Acute lung injury (ALI) is a severe illness with excess mortality and no specific therapy. Protective actions were recently uncovered for docosahexaenoic acid-derived mediators, including D-series resolvins. Here, we used a murine self-limited model of hydrochloric acid-induced ALI to determine the effects of aspirin-triggered resolvin D1 (AT-RvD1; 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) on mucosal injury. RvD1 and its receptor ALX/FPR2 were identified in murine lung after ALI. AT-RvD1 (∼0.5–5 μg kg−1) decreased peak inflammation, including bronchoalveolar lavage fluid (BALF) neutrophils by ∼75%. Animals treated with AT-RvD1 had improved epithelial and endothelial barrier integrity and decreased airway resistance concomitant with increased BALF epinephrine levels. AT-RvD1 inhibited neutrophil–platelet heterotypic interactions by downregulating both P-selectin and its ligand CD24. AT-RvD1 also significantly decreased levels of BALF pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, Kupffer cells, and tumor necrosis factor-α, and decreased nuclear factor-κB-phosphorylated p65 nuclear translocation. Taken together, these findings indicate that AT-RvD1 displays potent mucosal protection and promotes catabasis after ALI.

Introduction: Persistent innate immune activation contributes to tissue destruction in chronic obstructive pulmonary disease (COPD). Altered responses to glucocorticosteroids (GC) may further compromise host defense in chronic lung diseases. We previously identified SAA as a GC resistant systemic COPD biomarker and here, characterized its function in orchestrating mucosal inflammatory responses that contribute to neutrophil accumulation. Methods: Three separate patient cohorts were investigated involving 81 patients. Results: In a prospective study of competing ALX/FPR2 ligands during COPD exacerbation, circulating SAA levels were markedly and disproportionately increased relative to LXA4. Secreted SAA levels in COPD BAL fluid correlated with interleukin-8 and the neutrophil activation marker, neutrophil elastase. SAA was also detected in COPD lung in close proximity to airway epithelia, and in vitro SAA triggered pro-inflammatory mediator (MCP-1, GM-CSF and IL-8) release by airway epithelial cells in an ALX/FPR2 receptor-dependent manner. Lipoxin A4 (LXA4) blocked SAA initiated epithelial responses via allosteric inhibition at ALX/FPR2 (pA2 13 nM). When administered directly into murine lung, SAA initiated robust acute inflammation that was significantly inhibited by equivalent amounts of 15-epi-LXA4 but not dexamethasone. Tissue macrophages (CD68+) colocalised with lung SAA and the GC dexamethasone markedly increased SAA production by THP-1 macrophages (pEC50 43 nM). Conclusions: Together, these findings implicate airway SAA production as a mediator of GC resistant lung inflammation that can overwhelm organ protective signaling by lipoxins at ALX/FPR2 receptors.

The widespread use of statins for hypercholesterolemia has uncovered pleiotropic anti-inflammatory properties that were unexpected based on the drugs' original design; yet, mechanisms for these protective actions remain uncertain. In this study lovastatin triggered biosynthesis of the anti-inflammatory and pro-resolving mediator 15-epi-lipoxin A4 (15-epi-LXA4). During interactions between human neutrophils and airway epithelial cells, the statin-induced increase in 15-epi-LXA4 was associated with increased 14,15-epoxyeicosatrienoic acid (14,15-EET) generation. When added to activated neutrophils, 14,15-EET enhanced 15-epi-LXA4 biosynthesis. In a murine model of airway mucosal injury and inflammation, lovastatin increased 15-epi-LXA4 formation in vivo and markedly decreased acute lung inflammation. Administration of 15-epi-LXA4 also inhibited lung inflammation in an additive manner with lovastatin. Together, these results indicate that statin-triggered 15-epi-LXA4 generation during human leukocyte–airway epithelial cell interactions is an endogenous mechanism for statin-mediated tissue protection at mucosal surfaces that may also be relevant in the statins' ability to stimulate the resolution of inflammation.