Chapter 2 Inflammation and Repair
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.
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.
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.
|Protein content||<3 g/dL||>3 g/dL|
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.)
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.)
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.
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.
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:
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.
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.)
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.
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.
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.
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:
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.
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.