Search

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in premature infants and is mainly caused by hyperoxia exposure and mechanical ventilation. Alveolar simplification, pulmonary vascular abnormalities and pulmonary inflammation are the main pathological changes in hyperoxic lung injury animals. Lipoxin A4 (LXA4) is an important endogenous lipid that can mediate the regression of inflammation and plays a role in acute lung injury and asthma. The purpose of this study was to evaluate the effects of LXA4 on inflammation and lung function in neonatal rats with hyperoxic lung injury and to explore the mechanism of the PINK1 pathway. After 85% oxygen exposure in newborn rats for 7 days, the BPD model was established. We found that LXA4 could significantly reduce cell and protein infiltration and oxidative stress in rat lungs, improve pulmonary function and alveolar simplification, and promote weight gain. LXA4 inhibited the expression of TNF-α, MCP-1 and IL-1β in serum and BALF from hyperoxic rats. Moreover, we found that LXA4 could reduce the expression of the PINK1 gene and down-regulate the expression of PINK1, Parkin, BNIP3L/Nix and the autophagic protein LC3B.These protective effects of LXA4 could be partially reversed by addition of BOC-2.Thus, we concluded that LXA4 can alleviate the airway inflammatory response, reduce the severity of lung injury and improve lung function in a hyperoxic rat model of BPD partly through the PINK1 signaling pathway. • 7 day hyperoxic exposure resulted in obvious lung injury in neonatal rats. • LXA4 could reduce the severity of lung injury in hyperoxic neonatal rats. • LXA4 down-regulated the PINK1 pathway in hyperoxic lung. • BOC-2 partially reversed the protective effects of LXA4 in hyperoxic lung injury. [ABSTRACT FROM AUTHOR]

• TGF-β1 up-regulated YAP expression by activating Smad2/3, and then up-regulated cyclin D1 leading to rat ASMCs proliferation and migration. • Knockdown of YAP disrupted the pro-airway remodeling function of TGF-β1. • LXA4 inhibited TGF-β1 induced ASMCs proliferation and migration. • LXA4 blocked TGF-β1-induced activation of Smad2/3, YAP and cyclin D1 via its receptor FPRL1. The aims of the present study were to examine the signaling mechanisms for transforming growth factor-β1 (TGF-β1)-induced rat airway smooth muscle cells (ASMCs) proliferation and migration and to determine the effect of lipoxin A4 (LXA4) on TGF-β1-induced rat ASMCs proliferation and migration and its underlying mechanisms. TGF-β1 upregulated transcriptional coactivator Yes-associated protein (YAP) expression by activating Smad2/3 and then upregulated cyclin D1, leading to rat ASMCs proliferation and migration. This effect was reversed after treatment with the TGF-β1 receptor inhibitor SB431542. YAP is a critical mediator of TGF-β1-induced ASMCs proliferation and migration. Knockdown of YAP disrupted the pro-airway remodeling function of TGF-β1. Preincubation of rat ASMCs with LXA4 blocked TGF-β1-induced activation of Smad2/3 and changed its downstream targets, YAP and cyclin D1, resulting in the inhibition of rat ASMCs proliferation and migration. Our study suggests that LXA4 suppresses Smad/YAP signaling to inhibit rat ASMCs proliferation and migration and therefore has potential value in the prevention and treatment of asthma by negatively modulating airway remodeling. [ABSTRACT FROM AUTHOR]

Sepsis is a serious disease that leads to severe inflammation, dysregulation of immune system, multi-organ failure and death. Innate response activator (IRA) B cells, which produce granulocyte-macrophage colony-stimulating factor (GM-CSF), protect against microbial sepsis. Lipid mediator lipoxin A4 (LXA4) exerts anti-inflammatory and immunoregulatory effects, and it has been reported that LXA4 receptor ALX/FPR2 is expressed on B cells. Here, we investigated the potential role of LXA4 on IRA B cells in lipopolysaccharide (LPS)-induced sepsis. We found that LXA4 significantly promoted the expansion of splenic IRA B cells and increased GM-CSF expression in splenic B cells with LPS stimulation. After splenectomy, LXA4 treatment did not change the serum or peritoneal IL-1β, IL-6 and TNF-α levels in LPS-induced sepsis. LXA4 accelerated the migration of peritoneal B cells to spleen for their differentiation into IRA B cells, whereas this effect was independent of peritoneal macrophage. Furthermore, LXA4 enhanced the phosphorylation level of signal transducer and activator of transcription 5 (STAT5) in splenic B cells. These results suggest that LXA4 protects against LPS-induced sepsis by promoting the generation and migration of splenic IRA B cells, and the underlying molecular mechanism may be related to STAT5 activation. It might provide new insights and therapeutic approaches for treating sepsis. [ABSTRACT FROM AUTHOR]

• Nrf2 plays a key role in oxidative injury of podocytes cultured in high-glucose medium. • Lipoxin A 4 analog BML-111 attenuates oxidative injury of podocytes cultured in high-glucose medium in vitro. • BML-111 attenuates diabetic kidney injury via Nrf2 pathway in vivo. Numerous studies have shown that the activation of the Nrf2 pathway alleviates oxidative stress and podocyte damage. Emerging evidence indicates that the dual anti-inflammatory and pro-resolution lipid mediator, lipoxin A 4 (LXA 4), has antioxidant activity. The aim of the present study was to confirm that BML-111, an analog of LXA 4 , prevents oxidative injury in diabetic podocytes via the regulation of the Nrf2 pathway. Here, we found that BML-111 inhibited high glucose (HG)-induced oxidative injury in the podocyte cell line, MPC5, in vitro, through activating Nrf2. Mechanistically, BML-111 significantly activated Nrf2 and its phase II enzymes, including Nqo1 and Ho-1. Moreover, BML-111 suppressed the migration of MPC5 cells. Additionally, BML-111 decreased the expression of Vcam, Icam and inflammatory cytokines (Il-1α, Il-6, and Tnf) in MPC5 cells. Importantly, BML-111 ameliorated blood glucose levels (approximately 75% of that in the SMZ group) and kidney damage by activating Nrf2, and its phase II enzymes, in diabetic mice. These effects are mainly mediated by Fpr2, a specific LXA 4 receptor. Our findings demonstrate that BML-111 alleviates the injury of diabetic podocytes and kidneys by regulating the Nrf2 pathway. [ABSTRACT FROM AUTHOR]

Abstract: Lipoxin A4 (LXA4) is an endogenous lipid mediator with potent anti-inflammatory actions but its role in infectious processes is not well understood. We investigated the involvement of LXA4 and its receptor FPR2/ALX in the septic inflammatory dysregulation. Pneumosepsis was induced in mice by inoculation of Klebsiella pneumoniae. LXA4 levels and FPR2/ALX expression in the infectious focus as well as the effects of treatment with receptor agonists (LXA4 and BML-111) and antagonists (BOC-2 and WRW(4)) in early (1h) and late (24h) sepsis were studied. Sepsis induced an early increase in LXA4, FPR2/ALX lung expression, local and systemic infection and inflammation, and mortality. Treatment with BOC-2 in early sepsis increased leukocyte migration to the focus, and reduced bacterial load and dissemination. Inhibition of 5- and 15-lipoxygenase in early sepsis also increased leukocyte migration. Early treatment with WRW(4) and BOC-2 improved survival. Treatment with authentic LXA4 or BML-111 in early sepsis decreased cell migration and worsened the infection. In late sepsis, treatment with BOC-2 had no effect, but LXA4 improved the survival rate by reducing the excessive inflammatory response, this effect being abolished by pretreatment with BOC-2. Thus, the anti-inflammatory and pro-resolution mediator LXA4 and its receptor FPR2/ALX levels were increased in the early phase of sepsis, contributing to the septic inflammatory dysregulation. In addition, LXA4 has a dual role in sepsis and that its beneficial or harmful effects are critically dependent on the time. Therefore, a proper interference with LXA4 system may be a new therapeutic avenue to treat sepsis. [Copyright &y& Elsevier]

Abstract: Naringin is a flavanone with various bioactivities including expectorant effect, antitussive effect and inhibitory effects on asthma and acute lung injury. In present study we examined the effects of naringin on enhanced cough, airway hyperresponsiveness (AHR) and airway inflammation in chronic cigarette smoke (CS) exposure-induced chronic bronchitis in guinea pigs. To achieve this, guinea pigs were exposed to CS for 8weeks (10cigarettes/day, 6days/week). Oral administration of naringin (9.2, 18.4 and 36.8mg/kg) significantly attenuated the enhanced cough and AHR in smoke-exposed guinea pigs, reduced the concentrations of interleukin-8 (IL-8), leukotriene B4 (LTB4) and tumor necrosis factor-α (TNF-α) in bronchoalveolar lavage fluid (BALF) and decreased the myeloperoxidase (MPO) activity in both BALF and lung tissue, but did not significantly decrease the leukocytes in BALF. Naringin also improved superoxidase dismutase (SOD) activity in lung tissue and increased the content of lipoxin A4 (LXA4) in BALF in this guinea pig model of chronic bronchitis. These results suggested that naringin exhibited antitussive, anti-AHR and anti-inflammation effects on chronic CS exposure-induced chronic bronchitis in guinea pigs, and may possess novel therapeutic potential in the treatment of chronic bronchitis. [Copyright &y& Elsevier]

• There is a significant augment of lipoxin A4 level in A. fumigatus keratitis mice compared with uninfected control. • Lipoxin A4 exerts anti-inflammatory effect on A. fumigatus keratitis mouse model and A. fumigatus-stimulated RAW264.7 cells. • Lipoxin A4 attenuates inflammation through the ALX/FPR2 receptor. To explore the anti-inflammatory effect of lipoxin A4 (LXA4) in Aspergillus fumigatus (A. fumigatus) keratitis and the underlying mechanisms. In A. fumigatus keratitis mouse models, enzyme-linked immunosorbent assay (ELISA) was used to detect the level of LXA4. Clinical scores were utilized to evaluate fungal keratitis (FK) severity. Fungal load was assessed by plate count. Immunofluorescence staining, HE staining and myeloperoxidase (MPO) assays were carried out to evaluate the neutrophil infiltration and activity. In A. fumigatus infected mouse corneas and inactivated A. fumigatus- stimulated RAW264.7 cells, quantitative real time polymerase chain reaction (qRT-PCR) and ELISA were applied to assess the expression of pro-inflammatory mediators and anti-inflammatory factors. Reactive oxygen species (ROS) was determined by 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) staining in RAW264.7 cells. LXA4 level was significantly increased in mice with A. fumigatus keratitis. In an A. fumigatus keratitis mouse model, LXA4 treatment alleviated FK severity, reduced fungal load and repressed neutrophil infiltration and activity. Additionally, LXA4 inhibited the expression of pro-inflammatory mediators including IL-1β, TNF-α, IL-6, cyclooxygenase-2 (COX-2), TLR-2, TLR-4, Dectin-1 and iNOS, and promoted the expression of anti-inflammatory factors IL-10 and Arg-1. In RAW264.7 cells, LXA4 receptor/formyl peptide receptor 2 (ALX/FPR2) blockade reversed the anti-inflammatory effect of LXA4. LXA4 suppressed inactivated A. fumigatus induced elevated ROS production in RAW264.7 cells, which was abrogated by ALX/FPR2 antagonist Boc-2. LXA4 ameliorated inflammatory response by suppressing neutrophil infiltration, downregulating the expression of pro-inflammatory mediators and ROS production through ALX/FPR2 receptor in A. fumigatus keratitis. [ABSTRACT FROM AUTHOR]