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      Antitussive Activity of Pseudostellaria heterophylla (Miq.) Pax Extracts and Improvement in Lung Function via Adjustment of Multi-Cytokine Levels

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          Abstract

          Pseudostellaria heterophylla (Miq.) Pax is one of the most widespread herbal and healthcare products in China. Extensive clinical use has shown that it has functions which “strengthens qi and generates saliva, moistens the lung and relieves cough”. The ethyl acetate fraction extracted from the roots of the plant Pseudostellaria heterophylla exhibited a dose-dependent antitussive effect between 100 to 500 mg/kg. At a dose of 400 mg/kg, the ethyl acetate fraction treatment markedly prolonged the cough latent period and reduced the number of coughs in a guinea pig model induced by citric acid. Fall lung airway resistance, rise in dynamic lung compliance, decreased serum levels of IL-8, GM-CSF, TNF-α, and ET-1 in rat model of stable phase chronic obstructive pulmonary disease induced by cigarette smoke exposure were also observed. These results suggest that ethyl acetate fraction has antitussive activity related to its improvement in lung function via attenuation of airway inflammation by adjustment of multi-cytokine levels.

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          Neutrophil serine proteases fine-tune the inflammatory response.

          Neutrophil serine proteases are granule-associated enzymes known mainly for their function in the intracellular killing of pathogens. Their extracellular release upon neutrophil activation is traditionally regarded as the primary reason for tissue damage at the sites of inflammation. However, studies over the past several years indicate that neutrophil serine proteases may also be key regulators of the inflammatory response. Neutrophil serine proteases specifically process and release chemokines, cytokines, and growth factors, thus modulating their biological activity. In addition, neutrophil serine proteases activate and shed specific cell surface receptors, which can ultimately prolong or terminate cytokine-induced responses. Moreover, it has been proposed that these proteases can impact cell viability through their caspase-like activity and initiate the adaptive immune response by directly activating lymphocytes. In summary, these studies point to neutrophil serine proteases as versatile mediators that fine-tune the local immune response and identify them as potential targets for therapeutic interventions.
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            Neutralizing granulocyte/macrophage colony-stimulating factor inhibits cigarette smoke-induced lung inflammation.

            Cigarette smoke is the major cause of chronic obstructive pulmonary disease (COPD), and there is currently no satisfactory therapy to treat people with COPD. We have previously shown that granulocyte/macrophage colony-stimulating factor (GM-CSF) regulates lung innate immunity to LPS through Akt/Erk activation of nuclear factor-kappaB and activator protein (AP)-1. The aim of this study was to determine whether neutralization of GM-CSF can inhibit cigarette smoke-induced lung inflammation in vivo. Male BALB/c mice were exposed to cigarette smoke generated from 9 cigarettes per day for 4 days. Mice were treated intranasally with 100 microg 22E9 (anti-GM-CSF mAb) and isotype control antibody on Days 2 and 4, 1 hour before cigarette smoke or sham exposure. On the fifth day mice were killed, and the lungs were lavaged with PBS and then harvested for genomic and proteomic analysis. Cigarette smoke-exposed mice treated with anti-GM-CSF mAb had significantly less BALF macrophages and neutrophils, whole lung TNF-alpha, macrophage inflammatory protein (MIP)-2, and matrix metalloproteinase (MMP)-12 mRNA expression and lost less weight compared with smoke-exposed mice treated with isotype control. In contrast, smoke-induced increases in MMP-9 and net gelatinase activity were unaffected by treatment with anti-GM-CSF. In addition, neutralization of GM-CSF did not affect the phagocytic function of alveolar macrophages. GM-CSF is a key mediator in smoke-induced airways inflammation, and its neutralization may have therapeutic implications in diseases such as COPD.
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              Baicalin attenuates inflammation by inhibiting NF-kappaB activation in cigarette smoke induced inflammatory models.

              Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) is a key player in the inflammatory response. Baicalin is an extract from roots of the plant scutellaria baicalensis. Many studies show that baicalin has anti-inflammatory, anti-bacterial and antiviral activities. Here we investigated the influence of baicalin on COPD inflammation and the mechanism of anti-inflammatory effect in vivo and in vitro. In vivo, COPD rat model was established by cigarette smoke (CS) exposure. Thirty-six Sprague-Dawley (SD) rats were randomly assigned to six experimental groups: control, CS, dexamethasone (DXM), and baicalin (20 mg/kg, 40 mg/kg, 80 mg/kg). The lung pathology was observed and leukocytes in bronchoalveolar lavage fluid (BALF) were counted by Optical microscope. Pulmonary function was measured by using an animal plethysmograph. The production of cytokines was measured by ELISA and the expression levels of NF-kappaB p65 protein were detected by immunohistochemistry. The results in vivo show CS exposure significantly increased the expression of IL-8, IL-6 and TNF-alpha in plasma and BALF and enhanced NF-kappaB p65 expression in the lungs. Baicalin treatment markedly attenuated the inflammatory effects of CS. In vitro, cell model was established by using cigarette smoke extract (CSE) to stimulate type II pneumocytes. Type II pneumocytes were also divided into six groups: control, CSE, pyrrolidine dithiocarbamate (PDTC), and baicalin (5 mumol, 10 mumol, 20 mumol). Cytokines levels were measured by ELISA. Expression of IkappaB and p65 phosphorylation was detected by western blotting. NF-kappaB DNA-binding activity was detected by EMSA. The results show that CSE resulted in increasing IL-8, IL-6 and TNF-alpha expression and activation of NF-kappaB. The proinflammatory effects of CSE were inhibited by treatment of baicalin in a dose-dependent manner. It can be concluded that baicalin has significant anti-inflammatory effects on CS induced COPD rat models and CSE-induced cell models, and the effectiveness increases with increasing baicalin dosage. The anti-inflammatory effect is likely achieved by inhibiting the NF-kappaB pathway. Copyright 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                19 April 2011
                April 2011
                : 16
                : 4
                : 3360-3370
                Affiliations
                School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350108, China; E-Mails: pws@ 123456fjtcm.edu.cn (W.P.); linsd1985@ 123456126.com (S.L.); dqw3718150@ 123456163.com (Q.D.); arken20@ 123456163.com (H.Z.)
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: huj@ 123456fjtcm.edu.cn ; Tel.: +86 591 83570397; Fax: +86 591 22861027.
                Article
                molecules-16-03360
                10.3390/molecules16043360
                6260644
                21512444
                8daef55d-bb3f-478e-a726-a36be2f64859
                © 2011 by the authors;

                licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 07 February 2011
                : 28 March 2011
                : 31 March 2011
                Categories
                Article

                pseudostellaria heterophylla (miq.) pax,extracts,antitussive activity,improvement lung function,multi-cytokine adjusting

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