REVIEW article
Front. Pharmacol.
Sec. Pharmacology of Infectious Diseases
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1622754
The Potential of Exogenous Specialized Pro-resolving Mediators in Protecting Against Sepsis-related Lung Injury: A Review
Provisionally accepted
- Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Sepsis-associated lung injury (SALI) is a critical condition with high mortality. Current therapies are limited, necessitating novel approaches. This review highlights the potential of exogenous Specialized Pro-resolving Mediators (SPMs), including lipoxins, resolvins, protectins, and maresins, in mitigating SALI. SPMs, derived from polyunsaturated fatty acids, exert protective effects through multiple mechanisms: enhancing alveolar fluid clearance by upregulating ENaC, Na⁺/K⁺-ATPase, CFTR, and AQP5; reducing alveolar epithelial cell apoptosis and epithelial-mesenchymal transition; preserving endothelial glycocalyx integrity via modulating heparanase and exostosin-1 expression; alleviating oxidative stress and mitochondrial dysfunction by scavenging ROS and activating Nrf2; and immunomodulation by limiting neutrophil infiltration, promoting macrophage efferocytosis and M2 polarization, and dampening pro-inflammatory cytokine production. Notably, SPMs like RvD2 remain effective even during sepsis' immunosuppressive phase. While significant debates persist regarding endogenous SPM generation, receptor mechanisms, and critically the reliable detection and physiological relevance of specific SPMs in biological samples like lung tissue (with earlier reports often misidentifying analytical artifacts or failing LOD/LOQ validation), recent evidence suggests exogenous SPMs act via biased allosteric modulation of the EP4 receptor to stimulate phagocytosis and resolution. Extensive preclinical evidence underscores SPMs' promise in restoring immune homeostasis in SALI, though pharmacokinetic limitations of high-dose exogenous administration require consideration. Future high-quality clinical trials are essential to translate this resolution pharmacology approach into clinical practice.
Keywords: specialized pro-resolving mediators (SPMs), sepsis-associated lung injury, lipoxin, resolvin, protectin, maresins
Received: 04 May 2025; Accepted: 07 Jul 2025.
Copyright: © 2025 Shen, Shen, Sun, Fan, Zhang, SONG, An, Chen and Gao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yafen Gao, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.