Objective Treg/Th17 imbalance plays an important role in rheumatoid arthritis (RA). Maresin 1 (MaR1) prompts inflammation resolution and regulates immune responses. We explored the effect of MaR1 on RA progression and investigated the correlation between MaR1 and Treg/Th17 balance. Methods Both patients with RA and healthy controls were recruited into the study. Collagen-induced arthritis (CIA) model was constructed to detect the clinical score, histopathological changes and Treg/Th17 ratio. Purified naive CD4+ T-cells were used to study the effect of MaR1 on its differentiation process and microRNA microarray studies were performed to investigate MaR1 downstream microRNAs in this process. MicroRNA transfection experiments were conducted by lentivirus to verify the mechanism of MaR1 on Treg/Th17 balance. Results Compared with controls, the MaR1 concentration was higher in the patients with inactive RA and lower in the patients with active RA. Expression of the Treg transcription factor FoxP3 was the highest in inactive RA and the lowest in active RA, while the Th17 transcription factor RORc showed a reverse trend. An inverse correlation was observed between the FoxP3/RORc ratio and Disease Activity Score 28. Intervention of MaR1 in the CIA model reduced joint inflammation and damage, and improved the imbalanced Treg/Th17 ratio. MaR1 increased Treg cells proportion while reduced Th17 cells proportion under specific differentiation conditions. Furthermore, miR-21 was verified as MaR1 downstream microRNA, which was upregulated by MaR1, modulating the Treg/Th17 balance and thus ameliorating the RA progression. Conclusions MaR1 is a therapeutic target for RA, likely operating through effects on the imbalanced Treg/Th17 ratio found in the disease.

Resolvin D1 (7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) (RvD1), generated from ω-3 fatty docosahexaenoic acids, is believed to exert anti-inflammatory properties including inhibition of neutrophil activation and regulating inflammatory cytokines. In this study, we sought to investigate the effect of RvD1 in modulating alveolar fluid clearance (AFC) on LPS-induced acute lung injury. In vivo, RvD1 was injected i.v. (5 μg/kg) 8 h after LPS (20 mg/kg) administration, which markedly stimulated AFC in LPS-induced lung injury, with the outcome of decreased pulmonary edema. In addition, rat lung tissue protein was isolated after intervention and we found RvD1 improved epithelial sodium channel (ENaC) α, γ, Na,K-adenosine triphosphatase (ATPase) α1, β1 subunit protein expression and Na,K-ATPase activity. In primary rat alveolar type II epithelial cells stimulated with LPS, RvD1 not only upregulated ENaC α, γ and Na,K-ATPase α1 subunits protein expression, but also increased Na⁺ currents and Na,K-ATPase activity. Finally, protein kinase A and cGMP were not responsible for RvD1’s function because a protein kinase A inhibitor (H89) and cGMP inhibitor (Rp-cGMP) did not reduce RvD1’s effects. However, the RvD1 receptor (formyl-peptide receptor type 2 [FPR2], also called ALX [the lipoxin A4 receptor]) inhibitor (BOC-2), cAMP inhibitor (Rp-cAMP), and PI3K inhibitor (LY294002) not only blocked RvD1’s effects on the expression of ENaC α in vitro, but also inhibited the AFC in vivo. In summary, RvD1 stimulates AFC through a mechanism partly dependent on alveolar epithelial ENaC and Na,K-ATPase activation via the ALX/cAMP/PI3K signaling pathway.

Vitamin D regulates cell proliferation, inhibits cytokines release at sites of inflammation and reduces inflammatory responses. In this study, the aim was to investigate whether exogenous vitamin D attenuates LPS-induced lung injury via modulating epithelial cell proliferation, migration, apoptosis and epithelial mesenchymal transition (EMT). Murine and in vitro primary type II alveolar epithelial cell work were included in this study. In vivo, mice were mildly vitamin D deficient, 0.1, 1.5, 10mg/kg 1,25(OH)2-vitamin D3 or 25(OH)-vitamin D3 was administrated by means of an intra-gastric injection for 14 days pre-intra-tracheal (IT) LPS, which remarkedly promoted alveolar epithelial type II cells proliferation, inhibited ATII cells apoptosis and inhibited EMT, with the outcome of attenuated LPS-induced lung injury. In vitro, vitamin D stimulated epithelial cell scratch wound repair, reduced primary ATII cells apoptosis as well. Vitamin D promoted primary human ATII cells proliferation through the PI3K/AKT signaling pathway and activation of vitamin D receptor (VDR). Moreover, vitamin D inhibited EMT in response to TGF-β, which was vitamin D receptor dependent. In conclusion, vitamin D attenuates lung injury via stimulating ATII cells proliferation and migration, reducing epithelial cell apoptosis and inhibits TGF-β induced EMT. Together, these results suggest that vitamin D has therapeutic potential for the resolution of ARDS.

We hypothesized that posttreatment with 15-epi-16-parafluoro-phenoxy lipoxin A4 (ATL) could attenuate lipopolysaccharide (LPS)-induced acute lung injury in mice. All the animals were randomly assigned to one of six groups (n = 6 per group). In the sham-vehicle group, mice were treated with 0.9% saline 60 min after they were challenged with saline. The sham-ATL group was identical to the sham-vehicle group except that ATL (0.7 mg/kg, IV) was administered, and the sham-ZnPP group was identical to the sham-vehicle group except that Zinc protoporphyrin IX (ZnPP, 25 mg/kg IV) was administered. In the LPS-vehicle group, mice were treated with vehicle 60 min after they were challenged with LPS. The LPS-ATL group was identical to the LPS-vehicle group but received ATL. The ZnPP-ATL-LPS group was identical to the LPS-ATL group, but ZnPP was administered 30 min before ATL. Inhalation of LPS increased inflammatory cell counts, tumor necrosis factor-α, and protein concentration in bronchoalveolar lavage fluid and also induced lung histological injury and edema. Posttreatment with ATL inhibited tumor necrosis factor-α, nitric oxide, and malondialdehyde production, with the outcome of decreased pulmonary edema, lipid peroxidation, and the infiltration of neutrophils in lung tissues. In addition, ATL promoted the formation of heme oxygenase-1 in the lung tissues. Heme oxygenase-1 activity was also increased in the lung tissues after ATL stimulation. The beneficial effects of ATL were abolished by ZnPP. This study demonstrates that posttreatment with ATL significantly reduces LPS-induced acute lung injury in mice.