Inflammation and Repair

Chapter 2 Inflammation and Repair



Ivan Damjanov, MD, PhD




1 What is the difference between cell injury and inflammation?


Cell injury can be induced in isolated single cells, monocellular organisms (e.g., amoeba), or cells grown in tissue culture. In contrast, inflammation cannot be induced in monocellular organisms or in cells cultured in vitro. An inflammatory response is a reaction to cell injury that can occur only in vascularized tissues of multicellular organisms. The same noxious stimuli that cause cell injury, however, can cause inflammation as well.



2 What is the aim of inflammation?


In general, the aim of inflammation is to eliminate or neutralize the cause of injury and repair its consequences. For example, the ultimate goal of an inflammatory response to bacteria is to destroy them and/or neutralize their adverse effects by limiting their spread inside the body. The inflammatory response is also important for repairing the tissues damaged or destroyed by bacteria. Not all inflammations have such an obvious aim, and in some instances the initial salutary effect of inflammation is overshadowed by unforeseen adverse outcomes.



3 What are the main components of inflammation?


Every inflammatory response is based on a coordinated activation and interaction of numerous components, which can be grouped under three major headings:


image Vascular response

image Cellular response

image Humoral response (chemical mediators of inflammation)


4 What is the difference between acute and chronic inflammation?


Acute inflammation is an immediate reaction to injury. Typically, as its name implies (Latin acutus, “sharp”), it has a sudden onset and is of short duration. It lasts a few hours or days. In contrast, chronic inflammation (Greek chronos, “time”) lasts longer. Acute inflammation can become chronic, but the exact point of transition from one to another form of inflammation cannot be precisely defined. The onset of a chronic inflammation cannot be established in most cases.


Pathologic changes caused by acute inflammation differ from those caused by chronic inflammation. Acute inflammation is typically mediated by neutrophils. Chronic inflammation is mediated by macrophages, lymphocytes, and plasma cells, and it often involves fibroblasts, angioblasts, and other tissue components seen in repair reactions.



ACUTE INFLAMMATION



5 What are the three main sets of events taking place in tissues during acute inflammation?


Three main events in acute inflammation are:


image Hemodynamic changes

image Increased permeability of vessel walls

image Emigration of leukocytes from blood vessels into the tissues


6 What is the difference between an exudate and a transudate?


See Table 2-1.


TABLE 2-1 Differences Between Transudate and Exudate























  Transudate Exudate
Appearance Clear Turbid
Specific gravity <1.015 >1.020
Protein content <3 g/dL >3 g/dL
Cells Scant Numerous neutrophils


Key Points: Acute Inflammation



1. Acute inflammation is a rapid response to injury involving a sequential change in blood flow, the interaction of intravascular leukocytes and endothelial cells, and migration of leukocytes toward the pathogens.

2. Inflammation is moderated by mediators of inflammation found in the plasma or secreted by cells. The most important of these are biogenic amines, coagulation factors, complement proteins, arachidonic acid derivatives, and cytokines.


7 What is edema?


Edema (Greek oidema, “swelling”) is an excess of fluid in tissues or serous body cavities. It may develop as a result of transudation or exudation.



8 Why does edema develop in acute inflammation?


Inflammatory edema has three main causes:


image Increased hydrostatic pressure in microcirculation: Arteriolar dilatation associated with an increased influx of blood promotes transudation of fluid in capillaries and venules.

image Increased permeability of blood vessels: The vessel walls of capillaries and venules become leaky under the influence of mediators of inflammation, allowing the passage of plasma proteins and fluid. The loss of fluid leads to hemoconcentration, which promotes stasis of blood cells. Stasis is associated with increased blood pressure in venules, which in turn prevents the return of the fluids from the interstitial spaces into the bloodstream.

image Reduced oncotic pressure of the plasma: The loss of proteins as a result of increased transudation or exudation will gradually reduce the oncotic pressure of the plasma. Decreased oncotic pressure of the plasma facilitates the passage of fluid into the interstitial space. At the same time, the return of water from the interstitial space into the circulating blood at the venular end of microcirculation is reduced.


9 How does the permeability of small vessels increase during inflammation?


There are several mechanisms, the most important of which are the following:


image Formation of gaps between endothelial cells: This is the most common form of increased permeability. In early stages of inflammation, it occurs predominantly in venules under the influence of histamine or bradykinin. In later stages of inflammation, it is mediated by cytokines. These mediators of inflammation cause widening of intercellular gaps as a result of retraction of endothelial cells.

image Direct injury of endothelial cells: Usually a sign of severe injury caused by a variety of agents, it occurs in arterioles, as well as capillaries or venules. The defect in the vessel wall cannot be repaired easily, thus allowing indiscriminate leakage of cells and plasma components into the interstitial spaces.

image Leukocyte-mediated injury: Adherence of neutrophils to endothelial cells, especially in pulmonary venules or glomerular capillaries, increases their permeability.

image Increased transcytosis: Vesicular transport of fluids across the cytoplasm of venules may occur under the influence of vascular endothelial growth factor (VEGF). VEGF is also a cause of increased leakiness of newly formed blood vessels in the granulation tissue and chronic inflammation.

See Fig. 2-1.


image

Figure 2-1 Increased permeability of small blood vessels in inflammation is mediated by several mechanisms, the most important of which are illustrated here. A, Formation of gaps between endothelial cells. B, Direct injury of endothelial cell. Endothelial cell injury may be caused by a variety of chemicals but also by leukocytes. C, Increased transcytosis.


(From Damjanov I: Pathology Secrets, 2nd ed. Philadelphia, Mosby, 2005, p. 23.)



10 What are the main events leading to transmigration of leukocytes across the vessel wall?



image Margination: The slowing of the blood flow allows the neutrophils to exit from the center of the bloodstream into the peripheral part and thus establish contact with endothelial cells.

image Rolling: The leukocytes, which are normally found in the bloodstream, continue rolling over the endothelial cells. During this process, leukocytes and endothelial cells become activated and establish loose contacts with one another. These contacts are mediated by surface adhesion molecules called selectins.

image Adhesion: Progressive activation of leukocytes and endothelial cells leads to expression of polypeptide adhesion molecules called integrins. Integrins on the surface of neutrophils attach to complementary integrins or endothelial cells, thus firmly binding these cells to each other.

image Transmigration: Neutrophils attached to endothelial cells by integrins assume an amoeboid shape and begin actively crawling over the inside surface of venules until they reach the intercellular gaps. Finally, leukocytes squeeze through the intercellular gaps and enter the intercellular spaces outside the vessels.

See Fig. 2-2.


image

Figure 2-2 Transmigration of neutrophils across the blood vessel wall occurs in several continuous phases, such as margination, activation and rolling, firm adhesion, transmigration proper, and chemotaxis toward the bacteria or other sources of chemoattractants. These processes are mediated by selectins, integrins, immunoglobulin-like molecules, and chemoattractants.


From Damjanov I: Pathology Secrets, 2nd ed. Philadelphia, Mosby, 2005, p. 24.)



11 What is the difference between selectins and integrins?


Selectins, found on the surface of leukocytes, platelets, and endothelial cells, are proteins that bind specifically to carbohydrates. Integrins, on the other hand, are found only on leukocytes. They bind to intercellular adhesion molecules of the immunoglobulin family (e.g., ICAM-1 and VCAM-1) and extracellular matrix (ECM) molecules, such as fibronectin or laminin.



12 How are leukocytes activated?


Activation of leukocytes is triggered by cell surface phenomena, which stimulate the receptors in the plasma membrane. Typically, this occurs following binding of leukocytes to endothelial cells or binding of interleukins to receptors on the plasma membrane of leukocytes. Signals transmitted from the cell surface receptors may activate phospholipase C, which in turn generates lipid-derived messengers, such as diacylglycerol (DAG) and inositol triphosphate (IP3). The ensuing metabolic changes lead to an increased concentration of cytosolic calcium ions. Calcium has a pivotal role in activating several intracellular processes, which are important for the action of leukocytes.



13 What are the signs of leukocyte activation?


Activated leukocytes differ from inactive leukocytes in several respects:


image Expression of adhesion molecules: Selectins and integrins appear on the cell surface or are expressed in higher numbers and show higher affinity for liquids.

image Changes in the cytoskeleton: Owing to the polymerization and redistribution of microtubules and microfilaments, the cell shape changes from round to flattened or amoeboid. Leukocytes form pseudopods and start moving actively toward the stimuli. Cytoskeletal changes also contribute to the formation of phagocytic vacuoles.

image Degranulation: The contents of cytoplasmic granules are released into phagocytic vacuoles or the extracellular spaces. Inside the phagocytic vacuoles, these enzymes participate in the digestion of bacteria. Enzymes released from the granules into the outer spaces act on ECM molecules and basement membranes, allowing the leukocytes to penetrate the tissues.

image Oxidative burst: Activated leukocytes generate free oxygen radicals, which are important for killing bacteria.

image Protein synthesis: Proteins are synthesized to replenish those excreted during degranulation, as well as those used up as a result of increased cellular activity.


14 What is chemotaxis?


Chemotaxis is active movement of cells along a chemical gradient generated by a chemoattractant.



15 What are the most important chemotactic substances?


Chemoattractants can be exogenous or endogenous. Exogenous chemoattractants are derived from bacterial polypeptides, which carry a terminal formulated-methionine sequence. Similarly, endogenous chemoattractants are generated from mitochondrial polypeptides released from damaged cells. Other important endogenous chemotactic substances include the following:


image Products of complement system activation (e.g., C5a)

image Arachidonic acid derivatives formed through the lipoxygenase pathway (e.g., leukotriene B4)

image Cytokines (e.g., IL-8)


16 How do chemoattractants act on leukocytes?


Like many other stimuli, chemoattractants activate leukocytes. Sequentially, this activation involves the following:


image Binding the chemoattractant to the cell membrane and the release of G proteins

image G protein–mediated activation of phospholipases, which leads to the production of secondary messengers, such as DAG and IP3

image Increased concentration of calcium ions in the hyaloplasm

image Calcium-mediated assembly of microfilaments


17 What are pseudopods?


Literally translated from Greek, the term pseudopods means “false feet.” It refers to the extensions of the cell cytoplasm formed along the leading edge of activated leukocytes. Pseudopods contain aggregates of microfilaments composed of actin and myosin. Contraction of myosin leads to shortening of microfilaments, which act as ropes pulling the remainder of the cytoplasm toward the furthermost tip of the pseudopods.



18 How do leukocytes kill bacteria?


The killing of bacteria occurs in three stages and involves:


image Attachment of bacteria to the surface of the leukocyte

image Uptake of bacteria into phagocytic vacuoles

image Killing and degradation

See Fig. 2-3.


image

Figure 2-3 Phagocytosis of bacterium. A, Attachment of the bacterium to the surface plasma membrane of the leukocyte is mediated by opsonins covering the bacterium and promoting their attachment to the receptors on the surface of the plasma membrane. B, Uptake of the bacterium into the phagocyte vacuole formed from the invagination of the plasma membrane. C, Killing and degradation of the bacterium inside the phagocytic vacuole.


(From Damjanov I: Pathology Secrets, 2nd ed. Philadelphia, Mosby, 2005, p. 25.)



19 How do leukocytes attach to bacteria?


Like any other particular material, bacteria attach nonspecifically to the surface of migrating leukocytes. To improve the attachment of leukocytes to potentially harmful bacteria, body fluids coat the bacteria with opsonins (Greek, “condiment” or “delicacy”). Leukocytes have receptors for opsonins, allowing them to attach with greater efficiency to opsonized bacteria than to other particles.



20 What are the main opsonins?


Opsonins are proteins normally found in the plasma and interstitial fluids, but they also may be formed nonspecifically in response to injury. The main opsonins are:


image Immunoglobulin G (IgG)

image C3b fragment formed during the activation of the complement cascade

image Collectins, such as mannose binding protein, which act as natural lectins (carbohydrate-binding proteins)


21 How do leukocytes form phagocytic vacuoles?


The formation of phagocytic vacuoles involves focal invagination of the cell surface membrane accompanied by the elongation of the cytoplasmic process laterally to that invagination. These cytoplasmic changes depend on restructuring of cytoskeleton and resemble those leading to the formation of pseudopods. Cytoskeletal changes rely on the activation of metabolic events that are identical to those that occur in activated leukocytes responding to chemotactic stimuli.



22 What are the main bactericidal substances used by neutrophils?


Bacteria can be killed through two mechanisms:


image Oxygen-dependent killing: This mechanism depends on the oxygen burst resulting from the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Oxidation of NADPH generates superoxide, which spontaneously transforms into hydrogen peroxide (H2O2). H2O2 is the substrate for myeloperoxidase, which links it to a chloride ion, generating hypochloric acid. Hypochloric acid, similar to household Clorox, is the most potent bactericidal chemical generated in the phagosomes.

image Oxygen-independent killing: Although less efficient than oxygen-dependent killing, this mechanism plays an important role in the fight against bacteria. It depends on the action of lysozyme, lactoferrin, and cationic proteins (e.g., defensin). The overall acidic environment inside the phagocytic vacuoles is toxic to some bacteria. Oxygen-independent killing of bacteria is especially important in people suffering from congenital deficiency of NADPH oxidase (chronic granulomatous disease) or myeloperoxidase deficiency.


23 What are the clinical consequences of congenital defects of abnormal leukocyte functions?


Congenital defects of phagocytosis, or bacterial killing, present as increased susceptibility to infections. Infants born with one of these defects are especially prone to opportunistic infections—that is, infections caused by ubiquitous, often saprophytic bacteria and fungi of low virulence that do not cause infections in people without these defects.



24 What are the most important congenital defects of leukocyte function?


Congenital defects of leukocyte function are rare, occurring in less than 1 in 10,000 infants. Nevertheless, these “experiments of nature” are significant because they provide insight into the pathophysiology of leukocyte functions and how these cells combat infections. The most important examples of abnormal leukocyte function are as follows:


image Defects in leukocyte adhesion: This category encompasses deficiencies of various leukocyte adhesion molecules, integrins, and enzymes that synthesize the carbohydrate ligands for the selectins.

image Defects of phagocytosis: Deficiency of C3 complement impairs opsonization. Chediak–Higashi syndrome, a defect in microtubule polymerization, is characterized by defective leukocyte migration and phagocytosis. Neutrophils typically have giant granules and are unable to degranulate upon stimulation.

image Defective bactericidal activity: Deficiency of NADPH oxidase is the basic defect in children suffering from chronic granulomatous disease. In this disease, the leukocytes cannot generate superoxide, which impairs the oxygen-dependent killing of bacteria. These children are especially sensitive to infection with catalase-positive microbes such as Staphylococcus aureus. Catalase-negative streptococci are less dangerous. These bacteria produce peroxide that is used by the leukocytes to generate hypochloric acid and to kill the pathogens. Deficiency of myeloperoxidase is characterized by an inability of leukocytes to produce H2O2 and hypochloric acid. Affected children are prone to fungal infections.


25 What are the most important plasma-derived mediators of inflammation?


The most important mediators of inflammation are proteases that belong to one of several interrelated systems activated by Hageman factor (clotting factor XII):


image Kinin system: This results in the formation of kallikrein and bradykinin. Kallikrein itself is capable of activating Hageman factor and could play a role in autocatalytic propagation of the entire enzymatic cascade.

image Clotting system: This results in the formation of fibrin through the intrinsic clotting pathway.

image Fibrinolysis system: Activation of plasminogen into plasmin results in lysis of fibrin and also activation of the complement cascade.

image Complement system: This involves sequential activation of complement proteins C1 to C9 and their activators and inhibitors.

See Fig. 2-4.


image

Figure 2-4 Activation of Hageman factor (clotting factor XII) activates the kinin, coagulation, fibrinolysis, and complement systems.



26 What is bradykinin?


Bradykinin is a low-molecular-weight peptide formed from a high-molecular-weight kininogen through the action of the enzyme kallikrein. Like histamine, bradykinin increases vascular permeability. The action of bradykinin is short lived because it is inactivated by kininases.



27 What is histamine?


Histamine is a low-molecular-weight biogenic amine stored in the granules of mast cells, basophils, and platelets. Upon release, it binds to the H1 receptor on endothelial cells, increasing the permeability of venules, which leads to edema.

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Jul 23, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Inflammation and Repair

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