Omega-3 PUFA and SPM in critical patients
The prognosis of critical patients is closely related to their inflammatory status and the extent and duration of the inflammatory response. Until relatively recently, inflammation resolution was considered a passive process, whose conclusion was characterised by a reduction in levels of cytokines, prostaglandins (PGs) and reactive oxygen species (ROSs). However, inflammation resolution is now considered an active process, in which the actions of the specialised pro-resolving mediators (SPMs) resolvins (Rvs), protectins (PDs) and maresins (MaRs), and the omega-3 polyunsaturated fatty acids (n-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), modulate inflammation and its impact on leukocyte chemotaxis, the expression and interaction of adhesion molecules and proinflammatory cytokine production. Lipoxins (LXs), SPMs derived from the n-6 PUFA arachidonic acid (AA), also play an important role in inflammation resolution.
SPMs (LX, Rv, PD and MaR) are potent regulators of the mechanisms that control the onset, duration and resolution of inflammation. They are derived from the AA, EPA and DHA available at the site of the inflammatory response and their actions include inhibiting neutrophil migration, increasing phagocytosis of apoptotic neutrophils and reducing proinflammatory cytokines and chemokines.
SPM genetic expression and pattern correlates with results in acute critical patients. Rv, PD and MaR expression in lymphoid tissues, blood and other tissues is proportional to the regenerative, protective and pro-resolution effects. Furthermore, patients with complications and poorer clinical results have higher expression ratios between leukotriene (LT) pathway genes and Rv pathway genes. High circulating concentrations of n-3 PUFA could modulate the expression of genes critical to inflammatory processes, given that, for instance, EPA and DHA have been observed to reduce gene expression for interleukin 1β and tumour necrosis factor-α and also their levels of mRNA. Altering circulating concentrations of n-6 and n-3 PUFA can partly influence the inflammatory response through the capacity of their metabolites to regulate expression of signal transduction genes and down-regulate, at the transcriptional level, the expression of proinflammatory genes involved in the inflammatory response (cytokines, chemokines, and nuclear factor κB (NF-κB), the latter involved in the regulation of cyclooxygenase, adhesion molecules and inflammatory cytokines). Lipid mediators play an essential role in vascular damage and leukocyte recruitment, from the onset to the resolution of inflammation. SPMs, produced during the inflammatory response, act as signalling molecules and regulate the actions of PGs and LTs, reducing the duration of inflammation and stimulating re-epithelialisation, wound healing and tissue regeneration. They also have a positive effect on pain reduction and infection and strengthen the effects of antibiotics and improve adaptive immunity.
Experimental studies on animals show the important role SPMs play in the return to homeostasis after infection or injury and in improving survival after Rv administration in sepsis and burn injury models, while controlled, randomised clinical trials have shown a reduction in mortality and days on assisted breathing with IV administration of EPA and DHA in critical patients. A significant reduction in the number of patients affected by hospital-acquired infections has also been observed among critical or surgical patients supplemented with n-3 PUFA.
Both epidemiological studies and controlled, randomised trials have shown a positive relationship between EPA and DHA consumption and improvement in different inflammatory conditions; supplementation with n-3 PUFA alters the production and profile of proinflammatory cytokines, while increasing cell absorption of n-3 PUFA has also been shown to favour Rv and PD production. In critical patients, SPMs seem to regulate excessive inflammatory response, protecting organs from possible damage. This offers a potential therapeutic option with minimal side effects (compared to anti-inflammatory treatments).
Molfino A, Amabile MI, Monti M2 Muscaritoli M. Omega-3 Polyunsaturated Fatty Acids in Critical Illness: Anti-Inflammatory, Proresolving, or Both? Oxid Med Cell Longev. 2017;2017:5987082.