Chronic Inflammation Overview | Chapter 3 | ROBBINS PATHOLOGY Based Audio Podcast

ROBBINS PATHOLOGY CHAPTER 3 - Inflammation and Repair Chronic Inflammation Overview - Chronic inflammation is defined as a response of prolonged duration (weeks or months) where inflammation, tissue injury, and attempts at repair coexist in varying combinations . It may follow acute inflammation, or it can begin insidiously as a low-grade, smoldering response . Characteristics and Causes In contrast to acute inflammation, which is dominated by vascular changes and neutrophils, chronic inflammation is characterized by three main features : 1. Infiltration with mononuclear cells (macrophages, lymphocytes, and plasma cells) . 2. Tissue destruction, induced by the persistent offending agent or by the inflammatory cells . 3. Attempts at healing through connective tissue replacement of damaged tissue, accomplished by angiogenesis and, specifically, fibrosis . Chronic inflammation arises in several settings : • Persistent infections by microorganisms that are difficult to eliminate, such as mycobacteria, certain viruses, fungi, and parasites. These often evoke an immune reaction called delayed-type hypersensitivity, which may lead to a specific pattern called a granulomatous reaction . • Prolonged exposure to potentially toxic agents, which can be exogenous (e.g., particulate silica causing silicosis) or endogenous (e.g., excessive cholesterol and lipids inducing atherosclerosis) . • Hypersensitivity diseases, caused by excessive and inappropriate activation of the immune system against the individual's own tissues (autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis) or against common environmental substances (allergic diseases, such as bronchial asthma) Cells and Mediators of Chronic Inflammation The characteristic features of chronic inflammation result from the local activation of several cell types and the production of various mediators . Macrophages Macrophages are the dominant cells in most chronic inflammatory reactions, derived from hematopoietic stem cells in the bone marrow or from embryonic precursors (resident cells like Kupffer cells) . Their functions are central to the development and persistence of chronic inflammation : • They are professional phagocytes that ingest and eliminate microbes and dead tissues . • They secrete mediators of inflammation, such as cytokines (TNF, IL-1, chemokines) and eicosanoids, contributing to the initiation and propagation of the reaction . • They initiate the process of tissue repair, scar formation, and fibrosis . • They display antigens to T lymphocytes and respond to T cell signals, setting up a crucial feedback loop for cell-mediated immune responses . Macrophages are activated through two major pathways : 1. Classical Activation (M1): Induced by microbial products (endotoxin), IFN-γ (from T cells), or foreign substances . M1 macrophages enhance their ability to kill ingested organisms (producing NO, lysosomal enzymes) and secrete cytokines that stimulate inflammation . 2. Alternative Activation (M2): Induced by cytokines other than IFN-γ, such as IL-4 and IL-13 (from T cells) . M2 macrophages promote anti-inflammatory effects and tissue repair/fibrosis (producing IL-10, TGF-β, growth factors) . Although essential for defense, the impressive arsenal of mediators secreted by activated macrophages is largely responsible for the considerable tissue destruction that is a hallmark of chronic inflammation . Lymphocytes Microbes and antigens activate T and B lymphocytes, which amplify and propagate chronic inflammation, often making it persistent and severe . • CD4+ T lymphocytes promote inflammation via cytokine secretion and influence the nature of the reaction . Key subsets include: ◦ Th1 cells: Produce IFN-γ, which activates macrophages by the classical pathway . ◦ Th2 cells: Secrete IL-4, IL-5, and IL-13, responsible for alternative macrophage activation and the recruitment of eosinophils (important in parasitic/allergic inflammation) . ◦ Th17 cells: Secrete IL-17, which recruits neutrophils and monocytes . • Macrophage-Lymphocyte Interactions: T cells and macrophages interact bidirectionally, sustaining chronic inflammation . Macrophages present antigens and produce IL-12 to stimulate T cells; activated T cells, in turn, produce cytokines like IFN-γ to activate more macrophages . Other Cells Eosinophils are prominent in IgE-mediated immune reactions and parasitic infections, releasing major basic protein, which is toxic to helminths but can injure host tissues (e.g., in allergies) . Mast cells, which bind IgE, secrete various cytokines and promote inflammatory reactions . Although characteristic of acute inflammation, neutrophils can persist in many chronic forms, such as osteomyelitis, a pattern sometimes called "acute on chronic" inflammation .