CHRONIC INFLAMMATION



Chronic inflammation is a response of prolonged duration (weeks or months) in which inflammation, tissue injury, and attempts at repair coexist, in varying combinations.

It may follow acute inflammation, or may begin insidiously, as a smoldering, sometimes progressive, process without any signs of a preceding acute reaction.

Causes of Chronic Inflammation

Chronic inflammation arises in the following settings:

• Persistent infections by microorganisms that are difficult to eradicate, such as mycobacteria and certain viruses, fungi, and parasites. These organisms often evoke an immune reaction called delayed-type hypersensitivity. The inflammatory response sometimes takes a specific pattern called granulomatous inflammation. In other cases, unresolved acute inflammation evolves into chronic inflammation, such as when an acute bacterial infection of the lung progresses to a chronic lung abscess.

• Hypersensitivity diseases. Chronic inflammation plays an important role in a group of diseases that are caused by excessive and inappropriate activation of the immune system. In autoimmune diseases, self (auto) antigens evoke a self-perpetuating immune reaction that results in chronic inflammation and tissue damage; examples of such diseases are rheumatoid arthritis and multiple sclerosis. In allergic diseases, chronic inflammation is the result of excessive immune responses against common environmental substances, as in bronchial asthma. Because these autoimmune and allergic reactions are triggered against antigens that are normally harmless, the reactions serve no useful purpose and only cause disease. Such diseases may show morphologic patterns of mixed acute and chronic inflammation because they are characterized by repeated bouts of inflammation. Fibrosis may dominate the late stages.

• Prolonged exposure to potentially toxic agents, either exogenous or endogenous. An example of an exogenous agent is particulate silica, a non-degradable inanimate material that, when inhaled for prolonged periods, results in an inflammatory lung disease called silicosis

. Atherosclerosis is a chronic inflammatory process affecting the arterial wall that is thought to be induced, at least in part, by excessive production and tissue deposition of endogenous cholesterol and other lipids.

• Some forms of chronic inflammation may be important in the pathogenesis of diseases that are not convention- ally thought of as inflammatory disorders. These include neurodegenerative diseases such as Alzheimer disease, metabolic syndrome and the associated type 2 diabetes, and certain cancers in which inflammatory reactions promote tumor development. The role of inflammation in these conditions is discussed in the relevant chapters.

Morphologic Features



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

• Infiltration with mononuclear cells, which include macrophages, lymphocytes, and plasma cells

• Tissue destruction, induced by the persistent offending agent or by the inflammatory cells

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

Because angiogenesis and fibrosis are also components of wound healing and repair.

Cells and Mediators of Chronic Inflammation

The combination of leukocyte infiltration, tissue damage, and fibrosis that characterize chronic inflammation is the result of the local activation of several cell types and the production of mediators.

Role of Macrophages

The dominant cells in most chronic inflammatory reactions are macrophages, which contribute to the reaction by secreting cytokines and growth factors that act on various cells, by destroying foreign invaders and tissues, and by activating other cells, notably T lymphocytes.

Macrophages are professional phagocytes that act as filters for particulate matter, microbes, and senescent cells. They also function as effector cells that eliminate microbes in cellular and humoral immune responses.  But they serve many other roles in inflammation and repair.

Macrophages are tissue cells derived from hematopoietic stem cells in the bone marrow and from progenitors in the embryonic yolk sac and fetal liver during early development. Circulating cells of this lineage are known as monocytes. Macrophages are normally diffusely

scattered in most connective tissues. In addition, they are found in specific locations in organs such as the liver (where they are called Kupffer cells), spleen and lymph nodes (sinus histiocytes), central nervous system (microglial cells), and lungs (alveolar macrophages). Together these cells comprise the mononuclear phagocyte system, also known by the older (and inaccurate) name of reticuloendothelial system.

In inflammatory reactions, progenitors in the bone marrow give rise to monocytes, which enter the blood, migrate into various tissues, and differentiate into macrophages.

Entry of blood monocytes into tissues is governed by the same factors that are involved in neutrophil emigration, such as adhesion molecules and chemokines.

There are two major pathways of macrophage activation, called classical and alternative

• Classical macrophage activation may be induced by microbial products such as endotoxin, which engage TLRs and other sensors, and by T cell–derived signals, importantly the cytokine IFN-γ, in immune responses. Classically activated (also called M1) macrophages produce NO and ROS and upregulate lysosomal enzymes, all of which enhance their ability to kill ingested organisms, and secrete cytokines that stimulate inflammation. These macrophages are important in host defense against microbes and in many inflammatory

reactions.

• Alternative macrophage activation is induced by cytokines other than IFN-γ, such as IL-4 and IL-13, produced by T lymphocytes and other cells. These macrophages are not actively microbicidal; instead, the principal function of alternatively activated (M2) macrophages is in tissue repair. They secrete growth factors that promote angiogenesis, activate fibroblasts, and stimulate collagen synthesis.

The products of activated macrophages eliminate injurious agents such as microbes and initiate the process of repair, but are also responsible for much of the tissue injury in chronic inflammation.

• Macrophages display antigens to T lymphocytes and respond to signals from T cells, thus setting up a feedback loop that is essential for defense against many microbes by cell-mediated immune responses.

Role of Lymphocytes

Microbes and other environmental antigens activate T and B lymphocytes, which amplify and propagate chronic inflammation.

Although the major function of these lymphocytes is as the mediators of adaptive immunity, which provides defense against infectious pathogens, these cells are often present in chronic inflammation and, when they are activated, the inflammation tends to be persistent and severe. Some of the strongest chronic inflammatory reactions, such as granulomatous inflammation,

By virtue of their ability to secrete cytokines, CD4+ T lymphocytes promote inflammation and influence the nature of the inflammatory reaction. These T cells greatly amplify the early inflammatory reaction that is induced by recognition of microbes and dead cells as part of the innate immune response. There are three subsets of CD4+ T cells that secrete different cytokines and elicit different types of inflammation.

• TH1 cells produce the cytokine IFN-γ, which activates macrophages by the classical pathway.

• TH2 cells secrete IL-4, IL-5, and IL-13, which recruit and activate eosinophils and are responsible for the alternative pathway of macrophage activation.

• TH17 cells secrete IL-17 and other cytokines, which induce the secretion of chemokines responsible for recruiting neutrophils into the reaction.

Other Cells in Chronic Inflammation

Other cell types may be prominent in chronic inflammation induced by particular stimuli.

• Eosinophils are abundant in immune reactions mediated by IgE and in parasitic infections. Their recruitment is driven by adhesion molecules similar to those used by neutrophils, and by specific chemokines (e.g., eotaxin) derived from leukocytes and epithelial cells. Eosinophils have granules that contain major basic protein, a highly cationic protein that is toxic to parasites but also injures host epithelial cells. This is why eosinophils are of benefit in controlling parasitic infections, yet also contribute to tissue damage in immune reactions such as allergie.

• Mast cells are widely distributed in connective tissues and participate in both acute and chronic inflammatory reactions. Mast cells arise from precursors in the bone marrow. They have many similarities with circulating basophils, but they do not arise from basophils, are tissue-resident, and therefore play more significant roles in inflammatory reactions in tissues than basophils do.

• Although neutrophils are characteristic of acute inflammation, many forms of chronic inflammation, lasting for months, continue to show large numbers of neutrophils, induced either by persistent microbes or by cytokines and other mediators produced by activated macrophages and T lymphocytes. In chronic bacterial infection of bone (osteomyelitis), a neutrophilic exudate can persist for many months. Neutrophils also are important

in the chronic damage induced in lungs by smoking and other irritant stimuli. This pattern of inflammation has been called acute on chronic.

Granulomatous Inflammation

Granulomatous inflammation is a form of chronic inflammation characterized by collections of activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis. The activated macrophages may develop abundant cytoplasm and begin to resemble epithelial cells, and are called epithelioid cells.

Some activated macrophages may fuse, forming multinucleate giant cells. Granuloma formation is a cellular attempt to contain an offending agent that is difficult to eradicate.

In

• Immune granulomas are caused by a variety of agents that are capable of inducing a persistent T cell–mediated immune response. This type of immune response produces granulomas usually when the inciting agent cannot be readily eliminated, such as a persistent microbe or a self antigen. In such responses, macrophages activate T cells to produce cytokines, such asIL-2, which activates other T cells, perpetuating the response, and IFN-γ, which activates the macrophages.

• Foreign body granulomas are seen in response to relatively inert foreign bodies, in the absence of T cell– mediated immune responses. Typically, foreign body granulomas form around materials such as talc (associated with intravenous drug abuse), sutures, or other fibers that are large enough to preclude phagocytosis by a macrophage but are not immunogenic. Epithelioid cells and giant cells are apposed to the surface of the foreign body. The foreign material can usually be identified in the center of the granuloma, particularly if viewed with polarized light, in which it may appear refractile. Granulomas are encountered in certain specific pathologic states; recognition of the granulomatous pattern is important because of the limited number of conditions (some life threatening) that cause it (Table 3.9). In the setting of persistent T cell responses to certain microbes (e.g., M. tuberculosis, Treponema pallidum, or fungi), T cell–derived cytokines are responsible for chronic macrophage activation and granuloma formation. Granulomas may also develop in some immune-mediated inflammatory diseases, notably Crohn disease, which is one type of inflammatory bowel disease and an important cause of granulomatous inflammation in the United States, and in a disease of unknown etiology called sarcoidosis. Tuberculosis is the prototype of a granulomatous disease caused by infection and should always be excluded as the cause when granulomas are identified. In this disease the granuloma is referred to as a tubercle.