Chronic inflammation

Chronic Inflammation
Chronic inflammation is defined as inflammation 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 chronic inflammation or may begin insidiously as a low-grade response without any manifestations of an acute reaction. This latter type of chronic inflammation is the cause of tissue damage in some of the most common and disabling human diseases such as rheumatoid arthritis and pulmonary fibrosis.
Causes of chronic inflammation
1. 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 a granulomatous reaction.
2. Immune-mediated inflammatory diseases. Chronic inflammation plays an important role in a group of diseases that are caused by excessive and inappropriate activation of the immune system. Under certain conditions immune reactions develop against the individual s own tissues leading to autoimmune diseases. In these diseases auto-antigens evoke a self immune reaction that results in chronic tissue damage and inflammation examples of such diseases are rheumatoid arthritis and multiple sclerosis. Immune responses against common environmental substances are the cause of allergic diseases, such as bronchial asthma. Because these autoimmune and allergic reactions are inappropriately 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.
3. 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.







Morphologic features of chronic inflammation
In contrast to acute inflammation, which is manifested by vascular changes edema and predominantly neutrophilic infiltration chronic inflammation is characterized by:
1. Infiltration with mononuclear cells that include macrophages, lymphocytes, and plasma cells.
2. Tissue destruction induced by the persistent offending agent or by the inflammatory cells.
3. Attempts at healing by connective tissue replacement of damaged tissue accomplished by proliferation of small blood vessels (angiogenesis) and in particular fibrosis.
Role of macrophages in chronic inflammation
The macrophage is the dominant cellular player in chronic inflammation, and we begin our discussion with a brief review of its biology. Macrophages are one component of the mononuclear phagocyte system. The mononuclear phagocyte system (sometimes called reticuloendothelial system) consists of closely related cells of bone marrow origin that include blood monocytes and tissue macrophages that scattered in the connective tissue or located in organs such as the liver (Kupffer cells) spleen and lymph nodes (sinus histiocytes) lungs (alveolar macrophages) and central nervous system (microglia). Mononuclear phagocytes arise from a common precursor in the bone marrow which gives rise to blood monocytes. From the blood monocytes migrate into various tissues and differentiate into macrophages. The half-life of blood monocytes is about 1 day whereas the life span of tissue macrophages is several months or years. The journey from bone marrow stem cell to tissue macrophage is regulated by a variety of growth and differentiation factors cytokines adhesion molecules and cellular interactions.
The products of activated macrophages serve to eliminate injurious agents such as microbes and to initiate the process of repair and are responsible for much of the tissue injury in chronic inflammation. Activation of macrophages results in increased levels of lysosomal enzymes and reactive oxygen and nitrogen species and production of cytokines growth factors and other mediators of inflammation. Some of these products are toxic to microbes and host cells like reactive oxygen and nitrogen species or to extracellular matrix like 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). It is because of the activities of these macrophages that tissue destruction is one of the hallmarks of chronic inflammation. The ongoing tissue destruction can itself activate the inflammatory cascade, so that features of both acute and chronic inflammation may coexist in certain circumstances.
In short-lived inflammation macrophages eventually disappear. In chronic inflammation macrophage accumulation persists as a result of continuous recruitment from the circulation and local proliferation at the site of inflammation.
Other cells in chronic inflammation
Other cell types involved in chronic inflammation include lymphocytes, plasma cells, eosinophils, and mast cells:
Lymphocytes are mobilized in both antibody-mediated and cell-mediated immune reactions. Antigen-stimulated (effector and memory) lymphocytes of different types (T and B cells) use various adhesion molecule pairs (selectins, integrins and their ligands) and chemokines to migrate into inflammatory sites.
Cytokines from activated macrophages mainly TNF, IL-1, and chemokines, promote leukocyte recruitment, setting the stage for persistence of the inflammatory response.
Lymphocytes and macrophages interact in a bidirectional way and these reactions play an important role in chronic inflammation.
Plasma cells develop from activated B lymphocytes and produce antibodies directed either against persistent foreign or self antigens in the inflammatory site or against altered tissue components.
In some strong chronic inflammatory reactions the accumulation of lymphocytes antigen-presenting cells and plasma cells may assume the morphologic features of lymphoid organs particularly lymph nodes even containing well-formed germinal centers. These are called tertiary lymphoid organs this type of lymphoid organogenesis is often seen in the synovium of patients with long-standing rheumatoid arthritis.
Eosinophils are abundant in immune reactions mediated by IgE and in parasitic infections.
A chemokine that is especially important for eosinophil recruitment is eotaxin. Eosinophils have granules that contain major basic protein, a highly cationic protein that is toxic to parasites but also causes lysis of mammalian epithelial cells. This is why eosinophils are of benefit in controlling parasitic infections but they contribute to tissue damage in immune reactions such as allergies.
Mast cells are widely distributed in connective tissues and participate in both acute and chronic inflammatory reactions.
Mast cells express on their surface the receptor (Fc?RI) that binds the Fc portion of IgE antibody.
In immediate hypersensitivity reactions IgE antibodies bound to the cells Fc receptors specifically recognize antigen and the cells degranulate and release mediators such as histamine and prostaglandins.
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 mediators produced by activated macrophages and T lymphocytes.
In chronic bacterial infection of bone (osteomyelitis) a neutrophilic exudate can persist for many months. Neutrophils are also important in the chronic damage induced in lungs by smoking and other irritant stimuli.
In addition to cellular infiltrates, growth of blood vessels and lymphatic vessels is often prominent in chronic inflammatory reactions. This growth of vessels is stimulated by growth factors such as VEGF produced by macrophages and endothelial cells.