Resolution pharmacology and its potential as a therapy for infection
We have previously hypothesized that inflammation was a major contributor to tissue dysfunction and death associated with viral and bacterial infections (Garcia et al., 2010; Fagundes et al, 2012; Costa et al., 2022; Araujo et al., 2022; Machado et al., 2020; Melo et al., 2021, Tavares et al., 2022a, Boff et al., 2020). Formal demonstration of this hypothesis in humans was brought about by the COVID-19 (Coronavirus Disease 19) pandemic in which studies clearly showed the central contribution of excessive inflammation to end-organ damage and death associated with infection. SARS-CoV-2 infection caused a profound negative impact worldwide, leading to overwhelmed healthcare systems and numerous human losses. There are now good vaccines that prevent severe disease and a few antiviral treatments, such as Paxlovid®, that clearly impact disease development if started early in the course of infection (Najjar-Debbiny et al, 2022). For COVID-19, anti-inflammatory strategies, such as use of glucocorticoids and anti-IL-6, may provide additional benefit in severely ill patients (Maskin et al, 2022; Du et al, 2021). We have hypothesized that the use of pro-resolving strategies may be beneficial in the context of COVID-19 (Sousa et al, 2020).
For many other severe infections, such as Influenza, Ebola, and dengue, there are few therapeutic options and effective vaccines. Clearly, in addition to microbial-directed strategies (anti-microbials or vaccines), strategies targeting the host may be beneficial as they potentially have the capacity to treat various infections with similar pathogenic mechanisms. It is possible that targeting inflammation resolution may be beneficial for the host during bacterial and viral infections. In the next sections, we summarize the evidence demonstrating the expression, roles and effects of the best described pro-resolving molecules (see Sugimoto et al. 2019 for a comprehensive review of existing pro-resolving molecules) in the context of bacterial and viral infections. We focus on mediators and infections for which there is more significant data or analysis. We discuss the relevance of mediators of resolution in the context of bacterial and viral infections below and in Supplementary Tables 1 and 2. The latter tables also provide references on the role or effects of mediators of resolution beyond viral and bacterial infections.
Lipid Mediators
- Lipoxin A4 (LXA4)
Lipoxin A4 (LXA4) is an endogenous lipid mediator that has been demonstrated to possess anti-inflammatory and pro-resolutive properties in both sterile inflammation (Zhang et al., 2008; Vachier et al., 2005) and infection (Wu et al., 2015) models. In order to exert its effects, LXA4 binds to the Formyl peptide receptor 2 (FPR2), which is expressed on the membranes of various leukocytes, including macrophages and neutrophils. LXA4 is produced by lipoxygenases (LOs) from arachidonic acid, which also produces pro-inflammatory lipids, such as leukotrienes. Several pre-clinical studies have evaluated the impact of LXA4 during infection using 5-LO, 15-LO, and 12-LO genetically ablated mice. However, it is important to note that these enzymes are associated with the induction of various lipid mediators with both pro- and anti-inflammatory properties. Therefore, these genetically ablated mice will also lack pro-inflammatory lipids, which may certainly impact the final outcomes of the findings.