Abstract
Inflammation is an a physiological response instead an essential response of the organism to injury and its adequate resolution is essential to restore homeostasis. However, defective resolution can be the precursor of severe forms of chronic inflammation and fibrosis. Nowadays, it is known that an excessive inflammatory response underlies the most prevalent human pathologies worldwide. Therefore, great biomedical research efforts have been driven toward discovering new strategies to promote the resolution of inflammation with fewer side-effects and more specificity than the available anti-inflammatory treatments. In this line, the use of endogenous specialized pro-resolving mediators (SPMs) has gained a prominent interest. Among the different SPMs described, lipoxins stand out as one of the most studied and their deficiency has been widely associated with a wide range of pathologies. In this review, we examined the current knowledge on the therapeutic potential of lipoxins to treat diseases characterized by a severe inflammatory background affecting main physiological systems, paying special attention to the signaling pathways involved. Altogether, we provide an updated overview of the evidence suggesting that increasing endogenously generated lipoxins may emerge as a new therapeutic approach to prevent and treat many of the most prevalent diseases underpinned by an increased inflammatory response.
Highlights
Inflammation can be defined as the physiological response initiated by cells and tissues that aims to protect the organism against infections or injuries caused by exogenous or endogenous agents [1]
Within the molecules that actively participate in the resolution phase, special attention has been paid to specialized pro-resolving mediators (SPMs) [4], which promote resolution of inflammation by reducing the levels of pro-inflammatory cytokines and reactive oxygen species (ROS) and by modulating correct tissue repair [5,6,7,8,9], among other functions
These include lipoxins (LXs), which derivate from omega 6 arachidonic acid and are the subject of this review, and other SPMs such as resolvins, maresins and protectins, that are structurally distinct and result from a different biosynthetic pathway derived from omega 3 fatty acids
Summary
Inflammation can be defined as the physiological response initiated by cells and tissues that aims to protect the organism against infections or injuries caused by exogenous or endogenous agents [1]. An alternative biosynthetic route requiring aspirin-mediated acetylation or statin-induced nitrosylation of COX-2 generates LX 15-Repimers called 15-epi-lipoxins or aspirin-triggered lipoxins (ATLs) [14, 15] Both pathways of LX biosynthesis are driven by the coordinate interaction of distinct cell types such as neutrophils, eosinophils, macrophages, endothelial cells, epithelial cells, parenchymal cells or platelets in a process known as transcellular biosynthesis, which occurs in the Abbreviations: ACE2, Angiotensin-converting enzyme 2; AD, Alzheimer disease; AIA, Aspirin-intolerant asthma; ALI, Acute lung injury; ALXR, Lipoxin receptor; AMPK, AMP-activated protein kinase; AP-1, Activator protein 1; ARDS, Acute respiratory distress syndrome; ATA, Aspirin-tolerant asthma; ATL, Aspirin triggered lipoxin; ATLa, 15-epi-16-(p-fluoro)-phenoxy-lipoxin A4; CaMKK2, Calcium/calmodulin dependent protein kinase kinase 2; CF, Cystic fibrosis; CFTR, Cystic fibrosis transmembrane conductance regulator; ERK, Extracellular signal-regulated kinases; GSK3b, Glycogen synthase kinase 3 beta; HO-1, Hemeoxygenase 1; i.art., intra-articular; ICV, Intracerebroventricular; IFNg, Interferon gamma; IL, Interleukin; i.p., Intraperitoneal; IPF, Idiopathic pulmonary fibrosis; I/R, Ischemia/Reperfusion; i.t., Intratracheal; i.v., Intravenous; JNK, c-Jun Nterminal kinase; LO, Lipoxygenase; LX(s), Lipoxin(s); LXA4, Lipoxin A4; LXA4ME, LXA4-methyl ester; MAPK, Mitogen-activated protein kinase; MMP, Matrix metalloproteinase; NF-kB, Nuclear factor kB; NK, Natural killer cells; NRF2, Nuclear factor erythroid 2-related factor 2; PD, Periodontal disease; PI3K, Phosphatidylinositol 3-kinase; PMN, Polymorphonuclear cell; PPAR, Peroxisome proliferator- activated receptors; s.c., Subcutaneous; SPM, Specialized pro-resolving mediators; TGF-b, Transforming growth factor beta; TIMP, Tissue inhibitor of metalloproteinase; TNFa, Tumor necrosis factor alpha; RA, Rheumatoid arthritis; ROS, Reactive oxygen species.
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