Could Arachidonic Acid-Derived Pro-Resolving Mediators Be a New Therapeutic Strategy for Asthma Therapy?

Abstract

Asthma represents one of the leading chronic diseases worldwide and causes a high global burden of death and disability. In asthmatic patients, the exacerbation and chronification of the inflammatory response are often related to a failure in the resolution phase of inflammation. We reviewed the role of the main arachidonic acid (AA) specialized pro-resolving mediators (SPMs) in the resolution of chronic lung inflammation of asthmatics. AA is metabolized by two classes of enzymes, cyclooxygenases (COX), which produce prostaglandins (PGs) and thromboxanes, and lypoxygenases (LOX), which form leukotrienes and lipoxins (LXs). In asthma, two primary pro-resolving derived mediators from COXs are PGE2 and the cyclopentenone prostaglandin15-Deoxy-Delta-12,14-PGJ2 (15d-PGJ2) while from LOXs are the LXA4 and LXB4. In different models of asthma, PGE2, 15d-PGJ2, and LXs reduced lung inflammation and remodeling. Furthermore, these SPMs inhibited chemotaxis and function of several inflammatory cells involved in asthma pathogenesis, such as eosinophils, and presented an antiremodeling effect in airway epithelial, smooth muscle cells and fibroblasts in vitro. In addition, PGE2, 15d-PGJ2, and LXs are all able to induce macrophage reprogramming to an alternative M2 pro-resolving phenotype in vitro and in vivo. Although PGE2 and LXA4 showed some beneficial effects in asthmatic patients, there are limitations to their clinical use, since PGE2 caused side effects, while LXA4 presented low stability. Therefore, despite the strong evidence that these AA-derived SPMs induce resolution of both inflammatory response and tissue remodeling in asthma, safer and more stable analogs must be developed for further clinical investigation of their application in asthma treatment.

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

“…PGD 2 is reported to bind to two receptors DP1 and DP2 (also called chemoattractant homologous molecule expressed on T H 2 cells-CRTH2) [197]. Both, the hPGDS and the receptors DP1 and DP2 are expressed by eosinophils [132,198,199]. Hence, eosinophils are able to produce and release PGD 2 following stimulation [200].…”

“…PGE 2 is produced from PGH 2 by the action of prostaglandin E synthases [198]. While PGE 2 (together with LXA 4 and PGI 2 ) is hypothesized to be an arachidonic acid-derived pro-resolving mediator [199], it also shows pro-inflammatory activities such as exacerbating autoimmune diseases [208]. Moreover, due to its immunosuppressive actions, PGE 2 is considered detrimental in the tumor microenvironment [209][210][211].…”

Transcriptomic and Lipidomic Profiles in Nasal Polyps of Glucocorticoid Responders and Non-Responders: Before and After Treatment

“…In this study, we found that multiple SPMs were increased in nasal polyps, which could be explained by an excessive response to chronic inflammation, and dysfunction or resistance of SPMs. AA-derived SPMs could induce resolution of inflammatory response and tissue remodeling in asthma, although more stable and safer analogs should be developed for clinical use ( Insuela et al, 2020 ). The anti-inflammatory properties of omega-3 PUFAs are well documented, indicating their therapeutic potential in chronic inflammatory diseases ( Yates et al, 2014 ; Calder, 2017 ).…”

Role of liver‑X‑receptors in airway remodeling in mice with chronic allergic asthma

“…Its morbidity and mortality rate are increasing gradually with the development of the society. The symptoms include shortness of breath, cough and chest tightness (2). To date, the pathological mechanisms of asthma have remained to be fully elucidated.…”