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,Li Peng,Zhang Gehua,Li Yulu Inflammation research : official journal of the European Histamine Research Society ... [et al.] OBJECTIVE:To investigate the signal pathways involved in cyclooxygenase-2 (COX-2) expression in chronic rhinosinusitis (CRS). METHODS:The expressions of COX-2, p38 mitogen-activated protein kinase (p38MAPK), extracellular signal-regulated kinase (ERK), and nuclear factor kappa B (NF-kappaB) in nasal mucosa were detected by immunohistological stain and polymerase chain reaction (PCR). Their expressions and prostaglandin E2 (PGE(2)) release were determined by PCR, Western blot and enzyme immunoassay (EIA) in human nasal epithelia (HNE) cells after lipopolysaccharide (LPS) induction, and/or small interfering RNA (siRNA) transfection. RESULTS:Positive protein expressions of COX-2, p38MAPK, ERK, NF-kappaB subunits were detected in epithelial and inflammatory cells. Their mRNA levels were significantly higher in CRS than controls (P < 0.05). The expressions varied in time and concentration-dependent manner in LPS-induced HNE cells. COX-2 expression was suppressed by siRNAs of P38MAPK, ERK, and NF-kappaB; however, COX-2-specific siRNA had no blocking effect on them. SiRNAs of P38MAPK or ERK could block NF-kappaB, but NF-kappaB-specific siRNA had no blocking effect on the former. SiRNA of p38MAPK, or ERK did not inhibit each other. CONCLUSION: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. 10.1007/s00011-009-0030-x

The role of ADAM-like decysin 1 in non-eosinophilic chronic rhinosinusitis with nasal polyps. Sugimoto Naoki,Nakayama Tsuguhisa,Kasai Yoshiyuki,Asaka Daiya,Mitsuyoshi Ryoto,Tsurumoto Tadao,Takaishi Shinya,Omae Sachiko,Kojima Hiromi,Tanaka Yasuhiro,Haruna Shin-Ichi Acta oto-laryngologica BACKGROUND:Chronic rhinosinusitis with nasal polyps (CRSwNP) is classified into two subtypes: eosinophilic (ECRSwNP) and non-eosinophilic (NECRSwNP). Although the inflammatory patterns of ECRSwNP have been elucidated, NECRSwNP is poorly understood. AIMS/OBJECTIVES:The metalloproteinase ADAM-like decysin 1 (ADAMDEC1) has been reported to play a role in the early stages of the inflammatory response. We investigated the role of ADAMDEC1 in the pathogenesis of CRSwNP. MATERIAL AND METHODS:We compared ADAMDEC1 expression in nasal polyp tissue from CRS patients using immunohistochemistry and RT-qPCR. Macrophages were cultured and ADAMDEC1 expression was determined at baseline and after exposure to lipopolysaccharide (LPS). RESULTS:ADAMDEC1 was virtually undetectable in tissues from control patients but was highly expressed in the NECRSwNP group compared with the ECRSwNP group. In nasal polyp tissues, ADAMDEC1 was expressed by CD68-positive cells, with a positive correlation between ADAMDEC1-positive and CD68-positive cells, and also between ADAMDEC1 and CD68 mRNA levels. Furthermore, stimulation of monocyte-derived macrophages with LPS induced ADAMDEC1 expression. CONCLUSIONS AND SIGNIFICANCE:This study demonstrates that ADAMDEC1 is involved in the pathogenesis of NECRSwNP, and also bacterial endotoxin signalling in macrophages; however, the underlying mechanism remains to be elucidated. 10.1080/00016489.2018.1481296

Role of chromatin remodeling complex SWI/SNF and VDR in chronic rhinosinusitis. Kowalik Katarzyna,Waniewska-Łęczycka Martyna,Sarnowska Elżbieta,Rusetska Natalia,Sierdziński Janusz,Zagor Mariola Advances in clinical and experimental medicine : official organ Wroclaw Medical University BACKGROUND:The SWI/SNF (SWItch/sucrose non-fermentable) chromatin remodeling complex enables glucocorticoid receptor (GR) and vitamin D receptor (VDR) to function correctly and is engaged in inflammation response. The SWI/SNF may play an important role in chronic rhinosinusitis (CRS). OBJECTIVES:The aim of this study was to assess the following: 1) the gene and protein expression of the SWI/SNF complex subunits in sinonasal mucosa; 2) relation of SWI/SNF complex and VDR expression; and 3) correlation with clinical data. MATERIAL AND METHODS:The study population consisted of 52 subjects with CRS without nasal polyps, 55 with CRS with nasal polyps and 59 controls. The SWI/SNF protein expression level was analyzed in immunohistochemical (IHC) staining. Human nasal epithelial cells (HNECs) was stimulated using lipopolysaccharide (LPS), Staphylococcal enterotoxin B (SEB) and vitamin D3 (vitD3) in vitro. The transcript level of the SWI/SNF subunits was measured with polymerase chain reaction (PCR). RESULTS:In the control group, the intensity of the IHC staining for SWI/SNF subunits was significantly higher than in both groups of patients with CRS (p < 0.05). A positive correlation of the SWI/SNF protein expression was noticed with VDR expression level (p < 0.043). Association between SWI/SNF protein expression level and allergy, neutrophils and body mass index (BMI) has been observed (p < 0.05). The decreased transcript level of the SWI/SNF subunits genes in HNECs was observed after LPS stimulation and increased after vitD3 stimulation. CONCLUSIONS:The SWI/SNF complex may influence CRS through steroid hormone signaling and VDR. Thus, modification in therapy may be mandatory in patients with CRS and altered SWI/SNF signaling, reflecting resistance to steroids treatment. 10.17219/acem/117683

Lipopolysaccharide induces autophagy by targeting the AMPK-mTOR pathway in Human Nasal Epithelial Cells. Wang Xue-Hai,Zhang Zhong-Hua,Cai Xiao-Lan,Ye Ping,Feng Xin,Liu Ting-Ting,Li Xue-Zhong Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Chronic rhinosinusitis (CRS) is a well-known disease encountered in the department of otorhinolaryngology, yet little is known about its pathogenesis. Autophagy, a lysosome-dependent degradation process, has been reported to be involved in the process of many chronic inflammatory diseases. Here we tried to evaluate the function of autophagy in CRS as well as explore the related mechanisms. We first stained light chain 3B (LC3B) with immunohistochemistry in uncinate tissues (UT) from patients with and without CRS and found that its expression was up-regulated in CRS patients. Then, Human Nasal Epithelial Cells (HNEpC) were treated with lipopolysaccharide (LPS), one of the most common pathogenic elements in CRS, and we found that autophagy was induced in a dose- and time-dependent manner. This is supported by a rise in the expression of light chain 3B-II (LC3B-II), accumulation of GFP-LC3 vesicles, as well as decreased p62 expression. Furthermore, we found that LPS promoted AMPK phosphorylation and inactived mTOR, while AMPK inhibition by compound C significantly attenuated LPS-induced autophagy. Besides, treatment of HNEpC with LPS increased the amount of Toll-like receptor 4 (TLR4) while inhibiting TLR4 by Polymyxin B (PMB) declined autophagy caused by LPS. Taken together, our study first demonstrated that LPS caused autophagy in HNEpC, and this process was AMPK-mTOR dependent. These data suggested the relationship between LPS and autophagy in the pathogenesis of CRS. 10.1016/j.biopha.2017.12.011

Azithromycin and ciprofloxacin inhibit interleukin-8 secretion without disrupting human sinonasal epithelial integrity in vitro. Lim Dong-Jin,Thompson Harrison M,Walz Christopher R,Ayinala Samrath,Skinner Daniel,Zhang Shaoyan,Grayson Jessica W,Cho Do-Yeon,Woodworth Bradford A International forum of allergy & rhinology BACKGROUND:We recently developed a ciprofloxacin and azithromycin sinus stent (CASS) to target recalcitrant infections in chronic rhinosinusitis (CRS). The objective of this study was to evaluate the anti-inflammatory activity of azithromycin released from the CASS and assess the impact on the integrity and function of primary human sinonasal epithelial cells (HSNECs). METHODS:Pseudomonas aeruginosa lipopolysaccharide (LPS)-stimulated HSNECs were treated with azithromycin and/or ciprofloxacin at concentrations attainable from CASS release. Interleukin-8 (IL-8) secretion was quantified by enzyme-linked immunosorbent assay (ELISA). Epithelial integrity (transepithelial resistance [TEER], paracellular permeability [fluorescein isothiocyanate-labeled dextran], lactate dehydrogenase [LDH] assays) and function (ciliary beat frequency [CBF]) were also evaluated. RESULTS:Azithromycin significantly reduced secreted IL-8 from P. aeruginosa LPS-stimulated HSNECs at all concentrations tested (mean ± standard deviation; control = 5.77 ± 0.39 ng/mL, azithromycin [6 μg/mL] = 4.58 ± 0.40 ng/mL, azithromycin [60 µg/mL] = 4.31 ± 0.06, azithromycin [180 µg/mL] = 4.27 ± 0.26 ng/mL, p < 0.05). Co-incubation with azithromycin (6 µg/mL) and ciprofloxacin (2.4 µg/mL) in LPS-stimulated HSNECs also displayed a significant reduction in secreted IL-8 when compared to P. aeruginosa LPS alone (co-treatment = 4.61 ± 0.29 ng/mL, P. aeruginosa LPS = 7.35 ± 0.89 ng/mL, p < 0.01). The drugs did not negatively impact TEER, paracellular permeability, LDH release, or CBF, indicating retention of cell integrity and function. CONCLUSION:Azithromycin decreased P. aeruginosa LPS IL-8 production in HSNECs at drug concentrations attainable with sustained release of azithromycin from the CASS. In addition to antibacterial activity, anti-inflammatory properties of the CASS should provide further benefit for patients with recalcitrant CRS. 10.1002/alr.22656