onversion of the fibrinous exudate to scar tissue (organization) within the pericardial sac will lead either to opaque fibrous thickening of the pericardium and epicardium in the area of exudation or, more often, to the development of fibrous strands that bridge. According to the type of epithelium on which inflammatory process develops and depth of necrosis there are two types of fibrinous inflammation croupous and diphtheroid fibrinous inflammation. Usually croupous inflammation develops on the columnar epithelium. In this case the fibrinous membranes unfix easily, without any effort. Diphtheroid fibrinous inflammation develops on the squamous or intermediate epithelium, when the fibrinous membranes unfix with difficulties.
6. Pseudomembranous inflammation. It is inflammatory response of mucous surface (oral, respiratory, bowel) to toxins of diphtheria or irritant gases. As a result of denudation of epithelium, plasma exudes on the surface where it coagulates, and together with necrosed epithelium, forms false membrane that gives this type of inflammation its name.
7. Ulcer. Ulcer is a local defect on the surface of an organ produced by inflammation. In the acute stage, there is infiltration by polymorphs with vasodilatation while long-standing ulcers develop infiltration by lymfhocytes, plasma cells and macrophages with5 associated fibroblastic proliferation and scarring.
The acute inflammatory process can culminate one of the following 4 outcomes: resolution, healin by scarring, progression to suppuration, progressio to chronic inflammation.
Outcome. This means complete return to norma tissue following acute inflammation. It occurs when issue changes are slight and the cellular changes are reversible, e.g. resolution in lobar pneumonia.
Healing by scarring. This takes place when the issue destruction in acute inflammation is extensive so that there is no tissue regeneration but actually there is healing by fibrosis.
Progression to suppuration. When the pyogenic bacteria causing acute inflammation result in severe lissue necrosis, the process progresses to suppuration. Initially, there is intense neutrophilic infiltration. Subsequently, mixture of neutrophils, bacteria, Iiagments of necrotic tissue, cell debris and fibrin comprise pus which is contained in a cavity to form an abscess. The abscess, if not drained, may get organized by dense fibrous tissue, and in time, get caftified.
Progression to chronic inflammation. Acute inflammation may progress to chronic one in which the processes of inflammation and healing proceed side by side.
CHRONIC INFLAMMATION
Chronic inflammation is defined as prolonged process in which tissue destruction and inflammation occur at the same time.
Chronic inflammation can be caused by one of the following 3 ways:
1. Chronic inflammation following acute inflammation — when the tissue destruction is extensive, or the bacteria survive and persist in small numbers at the site of acute inflammation, e.g. in osteomyehtis, pneumonia terminating in lung abscess.
2. Recurrent attacks of acute inflammation — when repeated bouts of acute inflammation culminate in chronicity of the process, e.g. in recurrent urinary tract infection leading to chronic pyelonephritis, repeated acute infection of gall bladder leading to chronic cholecystitis.
3. Chronic inflammation starting de novo — when the infection with organisms of low pathogenicity is chronic from the beginning, e.g. infection with Mycobacterium tuberculosis.
Though there may be differences in chronic inflammatory response depending upon the tissue involved and causative organisms, there are some basic similarities amongst various types of chronic inflammation. These general features characterize any chronic inflammation.
1. Mononuclear infiltration. Chronic inflammatory lesions are infiltrated by mononuclear inflammatory cells like phagocytes and lymphoid cells. Phagocytes are represented by circulating monocytes, tissue macrophages, epithelioid cells and sometimes, multinucleated giant cells. The macrophages comprise the most important cells in chronic inflammation.
2. Tissue destruction and necrosis. Tissue destruction and necrosis are common in many chronic inflammatory lesions and are brought about by activated macrophages by release of a variety of biolotucally active substances.
3. Proliferative changes. As a result of necrosis, proliferation of small blood vessels and fibroblasts is stimulated resulting in formation of inflammatory granulation tissue. Eventually, healing by fibrosis and coflagen laying takes place.
Main classifications of chronic inflammation
Conventionally, chronic inflammation is subdivided into 2 types:
1. Nonspecific, when the irritant substance produces a non-specific chronic inflammatory reaction with formation of granulation tissue and healing by Jibrosis, e.g. chronic osteomyelitis, chronic ulcer.
2. Specific, when the injurious agent causes a characteristic histologic tissue response, e.g. tuberculosis, leprosy, syphilis.
However, for a more descriptive classification, histological features are used for classifying chronic inflammation into 3 corresponding types.
1. Chronic nonspecific interstitial inflammation. This is characterized by nonspecific inflammatory cell infiltration, e.g. chronic osteomyelitis, lung abscess. A variant of this type of chronic inflammatory response is chronic suppurative inflammation in which infiltration by polymorphs and abscess formation are additional features, e.g. actinomycosis. The inflammatory cell infiltration consist of lymphocytes, monocytes, plasmocytes, eosinophils and other cells.
2. Chronic nonspecific interstitial inflammation with formation of polyps and pointed condyloma. It occurs on the mucous membranes and in the areas borderline with squamous epithelium.
Polyps are the end result of prolonged chronic irritation. Nasal, cervical, colorectal polyps are common. Macroscopically they are gelatinous masses with smooth and shining surface. Microscopically they are composed of loose edematous connective tissue containing some mucous glands and varying number of inflammatory cells (lymphocytes, plasmocytes, eosinophils).
Condyloma is commonly located on the coronal sulcus on the penis or the perineal area.
3. Chronic granulomatous inflammation. This is characterized by formation of granulomas, e.g. tuberculosis, leprosy, syphilis, actinomycosis, sarcoidosis, etc. Granuloma is defined as a circum-scribed, tiny lesion, about
Necrosis may be a feature of some granulomatous conditions, e.g. centr & caseous necrosis of tuberculosis, so called because of cheese-like appearance and consistency of necrosis.
Fibrosis is due to proliferation of fibroblasts at the periphery of granuloma.
The following two factors favour the formation of granulomas:
1. Presence of poorly digestible irritant which may be organisms like Mycobacterium tuberculosis, particles of talc, etc.
2. Presence of cell-mediated immunity to the irritant, implying thereby the role of hypersensitivity in granulomatous inflammation.
A fully-developed tubercle is about
Granulomatous inflammation is typical of reaction to poorly digestible agents elicited by tuberculosis, leprosy, fungal infectiohs, schistoso-miasis, foreign particles, etc.
The outcomes of chronic inflammation depend on the type of inflammation, morphofunctional characteristic of the definite organ or tissue, where inflammation develops. Frequently sclerosis and hyalinosis may develop.
Stages of individual work in class
Study and describe macrospecimens
Fibrinopurulent pericarditis. Describe the macro-specimen, characterize the surface of the epicardium. What is the descriptive name for the specimen? Indicate the causes and I outcome; possible clinical determination of pericarditis.
Purulent leptomeningitis. Characterize the stage ofj haemorrhage in the pia mater of the brain, state of the gyri, sulci, exudative type. What are the causes of the inflammation, its complications and outcome.
Brain abscess. Appearance of the abscess walls and the content of the space. Which type of inflammation is it? Name. the causes of purulent inflammation and its outcome. Croupous pneumonia in the stage of grey hepatization. Describe the appearance of the lungs; aeration, pleura state, the character of the e)cudate. Etiological factors, the outcomes of the inflammation and possible complications.
Diphtheroid colitis. Describe the macro specimen. Characterize the thickness of the intestinal walls, the types of the film covering the mucous layer. Name the disease and state under which the above inflammation develops.
Unicameral hepatic echinococcosis. Describe the cavity shape, its internal layer, cyst contents. The appearance of
external layer of the cyst side. Name the sequence of changing the tissue reaction to the zone of parasitical inculcation.
Condyloma. Characterize the appearance of condyloma, its sizes. Describe the character of the growth. Name the localization of condyloma. Kind of the productive inflammation.
Polyp of small intestine. Describe the appearance of the intestine from the side of the tunica. Name the type of productive inflammation and possible complications, outcomes.
Miliary pulmonary tuberculosis. Characterize the appearance of the nodule and the nature of the process. Describe [he colour, size, quantity of them. Give the definition with the regard of the character of pathological process and its morphological form, etiology and degree of the prevalence. Name the way of pathogen dissemination. Translate the term (“miliary“. In what forms of tuberculosis is it observed? Possible outcomes of granuloma; the causes of death.
Syphilitic mesaortitis. Pay attention to localization of the pathological process with the regard of the aorta part. Describe [lie appearance of the aor.ta i the place of localization of pathological process. Pathogenesis of the disease. Name the Hgurative name of the changing aorta intima in the place of direct injury and the kind of pathological process (which underlie in the aorta changing), its form with the regard of etiology and morphology. in which period of syphilis do you observe these changes? Name the possible complication.
Flepatic solitary gummas. Pay attention to the heterogeneous hepatic appearance. Define the form of the gumma, its colour, periphery of the gumma. Give the definition of the term “gumma” with the regard of the character of the pathological process, its morphological form, etiology and degree of the prevalence. Translate the term “solitary”. In which period does syphilis develop in the gummas? Name the outcomes. Explain the essence of the changes in the liver.
