Acute and Chronic Inflammation

Acute inflammation

Acute inflammation is the immediate and early response to an injurious agent.

It has three major components:

alternations in vascular caliber that lead to an increase in blood flow

structural changes in the microvasculature that permit the plasma proteins and leukocytes to leave the circulation

emigration of the leukocytes from the microcirculation and their accumulation in the focus of injury

The escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities is known as exudation.

Exudate = an inflammatory extravascular fluid that has a high protein concentration, much cellular debris and a specific gravity above 1.020. It implies significant alteration in the normal permeability of small blood vessels in the area of injury.

Transudate = is a fluid with low protein content (most of which is albumin) and a specific gravity less than 1.012. It is essentially an ultrafiltrate of blood plasma and results from hydrostatic imbalance across the vascular endothelium.

Edema = an excess of fluid in the interstitial or serous cavities; it can be either an exudates or a transudate. Pus, a purulent exudates, is an inflammatory exudates rich in leukocytes (mostly neutrophils) and parenchymal cell debris.

Vascular changes

Changes in vascular flow and caliber

vasodilatation of arterioles and then results in opening of new capillary beds in the area; increased blood flow which is the cause of the heat and redness

slowing of the circulation is brought about by increased permeability of the microvasculature with the outpouring of protein-rich fluid into the extravascular space; the loss of fluid results in concentration of red cells in small vessels and increased of viscosity of the blood, reflected by the presence of dilated small vessels packed with red cells a condition termed stasis.

As stasis develops, one begins to see peripheral orientation of leukocytes, principally neutrophils, along the vascular endothelium, a process called leukocytic margination.

Increased vascular permeability

(vascular leakage)

Increased vascular permeability leading to the escape of a protein-rich fluid (exudates) into the interstitium is the hallmark of acute inflammation.

Mechanisms of vascular leakage in acute inflammation

• Formation of endothelial gaps in venules; it is known as immediate transient response occurs rapidly after exposure to the mediator (chemical mediators: histamine, bradykinin, leukotrienes, substance P) and is usually reversible and short-lived (15-30 min)
• Cytoskeletal reorganization (endothelial retraction) induced by citokine mediators as Interleukin-1, Tumor necrosis factor TNF and gamma interferon IFN-g, hypoxia and sublethal injury to endothelial cells

• Increased transcytosis across the endothelial cytoplasm; VEGF vascular endothelial growth factor appear to cause vascular leakage by increasing the number and perhaps the size of the endothelial channels.
• Direct endothelial injury, resulting in endothelial cell necrosis and detachment immediate sustained response; all levels of the microcirculation are affected, including venules, capillaries and arterioles.
• Delayed prolonged leakage a type of permeability that begins after a delay of 2 to 12 hours, lasts for several hours or even days, and involves venules as well as capillaries. (example: mild-moderate thermal injury, x-radiation or ultraviolet radiation)
• Leukocyte mediated endothelial injury leukocytes adhere to endothelium relatively early in inflammation; they can release toxic oxygen species and proteolytic enzymes
• Leakage from new blood vessels angiogenesis new blood vessels from endothelial cells proliferation

Cellular events:

Leukocyte Extravasation and Phagocytosis

The sequence of events in the journey of leukocytes from the lumen to the interstitial tissue, called extravasation, can be divided into the following steps:

In the lumen: margination, rolling and adhesion

Transmigration across the endothelium (diapedesis)

Migration in interstitial tissues toward a chemotactic stimulus

It is now clear that leukocyte adhesion and transmigration are determined largely by the binding of complementary adhesion molecules on the leukocytes and endothelial surfaces and that chemical mediators chemoattractants and certain cytokines affect these processes by modulating the surface expression or avidity of such adhesion molecules.

The adhesion receptors involved belong to four molecular families: the selectins, the immunoglobulins, the integrins and mucin-like glycoproteins.

Phagocytosis of the offending agent follows, which may lead to the death of the microorganism. During chemotaxis and phagocytosis, activated leukocytes may release toxic metabolites and proteases extracellularly, potentially causing tissue damage.

The two amines, histamine and serotonin, are especially important because they are available from preformed stores and are among the first mediators to be released during inflammation.

Histamine is widely distributed in tissues, the richest source being the mast cells that are normally present in the connective tissue adjacent to blood vessels.It is also found in blood basophils and platelets.

Serotonin is a second preformed vasoactive mediator with actions similar to those of histamine; it is present in platelets and enterochromaffin cells.

A variety of phenomena in the inflammatory response are mediated by three interrelated plasma-derived factors: the complement, kinin and clotting systems. The complement system consists of 20 component proteins, which are found in greatest concentration in plasma.

Outcomes of Acute Inflammation

complete resolution

abscess formation

healing by connective tissue replacement ( fibrosis)

Progression of the tissue response to chronic inflammation

Chronic Inflammation

Chronic inflammation is considered to be inflammation of prolonged duration (weeks or months) in which active inflammation, tissue destruction and attempts at repair are proceeding simultaneously.

Chronic inflammation occurs under the following situation:

persistent infections

prolonged exposure to potentially toxic agents, either exogenous or endogenous

autoimmunity: Under certain conditions, immune reactions are set up against the individuals own tissues leadind to autoimmune diseases

Histologic features

In contrast to acute inflammation, which is manifested by vascular changes, edema and largely neutrophilic infiltration, chronic inflammation is characterized by:

infiltration with mononuclear cells, which include macrophages, lymphocytes and plasma cells- a reflection of a persistent reaction to injury

tissue destruction induced by inflammatory cells

attempts at healing by connective tissue replacement of damaged tissue, accomplished by proliferation of small blood vessels ( angiogenesis) and in particular, fibrosis.

The macrophage is a central figure in the chronic inflammation because of the great number of substances the activated macrophage can produce. Some of them are toxic to cells ( oxygen and nitric oxide metabolites) or extracellular matrix (proteases); some cause influx of other cell types ( e.g. cytokines, chemotactic factors); and still others cause fibroblast proliferation, collagen deposition and angiogenesis ( e.g growth factors).

Granulomatous inflammation

Granulomatous inflammation is a distinctive pattern of chronic inflammatory reaction in which the predominant cell type is an activated macrophage with a modified epithelial-like (epithelioid) appearance.

Tuberculosis is the archetype of the granulomatous diseases, but sarcoidosis, cat-scratch disease, lymphogranuloma inguinale, leprosy, brucellosis, syphilis, are also included.

A granuloma is a focal area of granulomatous inflammation. It consists of a microscopic aggregation of macrophages that are transformed into the epithelium-like cells surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma cells. Frequently but not invariably, epithelioid cells fuse to form giant cells in the periphery or sometimes in the center of granulomas.

There are two types of granulomas, which differ in their pathogenesis: foreign body granulomas and immune granulomas.

Typically, foreign body granulomas form when material such as talc, sutures, or other fibers are large enough to preclude phagocytosis by a single macrophage and do not incite an inflammatory or an immune response.

Immune granulomas are caused by insoluble particles that are capable of inducing a cell-mediated immune response.

The prototype for immune granuloma is that caused by bacillus of tuberculosis. In this disease, the granuloma is referred to as a tubercle and is classically characterized by the presence of central caseous necrosis.

Serous inflammation

It 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 ( called effusion).

Fibrinous inflammation

With more severe injuries and the resulting greater vascular permeability, larger molecules such as fibrin pass the vascular barrier. A fibrinous exudates develops when the vascular leaks are large enough or there is a procoagulant stimulus in the intersitium.(e.g. cancer cells). 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 exudates to scar tissue = organization.

Suppurative and Purulent Inflammation

It is characterized by the production of large amounts of pus or purulent exudates consisting of neutrophils, necrotic cells and edema fluid.A common example of an acute suppurative inflammation is acute appendicitis.

Abscesses are focal localized collections of purulent inflammatory tissue caused by suppuration buried in a tissue, an organ or a confined space.

Ulcers

An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflammatory necrotic tissue.

Acute rheumatic myocarditis

Rheumatic heart disease is the most important manifestation of acute rheumatic fever because it alone can cause severe parenchymal injury or death.

Rheumatic fever is a systemic, nonsuppurative inflammatory complication of untreated pharyngeal infection with group A beta-hemolytic streptococci, which is characterized by inflammatory lesions primarily involving the heart, joints and subcutaneous tissue. Acute rheumatic carditis develops in 40 50% of patients with a first attack of acute rheumatic fever.

Acute rheumatic fever typically occurs in children between the ages of 5 and 15 years, most frequently in developing countries and in lower socioeconomic groups. Overall, less than 1% of untreated cases of group A streptococcal pharyngitis develops into acute rheumatic fever.

The precise mechanism of rheumatic fever is unknown, but it appears that an autoimmune reactin is involved. In patients with rheumatic fever, antibodies to several streptococcal antigens (streptococcal M protein and carbohydrate) have been found to cross-react with cardiac antigens. Although the specific cross-reacting antigens are unknown, myocardial myosin and sarcolemmic and vascular intimal structures are probably important. Heredity may also play a role.

Acute rheumatic carditis is a pancarditis all heart layers are affected: myocarditis, endocarditis and pericarditis.

Myocarditis is characterized by the presence of Aschoff bodies, wich are pathognomonical and, often, a diffuse nonspecific myocarditis (a variable amount of myocyte necrosis and chronic inflammation). Aschoff bodies may be found anywhere in the connective tissue of the heart and, in the myocardium, they often lie in close proximity to a small vessel and may encroach on its wall.

There are 3 histological stages in the development of Aschoff bodies:

1. Exudative stage: occurs within 4 weeks after the onset of carditis and is characterized by a focus of swollen, eosinophilic, perivascular collagen fibers (fibrinoid necrosis) associated with an inflammatory infiltrate of neutrophils and chronic  inflammatory cells (in a lesser degree).
2. Proliferative or granulomatous stage: extends from 4 to 13 weeks after the onset of carditis, when the focus of fibrinoid necrosis is surrounded by chronic inflammatory cells, fibroblasts and specific cells, called Anitschikow and Aschoff cells, also derived from macrophages.

Anitschikow cells are identified by the characteristic nuclei which have a caterpillar appearance when cut longitudinally and an owl-eye appearance when cut transversely. When these cells are multinucleate they are called Aschoff giant cells.

3. Fibrous or healed stage: extends from 3-4 months after the onset of carditis and the Aschoff bodies appears as non-specific hyalinized scars.

Pulmonary tuberculosis

Tuberculosis is a chronic infectious granulomatous disease caused by Mycobacterium tuberculosis. It usually involves the lungs, but may affect any organ or tissue in the body. Typically, the centers of tubercular granulomas undergo caseous necrosis.

Histologically, sites of active involvement are marked by a characteristic granulomatous inflammatory reaction that forms both caseating and noncaseating tubercles. Individual tubercles are microscopic; it is only when multiple granulomas coalesce that they become macroscopically visible.

The components of tuberculous granuloma:

caseous necrosis

giant cells of Aschoff type

epithelioid cells

lymphocytes

Caseous necrosis has, macroscopically, a granular, cheesy appearance; microscopically as an amorphous, granular, eosynophilic appearance; it is due by a combination of hypoxia and free radical injury.

Multinucleated giant cells are 40-50 μm in diameter and they consist of a large mass of cytoplasm and multiple nuclei in a horse-shoe pattern and derive from the fusion of 20 or more macrophages.

Epithelioid cells (activated macrophages) have a pink, granular cytoplasm with indistinct cell boundaries.

The lymphocytes surround the epithelioid cells.

Cytomegalovirus infection

Cytomegalovirus (CMV) is a congenital and opportunistic pathogen that infects many persons world wide but produces disease only rare. The fetus and immunocompromised persons are particularly vulnerable to the destructive effects of the virus. CMV infects 0.5 % to 2% of all fetuses and injures 10-20% of these, making it the most common congenital pathogen.

Affected children show predominantly neurologic defects, which range subtle learning disabilities to profound retardation.

In the immunocompromised patients, CMV infection causes necrotizing lesions, particularly in the gastrointestinal tract, brain, adrenals and lung.

Epidemiologically most persons become infected by adulthood: CMV spreads from person to person, by contact with infected secretions and fluids saliva, blood, urine, semen, breast milk and cervical secretions. The virus is transmitted to the fetus across the placenta.

The normal immune response rapidly controls CMV infection, and infected persons usually show no ill effects.

Destructive CMV infections of the fetus occur when a newly infected pregnant woman passes the virus to her fetus and the fetus is not protected by maternally derived antibodies; in that case the virus invades fetal cells with little immunologic response. The infection produces widespread cellular necrosis and inflammation and the similar situation occurs in immunosuppressed persons.

The CMV has a cytopathic effect.

Microscopically, the lesions of CMV disease show cellular necrosis and a characteristic cytopathic effect consisting of marked cellular and nuclear enlargement, with nuclear and cytoplasmic inclusions. The giant nucleus contains a large eosynophilic inclusion surrounded by a clear zone (owl eye). The cytoplasmic inclusions are less proeminent.

Actinomycosis

Actinomycosis is a slowly progressive suppurative, fibrosing infection involving the jaw, thorax, or abdomen.

The disease is caused by an anaerobic and microaerophilic bacteria termed actinomyces (Gram positive, branching, filamentous), which grow slowly under conditions of reduced oxygen and normally reside in the mouth, gastrointestinal tract and vagina.

Actinomyces is not ordinarily virulent and the organisms reside as saprophytes in the body without producing disease. Fr producing disease the organism must be inoculated into deeper tissues and an anaerobic atmosphere is necessary for the bacteria to proliferate. Trauma can produce tissue necrosis, providing an excellent anaerobic medium and can inoculate the organism into normally sterile tissue.

Sites of disease:

1. Cervico-facial actinomycosis results from jaw injury, dental extraction or manipulation
2. Thoracic actinomycosis: aspiration of organisms
3. Abdominal actinomycosis: after traumatic or surgical disruption of the bowel.
4. Pelvic actinomycosis is associated with the prolonged used of intrauterine devices.

Pathology

Macroscopically small abscesses that grow slowly, connected by sinus tracts and may penetrate onto an external surface or mucosal membrane, producing a draining sinus.

The wall of the abscess and tracts are composed of granulation tissue, fibrosis and chronic inflammation.

Within the abscesses are pus and colonies of organisms.

The colonies of actinomyces can grow to several millimeters in diameter and be visible to the naked eye as hard, yellow grains known as sulfur granules.

The filaments of actinomyces cannot be discerned on HE stain but are readily visible on Gram staining or silver impregnation.

Syphilis (lues)

Syphilis is a chronic, sexually transmitted, systemic infection caused by Treponema pallidum (a thin, long spirochete, too thin to be seen by routine light microscopy and techniques that amplify the width of the organism (silver impregnation stains) must be employed to demonstrate the organism in tissue and fluids.

The course of syphilis is classically divided into three stages:

1. Primary syphilis: the first lesion (a chancre) appears after three weeks of exposure of the inoculation site, where the number of the organisms is initially greatest.
2. Secondary syphilis : from the primary lesions the spirochetes are disseminated throughout the body producing systemic manifestations and widespread lesions
3. Tertiary syphilis: the continued presence of spirochetes of some sites (syphilitic aortitis, neurosyphilis and gumma) and the associated immunologic response produce chronic destructive lesions which often manifest years after primary and secondary syphilis.

Most of the pathologic processes associated with tertiary syphilis derive from focal ischemic necrosis secondary to obliterative endarteritis. Treponema incites mononuclear inflammatory infiltrate (plasma cells and lymphocytes) that infiltrate small arteries and arterioles, producing a characteristic obstructive vascular lesions (endarteritis obliterans).

Macroscopically, in syphilitic aortitis the intimal of the aorta appears rough and pitted (tree bark appearance).

Micotic pyelonephritis (Candida albicans)

Pyelonephritis is defined as a combined inflammation of the parenchyma calyces and renal pelvis. It occurs in two forms: acute and chronic pyelonephritis.

The Candida comprising over 20 species of yeasts include the most opportunistic pathogens. Many Candida species are endigenous human flora well adapted to life on or in the human body. However they are capable of causing disease when host defenses are compromised.

Candidal infections of deep tissues are much less common the superficial infections but can be life threatening. The most common deep sites affected are the brain, eye, kidney and heart.

Pathology

Fungi are visible on tissue sections stained with hematoxylin and eosin. Periodic acid Schiff and Gomori methenamine silver stains identify fungal cell walls and are commonly used to detect fungal infection in the tissues.

Yeasts, pseudohyphae and hyphae are present. The yeast cells are round and 3 to 4 μm in diameter, and the hyphae are septate.