Protectin DX increases alveolar fluid clearance in rats with lipopolysaccharide-induced acute lung injury.

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.

Saikosaponin a Inhibits Cigarette Smoke-Induced Oxidant Stress and Inflammatory Responses by Activation of Nrf2.

Saikosaponin a (SSa), a triterpenoid saponin, has numerous pharmacological properties, including anti-inflammatory and antioxidant effects. The purpose of this study was to investigate whether and how SSa protected against cigarette smoke (CS)-induced lung inflammation in mice. The mice were exposed to CS and SSa was administered by an intraperitoneal (i.p.) injection 1 h before CS treatment for 5 consecutive days. The results showed that SSa significantly inhibited CS-induced inflammatory cell infiltration, NO, TNF-α, and IL-1ß production in BALF. SSa also inhibited CS-induced MPO and MDA contents in lung tissues. Furthermore, SSa significantly inhibited CS-induced NF-κB and upregulated the expression of Nrf2 and HO-1. In conclusion, these results support a therapeutic potential for SSa in CS-induced lung inflammation.

Esculentoside A inhibits LPS-induced acute kidney injury by activating PPAR-γ.

Acute kidney injury (AKI) is a major clinical problem associated with high morbidity and mortality. Esculentoside A (EsA), a kind of saponin isolated from the root of the Chinese herb Phytolaca esculenta, has been reported to have anti-inflammatory effect. In this study, we aimed to investigate the protective effects of EsA on LPS-induced AKI in mice. The protective effects of EsA was evaluated by detecting kidney histological change, blood urea nitrogen (BUN) and creatinine levels, and inflammatory cytokines production. The results showed that EsA significantly attenuated LPS-induced kidney histological change, as well as BUN and creatinine levels. EsA also inhibited LPS-induced TNF-α, IL-1ß, and IL-6 production. LPS-induced NF-κB activation was significantly suppressed by treatment of EsA. In addition, EsA up-regulated the expression of PPAR-γ in a dose-dependent manner. In conclusion, EsA protected mice effectively from LPS-induced AKI by PPAR-γ, which subsequently inhibited LPS-induced inflammatory response.

Effects of Angelicin on Ovalbumin (OVA)-Induced Airway Inflammation in a Mouse Model of Asthma.

Angelicin, a furocoumarin found in Psoralea corylifolia L. fruit, has been reported to have anti-inflammatory activity. The purpose of this study was to determine the protective effects of angelicin on allergic asthma induced by ovalbumin (OVA) in mice. Mice were sensitized to OVA (on days 0 and 14) and challenged with OVA three times (on days 21 to 23). Angelicin (2.5, 5, 10 mg/kg) was given intraperitoneally 1 h before OVA treatment after the initial OVA sensitization. The production of IL-4, IL-5, and IL-13 in BALF and IgE in the serum were measured by ELISA. Lung histological changes were detected by using hematoxylin and eosin (H&E) stain. The results showed that angelicin significantly inhibited inflammatory cells infiltration into the lungs. Histological studies showed that angelicin significantly attenuated OVA-induced lung injury. Meanwhile, treatment of angelicin dose-dependently inhibited OVA-induced the production of IL-4, IL-5, and IL-13 in BALF and IgE in the serum. Furthermore, angelicin was found to inhibit airway hyperresponsiveness and NF-kB activation. In conclusion, our results suggested that angelicin inhibited allergic airway inflammation and hyperresponsiveness by inhibiting NF-kB activation.

Lipoxin A(4) activates alveolar epithelial sodium channel, Na,K-ATPase, and increases alveolar fluid clearance.

Edema fluid resorption is critical for gas exchange, and both alveolar epithelial sodium channel (ENaC) and Na,K-ATPase are accredited with key roles in the resolution of pulmonary edema. Alveolar fluid clearance (AFC) was measured in in situ ventilated lungs by instilling isosmolar 5% BSA solution with Evans Blue-labeled albumin tracer (5 ml/kg) and measuring the change in Evans Blue-labeled albumin concentration over time. Treatment with lipoxin A4 and lipoxin receptor agonist (5(S), 6(R)-7-trihydroxymethyl 17 heptanoate) significantly stimulated AFC in oleic acid (OA)-induced lung injury, with the outcome of decreased pulmonary edema. Lipoxin A4 and 5(S), 6(R)-7-trihydroxymethyl 17 heptanoate not only up-regulated the ENaC α and ENaC γ subunits protein expression, but also increased Na,K-ATPase α1 subunit protein expression and Na,K-ATPase activity in lung tissues. There was no significant difference of intracellular cAMP level between the lipoxin A4 treatment and OA group. However, the intracellular cGMP level was significantly decreased after lipoxin A4 treatment. The beneficial effects of lipoxin A4 were abrogated by butoxycarbonyl-Phe-Leu-Phe-Leu-Ph (lipoxin A4 receptor antagonist) in OA-induced lung injury. In primary rat alveolar type II epithelial cells stimulated with LPS, lipoxin A4 increased ENaC α and ENaC γ subunits protein expression and Na,K-ATPase activity. Lipoxin A4 stimulated AFC through activation of alveolar epithelial ENaC and Na,K-ATPase.

[Influence of the agents which maintain the coordination between spontaneous breathing and mechanical ventilation on haemodynamics and respiration].

OBJECTIVE: To investigate the haemodynamic and respiratory changes following intravenous administration with midazolam, pavulon or both of them in the patients having incoordination between spontaneous breathing and mechanical ventilation. METHODS: Thirty patients having incoordination between spontaneous breathing and mechanical ventilation were randomly assigned to receiving intravenous injection of pavulon (group 1), midazolam (group 3), and both (group 2) respectively with 10 cases in each group. The degree of coordination between spontaneous breathing and mechanical ventilation, blood pressure (BP), heart rate (HR), respiration frequency (RF), oxygen saturation of pulse (SpO(2)) were observed before the medication and at 5, 15, 30 and 60 minutes following the administration of drugs in all the patients. RESULTS: Incoordination between spontaneous breathing and mechanical ventilation, fast RF, decreased SpO(2) were observed before the drug in all patients. Improvement of respiratory was significant in group 2. Patients in group 2 were in excellent coordination between spontaneous breathing and mechanical ventilation, reaching 100% within 30 minutes after administration, and lasting longer. The haemodynamics maintained stable and a significant improvement in respiration and SpO(2) were found. BP and HR were elevated significantly, and RF and hypoxemia were improved, and the degree of coordination between spontaneous breathing and mechanical ventilation reached 100% 5 minutes after the drug, but with shorter duration in group 1. There were no obvious changes in BP, HR, RF and hypoxemia, and the degree of coordination between spontaneous breathing and mechanical ventilation was lowest in group 3. CONCLUSION: The combined use of midazolam and pavulon has little influence on circulation, and it also can maintain the coordination between spontaneous breathing and mechanical ventilation. It is suggested that the combined use of midazolam and pavulon is an optimal way to improve the ventilatory function in mechanical ventilation.