Involvement of mitogen-activated protein kinases and nuclear factor kappa B pathways in signaling COX-2 expression in chronic rhinosinusitis

Wang, Zhenlin; Zhang, Qiuhang; Li, Yuan; Zhang, Gehua; Li, Yulu

doi:10.1007/s00011-009-0030-x

Cited by 14 publications

(11 citation statements)

References 34 publications

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“…These results suggest that intracellularly generated S1P is more effective in ameliorating LPS-induced IL-6 secretion than exogenously added sphingosine or S1P. S1PL Regulates LPS-Induced IL-6 Secretion through p38 MAPK and NF-kB Signal Transduction LPS stimulated NF-KB and ERK1/2 and p38 MAPK ( Figures E4A and E4B), confirming earlier studies in other cell types (35)(36)(37). Inhibition of p38 MAPK and NF-kB with Bay11-7082 and SB203580, but not ERK with PD98059, partly blocked LPSmediated IL-6 secretion in HLMVECs (Figures E4C and E4D).…”

Section: Role Of S1pl and Sphks In Lps-mediated Il-6 Secretion In Hlmsupporting

confidence: 87%

Protection of LPS-Induced Murine Acute Lung Injury by Sphingosine-1-Phosphate Lyase Suppression

Zhao¹,

Горшкова²,

Berdyshev³

et al. 2011

Am J Respir Cell Mol Biol

111

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A defining feature of acute lung injury (ALI) is the increased lung vascular permeability and alveolar flooding, which leads to associated morbidity and mortality. Specific therapies to alleviate the unremitting vascular leak in ALI are not currently clinically available; however, our prior studies indicate a protective role for sphingosine-1-phosphate (S1P) in animal models of ALI with reductions in lung edema. As S1P levels are tightly regulated by synthesis and degradation, we tested the hypothesis that inhibition of S1P lyase (S1PL), the enzyme that irreversibly degrades S1P via cleavage, could ameliorate ALI. Intratracheal instillation of LPS to mice enhanced S1PL expression, decreased S1P levels in lung tissue, and induced lung inflammation and injury. LPS challenge of wild-type mice receiving 2-acetyl-4(5)-[1(R),2(S),3(R),4-tetrahydroxybutyl]-imidazole to inhibit S1PL or S1PL(+/-) mice resulted in increased S1P levels in lung tissue and bronchoalveolar lavage fluids and reduced lung injury and inflammation. Moreover, down-regulation of S1PL expression by short interfering RNA (siRNA) in primary human lung microvascular endothelial cells increased S1P levels, and attenuated LPS-mediated phosphorylation of p38 mitogen-activated protein kinase and I-κB, IL-6 secretion, and endothelial barrier disruption via Rac1 activation. These results identify a novel role for intracellularly generated S1P in protection against ALI and suggest S1PL as a potential therapeutic target.

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Section: Role Of S1pl and Sphks In Lps-mediated Il-6 Secretion In Hlmsupporting

confidence: 87%

Protection of LPS-Induced Murine Acute Lung Injury by Sphingosine-1-Phosphate Lyase Suppression

Zhao¹,

Горшкова²,

Berdyshev³

et al. 2011

Am J Respir Cell Mol Biol

111

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“…A previous study showed that ECM-induced MMP-9 expression in RAW 264.7 macrophages is inhibited by celecoxib or siRNA-mediated reduction of COX-2 expression (22). Wang et al (39) demonstrated that COX-2-specific siRNA had no blocking effect on p38 MAPK, ERK, and NF-B pathway in LPS-induced human nasal epithelia (HNE) cells. After COX-2-specific siRNA was transfected into HNE cells, the LPS-induced COX-2 expression was blocked, and PGE 2 release was inhibited.…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory effects of celecoxib in rat lungs with smoke-induced emphysema

Roh¹,

Yi²,

Cho

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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airway inflammation is a characteristic feature of destructive cigarette smoking (CS)-induced lung disease, particularly in patients with emphysema. Celecoxib, a specific cyclooxygenase-2 (COX-2) inhibitor, is widely used to treat inflammation. However, the exact mechanisms underlying this drug's anti-inflammatory effects have not yet been determined in pulmonary emphysema. Here, we explore whether celecoxib attenuates CSinduced inflammation in rat lungs. Rats were exposed to smoke and received celecoxib via intragastric feeding daily for 20 wk. We found that celecoxib inhibited interalveolar wall distance and pulmonary inflammation in the lungs of CS-treated rats. Celecoxib inhibited serum NO production, iNOS, COX-2 expression, and PGE 2 production in CS-treated lung tissues. Our immunohistochemical data showed that CS-induced CD68 and COX-2 expression were inhibited by celecoxib. Furthermore, celecoxib attenuated the activation of phospho-IB␣ and NF-B in CS-treated rat lung. In addition, there was an inhibitory effect of celecoxib on the COX-2 expression and NF-B activation in LPS-stimulated RAW 264.7 macrophages. Celecoxib also attenuated NF-B activation in COX-2 siRNA-transfected RAW 264.7 macrophages. Thus, our findings suggest that the antiinflammatory effects of celecoxib are mediated by its effects on NF-B-regulated gene expression, which ultimately reduces the progression of CS-induced pulmonary emphysema.

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“…5,6 Kinases are known to play an important role in posttranscriptional control of inflammatory gene expression, T cell differentiation, and cell apoptosis. 7 Of the protein kinases highlighted in this analysis, individual studies have linked P38 MAP kinase 8,9 and ERK1/2 kinase 10 to sinusitis, whereas AKT, PKC, and JNK have not been studied specifically. Although there is considerable interest in using targeted kinase inhibitors to treat asthma and chronic obstructive pulmonary disease (COPD), 11,12 a similar strategy has not been widely proposed for sinusitis with polyps.…”

Section: Discussionmentioning

confidence: 99%

Pathways Analysis of Molecular Markers in Chronic Sinusitis with Polyps

Platt

Soler

Metson

et al. 2011

Otolaryngol.--head neck surg.

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Objective To perform a comprehensive molecular pathways analysis of genes identified through genome-wide expression profiling and the published literature for chronic sinusitis with polyps. Study Design Molecular pathways analysis. Setting Academic medical center. Methods A molecular pathways analysis of gene biomarkers discovered through hypothesis-driven and high-throughput molecular studies was performed. Genes identified with a PubMed literature search were analyzed with Ingenuity Pathways Analysis software to identify central molecules implicated in the pathogenesis of chronic sinusitis with polyps. The central pathways were then compared with those identified through genome-wide expression profiling of ethmoid polyps. Results A total of 97 molecules were investigated with Ingenuity Pathways Analysis based on 55 studies that evaluated differences in gene expression (39), genetic variation (12), or proteomics (4). The analysis revealed 9 statistically significant molecular networks containing central nodes that included transcription factors, protein kinases, cytokines, and growth factors/receptors. The highest scoring networks implicated nuclear factor kappa-B, tumor necrosis factor, and mitogen-activated protein kinases. The majority of pathways in the literature review analysis overlapped with those identified through a single genome-wide expression study. Conclusions Chronic sinusitis with polyps is a complex disease with suspected contribution of multiple genetic and environmental factors. The search for causative genes has led to the discovery of numerous candidates. Pathways analysis applied to these candidate genes identified common central molecules that are likely to be key mediators of the disease process. Novel therapies targeting these molecules may be applicable for the treatment of chronic sinusitis with polyps.

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Involvement of mitogen-activated protein kinases and nuclear factor kappa B pathways in signaling COX-2 expression in chronic rhinosinusitis

Abstract: Upregulation of COX-2 expression suggested its role as a mediator in CRS. ERK and p38MAPK pathways were involved in signaling COX-2 through NF-kappaB pathway.

Cited by 14 publications

References 34 publications

Protection of LPS-Induced Murine Acute Lung Injury by Sphingosine-1-Phosphate Lyase Suppression

Protection of LPS-Induced Murine Acute Lung Injury by Sphingosine-1-Phosphate Lyase Suppression

Anti-inflammatory effects of celecoxib in rat lungs with smoke-induced emphysema

Pathways Analysis of Molecular Markers in Chronic Sinusitis with Polyps

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