phenanthrenes and Acute-Lung-Injury

Dihydrotanshinone (DIH) is an extract of Salvia miltiorrhiza Bunge. It has been reported that DIH could regulate NF-κB signaling pathway. The aim of this study was to investigate whether DIH could protect mice from lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. In this study, sixty mice were randomly divided into five groups, one group as blank control group, the second group as LPS control group, and the last three groups were pre-injected with different doses of DIH and then inhaled LPS for experimental comparison. After 12 h of LPS treatment, the wet-dry ratio, histopathlogical changes, and myeloperoxidase (MPO) activity of lungs were measured. In addition, ELISA kits were used to measure the levels of TNF-α and IL-1β inflammatory cytokines in bronchoalveolar lavage fluids (BALF), and western blot analysis was used to measure the activity of NF-κB signaling pathway. The results demonstrated that DIH could effectively reduce pulmonary edema, MPO activity, and improve the lung histopathlogical changes. Furthermore, DIH suppressed the levels of inflammatory cytokines in BALF, such as TNF-α and IL-1β. In addition, DIH could also downregulate the activity of NF-κB signaling pathway. We also found that DIH dose-dependently increased the expression of LXRα. In addition, DIH could inhibit LPS-induced IL-8 production and NF-κB activation in A549 cells. And the inhibitory effects were reversed by LXRα inhibitor geranylgeranyl pyrophosphate (GGPP). Therefore, we speculate that DIH regulates LPS-induced ALI in mice by increasing LXRα expression, which subsequently inhibiting NF-κB signaling pathway.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Biomarkers; Furans; Lipopolysaccharides; Liver X Receptors; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Phenanthrenes; Plant Extracts; Quinones; Random Allocation; Signal Transduction; Up-Regulation

Chlorine is a commonly used, reactive compound to which humans can be exposed via accidental or intentional release resulting in acute lung injury. Formulations of rolipram (a phosphodiesterase inhibitor), triptolide (a natural plant product with anti-inflammatory properties), and budesonide (a corticosteroid), either neat or in conjunction with poly(lactic:glycolic acid) (PLGA), were developed for treatment of chlorine-induced acute lung injury by intramuscular injection. Formulations were produced by spray-drying, which generated generally spherical microparticles that were suitable for intramuscular injection. Multiple parameters were varied to produce formulations with a wide range of in vitro release kinetics. Testing of selected formulations in chlorine-exposed mice demonstrated efficacy against key aspects of acute lung injury. The results show the feasibility of developing microencapsulated formulations that could be used to treat chlorine-induced acute lung injury by intramuscular injection, which represents a preferred route of administration in a mass casualty situation.

Topics: Acute Lung Injury; Animals; Budesonide; Chemistry, Pharmaceutical; Chlorine; Diterpenes; Drug Carriers; Drug Discovery; Drug Liberation; Epoxy Compounds; Inhalation Exposure; Injections, Intramuscular; Male; Mice, Inbred Strains; Microscopy, Electron, Scanning; Phenanthrenes; Rolipram; Surface Properties

Crytotanshinone (CTN), one of the main constituents of tanshinones, has been reported to exhibit anti-tumor, anti-inflammatory and other important therapeutic activities. The aim of this study was to investigate the potential therapeutic effects of CTN on murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Male BALB/c mice were pretreated with dexamethasone or CTN 1h before intranasal instillation of LPS. Seven hours after LPS administration, the myeloperoxidase (MPO) in lung tissues, lung wet/dry weight ratio and inflammatory cells in the bronchoalveolar lavage fluid (BALF) were determined. The effects of CTN on pro-inflammatory cytokines and signaling pathways were analyzed by enzyme-linked immunosorbent assay (ELISA) and Western blot. The results showed that CTN significantly inhibited LPS induced increases of macrophages and neutrophils infiltration of lung tissues, as well as markedly attenuated MPO activity. Furthermore, CTN significantly reduced the wet/dry weight ratio of lungs and the concentrations of TNF-α, IL-6 and IL-1β in BALF. Compared with LPS group, lung histopathologic changes were less pronounced in the CTN pretreated mice. Additionally, western blotting showed that CTN efficiently inhibited the phosphorylation of IκB-α, p65 NF-κB and the expression of TLR4. Taken together, our results suggest that the anti-inflammatory effects of CTN against LPS-induced acute lung injury may be due to its ability to inhibit TLR4 mediated NF-κB signaling pathways. CTN may be a promising potential therapeutic reagent for ALI treatment.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Cell Count; Cytokines; Lipopolysaccharides; Lung; Macrophages; Male; Mice; Mice, Inbred BALB C; Neutrophils; NF-kappa B; Phenanthrenes; Protective Agents; Toll-Like Receptor 4

Triptolide is one of the main active components of Chinese herb Tripterygium wilfordii Hook F, which has been demonstrated to have anti-inflammatory properties. The aim of this study was to investigate the effects of triptolide on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and to clarify the possible mechanisms. Mice were administered intranasally with LPS to induce lung injury. Triptolide was administered intraperitoneally 1 h before LPS challenge. Triptolide-treated mice exhibited significantly reduced leukocyte, myeloperoxidase (MPO) activity, edema of the lung, as well as TNF-α, IL-1β, and IL-6 production in the bronchoalveolar lavage fluid compared with LPS-treated mice. Additionally, Western blot analysis showed that triptolide inhibited the phosphorylation of inhibitor-kappa B kinase-alpha (IκB-α), p65, nuclear factor kappa B (NF-κB), p38, extracellular receptor kinase (ERK), and Jun N-terminal kinase (JNK) and the expression of Toll-like receptor 4 (TLR4) caused by LPS. In conclusion, our results suggested that the promising anti-inflammatory mechanism of triptolide may be that triptolide activates peroxisome proliferation-activated receptor gamma (PPAR-γ), thereby attenuating an LPS-induced inflammatory response. Triptolide may be a promising potential therapeutic reagent for ALI treatment.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Diterpenes; Epoxy Compounds; Interleukin-1beta; Interleukin-6; Leukocytes; Ligands; Lipopolysaccharides; Male; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; NF-kappa B; Peroxidase; Phenanthrenes; Plant Extracts; PPAR gamma; Tripterygium; Tumor Necrosis Factor-alpha

Triptolide is one of the main active components in the Chinese herb Tripterygium wilfordii Hook F, which has been demonstrated to possess anti‑inflammatory properties. The aim of this study was to investigate the effects of triptolide on lipopolysaccharide (LPS)‑induced acute lung injury (ALI) in mice and to explore the possible mechanisms. Mice were administered LPS intranasally to induce lung injury, and triptolide was administered intraperitoneally 1 h prior to the LPS challenge. Triptolide‑treated mice exhibited significantly reduced levels of leukocytes, myeloperoxidase activity and edema of the lung, as well as tumour necrosis factor‑α, interleukin (IL)‑1β and IL‑6 production in the bronchoalveolar lavage fluid compared with LPS‑treated mice. Additionally, western blot analysis showed that triptolide inhibited the LPS‑induced phosphorylation of nuclear factor of κ light polypeptide gene enhancer in B cells inhibitor‑α and nuclear factor κ‑light‑chain‑enhancer of activated B cells‑p65 (NF‑κB p65) and the expression of Toll‑like receptor 4 (TLR4). In conclusion, the results from the present study suggest that the anti‑inflammatory effect of triptolide against LPS‑induced ALI may be due to its ability to inhibit the TLR4‑mediated NF‑κB signalling pathway. Triptolide may therefore be a promising potential therapeutic agent for ALI treatment, which may ultimately aid the clinical therapy for patients with ALI.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bronchoalveolar Lavage Fluid; Chemokines; Disease Models, Animal; Diterpenes; Epoxy Compounds; I-kappa B Proteins; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; NF-kappa B; NF-KappaB Inhibitor alpha; Phenanthrenes; Phosphorylation; Signal Transduction; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the effect of triptolide on ATP‑binding cassette transporter A1 (ABCA1) expression in lipopolysaccharide (LPS)‑induced acute lung injury (ALI) in rats. Thirty male Sprague Dawley rats weighing 200‑250 g were randomly divided into six groups: Normal (N, n=5), Control (C, n=5), LPS (L, n=5), Triptolide 25 µg (TP1, n=5), Triptolide 50 µg (TP2, n=5) and Triptolide 100 µg (TP3, n=5). The N group was not administered anything; the C group was administered 5 ml/kg normal saline intravenously and 7.5 ml/kg 1% dimethylsulfoxide (DMSO) intraperitoneally; the L group was administered 5 mg/kg 0.1% LPS and 1% DMSO; and the TP1, TP2 and TP3 groups were separately injected with 0.1% LPS and 25, 50 or 100 µg/kg triptolide, respectively. All groups had the same liquid‑injection volume. Arterial blood gases, tumor necrosis factor‑α (TNF‑α) and ABCA1 expression and general pathology were examined following the treatments. It was found that increasing the triptolide dose in the TP1‑3 groups resulted in an increase in the expression of ABCA1 mRNA and protein. As compared with the L group, the ABCA1 expression showed a significant increase in TP2 and TP3 groups (P<0.05). In addition, the expression level of TNF‑α was significantly increased in the L and TP1 groups, as compared with that in the N or C groups (P<0.05). Conversely, a marked decrease in TNF‑α expression was detected in the TP2 and TP3 groups, as compared with the L or TP1 groups (P<0.05). In conclusion, this study found that triptolide could promote the expression of ABCA1 mRNA and protein and inhibit other inflammatory factors during LPS‑induced ALI in rats. Regulating the expression of ABCA1 may be one of the protective mechanisms of triptolide. Furthermore, triptolide‑induced increases in ABCA1 expression occurred in a dose‑dependent manner between 25 and 100 µg/kg.

Topics: Acute Lung Injury; Animals; ATP Binding Cassette Transporter 1; Diterpenes; Epoxy Compounds; Lipopolysaccharides; Lung; Male; Phenanthrenes; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tumor Necrosis Factor-alpha

Acute lung injury (ALI) is a serious clinical syndrome with a high rate of mortality. In this study, the effects of triptolide on lipopolysaccharide (LPS)-induced ALI in rats were investigated.. Sixty-five male Sprague Dawley rats(approved by ethics committee of the First Affiliated Hospital of Soochow University) were randomly divided into five groups. The control group was injected with 2.5 mL saline/kg body weight via the tail vein and intraperitoneally with 1% dimethyl sulfoxide (DMSO) (n = 5). The L group was administered with 0.2% LPS dissolved in saline (5 mg/kg) to induce ALI via the tail vein (n = 15). The TP1, TP2, and TP3 groups were treated as rats in the L group and then intraperitoneally injected with 25, 50, and 100 μg triptolide/kg body weight, respectively (15 rats per group). Blood samples from the left heart artery were taken for blood gas analysis at 1 hour before injection and at 1, 3, 6, and 12 hours after saline and DMSO administration in the control group, LPS injection in the L group, and triptolide injection in the TP1, TP2, and TP3 groups. Lung wet-to-dry weight (W/D) ratio, diffuse alveolar damage (DAD) score, TNF-α levels, and mRNA and protein expression of toll-like receptor 4 (TLR4) were analyzed.. Compared with the control group, the arterial partial pressure of oxygen (PaO2) declined (P <0.05), the W/D ratio and DAD score increased (P <0.05), and TNF-α levels in serum and bronchoalveolar lavage fluid (BALF) and mRNA and protein expression of TLR4 were significantly increased in the L group (P <0.05). Compared with the L group, PaO2 significantly increased in the TP2 and TP3 groups (P <0.05), while the W/D ratio and DAD score were significantly decreased in the TP2 and TP3 groups (P <0.05). TNF-α levels and mRNA and protein expression of TLR4 were significantly decreased in the TP2 and TP3 groups compared with the L group (P <0.05).. Triptolide can ameliorate LPS-induced ALI by reducing the release of the inflammatory mediator TNF-α and inhibiting TLR4 expression.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Carbon Dioxide; Diterpenes; Epoxy Compounds; Gene Expression Regulation; Hydrogen-Ion Concentration; Lipopolysaccharides; Male; Organ Size; Oxygen; Partial Pressure; Phenanthrenes; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; RNA, Messenger; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Poly(ADP-ribose) polymerase (PARP) is well known to be an enzyme that repairs damaged DNA and also induces cell death when overactivated. It has been reported that PARP plays a significant role in burn and smoke inhalation injury, and the pathophysiology is thought to be localized in the airway during early stages of activation. Therefore, we hypothesized that local inhibition of PARP in the airway by direct delivery of low dose PJ-34 [poly(ADP-ribose) polymerase inhibitor] into the bronchial artery would attenuate burn and smoke-induced acute lung injury. The bronchial artery in sheep was cannulated in preparation for surgery. After a 5-7 day recovery period, sheep were administered a burn and inhalation injury. Adult female sheep (n=19) were divided into four groups following the injury: (1) PJ-34 group A: 1h post-injury, PJ-34 (0.003mg/kg/h, 2mL/h) was continuously injected into the bronchial artery, n=5; (2) PJ-34 group B: 1h post-injury, PJ-34 (0.03mg/kg/h, 2mL/h) was continuously injected into bronchial artery, n=4; (3) CONTROL GROUP: 1h post-injury, an equivalent amount of saline was injected into the bronchial artery, n=5; (4) Sham group: no injury, no treatment, same operation and anesthesia, n=5. After injury, all animals were placed on a ventilator and fluid resuscitated equally. Pulmonary function as evaluated by measurement of blood gas analysis, pulmonary mechanics, and pulmonary transvascular fluid flux was severely deteriorated in the control group. However, the above changes were markedly attenuated by PJ-34 infusion into the bronchial artery (P/F ratio at 24h: PJ-34 group A 398±40*, PJ-34 group B 438±41*†‡, Control 365±58*, Sham 547±47; * vs. sham [p<0.05], † vs. control [p<0.05], ‡ vs. PJ-34 group A [p<0.05]). Our data strongly suggest that local airway production of poly(ADP-ribose) polymerase contributes to pulmonary dysfunction following smoke inhalation and burn.

Topics: Acute Lung Injury; Animals; Bronchial Arteries; Burns; Disease Models, Animal; Enzyme Inhibitors; Female; Lung; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Respiratory Function Tests; Sheep; Smoke Inhalation Injury

Tanshinone IIA (TIIA) is one of the main active components from Chinese herb danshen. Previous reports showed that TIIA reduced the production of pro-inflammatory mediators stimulated with lipopolysaccharide (LPS). However, the effects of TIIA on LPS-induced acute lung injury are not fully understood. Here, we observed the effects of TIIA on mortality and lung injury in LPS-treated mice and on LPS-induced pulmonary epithelial cell injury, and further studied the underlying mechanism. As revealed by survival study, pretreatment with TIIA reduced mortality of mice and prolonged their survival time. Meanwhile, TIIA pretreatment significantly improved LPS-induced lung histopathologic changes, decreased lung wet-to-dry and lung-to-body weight ratios, inhibited lung myeloperoxidase activity and reduced protein leakage. TIIA also alleviated LPS-induced pulmonary epithelial cell injury, as proved by methyl thiazolyl tetrazolium (MTT) and lactic dehydrogenase assay. Furthermore, TIIA suppressed LPS-induced phospholipase A2 (PLA2) activity in both lung homogenate and bronchoalveolar lavage fluid. TIIA also inhibited the metabolites of PLA2, which was confirmed by results of thromboxane B2, prostaglandin E2 and leukotriene B4 detection. Besides, TIIA in vitro inhibited LPS-induced PLA2 activity in a dose-dependent manner. Western blotting showed that TIIA markedly inhibited the activation of nuclear factor kappa B (NF-kappaB) in LPS-treated mice. Taken together, these data firstly provided the novel information that the protective role of TIIA against LPS-induced lung injury may attribute partly to the inhibition of PLA2 activity and NF-kappaB activation.

Topics: Abietanes; Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Epithelial Cells; Female; Lipopolysaccharides; Lung; Mice; NF-kappa B; Phenanthrenes; Phospholipase A2 Inhibitors; Survival Rate