8.4 Resolution of inflammation
2 min read•july 25, 2024
Acute inflammation resolution involves removing harmful stimuli, clearing debris, and repairing tissue damage. Key processes include cessation of pro-inflammatory mediators, vascular changes, and activation of anti-inflammatory factors like and resolvins.
Cellular processes like and efferocytosis play crucial roles in resolving inflammation. Impaired resolution can lead to persistent inflammation, tissue damage, fibrosis, and chronic conditions. Understanding these mechanisms is vital for developing targeted therapies.
Resolution of Acute Inflammation
Processes of acute inflammation resolution
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- Removal of inflammatory stimuli occurs through immune cells eliminating pathogens (, ) and neutralizing harmful substances (antibodies, complement proteins)
- Clearance of cellular debris involves phagocytes engulfing dead cells and tissue fragments while enzymes (matrix metalloproteinases) break down extracellular matrix components
- Cessation of pro-inflammatory mediator production achieved by downregulating cytokine and chemokine synthesis and reducing prostaglandin and leukotriene release
- Vascular changes include decreased permeability and restoration of normal blood flow as endothelial cells repair tight junctions
- Tissue repair initiation begins with activation of fibroblasts to produce collagen and stimulation of angiogenesis for new blood vessel formation
Role of anti-inflammatory mediators
- Lipoxins derived from arachidonic acid inhibit neutrophil recruitment and activation while promoting macrophage efferocytosis of apoptotic cells
- Resolvins from omega-3 fatty acids reduce vascular permeability and enhance macrophage phagocytosis of dying cells
- Protectins decrease pro-inflammatory cytokine production (TNF-α, IL-1β) and promote tissue repair through fibroblast activation
- Maresins stimulate macrophage phenotype switch to M2 anti-inflammatory state and enhance tissue regeneration by promoting stem cell differentiation
- Anti-inflammatory mediators inhibit leukocyte infiltration by downregulating adhesion molecules, promote resolution of edema through increased lymphatic drainage, and stimulate tissue repair processes by activating local stem cells
Cellular Processes and Consequences
Apoptosis and efferocytosis in inflammation
- Apoptosis of activated immune cells prevents excessive tissue damage and reduces release of pro-inflammatory cellular contents (DAMPs)
- Efferocytosis involves macrophages engulfing apoptotic cells preventing secondary necrosis and further inflammation while stimulating release of anti-inflammatory mediators (TGF-β, IL-10)
- Tissue repair promotion occurs as clearance of damaged cells allows for regeneration and efferocytic macrophages release growth factors (VEGF, PDGF)
- Immune response regulation achieved through induction of tolerance to self-antigens presented by apoptotic cells and suppression of adaptive immune responses by regulatory T cells
Consequences of impaired resolution
- Persistent inflammation leads to continued recruitment of inflammatory cells and prolonged release of pro-inflammatory mediators (IL-6, TNF-α)
- Tissue damage results from excessive production of reactive oxygen species and degradation of extracellular matrix components by unchecked proteases
- Fibrosis develops due to excessive deposition of collagen and other matrix proteins impairing organ function (liver cirrhosis, pulmonary fibrosis)
- Chronic inflammatory conditions may arise (rheumatoid arthritis, inflammatory bowel disease, atherosclerosis)
- Systemic effects include increased risk of cardiovascular diseases and metabolic dysregulation (insulin resistance)
- Autoimmune disorders can develop due to loss of self-tolerance and production of autoantibodies against cellular components exposed during prolonged inflammation
Key Terms to Review (13)
Apoptosis: Apoptosis is a programmed cell death process that allows cells to self-destruct in a controlled manner, which is essential for maintaining homeostasis and proper development in multicellular organisms. This mechanism is crucial for eliminating damaged, unnecessary, or potentially harmful cells without causing inflammation, and it plays vital roles in immune responses, tissue remodeling, and the prevention of cancer.
Charles Janeway: Charles Janeway was a pioneering immunologist known for his significant contributions to the understanding of the immune system, particularly in the area of pattern recognition receptors (PRRs) and their role in innate immunity. His work laid the groundwork for how the immune system recognizes pathogens, emphasizing the importance of PRRs in identifying pathogen-associated molecular patterns (PAMPs) and initiating immune responses. Janeway's research has also influenced our understanding of inflammation and its resolution, revealing critical mechanisms that help maintain homeostasis in the body.
Chronic inflammatory disease: Chronic inflammatory disease refers to a group of conditions characterized by prolonged inflammation that can last for months or even years. This persistent inflammatory response can lead to tissue damage and contribute to various health problems, affecting the body’s ability to heal and function properly. Inflammation is a natural response to injury or infection, but when it becomes chronic, it can result in significant consequences for overall health.
Clearance of apoptotic cells: Clearance of apoptotic cells refers to the process by which dying cells, undergoing programmed cell death or apoptosis, are removed from the body by phagocytes. This process is crucial for maintaining tissue homeostasis, preventing inflammation, and ensuring a proper resolution of inflammation following an immune response.
Early resolution phase: The early resolution phase is a crucial stage in the inflammatory response where the body begins to actively resolve inflammation and restore tissue homeostasis. This phase involves the cessation of pro-inflammatory signals and the promotion of anti-inflammatory processes, helping to prevent chronic inflammation and damage to tissues. Key cellular events, such as apoptosis of neutrophils and the recruitment of macrophages, play a significant role in this phase.
Immune Tolerance: Immune tolerance is a state of unresponsiveness of the immune system to specific antigens, which allows the body to coexist with certain proteins, tissues, or microbes without mounting an immune response. This phenomenon is essential for preventing autoimmune diseases and for the acceptance of transplanted tissues. Immune tolerance plays a significant role in maintaining a balanced immune response, ensuring that the body does not attack its own cells while still being able to respond to pathogens.
Jak/stat pathway: The JAK/STAT pathway is a crucial signaling mechanism in cells that transmits information from extracellular signals to the cell nucleus, influencing gene expression and cellular responses. This pathway is pivotal in regulating immune responses, inflammation, and hematopoiesis by activating transcription factors that modulate the expression of target genes, playing a significant role in the resolution of inflammation.
Late resolution phase: The late resolution phase is a crucial period during the inflammatory response where the body transitions from active inflammation to healing and restoration. This phase is marked by the removal of inflammatory cells, resolution of edema, and the initiation of tissue repair mechanisms, leading to restoration of homeostasis. Understanding this phase highlights the importance of resolving inflammation to prevent chronic conditions and promote healing.
Lipoxins: Lipoxins are specialized pro-resolving mediators that play a crucial role in the resolution of inflammation, acting to counteract the pro-inflammatory signals and promote healing. They are derived from arachidonic acid and are produced during the later stages of inflammation, signaling immune cells to transition from a state of active inflammation to a state of tissue repair and restoration. Their production highlights the importance of not only initiating an inflammatory response but also ensuring its timely resolution.
Macrophages: Macrophages are large immune cells that play a crucial role in the body's defense mechanisms by engulfing and digesting cellular debris, pathogens, and foreign substances. They originate from monocytes in the blood and are pivotal in both the innate and adaptive immune responses, acting as key players in inflammation, antigen presentation, and tissue repair.
Neutrophils: Neutrophils are a type of white blood cell that plays a vital role in the innate immune response, acting as the first line of defense against invading pathogens. They are essential for responding quickly to infections, especially bacterial and fungal, and are characterized by their ability to migrate to sites of inflammation and infection through the bloodstream and tissues.
Nf-kb pathway: The NF-kB pathway is a critical signaling cascade involved in regulating immune responses, inflammation, and cell survival. This pathway is activated in response to various stimuli, including pro-inflammatory cytokines and pathogens, leading to the translocation of NF-kB proteins into the nucleus, where they initiate the transcription of target genes important for B cell activation, differentiation, and the resolution of inflammation.
Ruslan Medzhitov: Ruslan Medzhitov is a prominent immunologist known for his research on the mechanisms of innate immunity, particularly in relation to pattern recognition receptors (PRRs) and their role in recognizing pathogen-associated molecular patterns (PAMPs). His work has significantly advanced our understanding of how the immune system detects and responds to infections, as well as how inflammation resolves, highlighting the delicate balance that the immune system maintains.