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postgraduate thesis: Effects of flavonoids on cigarette smoke and/or lipopolysaccharide induced inflammation and oxidative stress in human bronchial epithelial cells and rat lung

TitleEffects of flavonoids on cigarette smoke and/or lipopolysaccharide induced inflammation and oxidative stress in human bronchial epithelial cells and rat lung
Authors
Issue Date2018
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Zhang, P. [张鹏]. (2018). Effects of flavonoids on cigarette smoke and/or lipopolysaccharide induced inflammation and oxidative stress in human bronchial epithelial cells and rat lung. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.
AbstractChronic obstructive pulmonary disease (COPD) is characterized by progressive and irreversible airflow obstruction, and associated with airway inflammation and oxidative stress, which can be induced by cigarette smoke (CS) or lipopolysaccharide (LPS). Current pharmacological therapies have limited efficacy in suppressing inflammation in small airways or retarding the progression of COPD. Therefore, new therapeutic agents need to be developed. Flavonoids are naturally-occurring polyphenolic compounds with many biological effects including anti-oxidation and anti-inflammation. High dietary intake of flavonoids improves lung function and reduces the risk of developing COPD. However, whether or not flavonoids protect the airway against inflammation and oxidative stress has not been fully examined. In this study, the effects of 17 flavonoids on LPS-induced release of inflammatory mediators in human bronchial epithelial BEAS-2B cells were examined, with the aim to determine whether or not a structure-activity relationship exists. Moreover, the potential of three flavonoids [apigenin, genistein and quercetin] in reducing inflammatory responses and oxidative stress in CS medium (CSM) and/or LPS-stimulated BEAS-2B cells were studied, and the underlying mechanisms were investigated. Studies were also performed in rats to determine whether or not oral administration of genistein prevented lung damage due to CS and/or LPS exposure. In BEAS-2B cells, LPS increased the release of interleukin (IL)-8, IL-6 and monocyte chemotactic protein-1 (MCP-1). Among the 17 flavonoids, only some of them reduced LPS-induced release of inflammatory mediators. The effectiveness of the flavonoids in the inhibition depends on their chemical structure, and the inflammatory mediators examined. The presence of C5-hydroxyl (OH), C7-OH, C2=C3 and C4=O functional groups in the flavonoids (including apigenin and genistein) is associated with greater anti-inflammatory effects; by contrast, quercetin appeared to enhance LPS-induced inflammatory responses. In BEAS-2B cells stimulated with CSM and/or LPS, the levels of IL-8, 8-isoprostane and malondialdehyde (MDA) were increased, and the activities of anti-oxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)] were decreased; these changes were reversed by apigenin, genistein or quercetin [except in cells treated with LPS for quercetin]. CSM and/or LPS increased the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), p38 mitogen-activated protein kinases (p38), inhibitor of kappa B α (IκBα) and nuclear factor kappa B (NF-κB) p65; these increases were down-regulated in cells pretreated with flavonoids. The flavonoids also reduced CSM and/or LPS-induced increases in 5’-AMP level, and decreases in cyclic adenosine monophosphate (cAMP) level and cAMP-dependent protein kinase (PKA) activity. In rats exposed to CS and/or LPS, alveolar enlargement was observed; this change was ameliorated by genistein administration. CS and/or LPS exposure also increased the levels of cytokine-induced neutrophil chemoattractant-1 (CINC-1), IL-6 and MCP-1 in bronchoalveolar lavage fluid, which were attenuated by genistein. Moreover, genistein reduced CS and/or LPS-induced elevation of MDA level and normalized the activities of SOD and CAT in rat lung homogenates. In conclusion, some flavonoids, in particular genistein, reduced CSM and/or LPS-induced airway inflammation partly through activation of cAMP/PKA pathway, and partly through inhibition of ERK1/2 and p38 and reduction of oxidative stress. Therefore, genistein may be useful in preventing the development of COPD.
DegreeDoctor of Philosophy
SubjectFlavonoids
Diseases - Airway (Medicine)
Oxidative stress
Dept/ProgramPharmacology and Pharmacy
Persistent Identifierhttp://hdl.handle.net/10722/269867

 

DC FieldValueLanguage
dc.contributor.authorZhang, Peng-
dc.contributor.author张鹏-
dc.date.accessioned2019-05-07T01:50:56Z-
dc.date.available2019-05-07T01:50:56Z-
dc.date.issued2018-
dc.identifier.citationZhang, P. [张鹏]. (2018). Effects of flavonoids on cigarette smoke and/or lipopolysaccharide induced inflammation and oxidative stress in human bronchial epithelial cells and rat lung. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.-
dc.identifier.urihttp://hdl.handle.net/10722/269867-
dc.description.abstractChronic obstructive pulmonary disease (COPD) is characterized by progressive and irreversible airflow obstruction, and associated with airway inflammation and oxidative stress, which can be induced by cigarette smoke (CS) or lipopolysaccharide (LPS). Current pharmacological therapies have limited efficacy in suppressing inflammation in small airways or retarding the progression of COPD. Therefore, new therapeutic agents need to be developed. Flavonoids are naturally-occurring polyphenolic compounds with many biological effects including anti-oxidation and anti-inflammation. High dietary intake of flavonoids improves lung function and reduces the risk of developing COPD. However, whether or not flavonoids protect the airway against inflammation and oxidative stress has not been fully examined. In this study, the effects of 17 flavonoids on LPS-induced release of inflammatory mediators in human bronchial epithelial BEAS-2B cells were examined, with the aim to determine whether or not a structure-activity relationship exists. Moreover, the potential of three flavonoids [apigenin, genistein and quercetin] in reducing inflammatory responses and oxidative stress in CS medium (CSM) and/or LPS-stimulated BEAS-2B cells were studied, and the underlying mechanisms were investigated. Studies were also performed in rats to determine whether or not oral administration of genistein prevented lung damage due to CS and/or LPS exposure. In BEAS-2B cells, LPS increased the release of interleukin (IL)-8, IL-6 and monocyte chemotactic protein-1 (MCP-1). Among the 17 flavonoids, only some of them reduced LPS-induced release of inflammatory mediators. The effectiveness of the flavonoids in the inhibition depends on their chemical structure, and the inflammatory mediators examined. The presence of C5-hydroxyl (OH), C7-OH, C2=C3 and C4=O functional groups in the flavonoids (including apigenin and genistein) is associated with greater anti-inflammatory effects; by contrast, quercetin appeared to enhance LPS-induced inflammatory responses. In BEAS-2B cells stimulated with CSM and/or LPS, the levels of IL-8, 8-isoprostane and malondialdehyde (MDA) were increased, and the activities of anti-oxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)] were decreased; these changes were reversed by apigenin, genistein or quercetin [except in cells treated with LPS for quercetin]. CSM and/or LPS increased the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), p38 mitogen-activated protein kinases (p38), inhibitor of kappa B α (IκBα) and nuclear factor kappa B (NF-κB) p65; these increases were down-regulated in cells pretreated with flavonoids. The flavonoids also reduced CSM and/or LPS-induced increases in 5’-AMP level, and decreases in cyclic adenosine monophosphate (cAMP) level and cAMP-dependent protein kinase (PKA) activity. In rats exposed to CS and/or LPS, alveolar enlargement was observed; this change was ameliorated by genistein administration. CS and/or LPS exposure also increased the levels of cytokine-induced neutrophil chemoattractant-1 (CINC-1), IL-6 and MCP-1 in bronchoalveolar lavage fluid, which were attenuated by genistein. Moreover, genistein reduced CS and/or LPS-induced elevation of MDA level and normalized the activities of SOD and CAT in rat lung homogenates. In conclusion, some flavonoids, in particular genistein, reduced CSM and/or LPS-induced airway inflammation partly through activation of cAMP/PKA pathway, and partly through inhibition of ERK1/2 and p38 and reduction of oxidative stress. Therefore, genistein may be useful in preventing the development of COPD. -
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subject.lcshFlavonoids-
dc.subject.lcshDiseases - Airway (Medicine)-
dc.subject.lcshOxidative stress-
dc.titleEffects of flavonoids on cigarette smoke and/or lipopolysaccharide induced inflammation and oxidative stress in human bronchial epithelial cells and rat lung-
dc.typePG_Thesis-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplinePharmacology and Pharmacy-
dc.description.naturepublished_or_final_version-
dc.date.hkucongregation2018-
dc.identifier.mmsid991044040572103414-

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