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1.
Clin Exp Allergy ; 49(1): 44-53, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30107059

RESUMO

BACKGROUND: Omalizumab, a recombinant monoclonal anti-IgE antibody, was developed for the treatment of severe allergic asthma. Not all these patients respond to omalizumab. OBJECTIVE: This study aimed to evaluate whether the proinflammatory cytokine profiles in the severe allergic asthma patients were different between who responded and nonresponded to omalizumab therapy. METHODS: A prospective study was conducted to examine type 2 cytokines and epithelium-derived cytokines in the bronchial tissues by immunohistochemistry, Western blot and PCR analysis among patients with severe allergic asthma before and after omalizumab therapy. RESULTS: Fourteen of 23 patients with unstable severe allergic asthma improved their asthma control after 4 months of omalizumab treatment (Responders), while nine failed to improve (Non-Responders). Most of Responders were type 2-high endotype (12/14) with upregulated expression of IL-33, IL-25 and TSLP in their bronchial tissues, while most of Non-Responders were type 2-low endotype (8/9). Repeated bronchoscopic biopsy was done in nine responders after omalizumab treatment and showed a decline in IL-13, IL-33, IL-25 and TSLP expression in the bronchial tissues. Among 14 Responders who continued omalizuamb treatments to a total 12 months, six patients achieved a well control of asthma (ACT ≥ 23), while eight patients required additional treatment for asthma symptoms and had more rhinosinusitis comorbidities and a mixed eosinophilic and neutrophilic inflammation in their bronchial tissues. CONCLUSION: Most of the severe allergic asthma patients who benefited from omalizumab treatment were IL-33, IL-25 and TSLP aggravated type 2-high endotype. Rhinosinusitis or with a mixed eosinophilic and neutrophilic airway inflammation should be evaluated in patients who partially responded to omalizumab treatment.

2.
Biochem Pharmacol ; 151: 1-8, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29499168

RESUMO

IL-17A is implicated in many aspects of pathogenesis of severe asthma, including inducing neutrophilic inflammation, airway hyperresponsiveness, steroid insensitivity and airway remodeling. Diesel exhaust particles (DEP) emission from vehicles has been shown to expand Th17 cells to increase IL-17A release that contributes to DEP-mediated exacerbation of asthma severity. It is not known whether non-immune cells in airways may also release IL-17A in response to DEP exposure. In this study, We found IL-17A expression was upregulated in the epithelium of severe allergic asthma patients from high road traffic pollution areas compared to those in low. Furthermore, we found DEP concentration-dependently increased IL-17A synthesis and release by 122.3 ±â€¯15.72% and 235.5 ±â€¯18.37%, respectively in primary bronchial epithelial cells (PBEC), accompanied with increased ROS production. Pretreatment of ROS scavenger (NAC) significantly inhibited DEP-induced IL-17A mRNA expression. DEP-induced IκBα degradation can be inhibited by NAC. We also found DEP increased p65 and RelB subunits expression, and pretreatment of NF-κB inhibitor (SN50) also inhibited DEP-induced IL-17A expression. We further found DEP increased NF-κB subunit RelB recruitment to IL-17A promoter in PBEC and airway tissue of severe allergic asthma patients from high road traffic pollution areas. These results indicate DEP stimulates IL-17A expression in airway epithelium through ROS/NF-κB pathway, and provide a possible link between traffic pollution exposure and IL-17A-related responses in severe allergic asthma patients.


Assuntos
Asma/imunologia , Interleucina-17/genética , NF-kappa B/metabolismo , Material Particulado/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Emissões de Veículos/toxicidade , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Mucosa Respiratória/imunologia , Índice de Gravidade de Doença , Transdução de Sinais , Regulação para Cima
3.
Opt Express ; 25(17): 20466-20476, 2017 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-29041727

RESUMO

This study presents the low cost fabrication of flexible white-light-emitting diodes (w-LEDs) with nano-honeycomb-structured phosphor films. Extending the dimensions of the nano-honeycomb structures improved the color uniformity of the flexible samples, and the 950-nm pattern sample demonstrated optimal color uniformity because this nano-pattern exhibited an excellent diffusion ability owing to its pitch size. In addition to color uniformity, the use of this nano-pattern improved the luminous efficiency. The 750-nm pattern exhibited the highest luminous efficiency (235.8 lm/W), which was approximately 7% higher than that exhibited by a non-patterned phosphor film sample. Thus, flexible w-LEDs with nano-honeycomb structure optimization have great potential to be used as next-generation lighting sources.

4.
Biochem Pharmacol ; 88(3): 402-11, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24486572

RESUMO

Endothelin-1 (ET-1) acts as a key mediator of vasoconstriction and tissue repair. Overproduction of connective tissue growth factor (CTGF) underlies the development of lung fibrosis. ET-1 induces expression of matrix-associated genes in lung fibroblasts, however, little is known about the signaling pathway of CTGF expression caused by ET-1. In this study, we found that ET-1 caused concentration- and time-dependently increases in CTGF expression in human embryonic lung fibroblast cell line (WI-38). ET-1-induced CTGF expression was inhibited by BQ123 (ETAR antagonist), but not BQ788 (ETBR antagonist). Moreover, ET-1-induced CTGF expression was significantly reduced by JNK inhibitor (SP600125), the dominant-negative mutants of JNK1/2 (JNK1/2 DN), and AP-1 inhibitor (curcumin). ET-1 induced phosphorylations of JNK and c-Jun in time-dependent manners. AP-1 luciferase activity was concentration-dependently increased by ET-1, and this effect was attenuated by SP600125. We also found that ET-1-induced CTGF expression was most controlled by the AP-1 binding region of CTGF promoter. ET-1-indiced CTGF luciferase activity was predominately controlled by the sequence -747 to -408 bp upstream of the transcription start site on the human CTGF promoter. Furthermore, ET-1 caused the formation of AP-1-specific DNA-protein complex and the recruitment of c-Jun to the CTGF promoter. Moreover, we found that ET-1 induced α-smooth muscle actin (α-SMA) expression, which was inhibited by BQ123, SP600125, curcumin, and anti-CTGF antibody. These results suggest that ET-1 stimulates expressions of CTGF and α-SMA through ETAR/JNK/AP-1 signaling pathway, and CTGF is required for ET-1-induced α-SMA expression in human lung fibroblasts.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/metabolismo , Endotelina-1/metabolismo , Fibroblastos/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Pulmão/metabolismo , Receptor de Endotelina A/metabolismo , Fator de Transcrição AP-1/metabolismo , Actinas/metabolismo , Sítios de Ligação , Linhagem Celular , Fator de Crescimento do Tecido Conjuntivo/genética , Antagonistas do Receptor de Endotelina A , Antagonistas do Receptor de Endotelina B , Endotelina-1/farmacologia , Humanos , Pulmão/citologia , Regiões Promotoras Genéticas , Transdução de Sinais
5.
Biochim Biophys Acta ; 1833(12): 2823-2833, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23906792

RESUMO

Connective tissue growth factor (CTGF) plays an important role in lung fibrosis. In this study, we investigated the role of Rac1, mixed-lineage kinase 3 (MLK3), c-Jun N-terminal kinase (JNK), and activator protein-1 (AP-1) in CTGF-induced collagen I expression in human lung fibroblasts. CTGF caused concentration- and time-dependent increases in collagen I expression. CTGF-induced collagen I expression was inhibited by the dominant negative mutant (DN) of Rac1 (RacN17), MLK3DN, MLK3 inhibitor (K252a), JNK1DN, JNK2DN, a JNK inhibitor (SP600125), and an AP-1 inhibitor (curcumin). Treatment of cells with CTGF caused activation of Rac1, MLK3, JNK, and AP-1. The CTGF-induced increase in MLK3 phosphorylation was inhibited by RacN17. Treatment with RacN17 and the MLK3DN inhibited CTGF-induced JNK phosphorylation. CTGF caused increases in c-Jun phosphorylation and the recruitment of c-Jun and c-Fos to the collagen I promoter. Furthermore, stimulation of cells with the CTGF resulted in increases in AP-1-luciferase activity; this effect was inhibited by Rac1N17, MLK3DN, JNK1DN, and JNK2DN. Moreover, CTGF-induced α-smooth muscle actin (α-SMA) expression was inhibited by the procollagen I small interfering RNA (siRNA). These results suggest for the first time that CTGF acting through Rac1 activates the MLK3/JNK signaling pathway, which in turn initiates AP-1 activation and recruitment of c-Jun and c-Fos to the collagen I promoter and ultimately induces collagen I expression in human lung fibroblasts.


Assuntos
Colágeno Tipo I/metabolismo , Fator de Crescimento do Tecido Conjuntivo/farmacologia , Fibroblastos/enzimologia , Pulmão/citologia , MAP Quinase Quinase Quinases/metabolismo , Fator de Transcrição AP-1/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Actinas/metabolismo , Linhagem Celular , Ativação Enzimática/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Modelos Biológicos , Fosforilação/efeitos dos fármacos
6.
Am J Respir Crit Care Med ; 188(3): 298-308, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23795584

RESUMO

RATIONALE: Fibrocytes possess increased differentiability into α-smooth muscle actin (α-SMA)(+) myofibroblasts in chronic obstructive asthma (COA) and contribute to pulmonary fibrosis. Endothelin-1 (ET-1) induces matrix-associated gene expression through the ETA receptor (ETAR) and promotes fibroblast differentiation. However, the mechanism of fibrocyte differentiation remains unclear. OBJECTIVES: To define the roles of the ETAR and connective tissue growth factor (CTGF) expression in fibrocytes in the development of fibrosis in COA. METHODS: Blood nonadherent non-T (NANT) cells were isolated, and fibrocytes expressing CD45, collagen I, CTGF, ETAR, or α-SMA were identified by flow cytometry. MEASUREMENTS AND MAIN RESULTS: We showed the accumulation of fibrocytes in bronchial walls and overexpression of CTGF in fibrocytes from patients with COA. After being cultured, CTGF was increased in fibrocytes from patients with COA, but not from those of normal participants or patients with asthma without obstruction. Serum levels of ET-1 and the expression of the ETAR in fibrocytes were significantly higher in patients with COA compared with normal participants and patients with asthma without obstruction. Treatment with the ETAR antagonist (BQ123), but not ETBR antagonist (BQ788), reduced the expression of CTGF and α-SMA in fibrocytes and fibrocyte differentiation in patients with COA. Furthermore, treatment with BQ123 or an anti-CTGF antibody attenuated α-SMA expression induced by ET-1 in fibrocytes from normal participants. CONCLUSIONS: Our findings demonstrate for the first time that the ETAR pathway is vital for CTGF expression, which results in fibrocyte differentiation in COA, and suggests that an ETAR antagonist may be a potential antifibrotic agent in preventing the development of fibrosis in patients with COA.


Assuntos
Asma/metabolismo , Fator de Crescimento do Tecido Conjuntivo/biossíntese , Receptor de Endotelina A/biossíntese , Asma/complicações , Asma/patologia , Brônquios/metabolismo , Brônquios/patologia , Diferenciação Celular , Células Cultivadas , Doença Crônica , Progressão da Doença , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/metabolismo , Fibrose/patologia , Citometria de Fluxo , Humanos , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Prognóstico , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia
7.
J Leukoc Biol ; 93(1): 101-12, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23108098

RESUMO

Thrombin is a multifunctional serine protease and an important fibrotic mediator that induces CCN2 expression. We previously showed that thrombin induces CCN2 expression via an ASK1-dependent JNK/AP-1 pathway in human lung fibroblasts. In this study, we further investigated the roles of c-Src, JAK2, and STAT3 in thrombin-induced CCN2 expression. Thrombin-induced CCN2 expression and CCN2-Luc activity were attenuated by a JAK inhibitor (AG490) and JAK2DN, STAT3DN, and the STAT decoy ODN. Moreover, transfection of cells with a CCN2-mtSTAT-Luc construct inhibited thrombin-induced CCN2-Luc activity. Treatment of cells with thrombin caused JAK2 phosphorylation at Tyr1007/1008 and STAT3 phosphorylation at Tyr705 in time-dependent manners. Thrombin-induced STAT3 phosphorylation was inhibited by AG490 and JAK2DN. Thrombin-induced STAT3 binding to the CCN2 promoter was analyzed by a DNA-binding affinity pull-down assay. In addition, thrombin-induced CCN2 expression and CCN2-Luc activity were inhibited by c-SrcDN and PP2 (an Src inhibitor). Transfection of cells with c-SrcDN also inhibited thrombin-induced JAK2 and STAT3 phosphorylation. Taken together, these results indicate that thrombin might activate c-Src to induce JAK2 activation, which in turn, causes STAT3 activation, and finally induces CCN2 expression in human lung fibroblasts.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/biossíntese , Fibroblastos/metabolismo , Regulação da Expressão Gênica/fisiologia , Pulmão/metabolismo , Western Blotting , Linhagem Celular , Humanos , Janus Quinase 2/metabolismo , Pulmão/citologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologia , Trombina/metabolismo , Transfecção , Quinases da Família src/metabolismo
8.
Pharmacol Res ; 60(4): 247-53, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19717011

RESUMO

Our previous study demonstrated that 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) might activate the soluble guanylate cyclase (sGC)/cGMP/protein kinase G (PKG) pathway to induce cyclooxygenase-2 (COX-2) expression in human pulmonary epithelial cells (A549). In this study, we further investigated the role of Raf-1 in YC-1-induced nuclear factor-kappaB (NF-kappaB) activation and COX-2 expression in A549 cells. YC-1-induced COX-2 expression was attenuated by a Raf-1 inhibitor (GW 5074) in a concentration-dependent manner. Treatment of A549 cells with YC-1 or 8-bromo-cGMP, a cell-permeable cGMP analogue, induced Raf-1 Ser338 phosphorylation in a time-dependent manner. YC-1-mediated Raf-1 activation was inhibited by an sGC inhibitor (ODQ), a PKG inhibitor (KT-5823), a Ras inhibitor (manumycin A), a dominant negative Ras mutant (RasN17), a protein kinase C-alpha (PKC-alpha) inhibitor (Ro 32-0432), and a phosphoinositide-3-OH-kinase (PI3K) inhibitor (LY 294002). Pretreatment of A549 cells with either manumycin A or GW 5074 attenuated YC-1-induced p44/42 MAPK activation. The YC-1-mediated increase in IKKalpha/beta activation and kappaB-luciferase activity were attenuated by GW 5074, a MAPK/ERK kinase (MEK) inhibitor (PD 98059), and an ERK2 inhibitor (AG 126). Furthermore, YC-1-induced COX-2 promoter activity was also inhibited by GW 5074, PD 98059, and AG 126. These results indicate that YC-1 might activate the sGC/cGMP/PKG pathway to elicit Ras/Raf-1/p44/42 MAPK activation, which in turn induces IKKalpha/beta and NF-kappaB activation, and ultimately causes COX-2 expression in A549 cells. Moreover, PKC-alpha and PI3K signal might be involved in YC-1-induced Raf-1 activation.


Assuntos
Ciclo-Oxigenase 2/genética , Ativadores de Enzimas/farmacologia , Indazóis/farmacologia , NF-kappa B/genética , Proteínas Proto-Oncogênicas c-raf/metabolismo , Transdução de Sinais , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Células Epiteliais/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Quinase I-kappa B/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Alvéolos Pulmonares/citologia , Proteínas ras/metabolismo
9.
J Biomed Sci ; 16: 43, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19405983

RESUMO

In the present study, we explore the role of apoptosis signal-regulating kinase 1 (ASK1) in denbinobin-induced apoptosis in human lung adenocarcinoma (A549) cells. Denbinobin-induced cell apoptosis was attenuated by an ASK1 dominant-negative mutant (ASK1DN), two antioxidants (N-acetyl-L-cysteine (NAC) and glutathione (GSH)), a c-Jun N-terminal kinase (JNK) inhibitor (SP600125), and an activator protein-1 (AP-1) inhibitor (curcumin). Treatment of A549 cells with denbinobin caused increases in ASK1 activity and reactive oxygen species (ROS) production, and these effects were inhibited by NAC and GSH. Stimulation of A549 cells with denbinobin caused JNK activation; this effect was markedly inhibited by NAC, GSH, and ASK1DN. Denbinobin induced c-Jun phosphorylation, the formation of an AP-1-specific DNA-protein complex, and Bim expression. Bim knockdown using a bim short interfering RNA strategy also reduced denbinobin-induced A549 cell apoptosis. The denbinobin-mediated increases in c-Jun phosphorylation and Bim expression were inhibited by NAC, GSH, SP600125, ASK1DN, JNK1DN, and JNK2DN. These results suggest that denbinobin might activate ASK1 through ROS production to cause JNK/AP-1 activation, which in turn induces Bim expression, and ultimately results in A549 cell apoptosis.


Assuntos
Adenocarcinoma/enzimologia , Antraquinonas/toxicidade , Antineoplásicos/toxicidade , Apoptose , Neoplasias Pulmonares/enzimologia , MAP Quinase Quinase Quinase 5/metabolismo , Fenantrenos/toxicidade , Adenocarcinoma/metabolismo , Morte Celular , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio/metabolismo
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