Pulmonary Myeloperoxidase Activity Research Articles

C-Phycocyanin Prevents Oxidative Stress, Inflammation, and Lung Remodeling in an Ovalbumin-Induced Rat Asthma Model.

Asthma is a chronic immunological disease related to oxidative stress and chronic inflammation; both processes promote airway remodeling with collagen deposition and matrix thickening, causing pulmonary damage and lost function. This study investigates the immunomodulation of C-phycocyanin (CPC), a natural blue pigment purified from cyanobacteria, as a potential alternative treatment to prevent the remodeling process against asthma. We conducted experiments using ovalbumin (OVA) to induce asthma in Sprague Dawley rats. Animals were divided into five groups: (1) sham + vehicle, (2) sham + CPC, (3) asthma + vehicle, (4) asthma + CPC, and (5) asthma + methylprednisolone (MP). Our findings reveal that asthma promotes hypoxemia, leukocytosis, and pulmonary myeloperoxidase (MPO) activity by increasing lipid peroxidation, reactive oxygen and nitrogen species, inflammation associated with Th2 response, and airway remodeling in the lungs. CPC and MP treatment partially prevented these physiological processes with similar action on the biomarkers evaluated. In conclusion, CPC treatment enhanced the antioxidant defense system, thereby preventing oxidative stress and reducing airway inflammation by regulating pro-inflammatory and anti-inflammatory cytokines, consequently avoiding asthma-induced airway remodeling.

PEBP4 deficiency aggravates LPS-induced acute lung injury and alveolar fluid clearance impairment via modulating PI3K/AKT signaling pathway

Acute lung injury (ALI) is a common clinical syndrome, which often results in pulmonary edema and respiratory distress. It has been recently reported that phosphatidylethanolamine binding protein 4 (PEBP4), a basic cytoplasmic protein, has anti-inflammatory and hepatoprotective effects, but its relationship with ALI remains undefined so far. In this study, we generated PEBP4 knockout (KO) mice to investigate the potential function of PEBP4, as well as to evaluate the capacity of alveolar fluid clearance (AFC) and the activity of phosphatidylinositide 3-kinases (PI3K)/serine-theronine protein kinase B (PKB, also known as AKT) signaling pathway in lipopolysaccharide (LPS)-induced ALI mice models. We found that PEBP4 deficiency exacerbated lung pathological damage and edema, and increased the wet/dry weight ratio and total protein concentration of bronchoalveolar lavage fluid (BALF) in LPS-treated mice. Meanwhile, PEBP4 KO promoted an LPS-induced rise in the pulmonary myeloperoxidase (MPO) activity, serum interleuin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels, and pulmonary cyclooxygenase-2 (COX-2) expression. Mechanically, PEBP4 deletion further reduced the protein expression of Na+ transport markers, including epithelial sodium channel (ENaC)-α, ENaC-γ, Na,K-ATPase α1, and Na,K-ATPase β1, and strengthened the inhibition of PI3K/AKT signaling in LPS-challenged mice. Furthermore, we demonstrated that selective activation of PI3K/AKT with 740YP or SC79 partially reversed all of the above effects caused by PEBP4 KO in LPS-treated mice. Altogether, our results indicated the PEBP4 deletion has a deterioration effect on LPS-induced ALI by impairing the capacity of AFC, which may be achieved through modulating the PI3K/AKT pathway.

Protective effect of zerumbone on sepsis-induced acute lung injury through anti-inflammatory and antioxidative activity via NF-κB pathway inhibition and HO-1 activation.

Sepsis is a systemic illness for which there are no effective preventive or therapeutic therapies. Zerumbone, a natural molecule, has anti-oxidative and anti-inflammatory properties that may help to prevent sepsis. In the present study, we have assessed the protective effect of zerumbone against sepsis-induced acute lung injury (ALI) and its underlying mechanisms. During the experiment, mice were divided into five groups: a sham group, a sepsis-induced ALI group, and three sepsis groups that are pre-treated with zerumbone at different concentrations. We found that zerumbone greatly decreased the sepsis-induced ALI using histological investigations. Also, zerumbone treatment reduced the sepsis-induced inflammatory cytokine concentrations as well as the number of infiltrating inflammatory cells in BALF compared to non-treated sepsis animals. The zerumbone-pretreated sepsis groups had reduced pulmonary myeloperoxidase (MPO) activity than the sepsis groups. Moreover, the mechanism underlying the protective action of zerumbone on sepsis is accomplished by the activation of antioxidant genes such as nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), superoxide dismutase (SOD), and heme oxygenase 1 (HO-1). The obtained results revealed that zerumbone inhibited the sepsis-induced ALI through its anti-inflammatory and antioxidative activity via inhibition of the NF-κB pathway and activation of HO-1 pathway. Our findings demonstrate that zerumbone pretreatment suppresses sepsis-induced ALI via antioxidative activities and anti-inflammatory, implying that zerumbone could be a viable preventive agent for sepsis-induced ALI.

A natural sesquiterpene lactone isolinderalactone attenuates lipopolysaccharide-induced inflammatory response and acute lung injury through inhibition of NF-κB pathway and activation Nrf2 pathway in macrophages

Isolinderalactone is the main sesquiterpene lactone isolated from Lindera aggregata, a traditional Chinese medicine widely used to treat pain and inflammation. Although isolinderalactone has been demonstrated to possess anti-cancer effect, its anti-inflammatory activity and underlying mechanism has not been well characterized. Herein, isolinderalactone was able to significantly inhibit the production of NO and PGE2 by reducing the expressions of iNOS and COX2 in LPS-stimulated RAW264.7 macrophages and BMDMs, and decreased the mRNA levels of IL-1β, IL-6, and TNF-α in LPS-induced RAW264.7 cells. In vivo, isolinderalactone effectively alleviated LPS-induced acute lung injury (ALI), which manifested as reduction in pulmonary inflammatory infiltration, myeloperoxidase activity, and production of PGE2, IL-1β, IL-6, TNF-α, and malondialdehyde. Furthermore, isolinderalactone inhibited phosphorylation of IKKα/β, phosphorylation and degradation of IκBα, and nuclear translocation of NF-κB p65, thereby blocking NF-κB pro-inflammatory pathway. Meanwhile, isolinderalactone reduced the intracellular ROS through promoting the activation of Nrf2-HMOX1 antioxidant axis. By using drug affinity responsive target stability assay and molecular docking, isolinderalactone was found to covalently interact with IKKα/β and Keap1, which may contribute to its anti-inflammatory action. Additionally, a thiol donor β-mercaptoethanol significantly abolished isolinderalactone-mediated anti-inflammatory action in vitro, indicating the crucial role of the unsaturated lactone of isolinderalactone on its anti-inflammatory effects. Taken together, isolinderalactone protected against LPS-induced ALI in mice, which may be associated with its inhibition of NF-κB pathway and activation of Nrf2 signaling in macrophages.

Overexpressing six-transmembrane protein of prostate 2 (STAMP2) alleviates sepsis-induced acute lung injury probably by hindering M1 macrophage polarization via the NF-κB pathway.

Acute lung injury (ALI) is a major cause of death in sepsis patients. The Six-transmembrane protein of prostate 2 (STAMP2) is a key regulator of inflammation, while its role in septic ALI remains unclear. Male C57BL/6 mice were subjected to cecal ligation puncture (CLP) to induce experimental sepsis whereas lipopolysaccharide (LPS)-stimulated RAW 264.7 cells were used as the models of septic ALI in vivo and in vitro, respectively. Overexpression of STAMP2 in mouse lungs and RAW264.7 cells was performed with an adenoviral vector. We measured histological lung injury, lung wet/dry weight (W/D) ratio, and pulmonary myeloperoxidase (MPO) activity to assess lung injury extent. Cell counts in bronchoalveolar lavage fluid (BALF) were measured using Giemsa staining. The concentration of inflammatory factors was detected by enzyme-linked immunosorbent assay. The polarization of macrophages was evaluated by inducible nitric oxide synthase (iNOS) and F4/80 staining. The activation of cell apoptosis and NF-κB pathway was evaluated using Western blot, TUNEL staining, immunofluorescence, and immunohistochemistry. Overexpression of STAMP2 alleviated CLP-induced lung injury of mice with decreased W/D ratio of the lung, and MPO activity in lung tissue. STAMP2 overexpression reduced the lung infiltration of inflammatory cells, and the levels of TNF-a, IL-6, and macrophage chemoattractant protein-1 (MCP-1) in BALF. Overexpressed STAMP2 inhibited macrophage M1 polarization in lung tissues as indicated by F4/80 and iNOS stainings in lung tissue. STAMP2 overexpression inhibited RAW 264.7 cell apoptosis by increasing Bcl-2 and decreasing Bax and cleaved-caspase 3 expression. Besides, STAMP2 overexpression suppressed nuclear factor κB (NF-κB) p65 pathway activation, as evidenced by reduced phosphorylation of IκBα, and phosphorylation and translocation of NF-κB p65. In vitro study further proved that STAMP2 overexpression suppressed the NF-κB pathway (IκBα/p65) in macrophages and decreased macrophage M1 polarization and M1-associated inflammatory factor production (TNF-a, IL-6, and MCP-1). Our study for the first time demonstrated that STAMP2 might be able to reduce inflammation in sepsis-induced ALI by inhibiting macrophage M1 polarization through repressing NF-κB signaling activation.

Pulmonary Delivery of Favipiravir in Rats Reaches High Local Concentrations without Causing Oxidative Lung Injury or Systemic Side Effects.

Favipiravir displays a rapid viral clearance, a high recovery rate and broad therapeutic safety; however, its oral administration was associated with systemic side effects in susceptible patients. Considering that the pulmonary route could provide a high drug concentration, and a safer application with less absorption into systemic circulation, it was aimed to elucidate whether favipiravir delivered via soft-mist inhaler has any deleterious effects on lung, liver and kidney tissues of healthy rats. Wistar albino rats of both sexes (n = 72) were placed in restrainers, and were given either saline or favipiravir (1, 2.5, 5 or 10 mg/kg in 1 mL saline) by inhalation within 2 min for 5 consecutive days. On the 6th day, electrocardiographic recording was obtained, and cardiac blood and lung tissues were collected. Favipiravir did not alter cardiac rhythm, blood cell counts, serum levels of alanine transaminase, aspartate transaminase, blood urea nitrogen, creatinine, urea or uric acid, and did not cause any significant changes in the pulmonary malondialdehyde, myeloperoxidase activity or antioxidant glutathione levels. Our data revealed that pulmonary use of favipiravir via soft-mist inhaler enables a high local concentration compared to plasma without oxidative lung injury or cardiac or hepatorenal dysfunction.

Inosine Pretreatment Attenuates LPS-Induced Lung Injury through Regulating the TLR4/MyD88/NF-κB Signaling Pathway In Vivo.

Inosine is a type of purine nucleoside, which is considered to a physiological energy source, and exerts a widely range of anti-inflammatory efficacy. The TLR4/MyD88/NF-κB signaling pathway is essential for preventing host oxidative stresses and inflammation, and represents a promising target for host-directed strategies to improve some forms of disease-related inflammation. In the present study, the results showed that inosine pre-intervention significantly suppressed the pulmonary elevation of pro-inflammatory cytokines (including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)), malondialdehyde (MDA), nitric oxide (NO), and reactive oxygen species (ROS) levels, and restored the pulmonary catalase (CAT), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and myeloperoxidase (MPO) activities (p < 0.05) in lipopolysaccharide (LPS)-treated mice. Simultaneously, inosine pre-intervention shifted the composition of the intestinal microbiota by decreasing the ratio of Firmicutes/Bacteroidetes, elevating the relative abundance of Tenericutes and Deferribacteres. Moreover, inosine pretreatment affected the TLR4/MyD88/NF-κB signaling pathway in the pulmonary inflammatory response, and then regulated the expression of pulmonary iNOS, COX2, Nrf2, HO-1, TNF-α, IL-1β, and IL-6 levels. These findings suggest that oral administration of inosine pretreatment attenuates LPS-induced pulmonary inflammatory response by regulating the TLR4/MyD88/NF-κB signaling pathway, and ameliorates intestinal microbiota disorder.

Azilsartan attenuates lipopolysaccharide-induced acute lung injury via the Nrf2/HO-1 signaling pathway.

Acute lung injury (ALI) is a severe complication of sepsis and hemorrhagic shock with high morbidity. In the present study, the protective effect of Azilsartan on lipopolysaccharide (LPS)-induced ALI in mice was investigated to explore the potential therapeutic property of Azilsartan for the treatment of ALI. LPS was used to induce an ALI model in mice. Hematoxylin-eosin (HE) staining sections were then evaluated for the pathological state of lung tissues. Bronchoalveolar lavage fluid (BALF) protein concentration, wet/dry weight ratios of lung tissues, and pulmonary myeloperoxidase (MPO) activity were detected to determine the degree of pulmonary injury. The number of total cells, macrophages, and neutrophils in BALF were counted using a hemocytometer to illustrate the inflammatory cell infiltration. The lung function was monitored using a spirometer. The concentrations of interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) were determined using enzyme-linked immunosorbent assay (ELISA). Oxidative stress was evaluated by the superoxide dismutase (SOD) activity, glutathione (GSH), and malondialdehyde (MDA) concentrations in the lung tissue. The expressions of nuclear erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were determined using Western blot analysis. Azilsartan therapy alleviated LPS-induced lung tissue damage, increased BALF protein concentration, lung wet to dry weight ratio, MPO activity, and macrophage and neutrophils infiltration. Also, Azilsartan ameliorated the production of inflammatory factors (IL-1β, MCP-1, and IL-8). Azilsartan ameliorated LPS-impaired lung SOD activity, the GSH concentration, and the MDA concentration. Mechanistically, Azilsartan activated the LPS-impaired Nrf2/HO-1 signaling pathway. Azilsartan therapy attenuates LPS-induced ALI via the Nrf2/HO-1 signaling pathway.

Pretreatment with Propofol Reduces Pulmonary Injury in a Pig Model of Intestinal Ischemia-Reperfusion via Suppressing the High-Mobility Group Box 1 Protein (HMGB1)/Toll-Like Receptor 4 (TLR4)/Protein Kinase R (PKR) Signaling Pathway.

BackgroundPropofol improves rodent pulmonary injury after intestinal ischemia-reperfusion (IIR). However, its effect and underlying mechanisms in large animals remain unclear. Here, we examined whether pretreatment with propofol could relieve lung injury during IIR in pigs, then investigated the underlying mechanism.Material/MethodsA porcine model of IIR-induced lung injury was built by clamping the super mesenteric artery for 2 h and loosening the clamp for 4 h. Randomized grouping was used, and pigs were assigned to a sham-operated group, an IIR with saline pretreatment group, and an IIR with propofol pretreatment group. Pulmonary histopathologic changes, permeability, and oxygenation were assessed to evaluate the effect of propofol. We assessed levels of methane dicarboxylic aldehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), high-mobility group box 1 protein (HMGB1), Toll-like receptor 4 (TLR4), and double-stranded RNA activated protein kinase R (PKR) to investigate the underlying mechanism.ResultsIIR caused severe lung damage, including morphological changes, high permeability, airway resistance, low static compliance, hypoxemia, and acidemia. Pulmonary and plasma MDA content and MPO activity increased, whereas SOD activity decreased. The HMGB1/TLR4/PKR signaling pathway was activated following IIR. Pretreatment with propofol markedly attenuated lung injury (such as reducing the lung edema and permeability), increased MDA content and MPO activity, and restored SOD activity induced by IIR, accompanied by inhibiting the effect of the HMGB1/TLR4/PKR signaling pathway.ConclusionsIIR caused acute lung injury in pigs. Pretreatment with propofol alleviated the lung injury, which was related to its suppression of the HMGB1/TLR4/PKR signaling pathway.

RETRACTED: LncRNA NEAT1 inhibition upregulates miR-16-5p to restrain the progression of sepsis-induced lung injury via suppressing BRD4 in a mouse model

Long non-coding RNAs (lncRNAs) are known to sponge microRNAs (miRNAs) to regulate biological processes. However, the role of nuclear paraspeckle assembly transcript 1 (NEAT1) binding miR-16-5p in sepsis-induced lung injury remains largely unknown. We aim to explore the effect of NEAT1 sponging miR-16-5p on sepsis-induced lung injury via regulating bromodomain containing 4 (BRD4). A mouse model of sepsis-induced lung injury was established. Expression of NEAT1, miR-16-5p and BRD4 was determined. The pulmonary edema, myeloperoxidase (MPO) activity, pathological changes, levels of inflammatory factors, cell viability and apoptosis in mouse lung tissues were evaluated. The binding relationships between NEAT1 and miR-16-5p, and between miR-16-5p and BRD4 were confirmed. NEAT1 and BRD4 were upregulated while miR-16-5p was downregulated in sepsis-induced lung injury. NEAT1 inhibition or miR-16-5p elevation suppressed pulmonary edema, MPO activity, pathological changes, inflammation and apoptosis, and promoted cell viability in mouse lung tissues. NEAT1 bound with miR-16-5p and miR-16-5p targeted BRD4. NEAT1 inhibition upregulates miR-16-5p to repress the progression of sepsis-induced lung injury via downregulating BRD4.

Protective effect of ginsenoside rd on lipopolysaccharide-induced acute lung injury through its anti-inflammatory and anti-oxidative activity

Background: Inflammation and oxidation stress are key factors in the mechanism of acute lung injury (ALI). Therefore, suppression of the inflammatory response and oxidative stress could be a potential strategy to treat lipopolysaccharide (LPS)-induced ALI. Ginsenoside Rd (Rd), a natural Ginseng extract, alleviates inflammation and oxidative stress in several diseases such as Alzheimer's disease and cerebral ischemia, but its effect on ALI is still unclear. Aims and Objectives: To explore the protective effect of Rd on LPS-induced ALI and explored associated mechanisms. Materials and Methods: Mice were divided into five groups: A sham-operated group, a LPS-induced ALI group, and three LPS groups pretreated with Rd doses of 20, 40, and 80 mg/kg, respectively. The pathological changes of lung, collagen deposition, pulmonary edema, inflammatory cytokine, oxidative stress and the expression levels of TLR4 and NF-κB were detected. Results: The oral administration of Rd dose dependently attenuated histopathologic changes in the lung, lung edema, pulmonary collagen deposition, protein concentration in bronchoalveolar lavage fluid (BALF), myeloperoxidase (MPO) activity, and inflammatory cell infiltration. In addition, Rd suppressed the LPS-induced inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-6, and IL-1 β in BALF. The productions of oxidative stress-related enzymes (catalase, superoxide dismutase, and glutathione peroxidase) in lung tissue were significantly upregulated by Rd administration. However, malondialdehyde and pulmonary MPO activity was reduced in the Rd-pretreated groups when compared with LPS-induced ALI group. Rd treatment also dose dependently suppressed LPS-induced NF-κB activation and TLR4 expression. Conclusion: Overall, these findings provide evidence that Rd pretreatment inhibits LPS-induced ALI through anti-inflammatory and antioxidative actions, suggesting that it could be a promising protective drug for LPS-induced ALI.

Protective effect of ginsenoside Rd on lipopolysaccharide-induced acute lung injury through its anti-inflammatory and anti-oxidative activity

Background: Inflammation and oxidation stress are key factors in the mechanism of acute lung injury (ALI). Therefore, suppression of the inflammatory response and oxidative stress could be a potential strategy to treat lipopolysaccharide (LPS)-induced ALI. Ginsenoside Rd (Rd), a natural Ginseng extract, alleviates inflammation and oxidative stress in several diseases such as Alzheimer's disease and cerebral ischemia, but its effect on ALI is still unclear. Aims and Objectives: To explore the protective effect of Rd on LPS-induced ALI and explored associated mechanisms. Materials and Methods: Mice were divided into five groups: A sham-operated group, a LPS-induced ALI group, and three LPS groups pretreated with Rd doses of 20, 40, and 80 mg/kg, respectively. The pathological changes of lung, collagen deposition, pulmonary edema, inflammatory cytokine, oxidative stress and the expression levels of TLR4 and NF-κB were detected. Results: The oral administration of Rd dose dependently attenuated histopathologic changes in the lung, lung edema, pulmonary collagen deposition, protein concentration in bronchoalveolar lavage fluid (BALF), myeloperoxidase (MPO) activity, and inflammatory cell infiltration. In addition, Rd suppressed the LPS-induced inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-6, and IL-1 β in BALF. The productions of oxidative stress-related enzymes (catalase, superoxide dismutase, and glutathione peroxidase) in lung tissue were significantly upregulated by Rd administration. However, malondialdehyde and pulmonary MPO activity was reduced in the Rd-pretreated groups when compared with LPS-induced ALI group. Rd treatment also dose dependently suppressed LPS-induced NF-κB activation and TLR4 expression. Conclusion: Overall, these findings provide evidence that Rd pretreatment inhibits LPS-induced ALI through anti-inflammatory and antioxidative actions, suggesting that it could be a promising protective drug for LPS-induced ALI.

Pathogenic role leukotriene B4 in lung injury induced by lung-protective mechanical ventilation in rabbits

To elucidate the pathogenic role of leukotriene B4 (LTB4) in pulmonary hyper-permeability and inflammation induced by lung-protective mechanical ventilation (LPMV) in rabbits. Thirty-two healthy Japanese white rabbits were randomized into 4 groups for treatment with vehicle or bestatin (a leukotriene A4 hydrolase inhibitor that inhibits LTB4 production) administered intragastrically at the daily dose of 8 mg/kg for 5 days, followed by sham operation (group S and group BS, respectively, in which the rabbits were anesthetized only) or LPMV (group PM and group BPM, respectively, in which the rabbits received ventilation with 50% oxygen at a tidal volume of 8 mL/kg for 5 h). The concentrations of LTB4 and cyclic adenosine monophosphate (cAMP) in the lung tissues were analyzed by ELISA. cAMP content, protein kinase A (PKA) protein expression and the Rap1-GTP protein to total Rap1 protein ratio were determined to assess the activities of cAMP/PKA and Rap1 signaling pathways. The lung injury was evaluated by assessing lung permeability index, lung wet/dry weight ratio, polymorphonuclear leukocyte (PMN) count in bronchoalveolar lavage fluid (BALF), pulmonary myeloperoxidase (MPO) activity and lung histological scores. None of the examined parameters differed significantly between group S and group BS. All the parameters with the exception of lung histological score increased significantly in group PM and group BPM as compared to those in group S (P < 0.05). Compared with those in PM group, the rabbits in group BPM showed significantly reduced LTB4 production in the lungs (P < 0.05), up-regulated cAMP/ PKA and Rap1 signaling pathway activities (P < 0.05), and alleviated lung hyper-permeability and inflammation (P < 0.05). LPMV can induce LTB4 overproduction to down-regulate cAMP/PKA and Rap1 signaling pathways in the lungs of rabbits, which results in lung hyper-permeability and inflammation. Bestatin can inhibit LTB4 production in the lungs to protect against LPMV-induced lung hyper-permeability and inflammation.

Recombinant thrombomodulin prevents acute lung injury induced by renal ischemia-reperfusion injury

Acute kidney injury (AKI) complicated by acute lung injury has a detrimental effect on mortality among critically ill patients. Recently, a renal ischemia-reperfusion (IR) model suggested the involvement of histones and neutrophil extracellular traps (NETs) in the development of distant lung injury after renal IR. Given that recombinant thrombomodulin (rTM) has anti-inflammatory roles by binding to circulating histones, we aimed to clarify its effect on distant lung injury induced by AKI in a murine bilateral renal IR model. Both pretreatment and delayed treatment with rTM significantly decreased pulmonary myeloperoxidase activity, but they did not affect renal dysfunction at 24 h after renal IR. Additionally, rTM mitigated the renal IR-augmented expression of proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, and keratinocyte-derived chemokine), and vascular leakage, as well as the degree of lung damage. Intense histone accumulation and active NET formation occurred in both the kidneys and the lungs; however, rTM significantly decreased the histone and NET accumulation only in the lungs. Administration of rTM may have protective impact on the lungs after renal IR by blocking histone and NET accumulation in the lungs, although no protection was observed in the kidneys. Treatment with rTM may be an adjuvant strategy to attenuate distant lung injury complicating AKI.

Protective effect of luteolin on acute lung injury in sepsis mice

Objective To investigate the potential therapeutic effect of luteolin on sepsis-induced ALI and the underlying mechanisms. Methods Total of 50 mice were randomly(random number) divided into five groups: a sham control group, a sepsis-induced ALI group, and three sepsis groups pre-treated with 20, 40, and 80 mg/kg body weight luteolin. Mice in the treatment groups were pre-treated with luteolin at the respective oral dose two days before ALI induction. The lungs were isolated for histopathological examinations, and the bronchoalveolar lavage fluid (BALF) was collected for biochemical analyses. Results Luteolin significantly attenuated sepsis-induced ALI. Additionally, luteolin treatment decreased protein and inflammatory cytokine concentration and the number of infiltrated inflammatory cells in BALF compared with that in the non-treated sepsis mice. Pulmonary myeloperoxidase (MPO) activity was lower in the luteolin-pre-treated sepsis groups than in the sepsis group. The mechanism underlying the protective effect of luteolin on sepsis is related to the up-regulation of certain antioxidation genes, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), superoxide dismutases (SODs), and heme oxygenase 1 (HO-1), and the reduction of inflammatory responses through blockage of the activation of the nuclear factor (NF)-κB pathway. Conclusions Luteolin pre-treatment inhibits sepsis-induced ALI through its anti-inflammatory and antioxidative activity, suggesting that luteolin may be a potential therapeutic agent for sepsis-induced ALI. Key words: Luteolin; Sepsis; COX-2; SODs; iNOS

Sulfur dioxide reduces lipopolysaccharide-induced acute lung injury in rats.

IntroductionRecent studies suggested that sulfur dioxide (SO2) can be produced endogenously by pulmonary vessels and attenuate acute lung injury (ALI) with vasorelaxant effects. This study was conducted to determine whether SO2 can inhibit lung inflammation and relax pulmonary arteries via inhibition of the mitogen-activated protein kinase (MAPK) pathway.Material and methodsForty-eight adult male Sprague Dawley rats (250~300 g) were randomly divided into six treatment groups: control (n = 8), control + SO2 (n = 8), control + L-aspartic acid-β-hydroxamate (HDX) (n = 8), LPS (n = 8), LPS + SO2 (n = 8) and LPS + HDX (n = 8).ResultsSix hours after LPS treatment, rats exhibited elevated pulmonary artery hypertension (PAH), marked pulmonary structure injury with elevated pulmonary myeloperoxidase (MPO) activity and increased expression of intercellular adhesion molecule 1 (ICAM-1) and CD11b, along with decreased pulmonary SO2 production and reduced pulmonary aspartate aminotransferase (AAT) activity. Pretreatment with SO2 saline solution significantly reduced, while HDX (AAT inhibitor) aggravated, the pathogenesis of LPS-induced ALI. Moreover, SO2 saline solution significantly down-regulated expression of Raf-1, MEK-1 and phosphorylated ERK (p-ERK). It also prevented pulmonary hypertension in association with an up-regulated SO2/AAT pathway. However, HDX advanced pulmonary hypertension and inflammatory responses in the lung were associated with a down-regulated SO2/AAT pathway.ConclusionsOur results suggest that SO2 markedly relieved inflammatory responses, in association with Raf-1, MEK-1 and p-ERK during ALI induced by LPS. The down-regulation of the SO2/AAT pathway may be involved in the mechanism(s) of LPS-induced lung injury.

An omega-3 polyunsaturated fatty acid derivative, 18-HEPE, protects against CXCR4-associated melanoma metastasis.

Melanoma has a high propensity to metastasize and exhibits a poor response to classical therapies. Dysregulation of the chemokine receptor gene CXCR4 is associated with melanoma progression, and although n-3 polyunsaturated fatty acids (PUFAs) are known to be beneficial for melanoma prevention, the underlying mechanism of this effect is unclear. Here, we used the n-3 fatty acid desaturase (Fat-1) transgenic mouse model of endogenous n-3 PUFA synthesis to investigate the influence of elevated n-3 PUFA levels in a mouse model of metastatic melanoma. We found that relative to wild-type (WT) mice, Fat-1 mice exhibited fewer pulmonary metastatic colonies and improved inflammatory indices, including reduced serum tumor necrosis factor alpha (TNF-α) levels and pulmonary myeloperoxidase activity. Differential PUFA metabolites in serum were considered a key factor to alter cancer cell travelling to lung, and we found that n-6 PUFAs such as arachidonic acid induced CXCR4 protein expression although n-3 PUFAs such as eicosapentaenoic acid (EPA) decreased CXCR4 levels. In addition, serum levels of the bioactive EPA metabolite, 18-HEPE, were elevated in Fat-1 mice relative to WT mice, and 18-HEPE suppressed CXCR4 expression in B16-F0 cells. Moreover, relative to controls, numbers of pulmonary metastatic colonies were reduced in WT mice receiving intravenous injections either of 18-HEPE or 18-HEPE-pretreated melanoma cells. Our results indicate that 18-HEPE is a potential anticancer metabolite that mediates, at least in part, the preventive effect of n-3 PUFA on melanoma metastasis.

Protective Effect of 2-Hydroxymethyl Anthraquinone from Hedyotis diffusa Willd in Lipopolysaccharide-Induced Acute Lung Injury Mediated by TLR4-NF-κB Pathway.

Chronic inflammation and oxidant/antioxidant imbalance play a prominent role in inflammatory lung diseases. 2-Hydroxymethyl anthraquinone (HMA), an anthraquinone derivative found in Hedyotis diffusa Willd, has been reported to have broad-spectrum anti-inflammatory effects; the present study was conducted to investigate the protective effect of HMA in LPS-induced acute lung injury (ALI) and to explore its potential molecular mechanisms. The results showed that HMA remarkably attenuated LPS-induced pulmonary edema, myeloperoxidase activity, and inflammatory cytokine production. Besides, HMA showed significant antioxidative activity; it raised the levels of SOD and GSH and depleted the MDA level in serum of ALI mice. In vitro, HMA suppressed the production NO, TGF-β1, TNF-α, IL-6, and IL-1β in LPS-stimulated RAW 264.7 macrophage cells. The western blot analysis showed that TLR4 expression and the activation of NF-κB were antagonized by HMA. Moreover, addition of exogenous NF-κB inhibitor BAY11-7082 weakened the inhibitory effects of HMA in inflammatory cytokines and ROS production. Taken together, these findings provide the first experimental evidence supporting that HMA has protective effects on LPS-induced inflammation, which is mediated by TLR4-NF-κB pathway.

Linarin prevents LPS‑induced acute lung injury by suppressing oxidative stress and inflammation via inhibition of TXNIP/NLRP3 and NF‑κB pathways.

Acute lung injury (ALI) is an important cause of morbidity and mortality for critically ill patients, and linarin (LR) may be a potential treatment for ALI as it reportedly has antioxidant, anti-inflammatory and apoptotic-regulating activity. In the present study, the authors report that saline and LR (12.5, 25 and 50 mg/kg) were applied to male C57BL/6 mice via gavage. Then, mice were intratracheally injected with either saline or lipopolysaccharide (LPS). LR-pretreatment attenuated LPS-induced ALI and platelet activation and reduced CD41 expression levels and neutrophil platelet aggregates. Additionally, LPS-triggered pulmonary myeloperoxidase activity and neutrophil infiltration in lung tissues, and this was eliminated by LR dose-dependently. Furthermore, LPS-induced oxidative stress and pro-inflammatory cytokine release were downregulated by LR by inhibiting thioredoxin-interacting protein and nuclear factor-κB signaling pathways, including their downstream and upstream signals, such as xanthine oxidase, NLR family WHAT, pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), caspase-1, IκB kinase-α (IKK-α) and IκBα. Moreover, in LPS-induced mice, the mitogen-activated protein kinase pathway was inactivated by LR. In vitro, LR reduced LPS-induced inflammation and oxidative stress, which was linked to reduction of ROS. In conclusion, LR pretreatment may be protective against LPS-induced ALI.

Protective effect of acacetin on sepsis-induced acute lung injury via its anti-inflammatory and antioxidative activity

Sepsis is a clinical syndrome with no effective protective or therapeutic treatments. Acacetin, a natural flavonoid compound, has anti-oxidative and anti-inflammatory effects which can potentially work to reduce sepsis. We investigated the potential protective effect of acacetin on sepsis-induced acute lung injury (ALI) ALI and dissect out the underlying mechanisms. Mice were divided into five groups: a sham group, a sepsis-induced ALI group, and three sepsis groups pre-treated with 20, 40, and 80 mg/kg body weight of acacetin. We found that acacetin significantly attenuated sepsis-induced ALI, in histological examinations and lung edema. Additionally, acacetin treatment decreased protein and inflammatory cytokine concentration and the number of infiltrated inflammatory cells in BALF compared with that in the non-treated sepsis mice. Pulmonary myeloperoxidase (MPO) activity was lower in the acacetin-pre-treated sepsis groups than in the sepsis group. The mechanism underlying the protective effect of acacetin on sepsis is related to the regulation of certain antioxidation genes, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), superoxide dismutases (SODs), and heme oxygenase 1 (HO-1).Taken together, our results indicate that acacetin pre-treatment inhibits sepsis-induced ALI through its anti-inflammatory and antioxidative activity, suggesting that acacetin may be a potential protective agent for sepsis-induced ALI.