INFLAMMATION

Inflammation is defined as the local vascular-mesenchymal response of living tissues to injury caused by any agent. It is body defense reaction in order to eliminate or limit the spread of injurious agent.

Causes. The agents causing inflammation may be as 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).

Inflammation is characterised by five major signs described by Celsus and Virchow (rubor (redness), tumor (swelling), calor (heat), dolor (pain) and functio laesa (loss of function).

Rubor (redness). An acutely inflamed tissue appears red, for example skin affected by sunburn. This is due to dilatation of small blood vessels within the damaged area.

Tumor (swelling). Swelling results from edema – the accumulation of fluid in the extravascular space as a part of the fluid exudate – and, to a much lesser extent, from the physical mass of the inflammatory cells migrating into the area.

Calor (heat). It is due to increased blood flow (hyperaemia) through the region, resulting in vascular dilatation and the delivery of warm blood to the area.

Dolor (pain). It is due to increased pressure exerted by the accumulation of interstitial fluid and mediators such as bradykinin.

Functio laesa (loss of function). Movement of an inflamed area is consciously and reflexly inhibited by pain, while severe swelling may physically immobilize the tissues.

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.

Inflammation can be focal and diffuse. Sometimes inflammation arises in system of tissues, in that case it is spoken about systemic inflammatory disease (rheumatic diseases at systemic involvement of connective tissue). Inflammation develops in the territory of histion (the structural unit of the connective tissue, which consists of cells, connective tissue fibers, intercellular substance, elements of the microcirculation system and nervous fibers).

Inflammation consists of following three phases: alteration, exudation and proliferation.

Alteration – tissue damage – is initial phase of inflammation. This phase of inflammation is characterized by degeneration and necrosis. It is accompanied by emission of biologically active substances – mediators of inflammation.

 Cells involved in inflammation:

Neutrophils (also known as polymorphonuclear neutrophils) are the predominant cells in acute inflammation as well as in abscess formation, loculation 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 multilobate nucleus 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 slow-reacting substance of anaphylaxis (SRS-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 of allergy and parasitic infestation. Eosinophils are readily chemotactic upon the 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 SRS-A. 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 IgE, 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 when needed.

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 pinocytosis the cell membrane engulfs extracellular fluid along with the particles. The lysosomes of macrophages contain degradative substances similar to those in neutrophils. Macrophages have surface receptors for the Fc segment of the immunoglobulin G (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 Т lymphocytes. B-cell activation requires IL-1, 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 contain numerous granules that stain metachromatically with basic dyes. Like basophilic granules, mast cell granules release histamine, heparin and SRS-A during type I reactions. 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 these 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 – Т cells and B cells, which serve different functions. (See Immunopathology).

Morphological manifestations of inflammation depend upon a number of factors and processes. They are 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. three strains of Corynebacterium 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 only if administered by particular route, e.g. Vibrio cholerae is not pathogenic if injected subcutaneously but causes cholera if swallowed.

5. Product of organisms. Some organisms produce enzymes that help in spread of infections, e.g. hyaluronidase by Clostridium welchii, 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 helps 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.

ACUTE  INFLAMMATION

Inflammation of an organ is usually named by adding the suffix- «itis» to its Latin name e.g. appendicitis, hepatitis, cholecystitis, meningitis, etc. A few morphologic varieties of acute inflammation are described below:

1. Serous inflammation. The serous inflammation is characterized by formation of serous exudate, which contains about 2% of proteins (mainly albumin) and small number of cellular elements. The serous inflammation is marked by the outpouring of a thin fluid that, depending on the size of injury, is derived from either the blood serum or the secretions of mesothelial cells, lining the peritoneal, pleural and pericardial cavities. The skin blister resulting from a burn or viral infections represents a large accumulation of serous fluid, either within or immediately beneath the epidermis of the skin. The serous inflammation proceeds sharply. The outcome of serous inflammation usually is favorable (resolution).

2. 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 procoagulant 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. Conversion 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 the pericardial space.

According to the type of epithelium on which inflammatory process develops and depth of necrosis there are two types of fibrinous inflammation – croupous and diphtheritic inflammation. Usually croupous inflammation develops on the columnar epithelium. In this case the fibrinous membranes unfix easily, without any effort. Diphtheritic inflammation develops on the squamous or intermediate epithelium, when the fibrinous membranes unfix with difficulties.

3. 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.

4. 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 inflamed 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, macrophages 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 scarring takes place.

Abscess may be acute and chronic. The wall of acute abscess consists of an internal pyogenic membrane and the layer of granulation tissue. The wall of chronic abscess is represented by an internal pyogenic membrane, layer of granulation tissue and mature connective tissue.

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: soft and dense.

If purulent exudate appears in the human cavities it is called empyema.

Furuncle is an acute inflammation via hair follicles 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 three conditions: bacteremia, septicemia, pyemia.

Bacteremia is defined as presence of small number of 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 coli, 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.

5. Putrid inflammation. Putrid inflammation is accompanied with tissue destruction and excretion of gases with objectionable odor. It is caused by putrefactive bacteria. The exudation looks like ichor.

6. 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).

7. Catarrhal inflammation. The catarrhal inflammation arises on the mucous membranes and is characterized by formation and accumulation of exudate on the surface of the mucous membranes. The catarrhal inflammation has an acute and chronic form.

8. 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 lymphocytes, plasma cells and macrophages with associated fibroblastic proliferation and scarring.

9. Mixed inflammation. Mixed inflammation develops in cases where one type of inflammation joins another one (fibrino-purulent, fibrino-hemorrhagic, serous-fibrinous inflammation).

Outcome. The acute inflammatory process can culminate in one of the following four outcomes: resolution, healing by scarring, progression to suppuration, progression to chronic inflammation.

Resolution. This means complete return to normal tissue following acute inflammation. It occurs when tissue changes are slight and the cellular changes are reversible, e.g. resolution in lobar pneumonia.

Healing by scarring. This takes place when the tissue 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 tissue necrosis, the process progresses to suppuration. Initially, there is intense neutrophilic infiltration. Subsequently, mixture of neutrophils, bacteria, fragments 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 calcified.

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 or productive inflammation is the type of inflammation, characterized by predominance of proliferation over alteration and exudation.

Chronic inflammation can be caused by one of the following three 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 osteomyelitis, 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 biologically 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 collagen laying takes place.

Chronic inflammation is found in every tissue and in any organ. Conventionally, chronic inflammation is subdivided into two types.

1. Nonspecific, when the irritant substance produces a nonspecific chronic inflammatory reaction with formation of granulation tissue and healing by fibrosis, 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 three 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).

In the areas of squamous epithelium, which is located near the prismatic epithelium (e.g., in anus, genitals), the secrets of the mucous membranes irritate constantly squamous epithelium, causing a proliferation of epithelium and stroma. As a result of it pointed condyloma or condyloma acuminatum is formed. They occur in people with syphilis, gonorrhea and other diseases accompanied by chronic inflammation.

3. Chronic granulomatous inflammation. This is characterized by formation of granulomas, e.g. tuberculosis, leprosy, syphilis, actinomycosis, sarcoidosis, etc. Granuloma is defined as a circumscribed, tiny lesion, about 1 mm in diameter, composed predominantly of collection of modified macrophages called epithelioid cells, and rimmed at the periphery by lymphoid cells. The word «granuloma» is composed of granule meaning circumscribed granule-like lesion and -oma which is a suffix commonly used for true tumours but here indicates inflammatory mass or collection of macrophages.