Overview of Inflammation

 

OVERVIEW OF INFLAMMATION: 

DEFINITIONS AND GENERAL FEATURES

Inflammation is a response of vascularized tissues to infections and tissue damage that brings cells and molecules of host defense from the circulation to the sites where they are needed, to eliminate the offending agents.

 Inflammation is a protective response that is essential for survival. It serves to get rid the host of both the initial cause of cell injury (e.g., microbes, toxins) and the consequences of such injury (e.g., necrotic cells and tissues). The mediators of defense include phagocytic leukocytes, antibodies, and complement proteins.

Most of these normally circulate in the blood, where they are sequestered so they cannot damage normal tissues but can be rapidly recruited(enroll) to any site in the body. Some of the cells involved in inflammatory responses also reside in tissues, where they function as sentinels on the lookout for threats. 

In the process of inflammation leukocytes and proteins are delivered to foreign invaders, such as microbes, and to damaged or necrotic tissues, and it activates the recruited cells and molecules, which then function to eliminate the harmful or unwanted substances. 

Without inflammation, infections would go unchecked, wounds would never heal, and injured tissues might remain permanent festering sores.

Mechanism Of Inflammation:

The typical inflammatory reaction develops through a series of sequential steps:

• The offending agent (something that is causing a problem that needs to be dealt with) which is located in extravascular tissues, is recognized by host cells and molecules.

• Leukocytes and plasma proteins are recruited from the circulation to the site where the offending agent is located.

• The leukocytes and proteins are activated and work together to destroy and eliminate the offending substance.

• The reaction is controlled and terminated.

• The damaged tissue is repaired.

Inflammation may be of two types, acute and chronic . 

The initial, rapid response to infections and tissue damage is called acute inflammation. It typically develops within minutes or hours and is of short duration, lasting for several hours or a few days. Its main characteristics are the exudation of fluid and plasma proteins (edema) and the emigration of leukocytes, predominantly neutrophils (also called polymorphonuclear leukocytes). When acute inflammation achieves its desired goal of eliminating the offenders, the reaction subsides and residual injury is repaired. 

But if the initial response fails to clear the stimulus, the reaction progresses to a protracted type of inflammation that is called chronic inflammation. Chronic inflammation may follow acute inflammation or arise de novo(starting from the beginning.). It is of longer duration and is associated with more tissue destruction, the presence of lymphocytes and macrophages, the proliferation of blood vessels, and fibrosis.

Inflammation is induced by chemical mediators that are produced by host cells in response to injurious stimuli. When a microbe enters a tissue or the tissue is injured, the presence of the infection or damage is sensed by resident cells, including macrophages, dendritic cells, mast cells, and other cell types. These cells secrete molecules (cytokines and other mediators) that induce and regulate the subsequent inflammatory response. Inflammatory mediators are also produced from plasma proteins that react to the microbes or to products of necrotic cells. Some of these mediators promote the efflux of plasma and the recruitment of circulating leukocytes to the site where the offending agent is located. Mediators also activate the recruited leukocytes, enhancing their ability to destroy and remove the offending agent. Understanding the role of chemical mediators is important because most anti-inflammatory drugs target specific mediators.

The external manifestations of inflammation, often called its cardinal signs, are heat (calor in Latin), redness (rubor), swelling (tumor), pain (dolor), and loss of function (functio laesa). The first four of these were described more than 2000 years ago by a Roman encyclopedist named Celsus, who wrote the then-famous text De Medicina, and the fifth was added in the late 19th century by Rudolf Virchow, known as the “father of modern pathology.” These manifestations occur as consequences of the vascular changes and leukocyte recruitment and activation, as will be evident from the discussion that follows.

Although normally protective, in some situations, the inflammatory reaction becomes the cause of disease, and the damage it produces is its dominant feature. For example, inflammatory reactions to infections are often accompanied by local tissue damage and its associated signs and symptoms (e.g., pain and functional impairment). Typically, however, these harmful consequences are self-limited and resolve as the inflammation abates, leaving little or no permanent damage. In contrast, there are many diseases in which the inflammatory reaction is misdirected (e.g., against self tissues in autoimmune diseases), occurs against normally harmless environmental substances that evoke an immune response (e.g., in allergies), or is excessively prolonged (e.g., in infections by microbes that resist eradication).

Inflammatory reactions underlie common chronic diseases, such as rheumatoid arthritis, atherosclerosis, and lung fibrosis, as well as life-threatening hypersensitivity reactions to insect bites, drugs, and toxins (Table 3.2). For this reason our pharmacies abound with anti-inflammatory drugs, which ideally would control the harmful sequelae of inflammation yet not interfere with its beneficial effects. In fact, inflammation may contribute to a variety of diseases that are thought to be primarily metabolic, degenerative, or genetic disorders, such as type 2 diabetes, Alzheimer disease, and cancer.

Inflammation is terminated when the offending agent is eliminated. The reaction resolves because mediators are broken down and dissipated, and leukocytes have short life spans in tissues. In addition, anti-inflammatory mechanisms are activated, serving to control the response and prevent it from causing excessive damage to the host. After inflammation has achieved its goal of eliminating the offending agents, it sets into motion the process of tissue repair. Repair consists of a series of events that heal damaged tissue. In this process, the injured tissue is replaced through regeneration of surviving cells and filling of residual defects with connective tissue (scarring).

CAUSES OF INFLAMMATION

Inflammatory reactions may be triggered by a variety of stimuli:

• Infections (bacterial, viral, fungal, parasitic) and microbial toxins are among the most common and medically important causes of inflammation. Different infectious pathogens elicit distinct inflammatory responses, from mild acute inflammation that causes little or no lasting damage and successfully eradicates the infection, to severe systemic reactions that can be fatal, to prolonged chronic reactions that cause extensive tissue injury. The morphologic pattern of the response can be useful in identifying its etiology.

• Tissue necrosis elicits inflammation regardless of the cause of cell death, which may include ischemia (reduced blood flow, the cause of myocardial infarction), trauma, and physical and chemical injury (e.g., thermal injury, as in burns or frostbite; irradiation; exposure to some environmental chemicals). Several molecules released from necrotic cells are known to trigger inflammation.

• Foreign bodies (splinters, dirt, sutures) may elicit inflammation by themselves or because they cause traumatic tissue injury or carry microbes. Even some endogenous substances stimulate potentially harmful inflammation if large amounts are deposited in tissues; such substances include urate crystals (in the disease gout), and cholesterol crystals (in atherosclerosis).

• Immune reactions (also called hypersensitivity) are reactions in which the normally protective immune system damages the individual’s own tissues. The injurious immune responses may be directed against self antigens, causing autoimmune diseases, or may be inappropriate reactions against environmental substances, as in allergies, or against microbes. Inflammation is a major cause of tissue injury in these diseases. Because the stimuli for the inflammatory responses in autoimmune and allergic diseases (self and environmental antigens) cannot be eliminated, these reactions tend to be persistent and difficult to cure, are often associated with chronic inflammation, and are important causes of morbidity and mortality.

ACUTE INFLAMMATION

Acute inflammation has three major components:

(1) dilation of small vessels, leading to an increase in blood flow,

(2) increased permeability of the microvasculature, enabling plasma proteins and leukocytes to leave the circulation, and

(3) emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent (Fig. 3.1).

 When an injurious agent, such as an infectious microbe or dead cells, is encountered, phagocytes that reside in all tissues try to eliminate these agents. At the same time, phagocytes and other sentinel cells in the tissues recognize the presence of the foreign or abnormal substance and react by liberating soluble molecules that mediate inflammation. Some of these mediators act on small blood vessels in the vicinity and promote the efflux of plasma and the recruitment of circulating leukocytes to the site where the offending agent is located.

Reactions of Blood Vessels in Acute Inflammation

The vascular reactions of acute inflammation consist of changes in the flow of blood and the permeability of vessels, both designed to maximize the movement of plasma proteins and leukocytes out of the circulation and into the site of infection or injury.

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

(Fig. 3.2). An exudate is an extravascular fluid that has a high protein concentration and contains cellular debris. Its presence implies that there is an increase in the permeability of small blood vessels, typically during an inflammatory reaction. In contrast, a transudate is a fluid with low protein content, little or no cellular material, and low specific gravity. It is essentially an ultrafiltrate of blood plasma that is produced as a result of osmotic or hydrostatic imbalance across vessels with normal vascular permeability

. Edema denotes an excess of fluid in the interstitial tissue or serous cavities; it can be either an exudate or a transudate. Pus, a purulent exudate, is an inflammatory exudate rich in leukocytes (mostly neutrophils), the debris of dead cells, and, in many cases, microbes.

Changes in Vascular Flow and Caliber

Changes in vascular flow and caliber begin early after injury and consist of the following:

• Vasodilation is induced by the action of several mediators, notably histamine, on vascular smooth muscle. It is one of the earliest manifestations of acute inflammation, and may be preceded by transient vasoconstriction. Vasodilation first involves the arterioles and then leads to the opening of new capillary beds in the area. The result is increased blood flow, which is the cause of heat and redness (erythema) at the site of inflammation.

• Vasodilation is quickly followed by increased permeability of the microvasculature, with the outpouring of protein-rich fluid (an exudate) into the extravascular

tissues.

• The loss of fluid and increased vessel diameter lead to slower blood flow, concentration of red cells in small

vessels, and increased viscosity of the blood. These changes result in stasis of blood flow, engorgement of small vessels jammed with slowly moving red cells, seen histologically as vascular congestion and externally as localized redness (erythema) of the involved tissue.

• As stasis develops, blood leukocytes, principally neutrophils, accumulate along the vascular endothelium. At the same time endothelial cells are activated by mediators produced at sites of infection and tissue damage, and express increased levels of adhesion molecules. Leukocytes then adhere to the endothelium, and soon afterward they migrate through the vascular wall into the interstitial tissue, in a sequence that is described later.

Increased Vascular Permeability (Vascular Leakage)

Several mechanisms are responsible for increased vascular permeability in acute inflammation (Fig. 3.3), which include:

• Retraction of endothelial cells resulting in opening of interendothelial spaces is the most common mechanism of vascular leakage. It is elicited by histamine, bradykinin, leukotrienes, and other chemical mediators. It occurs rapidly after exposure to the mediator (within 15 to 30 minutes) and is usually short-lived; hence, it is referred to as the immediate transient response, to distinguish it from the delayed prolonged response that follows endothelial injury. The main sites for this rapid increase in vascular permeability are postcapillary venules.

• Endothelial injury, resulting in endothelial cell necrosis and detachment. Direct damage to the endothelium is encountered in severe injuries, for example, in burns, or is induced by the actions of microbes and microbial

toxins that target endothelial cells. Neutrophils that adhere to the endothelium during inflammation may also injure the endothelial cells and thus amplify the reaction. In most instances leakage starts immediately after injury and is sustained for several hours until the damaged vessels are thrombosed or repaired.

• Increased transport of fluids and proteins, called transcytosis, through the endothelial cell. This process, documented in experimental models, may involve intracellular channels that open in response to certain factors, such as

vascular endothelial growth factor (VEGF), that promote vascular leakage. Its contribution to the vascular permeability seen in acute inflammation in humans is unclear. Although these mechanisms of increased vascular permeability are described separately, all probably contribute in varying degrees in responses to most stimuli. For example, at different stages of a thermal burn, leakage results from endothelial retraction caused by inflammatory mediators and direct and leukocyte-dependent endothelial injury.

Responses of Lymphatic Vessels and Lymph Nodes

In addition to blood vessels, lymphatic vessels also participate in acute inflammation. The system of lymphatics and lymph nodes filters and polices the extravascular fluids.

Lymphatics drain the small amount of extravascular fluid that seeps out of capillaries under normal circumstances. In inflammation, lymph flow is increased to help drain edema fluid that accumulates because of increased vascular permeability. In addition to fluid, leukocytes and cell debris, as well as microbes, may find their way into lymph. Lymphatic vessels, like blood vessels, proliferate during inflammatory reactions to handle the increased load. The lymphatics may become secondarily inflamed (lymphangitis), as may the draining lymph nodes (lymphadenitis).

Inflamed lymph nodes are often enlarged because of increased cellularity. This constellation of pathologic changes is termed reactive, or inflammatory, lymphadenitis.

Leukocytes that are recruited to sites of inflammation perform the key function of eliminating the offending agents. The most important leukocytes in typical inflammatory reactions are the ones capable of phagocytosis, namely, neutrophils and macrophages. Neutrophils are produced in the bone marrow and rapidly recruited to sites of inflammation. Macrophages are slower responders.

The journey of leukocytes from the vessel lumen to the tissue is a multistep process that is mediated and controlled by adhesion molecules and cytokines. Leukocytes normally flow rapidly in the blood, and in inflammation, they have to be stopped and then brought to the offending agent or the site of tissue damage, outside the vessels. This process can be divided into phases, consisting first of adhesion of leukocytes to endothelium at the site of inflammation, then transmigration of the leukocytes through the vessel wall, and movement of the cells toward the offending agent. Different molecules play important roles in each of these steps (Fig. 3.4).

Leukocyte Adhesion to Endothelium

When blood flows from capillaries into postcapillary venules, circulating cells are swept by laminar flow against the vessel wall. Red cells, being smaller, tend to move faster than the larger white cells. As a result, red cells are confined to the central axial column, and leukocytes are pushed out toward the wall of the vessel, but the flow prevents the cells from attaching to the endothelium. As the blood flow slows early in inflammation (stasis), hemodynamic conditions change (wall shear stress decreases), and more white cells assume a peripheral position along the endothelial surface.

This process of leukocyte redistribution is called margination. By moving close to the

vessel wall, leukocytes are able to detect and react to changes in the endothelium. If the endothelial cells are activated by cytokines and other mediators produced locally, they express adhesion molecules to which the leukocytes attach loosely. These cells bind and detach and thus begin to tumble on the endothelial surface, a process called rolling. The cells finally come to rest at some point where they adhere firmly (resembling pebbles over which a stream runs without disturbing them).

The attachment of leukocytes to endothelial cells is mediated by complementary adhesion molecules on the two cell types whose expression is enhanced by cytokines.

Cytokines are secreted by cells in tissues in response to microbes and other injurious agents, thus ensuring that leukocytes are recruited to the tissues where these stimuli

are present. The two major families of molecules involved in leukocyte adhesion and migration are the selectins and integrins (Table 3.4). These molecules are expressed on leukocytes and endothelial cells, as are their ligands.

• Selectins mediate the initial weak interactions between leukocytes and endothelium. Selectins are receptors expressed on leukocytes and endothelium that contain an extracellular domain that binds sugars (hence the lectin part of the name). The three members of this family are E-selectin (also called CD62E), expressed on

endothelial cells; P-selectin (CD62P), present on platelets and endothelium; and L-selectin (CD62L), found on the surface of most leukocytes.

• Firm adhesion of leukocytes to endothelium is mediated by a family of leukocyte surface proteins called integrins. Integrins are transmembrane two-chain glycoproteins that mediate the adhesion of leukocytes to endothelium and of various cells to the extracellular matrix.

Leukocyte Migration Through Endothelium

After being arrested on the endothelial surface, leukocytes migrate through the vessel wall primarily by squeezing between cells at intercellular junctions. This extravasation of leukocytes, called transmigration, occurs mainly in postcapillary venules, the site at which there is maximal retraction of endothelial cells. Further movement of leukocytes is driven by chemokines produced in extravascular tissues, which stimulate leukocytes to travel along a chemical gradient

Chemotaxis of Leukocytes

After exiting the circulation, leukocytes move in the tissues toward the site of injury by a process called chemotaxis, which is defined as locomotion along a chemical gradient. Both exogenous and endogenous substances can act as chemoattractants,

including the following:

• Bacterial products, particularly peptides with Nformylmethionine termini

• Cytokines, especially those of the chemokine family

• Components of the complement system, particularly C5a

• Products of the lipoxygenase pathway of arachidonic acid (AA) metabolism, particularly leukotriene B4 (LTB4)

These chemoattractants are produced by microbes and by host cells in response to infections and tissue damage and during immunologic reactions. All act by binding to seventransmembrane

.

Recognition of microbes or dead cells induces several responses in leukocytes that are collectively called leukocyte activation (Fig. 3.6). After leukocytes (particularly neutrophils and monocytes) have been recruited to a site of infection or tissue injury they must be activated to perform their functions. This makes perfect sense because, while we want our defenders to patrol our body constantly, it would be wasteful to keep them at a high level of alert and expending energy before they are required. The functional responses that are most important for destruction

of microbes and other offenders are phagocytosis and

intracellular killing. Several other responses aid in the defensive functions of inflammation and may contribute to its injurious consequences.

Phagocytosis

Phagocytosis involves three sequential steps: (1) recognition and attachment of the particle to be ingested by the leukocyte; (2) engulfment, with subsequent formation of a phagocytic vacuole; and (3) killing or degradation of the ingested material (Fig. 3.7).

 These steps are triggered by activation of phagocytes by microbes, necrotic debris, and various mediators.

Recognition by Phagocytic Receptors. Mannose receptors, scavenger receptors, and receptors for various opsonins bind and ingest microbes. The macrophage mannose receptor is a lectin that binds terminal mannose and fucose residues of glycoproteins and glycolipids. These sugars are typically part of molecules found on microbial cell walls, whereas mammalian glycoproteins and glycolipids contain terminal sialic acid or N-acetylgalactosamine.

Engulfment. After a particle is bound to phagocyte receptors, extensions of the cytoplasm (pseudopods) flow around it, and the plasma membrane pinches off to form a cytosolic vesicle (phagosome) that encloses the particle. The phagosome then fuses with lysosomes, resulting in the discharge of lysosomal contents into the phagolysosome. During this process the phagocyte also may release some granule contents into the extracellular space, thereby damaging innocent bystander normal cells.

Intracellular Destruction of Microbes and Debris

The killing of microbes and the destruction of ingested materials are accomplished by reactive oxygen species (ROS, also called reactive oxygen intermediates), reactive nitrogen species, mainly derived from nitric oxide (NO),

and lysosomal enzymes. This is the final step in the elimination of infectious agents and necrotic cells. The killing and degradation of microbes and elimination of dead-cell debris within neutrophils and macrophages occur most efficiently after their activation. All these killing mechanisms are normally sequestered in lysosomes, to which phagocytosed materials are brought. Thus, potentially harmful substances are segregated from the cell’s cytoplasm and nucleus to avoid damage to the phagocyte while it is performing its normal function.

MEDIATORS OF INFLAMMATION

The mediators of inflammation are the substances that initiate and regulate inflammatory reactions.

The most important mediators of acute inflammation are vasoactive amines, lipid products (prostaglandins and leukotrienes), cytokines (including chemokines), and products of complement activation.

 

 

 

MORPHOLOGIC PATTERNS OF

ACUTE INFLAMMATION

The morphologic hallmarks of acute inflammatory reactions are dilation of small blood vessels and accumulation of leukocytes and fluid in the extravascular tissue.

The vascular and cellular reactions account for the signs and symptoms of the inflammatory response. Increased blood flow to the injured area and increased vascular permeability lead to the accumulation of extravascular fluid rich in plasma proteins (edema) and account for the redness (rubor), warmth (calor), and swelling (tumor) that accompany acute inflammation. Leukocytes that are recruited and activated by the offending agent and by endogenous mediators may release toxic metabolites and proteases extracellularly, causing tissue damage and loss of function (functio laesa).

During the damage, and in part as a result of the liberation of prostaglandins, neuropeptides, and cytokines, one of the local symptoms is pain (dolor). Although these general features are characteristic of most acute inflammatory reactions, special morphologic patterns are often superimposed on them, depending on the severity of the reaction, its specific cause, and the particular tissue and site involved. The importance of recognizing distinct gross and microscopic patterns of inflammation is that they often provide valuable clues about the underlying cause.

Serous Inflammation

Serous inflammation is marked by the exudation of cell poor fluid into spaces created by injury to surface epithelia or into body cavities lined by the peritoneum, pleura, or pericardium. Typically, the fluid in serous inflammation is not infected by destructive organisms and does not contain large numbers of leukocytes (which tend to produce purulent inflammation). In body cavities the fluid may be derived from the plasma (as a result of increased vascular permeability) or from the secretions of mesothelial cells (as a result of local irritation); accumulation of fluid in these cavities is called an effusion. (Effusions consisting of transudates also occur in noninflammatory conditions, such as reduced blood outflow in heart failure, or reduced plasma protein levels in some kidney and liver diseases.) The skin blister resulting from a burn or viral infection represents accumulation of serous fluid within or immediately beneath the damaged epidermis of the skin (Fig. 3.12).

Fibrinous Inflammation

A fibrinous exudate develops when the vascular leaks are large or there is a local procoagulant stimulus. With a large increase in vascular permeability, higher-molecularweight proteins such as fibrinogen pass out of the blood, and fibrin is formed and deposited in the extracellular space. A fibrinous exudate is characteristic of inflammation in the lining of body cavities, such as the meninges, pericardium, and pleura. Histologically, fibrin appears as an eosinophilic meshwork of threads or sometimes as an amorphous coagulum. Fibrinous exudates may be dissolved by fibrinolysis and cleared by macrophages. If the fibrin is not removed, with time, 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 leads to opaque fibrous thickening of the pericardium and epicardium in the area of exudation and, if the fibrosis is extensive, obliteration of the pericardial space.

Purulent (Suppurative) Inflammation, Abscess

Purulent inflammation is characterized by the production of pus, an exudate consisting of neutrophils, the liquefied debris of necrotic cells, and edema fluid. The most frequent cause of purulent (also called suppurative) inflammation is infection with bacteria that cause liquefactive tissue necrosis, such as staphylococci; these pathogens are referred to as pyogenic (pus-producing) bacteria. A common example of an acute suppurative inflammation is acute appendicitis. Abscesses are localized collections of pus caused by suppuration buried in a tissue, an organ, or a confined space. They are produced by seeding of pyogenic bacteria into a tissue. Abscesses have a central region that appears as a mass of necrotic leukocytes

and tissue cells. There is usually a zone of preserved neutrophils around this necrotic focus, and outside this region there may be vascular dilation and parenchymal and fibroblastic proliferation, indicating chronic inflammation and repair. In time the abscess may become walled off and ultimately replaced by connective tissue. When persistent or at critical locations (such as the brain), abscesses may have to be drained surgically.

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 inflamed necrotic tissue (Fig. 3.15). Ulceration can occur only when tissue necrosis and resultant inflammation exist on or near a surface. It is most commonly encountered in (1) the mucosa of the mouth,

stomach, intestines, or genitourinary tract, and (2) the skin and subcutaneous tissue of the lower extremities in older persons who have circulatory disturbances that predispose to extensive ischemic necrosis. Acute and chronic inflammation

often coexist in ulcers, such as peptic ulcers of the stomach or duodenum and diabetic ulcers of the legs. During the acute stage there is intense polymorphonuclear infiltration and vascular dilation in the margins of the defect. With chronicity, the margins and base of the ulcer develop fibroblast proliferation, scarring, and the accumulation of lymphocytes, macrophages, and plasma cells.