Maresin1 (MaR1) is a new docosahexaenoic acid-derived pro-resolving agent that promotes the resolution of inflammation. In this study, we sought to investigate the effect and underlining mechanisms of MaR1 in modulating alveolar fluid clearance (AFC) on LPS-induced acute lung injury. MaR1 was injected intravenously or administered by instillation (200 ng/kg) 8 h after LPS (14 mg/kg) administration and AFC was measured in live rats. In primary rat alveolar type II epithelial cells, MaR1 (100 nM) was added to the culture medium with lipopolysaccharide for 6 h. MaR1 markedly stimulated AFC in LPS-induced lung injury, with the outcome of decreased pulmonary edema and lung injury. In addition, rat lung tissue protein was isolated after intervention, and we found MaR1 improved epithelial sodium channel (ENaC), Na,K-adenosine triphosphatase (ATPase) protein expression and Na,K-ATPase activity. MaR1 down-regulated Nedd4-2 protein expression though PI3k/Akt but not though PI3k/SGK1 pathway in vivo. In primary rat alveolar type II epithelial cells stimulated with LPS, MaR1-upregulated ENaC and Na,K-ATPase protein abundance in the plasma membrane. Finally, the lipoxin A4 Receptor inhibitor (BOC-2) and PI3K inhibitor (LY294002) not only blocked MaR1's effects on cAMP/cGMP, the expression of phosphorylated Akt and Nedd4-2, but also inhibited the effect of MaR1 on AFC in vivo. In conclusion, MaR1 stimulates AFC through a mechanism partly dependent on alveolar epithelial ENaC and Na,K-ATPase activation via the ALX/PI3K/Nedd4-2 signaling pathway. Our findings reveal a novel mechanism for pulmonary edema fluid reabsorption and MaR1 may provide a new therapy for the resolution of ALI/ARDS.

Acute respiratory distress syndrome is a life-threatening critical syndrome resulting largely from the accumulation of and the inability to clear pulmonary edema. Protectin DX, an endogenously produced lipid mediator, is believed to exert anti-inflammatory and pro-resolution effects. Protectin DX (5 µg/kg) was injected i.v. 8 h after LPS (14 mg/kg) administration, and alveolar fluid clearance was measured in live rats (n = 8). In primary rat ATII epithelial cells, protectin DX (3.605 × 10−3 mg/l) was added to the culture medium with LPS for 6 h. Protectin DX improved alveolar fluid clearance (9.65 ± 1.60 vs. 15.85 ± 1.49, p < 0.0001) and decreased pulmonary edema and lung injury in LPS-induced lung injury in rats. Protectin DX markedly regulated alveolar fluid clearance by upregulating sodium channel and Na, K-ATPase protein expression levels in vivo and in vitro. Protectin DX also increased the activity of Na, K-ATPase and upregulated P-Akt via inhibiting Nedd4–2 in vivo. In addition, protectin DX enhanced the subcellular distribution of sodium channels and Na, K-ATPase, which were specifically localized to the apical and basal membranes of primary rat ATII cells. Furthermore, BOC-2, Rp-cAMP, and LY294002 blocked the increased alveolar fluid clearance in response to protectin DX. Protectin DX stimulates alveolar fluid clearance through a mechanism partly dependent on alveolar epithelial sodium channel and Na, K-ATPase activation via the ALX/PI3K/Nedd4–2 signaling pathway.

The clinical and experimental postcardiac arrest treatment has not reached therapeutic success. The present study investigated the effect of PD98059 (PD) in rats subjected to cardiac arrest (CA)/cardiopulmonary resuscitation (CPR). Experimental rats were divided randomly into 3 groups: sham, CA, and PD. The rats except for sham group were subjected to CA for 5 min followed by CPR operation. Once spontaneous circulation was restored, saline and PD were injected in CA and PD groups, respectively. The survival rates and neurologic deficit scores (NDS) were observed, and the following indices of brain tissue were evaluated: ROS, MDA, SOD, p-ERK1/2/ERK1/2, caspase-3, Bax, Bcl-2, TUNEL positive cells, and double fluorescent staining of p-ERK/TUNEL. Our results indicated that PD treatment significantly reduced apoptotic neurons and improved the survival rates and NDS. Moreover, PD markedly downregulated the ROS, MDA, p-ERK, and caspase-3, Bax and upregulated SOD and Bcl-2 levels. Double staining p-ERK/TUNEL in choroid plexus and cortex showed that cell death is dependent on ERK activation. The findings in present study demonstrated that PD provides neuroprotection via antioxidant activity and antiapoptosis in rats subjected to CA/CPR.

Background: Several studies have shown that patients with type 2 diabetes mellitus (T2DM) have worse clinical outcomes in comparison to patients without diabetes mellitus (DM) following Percutaneous Coronary Intervention (PCI). However, the adverse clinical outcomes were not similarly reported in all the studies. Therefore, in order to standardize this issue, a meta-analysis including 139,774 patients was carried out to compare the in-hospital, short-term (<1 year) and long-term (≥1 year) adverse clinical outcomes in patients with and without T2DM following PCI. Methods: Electronic databases including MEDLINE, EMBASE, and the Cochrane Library were searched for Randomized Controlled Trials (RCTs) and observational studies. The adverse clinical outcomes which were analyzed included mortality, myocardial infarction (MI), major adverse cardiac events (MACEs), stroke, bleeding, target vessel revascularization (TVR), target lesion revascularization (TLR), and stent thrombosis. Risk Ratios (RR) with 95% confidence intervals (CI) were used to express the pooled effect on discontinuous variables and the analysis was carried out by RevMan 5.3 software. Results: A total number of 139,774 participants were assessed. Results of this analysis showed that in-hospital mortality and MACEs were significantly higher in patients with T2DM (RR 2.57; 95% CI: 1.95–3.38; P = .00001) and (RR: 1.38; 95% CI: 1.10–1.73; P = .005) respectively. In addition, majority of the short and long-term adverse clinical outcomes were also significantly higher in the DM group as compared to the non-DM group. Stent thrombosis was significantly higher in the DM compared to the non-DM group during the short term follow-up period (RR 1.59; 95% CI: 1.16–2.18; P = .004). However, long-term stent thrombosis was similarly manifested. Conclusion: According to this meta-analysis including a total number of 139,774 patients, following PCI, those patients with T2DM suffered more in-hospital, short as well as long-term adverse outcomes as reported by most of the Randomized Controlled Trials and Observational studies, compared to those patients without diabetes mellitus.