Miaomiao Wei

Effects of a Natural Prolyl Oligopeptidase Inhibitor, Rosmarinic Acid, on Lipopolysaccharide-Induced Acute Lung Injury in Mice

Rosmarinic acid (RA), a polyphenolic phytochemical, is a natural prolyl oligopeptidase inhibitor. In the present study, we found that RA exerted potent anti-inflammatory effects in in vivo models of acute lung injury (ALI) induced by lipopolysaccharide (LPS). Mice were pretreated with RA one hour before challenge with a dose of 0.5 mg/kg LPS. Twenty-four hours after LPS was given, bronchoalveolar lavage fluid (BALF) was obtained to measure pro-inflammatory mediator and total cell counts. RA significantly decreased the production of LPS-induced TNF-α, IL-6, and IL-1β compare with the LPS group. When pretreated with RA (5, 10, or 20 mg/kg) the lung wet-to-dry weight (W/D) ratio of the lung tissue and the number of total cells, neutrophils and macrophages in the BALF were decreased significantly. Furthermore, RA may enhance oxidase dimutase (SOD) activity during the inflammatory response to LPS-induced ALI. And we further demonstrated that RA exerts anti-inflammation effect in vivo models of ALI through suppresses ERK/MAPK signaling in a dose dependent manner. These studies have important implications for RA administration as a potential treatment for ALI.

Licochalcone a inhibits lipopolysaccharide-induced inflammatory response in vitro and in vivo.

Licochalcone A (Lico A), a flavonoid found in licorice root (Glycyrrhiza glabra), is known for its antimicrobial activity and its reported ability to inhibit cancer cell proliferation. In the present study, we found that Lico A exerted potent anti-inflammatory effects in in vitro and in vivo models induced by lipopolysaccharide (LPS). The concentrations of TNF-α, interleukin (IL)-6, and IL-1β in the culture supernatants of RAW 264.7 cells were determined at different time points following LPS administration. LPS (0.5 mg/kg) was instilled intranasally (i.n.) in phosphate-buffered saline to induce acute lung injury, and 24 h after LPS was given, bronchoalveolar lavage fluid was obtained to measure pro-inflammatory mediator and total cell counts. The phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) p65 protein was analyzed by Western blotting. Our results showed that Lico A significantly reduced the amount of inflammatory cells, the lung wet-to-dry weight (W/D) ratio, protein leakage, and myeloperoxidase activity and enhances oxidase dimutase activity in mice with LPS-induced acute lung injury (ALI). Enzyme-linked immunosorbent assay results indicated that Lico A can significantly down-regulate TNF-α, IL-6, and IL-1β levels in vitro and in vivo, and treatment with Lico A significantly attenuated alveolar wall thickening, alveolar hemorrhage, interstitial edema, and inflammatory cells infiltration in mice with ALI. In addition, we further demonstrated that Lico A exerts an anti-inflammation effect in an in vivo model of acute lung injury through suppression of NF-κB activation and p38/ERK MAPK signaling in a dose-dependent manner.

Astragalin attenuates lipopolysaccharide-induced inflammatory responses by down-regulating NF-κB signaling pathway.

Astragalin (AG), a flavonoid from many traditional herbs and medicinal plants, has been described to exhibit in vitro anti-inflammatory activity. The present study aimed to determine the protective effects and the underlying mechanisms of astragalin on lipopolysaccharide-induced endotoxemia and lung injury in mice. Mice were injected intraperitoneally (i.p.) with lipopolysaccharide (LPS) (dose range: 5-40 mg/kg). We observed mice on mortality for 7 days twice a day and recorded survival rates. In drug testing, we examined the therapeutic effects of astragalin (25, 50 or 75 mg/kg) on LPS- induced endotoxemia by dosing orally astragalin 1 hour before LPS challenge. Using an experimental model of LPS-induced acute lung injury (ALI), we examined the effect of astragalin in resolving lung injury. The investigations revealed that pretreatment with astragalin can improve survival during lethal endotoxemia and attenuate inflammatory responses in a murine model of lipopolysaccharide-induced acute lung injury. The mechanisms by which Astragalin exerts its anti-inflammatory effect are correlated with inhibition of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) production via inactivation of NF-κB.

In vitro and in vivo protection provided by pinocembrin against lipopolysaccharide-induced inflammatory responses

Pinocembrin or 5, 7-dihydroxyflavanone is a flavanone, a type of flavonoid. In the present study, we first assessed the anti-inflammatory effects of pinocembrin in RAW macrophage cells; and based on these effects, we investigated the therapeutic effects of pinocembrin in murine model of endotoxin-induced acute lung injury. We found that in vitro pretreatment with pinocembrin remarkably regulated the production of TNF-α, IL-1β, IL-6 and IL-10 via inhibiting the phosphorylation of IκBα, ERK1/2, JNK and p38MAPK. In the mouse model of LPS-induced acute lung injury, pinocembrin (20 or 50 mg/kg, i.p.) attenuated the development of pulmonary edema, histological severities, as well as neutrophil, lymphocyte and macrophage infiltration, which were increased by LPS administration. Additionally, TNF-α, IL-1β and IL-6 concentrations decreased significantly while the concentration of IL-10 was significantly increased after pinocembrin pretreatment. Our results also showed that pinocembrin attenuated LPS-induced lung injury through suppression of IκBα, JNK and p38MAPK activation. These findings suggest that pinocembrin may represent a novel candidate for the modulation of inflammatory responses.

Zingerone attenuates lipopolysaccharide-induced acute lung injury in mice

Zingerone, one of the active components of ginger, is a phenolic alkanone with antioxidant and anti-inflammatory properties. In the present study, we analyzed the role of zingerone against RAW 264.7 cells and acute lung injury induced by lipopolysaccharide (LPS) in mice. RAW cells or BALB/c mice were pretreated with zingerone one hour before stimulated with LPS. We found that zingerone significantly inhibited the production of LPS-induced proinflammatory cytokines in vitro and in vivo. When pretreated with zingerone, pulmonary histopathologic changes, as well as alveolar hemorrhage and neutrophil infiltration were substantially suppressed in lung tissues, with evidence of reduced myeloperoxidase (MPO) activity in murine acute lung injury model. The lung wet-to-dry weight (W/D) ratios, as the index of pulmonary edema, were markedly decreased by zingerone pretreatment. Furthermore, we demonstrated that zingerone attenuates the mitogen-activated protein kinases (MAPK) and nuclear factor-kappaB (NF-κB) signaling pathways through blocking the phosphorylation of ERK, p38/MAPK and IκBα, NF-κB/P65. These results suggest that zingerone may provide protective effects against LPS-induced ALI.

Different effects of farrerol on an OVA-induced allergic asthma and LPS-induced acute lung injury.

Background Farrerol, isolated from rhododendron, has been shown to have the anti-bacterial activity, but no details on the anti-inflammatory activity. We further evaluated the effects of this compound in two experimental models of lung diseases. Methodology/Principal Findings For the asthma model, female BALB/c mice were challenged with ovalbumin (OVA), and then treated daily with farrerol (20 and 40 mg/kg, ip) as a therapeutic treatment from day 22 to day 26 post immunization. To induce acute lung injury, female BALB/c mice were injected intranasally with LPS and treated with farrerol (20 and 40 mg/kg, i.p.) 1 h prior to LPS stimulation. Inflammation in the two different models was determined using ELISA, histology, real-time PCR and western blot. Farrerol significantly regulated the phenotype challenged by OVA, like cell number, Th1 and Th2 cytokines levels in the BALF, the OVA-specific IgE level in the serum, goblet cell hyperplasia in the airway, airway hyperresponsiveness to inhaled methacholine and mRNA expression of chemokines and their receptors. Furthermore, farrerol markedly attenuated the activation of phosphorylation of Akt and nuclear factor-κB (NF-κB) subunit p65 both in vivo and in vitro. However, farrerol has no effect on the acute lung injury model. Conclusion/Significance Our finding demonstrates that the distinct anti-inflammatory effect of farrerol in the treatment of asthma acts by inhibiting the PI3K and NF-κB pathway.

Phillyrin attenuates LPS-induced pulmonary inflammation via suppression of MAPK and NF-κB activation in acute lung injury mice.

Phillyrin (Phil) is one of the main chemical constituents of Forsythia suspensa (Thunb.), which has shown to be an important traditional Chinese medicine. We tested the hypothesis that Phil modulates pulmonary inflammation in an ALI model induced by LPS. Male BALB/c mice were pretreated with or without Phil before respiratory administration with LPS, and pretreated with dexamethasone as a control. Cytokine release (TNF-α, IL-1β, and IL-6) and amounts of inflammatory cell in bronchoalveolar lavage fluid (BALF) were detected by ELISA and cell counting separately. Pathologic changes, including neutrophil infiltration, interstitial edema, hemorrhage, hyaline membrane formation, necrosis, and congestion during acute lung injury in mice were evaluated via pathological section with HE staining. To further investigate the mechanism of Phil anti-inflammatory effects, activation of MAPK and NF-κB pathways was tested by western blot assay. Phil pretreatment significantly attenuated LPS-induced pulmonary histopathologic changes, alveolar hemorrhage, and neutrophil infiltration. The lung wet-to-dry weight ratios, as the index of pulmonary edema, were markedly decreased by Phil pretreatment. In addition, Phil decreased the production of the proinflammatory cytokines including (TNF-α, IL-1β, and IL-6) and the concentration of myeloperoxidase (MPO) in lung tissues. Phil pretreatment also significantly suppressed LPS-induced activation of MAPK and NF-κB pathways in lung tissues. Taken together, the results suggest that Phil may have a protective effect on LPS-induced ALI, and it potentially contributes to the suppression of the activation of MAPK and NF-κB pathways. Phil may be a new preventive agent of ALI in the clinical setting.

A Novel Anti-Inflammatory Role for Ginkgolide B in Asthma via Inhibition of the ERK/MAPK Signaling Pathway

Ginkgolide B is an anti-inflammatory extract of Ginkgo biloba and has been used therapeutically. It is a known inhibitor of platelet activating factor (PAF), which is important in the pathogenesis of asthma. Here, a non-infectious mouse model of asthma is used to evaluate the anti-inflammatory capacity of ginkgolide B (GKB) and characterize the interaction of GKB with the mitogen activated protein kinase (MAPK) pathway. BALB/c mice that were sensitized and challenged to ovalbumin (OVA) were treated with GKB (40 mg/kg) one hour before they were challenged with OVA. Our study demonstrated that GKB may effectively inhibit the increase of T-helper 2 cytokines, such as interleukin (IL)-5 and IL-13 in bronchoalveolar lavage fluid (BALF). Furthermore, the eosinophil count in BALF significantly decreased after treatment of GKB when compared with the OVA-challenged group. Histological studies demonstrated that GKB substantially inhibited OVA-induced eosinophilia in lung tissue and mucus hyper-secretion by goblet cells in the airway. These results suggest that ginkgolide B may be useful for the treatment of asthma and its efficacy is related to suppression of extracellular regulating kinase/MAPK pathway.

Hesperidin Suppresses Ovalbumin-Induced Airway Inflammation in a Mouse Allergic Asthma Model

Hesperidin, a flavanone glycoside comprised of the flavanone hesperetin and the disaccharide rutinose, is a plentiful and inexpensive by-product of citrus cultivation. It has been reported to exert a wide range of pharmacological effects that include antioxidant, anti-inflammatory, and anticarcinogenic properties. In this study, we attempt to determine whether hesperidin inhibits inflammatory mediators in the mouse allergic asthma model. Mice were sensitized and challenged by ovalbumin (OVA) to induce chronic airway inflammation and airway remodeling. The administration of hesperidin significantly decreased the number of infiltrating inflammatory cells and Th2 cytokines in bronchoalveolar lavage (BAL) fluid compared with the OVA-induced group of mice. In addition, hesperidin reduced OVA-specific IgE levels in serum. Hesperidin markedly alleviated the OVA-induced airway hyperresponsiveness (AHR) to inhaled methacholine. Based on lung histopathological studies using hematoxylin and eosin and alcian blue-periodic acid-Schiff staining, hesperidin inhibited inflammatory cell infiltration and mucus hypersecretion compared with the OVA-induced group of mice. These findings provide new insight into the immunopharmacological role of hesperidin in terms of its effects in a murine model of asthma.

Effects of an anthraquinone derivative from Rheum officinale Baill, emodin, on airway responses in a murine model of asthma

Emodin is a component from traditional Chinese herbal medicines. We focused on investigating whether emodin possesses distinct anti-inflammatory activity on a non-infectious mouse model of asthma, and we aimed to elucidate its involvement with the NF-κB pathway. BALB/c mice that were sensitized and challenged to ovalbumin were treated with emodin (40 mg/kg) 1h before they were challenged with OVA. Our study demonstrated that emodin inhibited OVA-induced increases in eosinophil count; interleukin (IL)-4, IL-5, and IL-13 levels were recovered in bronchoalveolar lavage fluid and reduced serum levels of OVA-specific IgE, IgG, and IgG1. Histological studies demonstrated that emodin substantially inhibited OVA-induced eosinophilia in lung tissue and mucus hyper-secretion by goblet cells in the airway. Furthermore, pretreatment with emodin resulted in a significant reduction in mRNA expression of acidic mammalian chitinase (AMCase), chitinase 3-like protein 4 (Ym2) and Muc5ac in lung tissues and airway hyperresponsiveness to methacholine. These findings suggest that emodin may effectively delay the progression of airway inflammation and could be used as a therapy for patients with allergic airway inflammation.