Chronic Inflammation

Chronic inflammation occurs when tissue injury and repair attempts overlap. It is characterized by infiltration of mononuclear cells, particularly macrophages and lymphocytes, which interact dynamically over the course of inflammation (recall that acute inflammation is characterized by neutrophil infiltration). As a result of infectious agents and/or prolonged inflammatory response, tissue damage occurs. Tissue repair attempts include angiogenesis (formation of blood vessels, which ultimately regress) and fibrosis, aka, scarring. Because macrophages constitute the primary leukocyte in chronic inflammation, we'll focus on their origins and activation; however, be aware that other leukocytes, including neutrophils, can be found at sites of chronic inflammation. Macrophages arise from hematopoietic cells that reside in the bone marrow of adults (in the fetus, hematopoietic cells reside in the yolk sac and liver). These cells give rise to various blood cell lines, including the monocytes, which circulate in the vasculature. Outside of the circulation, monocytes differentiate to become macrophages, and reside scattered throughout the connective tissues of the body. Additionally, tissue resident macrophages reside in the liver (Kupffer cells), spleen and lymph nodes (sinus histocytes), central nervous system (microglial cells) and in the alveoli of the lungs. Collectively, we can refer to these macrophages as the mononuclear phagocyte system (formerly called the "reticuloendothelial system"; some authors even reject the notion of a "mononuclear phagocyte system"). Upon activation, macrophages engage in various activities: – Presentation of antigens to T lymphocytes. – Production of cytokines, which mediate inflammatory responses. – Production of growth factors and enzymes that promote tissue repair and inhibit inflammation. To accomplish these goals, macrophages have dynamic phenotypes reflective of their microenvironments. Be aware that some texts describe two distinct types of macrophage activation, classical and alternative, and the resulting macrophages as either Type 1 (aka, classical type) or Type 2 (aka, alternative type); however, research now suggests that these should not be thought of as dichotomous types, but, rather, as potential phenotypes that macrophages express in response to environmental stimuli. Stimulation by specific cytokines, such as interferon gamma (aka, type II interferon) and/or by microbes activate macrophages to produce inducible nitric oxide, reactive oxygen species, and lysosomal enzymes, which are antimicrobial. These activated macrophages also produce inflammatory cytokines and chemokines: Tumor necrosis factor and chemokines activate lymphocytes. Activated T lymphocytes produce interferon gamma, which, as we've indicated, triggers pro-inflammatory macrophage activation. Thus, T lymphocytes can act as part of a positive feedback loop with pro-inflammatory activated macrophages. Anti-inflammatory stimuli include interleukins 13 and 4 (IL-13, IL-4). In response to these stimuli, activated macrophages produce cytokines, such as interleukin-10 (IL-10), that inhibit inflammatory activity of T lymphocytes, natural killer cells, and macrophages; thus, interleukin 10 prevents excessive inflammation and damage to host cells. These "alternatively activated" macrophages also produce growth factors that promote tissue repair, including vascular endothelial growth factor (VEGF), which facilitates angiogenesis, and transforming growth factor beta (TGF-ß), which facilitates deposition of extracellular matrix proteins for fibrosis. Interleukins 13 and 4 (IL-13 and IL-4) are produced by T lymphocytes; thus, T lymphocytes can also promote anti-inflammatory macrophage activation. Unfortunately, the pro-inflammatory feedback loop can be maladaptive when prolonged macrophage-lymphocyte interactions promote chronic inflammation, as seen in fibrosis of the lung. Fibrosis is characterized by excessive collagen deposition in response to persistent stimulation; it results in tissue loss and organ failure. Some common pathological conditions caused by organ fibrosis include liver cirrhosis, constrictive pericarditis, scleroderma, and lung fibrosis disorders. Occurs when early anti-inflammatory immune responses are unable to eradicate the pathogens. Tuberculosis is a classic example of a disease in which the infectious agent (Myocbacterium tuberculosis) persists via the formation of granulomas. Granulomas are organized collections of differentiated macrophages and lymphocytes that can form around infectious or non-infectious agents. Once thought to be a protective structure formed by the host to "wall off" a potential threat, it is becoming clear that granulomas can actually promote bacterial proliferation, depending on the outcomes of host-pathogen interactions. The granulomas of tuberculosis are characterized by caseous necrotic centers ("caseous" means they have a cheese-like appearance). It is thought that these centers may, in some cases, facilitate the spread of bacteria: as necrotic macrophages release their bacterial contents, new macrophages may engulf them and carry them to new sites. In the periphery of the granuloma, we can identify macrophages that have merged to become multinucleated "giant cells". Other macrophages differentiate to form epithelioid cells, which have interdigitating cell membranes, or foam cells, which contain lipids. Lymphocytes may also be found at the periphery of the granuloma. Chronic inflammation can also occur as the result of hypersensitivity. Asthma is characterized by late phase leukocyte recruitment and subsequent tissue destruction. More specifically, some forms of asthma are associated with increased eosinophil activity; eosinophils are leukocytes that release Major Basic Protein, which is highly toxic to tissues. Eosinophils also contain lipid bodies that enhance eicosanoid production. As a result, chronic inflammation and bronchial wall remodeling narrow the airways. Continued exposure to exogenous or endogenous toxic agents can produce chronic inflammatory disease. Atherosclerosis can occur as the result of chronic inflammatory responses that promote deposition and accumulation of cells and extracellular materials in vascular walls. Monocytes pass through the epithelium and become caught in the intima, where they differentiate to become macrophages and promote inflammatory responses that allow cells, lipids, and collagenous materials to accumulate to form a plaque. Ultimately, this plaque can obstruct blood flow or break free and embolize.