Lipoxins are a class of specialized pro-resolving lipid mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) that play a crucial role in inflammation resolution. These endogenous lipid compounds are synthesized by various cells in response to inflammatory stimuli and serve as potent anti-inflammatory and pro-resolving molecules. Lipoxins actively stimulate the resolution phase of the immune response by enhancing the clearance of damaged cells. They also promote tissue repair and regeneration, and suppressing ongoing inflammation. Lipoxins play a important role in the restoration of tissue homeostasis and prevent chronic inflammation.
Learn more about Function and Detection Methods of Polyunsaturated Fatty Acids.
Lipoxins are generated through a series of enzymatic reactions involving arachidonic acid (AA), which is released from membrane phospholipids by phospholipase A2 (PLA2). AA is then converted into 15-hydroperoxyeicosatetraenoic acid (15-HpETE) by 15-lipoxygenase (15-LOX). Further, 15-HpETE is converted into lipoxin A4 (LXA4) or lipoxin B4 (LXB4) through transcellular metabolism, involving interactions between leukocytes, platelets, and endothelial cells.
Lipoxins have a triene-containing core, characteristic of all lipoxin family members. Conjugated tetraene is present in LXA4, while conjugated triene is present in LXB4. The biological actions of lipoxins depend on these structural features.
Anti-inflammatory effects. Lipoxins are potent anti-inflammatory mediators that modulate leukocyte recruitment, inhibit pro-inflammatory cytokine production and promote inflammation resolution. They exert their effects through interactions with specific receptors, such as ALX/FPR2 receptors, expressed on leukocytes and other immune cells. Activation of these receptors initiates intracellular signaling cascades that suppress pro-inflammatory responses. Lipoxins can inhibit the production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-8 (IL-8), in various cell types including neutrophils, monocytes, and endothelial cells. Additionally, lipoxins encourage the removal of neutrophils that have died, which is an essential step in the treatment of inflammation.
One of the hallmark features of lipoxins is their ability to promote the resolution of inflammation. Lipoxins actively stimulate the resolution phase of the inflammatory response by enhancing the clearance of inflammatory cells, promoting tissue repair and regeneration, and suppressing ongoing inflammation. These actions contribute to the restoration of tissue homeostasis and prevent the development of chronic inflammation.
Given the therapeutic potential of lipoxins, researchers have developed synthetic analogs called lipoxin mimetics. These mimetics are designed to mimic the structure and functions of endogenous lipoxins, offering a more stable and pharmacologically optimized alternative for therapeutic interventions. Lipoxin mimetics have shown promise in preclinical studies and hold potential for the treatment of various inflammatory diseases, including asthma, arthritis, and inflammatory bowel disease.
Resolvins, another class of SPMs, interact closely with lipoxins to regulate inflammation and promote tissue resolution. Resolvins are derived from omega-3 PUFAs, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Lipoxins and resolvins together form an integrated network of lipid mediators that orchestrate inflammation resolution in a coordinated manner.
Lipoxins and resolvins interact in various ways. For instance, lipoxins can stimulate resolvin production and vice versa. This cross-talk between lipoxins and resolvins enhances their overall pro-resolving effects and reinforces inflammation resolution.
Stages of inflammatory process (Jaén RI, et al., 2021)
The synthesis of lipoxin A4 (LXA4), one of the key lipoxin molecules, involves a series of enzymatic reactions that occur in response to inflammatory stimuli. The detailed synthesis of lipoxin A4 as follows.
During transcellular metabolism, 15-HpETE generated by one cell type is transferred to another cell type, where it undergoes further modifications. For example, neutrophils can convert 15-HpETE to 5S, 6R, 15S-trihydroxy-7E, 9E, 11Z, 13E-eicosatetraenoic acid (5S, 6R, 15S-TriHETrE), which is subsequently converted to lipoxin A4 by interacting with platelets or endothelial cells.
Once formed, lipoxin A4 exerts its anti-inflammatory and pro-resolving effects by interacting with specific receptors, such as ALX/FPR2 receptors, expressed on immune cells and other cell types involved in the inflammatory process. Lipoxin A4 plays a crucial role in the resolution of inflammation and acts as a potent anti-inflammatory mediator in various inflammatory disorders.
The potential therapeutic applications of lipoxins and lipoxin mimetics have led to novel drugs that target inflammation resolution. These drugs aim to harness lipoxins' anti-inflammatory and pro-resolving properties to treat a wide range of inflammatory disorders.
Benzo-LXA4, a synthetic lipoxin mimic that has demonstrated potential in preclinical inflammation models, is one example of a lipoxin-based therapy. Benzo-LXA4 exhibits potent anti-inflammatory effects, enhances tissue repair, and promotes inflammation resolution.
The analysis of lipoxins, which are specialized pro-resolving lipid mediators, typically involves a combination of analytical techniques that allow for their detection, quantification, and characterization. Here are some commonly used lipoxin analysis methods.