Background Mucus hypersecretion in the respiratory tract and goblet cell metaplasia in the airway epithelium contribute to the morbidity and mortality associated with airway inflammatory diseases. This study aimed to ...Background Mucus hypersecretion in the respiratory tract and goblet cell metaplasia in the airway epithelium contribute to the morbidity and mortality associated with airway inflammatory diseases. This study aimed to examine the effect and mechanisms of simvastatin on airway mucus hypersecretion in rats treated with lipopolysaccharide （LPS）. Methods Mucus hypersecretion in rat airways was induced by intra-tracheal instillation of LPS. Rats treated with or without LPS were administered intra-peritoneally simvastatin （5 and 20 mg/kg） for 4 days. Expression of Muc5ac, RhoA and mitogen-activated protein kinases （MAPK） p38 in lung were detected by real-time polymerase chain reaction （PCR）, immunohistochemistry or Western blotting. Tumor necrosis factor （TNF）-α and IL-8 in bronchoalveolar lavage fluid （BALF） were assayed by an enzyme-linked lectin assay and enzyme linked immunosorbent assay （ELISA）. Results Simvastatin attenuated LPS-induced goblet cell hyperplasia in bronchial epithelium and Muc5ac hypersecretion at both the gene and protein levels in lung （P 〈0.05）. Moreover, simvastatin inhibited neutrophil accumulation and the increased concentration of TNF-α and IL-8 in BALF follows LPS stimulation （P 〈0.05）. The higher dose of simvastatin was associated with a more significant reduction in Muc5ac mRNA expression, neutrophil accumulation and inflammatory cytokine release. Simultaneously, the increased expression of RhoA and p38 MAPK were observed in LPS-treated lung （P 〈0.05）. Simvastatin inhibited the expression of RhoA and p38 phosphorylation in lung following LPS stimulation （P 〈0.05）. However, the increased expression of p38 protein in LPS-treated lung was not affected by simvastatin administration. Conclusions Simvastatin attenuates airway mucus hypersecretion and pulmonary inflammatory damage induced by LPS. The inhibitory effect of simvastatin on airway mucus hypersecretion may be through, at least in part, the suppression of neutrophil accumulation and inflammatory cytokine release via inactivation of RhoA and p38 signaling pathway.展开更多
Mucus hypersecretion is a distinguishing feature of chronic inflammation diseases, such as asthma,chronic bronchitis, bronchiectasis and cystic fibrosis Mucus hypersecretion leads to impairment of mucociliary clearanc...Mucus hypersecretion is a distinguishing feature of chronic inflammation diseases, such as asthma,chronic bronchitis, bronchiectasis and cystic fibrosis Mucus hypersecretion leads to impairment of mucociliary clearance, abnormal bacterial plantation, mucus plug in the airway, and dysfunction of gas exchange.5 To block this vicious cycle, chronic inflammation in the airway must be controlled and mucus hypersecretion must be reduced.展开更多
Background Airway mucus hypersecretion is an important pathophysiological feature of chronic obstructive pulmonary disease, which is closely associated with cigarette smoking. However, the signal transduction pathway ...Background Airway mucus hypersecretion is an important pathophysiological feature of chronic obstructive pulmonary disease, which is closely associated with cigarette smoking. However, the signal transduction pathway from the cell surface to the nucleus through which cigarette smoke causes upregulation of mucin gene expression is not well known. This study was designed to investigate the role of extracellular signal-regulated Kinase 1/2 （ERK 1/2） in airway mucus hypersecretion induced by cigarette smoke in rats. Methods A rat model of airway mucus hypersecretion was induced by exposure to cigarette smoke for 4 weeks. Rats exposed to inhalation of cigarette smoke or normal saline were given an intraperitoneal injection of U0126, a specific MEK1 kinase inhibitor, at doses of 0.25 mg/kg, 0.5 mg/kg and 1 mg/kg for 14 days. Expression of MUC5AC mRNA and protein, ERK 1/2 and phosphorylated-ERK 1/2 （p-ERK 1/2） were detected by RT-PCR, immunohistochemistry and Western blotting. Results Cigarette smoke significantly increased airway goblet cells metaplasia, induced the overexpression of MUC5AC mRNA and protein in bronchial epithelia, and increased the ratio of p-ERK 1/2 and ERK 1/2. U0126 significantly attentuated the expression of MUC5AC mRNA and protein induced by cigarette smoke （P 〈0.05）. Moreover, there was a significant positive correlation between the ratio of p-ERK1/2 to ERK1/2 and the expression of MUC5AC mRNA and protein （P 〈0.05）. Conclusions Inhibition of ERK 1/2 by U0126 decreased the ratio of p-ERK 1/2 to ERK 1/2 and expression of MUC5AC mRNA and protein. ERK 1/2 may play an essential role in cigarette smoke-induced mucus hypersecretion in vivo.展开更多
Background:Mounting evidence,consistent with our previous study,showed thatγ-aminobutyric acid type A receptor(GABAAR)played an indispensable role in airway inflammation and mucus hypersecretion in asthma.Monocyte ch...Background:Mounting evidence,consistent with our previous study,showed thatγ-aminobutyric acid type A receptor(GABAAR)played an indispensable role in airway inflammation and mucus hypersecretion in asthma.Monocyte chemotactic protein-inducing protein 1(MCPIP1)was a key negative regulator of inflammation.Recent studies showed that inflammation was largely suppressed by enhanced MCPIP1 expression in many inflammatory diseases.However,the role and potential mechanism of MCPIP1 in airway inflammation and mucus hypersecretion in asthma were still not well studied.This study was to explore the role of MCPIP1 in asthmatic airway inflammation and mucus hypersecretion in both mice and BEAS-2B cells,and its potential mechanism.Methods:In vivo,mice were sensitized and challenged by ovalbumin(OVA)to induce asthma.Airway inflammation and mucus secretion were analyzed.In vitro,BEAS-2B cells were chosen.Interleukin(IL)-13 was used to stimulate inflammation and mucus hypersecretion in cells.MCPIP1 Lentiviral vector(LA-MCPIP1)and plasmid-MCPIP1 were used to up-regulate MCPIP1 in lung and cells,respectively.MCP-1,thymic stromal lymphopoietin(TSLP),mucin 5AC(MUC5AC),MCPIP1,and GABAARβ2 expressions were measured in both lung and BEAS-2B cells.Immunofluorescence staining was performed to observe the expression of GABAARβ2 in cells.Results:MCPIP1 was up-regulated by LA-MCPIP1(P<0.001)and plasmid-MCPIP1(P<0.001)in lung and cells,respectively.OVA-induced airway inflammation and mucus hypersecretion,OVA-enhanced MCP-1,TSLP,MUC5AC,and GABAARβ2 expressions,and OVA-reduced MCPIP1 were significantly blunted by LA-MCPIP1 in mice(all P<0.001).IL-13-enhanced MCP-1,TSLP,MUC5AC,and GABAARβ2 expressions,and IL-13-reduced MCPIP1 were markedly abrogated by plasmid-MCPIP1 in BEAS-2B cells(all P<0.001).Conclusion:The results of this study suggested that OVA and IL-13-induced airway inflammation and mucus hypersecretion were negatively regulated by MCPIP1 in both lung and BEAS-2B cells,involving GABAAR signaling pathway.展开更多
The choroid plexus(ChP)serves as the principal origin of cerebrospinal fluid(CSF).CSF hypersecretion due to ChP inflammation has emerged as an important pathogenesis of hydrocephalus recently.Nevertheless,the precise ...The choroid plexus(ChP)serves as the principal origin of cerebrospinal fluid(CSF).CSF hypersecretion due to ChP inflammation has emerged as an important pathogenesis of hydrocephalus recently.Nevertheless,the precise mechanisms of ChP inflammation and the ensuing CSF hypersecretion in hydrocephalus remain ill-defined.In the present study,we elucidate the critical role of macrophages in the pathogenesis of ChP inflammation.Specifically,we identify the chemokine CCL2,released by ChP epithelial cells,recruits CCR2+monocytes to the ChP thereby inciting hydrocephalus pathogenesis.The accumulated ChP macrophages increase the inflammation in ChP epithelial cells through TNF-α/TNFR1/NF-κB signaling cascade,thereby leading to CSF hypersecretion.Strikingly,augmentation of ChP‒CCL2 using an adeno-associated viral approach(AAV)exacerbates macrophage recruitment,activation,and ventriculomegaly in rat PHH models.Systemic application of Bindarit,a specific CCL2 inhibitor,significantly inhibits ChP macrophage infiltration and activation and reduces CSF secretion rate.Furthermore,the administration of CCR2 antagonist(INCB 3284)reduces ChP macrophage accumulation and ventriculomegaly.This study not only unveils the ChP CCL2‒CCR2 signaling in the pathophysiology of hydrocephalus but also unveils Bindarit as a promising therapeutic choice for the management of posthemorrhagic hydrocephalus.展开更多
AIM： To examine the effect of acute infection caused by herpesvirus （pseudorabies virus, PRV） on pancreatic ductal secretion. METHODS： The virulent Ba-DupGreen （BDG） and non- virulent Ka-RREp01acgfp （KEG） gene...AIM： To examine the effect of acute infection caused by herpesvirus （pseudorabies virus, PRV） on pancreatic ductal secretion. METHODS： The virulent Ba-DupGreen （BDG） and non- virulent Ka-RREp01acgfp （KEG） genetically modified strains of PRV were used in this study and both of them contain the gene for green fluorescent protein （GFP）. Small intra/ interlobular ducts were infected with BDG virus （10^7 PFU/mL for 6 h） or with KEG virus （10^10 PFU/mL for 6 h）, while non-infected ducts were incubated only with the culture media. The ducts were then cultured for a further 18 h. The rate of HCO3 secretion [base efflux -λ（B）] was determined from the buffering capacity of the cells and the initial rate of intracellular acidification （1） after sudden blockage of basolateral base loaders with dihydro-4,4,- diisothiocyanatostilbene-2,2,-disulfonic acid （500 μmol/L） and amiloride （200 μmol/L）, and （2） after alkali loading the ducts by exposure to NH4Cl. All the experiments were performed in HCO3-buffered Ringer solution at 37 ℃ （n = 5 ducts for each experimental condition）. Viral structural proteins were visualized by immunohistochemistry. Virallyencoded GFP and immunofluorescence signals were recorded by a confocal laser scanning microscope.RESULTS： The BDG virus infected the majority of accessible cells of the duct as judged by the appearance of GFP and viral anUgens in the ductal cells. KEG virus caused a similarly high efficiency of infection. After blockage of basolateral base loaders, BDG infection significantly elevated -λB-） 24 h after the infection, compared to the non-infected group. However, KEG infection did not modify -λB-）. After alkali loading the ducts, -λB-） was significantly elevated in the BDG group compared to the control group 24 h after the infection. As we found with the inhibitor stop method, no change was observed in the group KEG compared to the non-infected group. CONCLUSION： Incubation with the BDG or KEG strains of PRV results in an effective infection of ductal epithelial cells. The BDG strain of PRV, which is able to initiate a lytic viral cycle, stimulates HCO3 secretion in guinea pig pancreatic duct by about fourto fivefold, 24 h after the infection. However, the KEG strain of PRV, which can infect, but fails to replicate, has no effect on HCO3 secretion. We suggest that this response of pancreatic ducts to virulent PRV infection may represent a defense mechanism against invasive pathogens to avoid pancreatic injury.展开更多
Gastric acid plays an important role in digesting food （especially protein）, iron absorption, and destroying swallowed micro-organisms. H＋ is secreted by the oxyntic parietal cells and its secretion is regulated by...Gastric acid plays an important role in digesting food （especially protein）, iron absorption, and destroying swallowed micro-organisms. H＋ is secreted by the oxyntic parietal cells and its secretion is regulated by endocrine, neurocrine and paracrine mechanisms. Gastrin released from the antral G cell is the principal physiological stimulus of gastric acid secretion. Activation of the enterochromaffin-like （ECL） cell is accepted as the main source of histamine participating in the regulation of acid secretion and is functionally and trophically controlled by gastrin, which is mediated by gastrin/CCK-2 receptors expressed on the ECL cell. However, longterm hypergastrinemia will induce ECL cell hyperplasia and probably carcinoids. Clinically, potent inhibitors of acid secretion have been prescribed widely to patients with acid-related disorders. Long-term potent acid inhibition evokes a marked increase in plasma gastdn levels, leading to enlargement of oxyntic mucosa with ECL cell hyperplasia. Accordingly, the induction of ECL cell hyperplasia and carcinoids remains a topic of considerable concern, especially in long-term use. In addition, the activation of ECL cells also induces another clinical concem, i.e., rebound acid hypersecretion after acid inhibition. Recent experimental and clinical findings indicate that the activation of ECL cells plays a critical role both physiologically and dinically in the regulation of gastric acid secretion.展开更多
Objective:To observe the effect of Elephantopus scaber Linn on chronic obstructive pulmonary disease(COPD),to investigate its effect on the MUC5AC hypersecretion of airway mucus mediated by neutrophil elastin in patie...Objective:To observe the effect of Elephantopus scaber Linn on chronic obstructive pulmonary disease(COPD),to investigate its effect on the MUC5AC hypersecretion of airway mucus mediated by neutrophil elastin in patients with acute exacerbation of COPD,and to observe its effect on lung function(FEV1,FEV1/FVC),so as to provide new ideas and theoretical basis for the prevention and treatment of COPD.Methods:160 patients with acute exacerbation of COPD were randomly divided into observation group and control group with 80 cases each according to the numerical table method.The observation group was treated with aerosol inhalation of Elephantopus scaber Linn on the basis of conventional treatment.Both groups were treated for 2 weeks.During the same period,80 healthy patients were selected as the healthy control group.The expression of NE and MUC5AC in serum of observation group,control group and healthy control group before and after treatment was detected by enzymelinked immunosorbent assay(ELISA).The changes of lung function(FEV1,FEV1/FVC)after treatment in the observation group and the control group were compared and analyzed,and the efficacy of Elephantopus scaber Linn in patients with acute exacerbation of copd was observed.Results:Compared with the control group,the total effective rate of the observation group was significantly better than that of the control group,with statistical significance(P<0.05).Compared with the healthy control group,there were significant differences in serum NE and MUC5AC between the observation group and the control group(P<0.05).Serum NE,MUC5AC,FEV1 and FEV1/FVC were significantly different in the observation group before and after treatment(P<0.05).Serum NE,MUC5AC,FEV1 and FEV1/FVC were significantly different in the observation group before and after treatment(P<0.05).Compared with the control group after treatment,there were significant differences in serum NE and MUC5AC in the observation group after treatment(P<0.05),and the increase of FEV1/FVC and FEV1 was significantly better than that of the control group after treatment(P<0.05).Conclusion:Elephantopus scaber Linn can significantly improve the clinical treatment effect of patients with acute exacerbation of COPD,improve lung function and airway mucus hypersecretion.It can effectively inhibit the expression of NE and MUC5AC in the blood.There were significant differences in serum NE and MUC5AC between the observation group and the control group after treatment(P<0.05),showing a positive correlation,suggesting that inhibition of MUC5AC secretion by Elephantopus scaber Linn in patients with COPD may be related to NE-mediated pathways.展开更多
Objective:To explore the role of NLRP3 in mucus hypersecretion in asthmatic patients.Methods:From January 2020 to June 2022,90 patients with asthma and 60 healthy patients under the Department of Pulmonary and Critica...Objective:To explore the role of NLRP3 in mucus hypersecretion in asthmatic patients.Methods:From January 2020 to June 2022,90 patients with asthma and 60 healthy patients under the Department of Pulmonary and Critical Care Medicine of the First Affiliated Hospital of Xi’an Medical University were selected.Immunohistochemistry and enzyme-linked immunosorbent assay were performed.NLRP3 inflammasome and mucins MUC5AC and MUC5B levels in lung tissue and sputum were detected.Results:Compared to the healthy control group,the asthma group had significantly higher sputum MUC5A(20.12±5.07 versus 36.21±6.13)and NLRP3(72.31±15.13 versus 119.21±31.21)levels(P<0.05)but lower MUC5B levels(1.35±0.12 versus 0.53±0.11,P<0.05).Immunohistochemistry showed that NLRP3,MUC5AC,and MUC5B expressions were consistent with the sputum results.Conclusion:NLRP3 and MUC5AC levels are significantly increased in asthmatic patients,whereas MUC5B levels are reduced in these patients.They can be used as targets for the diagnosis and treatment of asthma.展开更多
While the skin is among the most commonly affected organ systems in systemic lupus erythematosus(SLE),the role of the skin in driving disease onset remains unresolved.In their recent work,Tian et al.reported that PPAR...While the skin is among the most commonly affected organ systems in systemic lupus erythematosus(SLE),the role of the skin in driving disease onset remains unresolved.In their recent work,Tian et al.reported that PPARy deficiency in keratinocytes(KCs)leads to epidermal hypersecretion of type I IFN.The resulting IFNrich environment activates local dendritic cells(DCs),which in turn activate autoreactive T cells to precipitate SLE-like autoimmune disease[1].展开更多
Background Chronic obstructive pulmonary disease （COPD） is associated not only with airway inflammation characterized by mucin hypersecretion but also with systemic inflammation. Tumor necrosis factor alpha （TNF-α...Background Chronic obstructive pulmonary disease （COPD） is associated not only with airway inflammation characterized by mucin hypersecretion but also with systemic inflammation. Tumor necrosis factor alpha （TNF-α） is found to take part in systemic inflammation, and ErbB3 plays an important role in mucin hypersecretion of COPD. Since TNF-α converting enzyme （TACE） is involved in the activation of both TNF-α and ErbB3, we established rat models of COPD to investigate the expressions of TACE, TNF-α and ErbB3 and to explore the correlations among TACE,TNF-α and ErbB3 respectively. Methods Thirty Wistar male rats were randomly divided into COPD group （group C, n=10）, saline solution parallel group （group P, n=-8）, and normal control group （group N, n=-8）. Group C was challenged with passive cigarette smoking and intratracheal instillation of lipopolysaccharide. Six weeks later pulmonary functions were tested, bronchoalveolar fluid and arterial blood gases were assayed, and histopathological evaluations were performed in turn. The expressions of TACE, TNF-α and ErbB3 in lungs of all rats were determined histochemically. Results The expressions of TACE, TNF-α and ErbB3 were significantly higher in group C than in group N （P〈0.01）. The contents of TNF-α in serum （P〈0.01） and bronchoalveolar lavage fluid （BALF） （P〈0.01） were elevated more significantly in group C than in group N. A positive correlation existed between TACE and TNF-α （r=0.784, P〈0.01） and between TACE and ErbB3 （r=0.526, P〈0.01） respectively. Conclusions TNF-α and ErbB3 are involved in the pathogenesis of COPD. TACE contributes to the progress of COPD indirectly through the function of TNF-α and ErbB3.展开更多
Brain-specific serine/threonine-protein kinase 2(BRSK2)plays critical roles in insulin secretion andβ-cell biology.However,whether BRSK2 is associated with human type 2 diabetes mellitus(T2DM)has not been determined....Brain-specific serine/threonine-protein kinase 2(BRSK2)plays critical roles in insulin secretion andβ-cell biology.However,whether BRSK2 is associated with human type 2 diabetes mellitus(T2DM)has not been determined.Here,we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population.BRSK2 protein levels are significantly elevated inβcells from T2DM patients and high-fat diet(HFD)-fed mice due to enhanced protein stability.Mice with inducibleβ-cell-specific Brsk2 knockout(βKO)exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions.Moreover,βKO mice are protected from HFD-induced hyperinsulinemia,obesity,insulin resistance,and glucose intolerance.Conversely,gain-of-function BRSK2 in matureβcells reversibly triggers hyperglycemia due toβ-cell hypersecretion-coupled insulin resistance.Mechanistically,BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner.The enhanced basal insulin secretion drives insulin resistance andβ-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 inβcells.These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay betweenβcells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.展开更多
基金This study was supported by grants from National Natural Science Foundation of China to Dr. WEN Fu-qing （No. 30425007, 30370627, 30670921） and from China Medical Board of New York to Dr. WEN Fu-qiang （No. 0-722）.
文摘Background Mucus hypersecretion in the respiratory tract and goblet cell metaplasia in the airway epithelium contribute to the morbidity and mortality associated with airway inflammatory diseases. This study aimed to examine the effect and mechanisms of simvastatin on airway mucus hypersecretion in rats treated with lipopolysaccharide （LPS）. Methods Mucus hypersecretion in rat airways was induced by intra-tracheal instillation of LPS. Rats treated with or without LPS were administered intra-peritoneally simvastatin （5 and 20 mg/kg） for 4 days. Expression of Muc5ac, RhoA and mitogen-activated protein kinases （MAPK） p38 in lung were detected by real-time polymerase chain reaction （PCR）, immunohistochemistry or Western blotting. Tumor necrosis factor （TNF）-α and IL-8 in bronchoalveolar lavage fluid （BALF） were assayed by an enzyme-linked lectin assay and enzyme linked immunosorbent assay （ELISA）. Results Simvastatin attenuated LPS-induced goblet cell hyperplasia in bronchial epithelium and Muc5ac hypersecretion at both the gene and protein levels in lung （P 〈0.05）. Moreover, simvastatin inhibited neutrophil accumulation and the increased concentration of TNF-α and IL-8 in BALF follows LPS stimulation （P 〈0.05）. The higher dose of simvastatin was associated with a more significant reduction in Muc5ac mRNA expression, neutrophil accumulation and inflammatory cytokine release. Simultaneously, the increased expression of RhoA and p38 MAPK were observed in LPS-treated lung （P 〈0.05）. Simvastatin inhibited the expression of RhoA and p38 phosphorylation in lung following LPS stimulation （P 〈0.05）. However, the increased expression of p38 protein in LPS-treated lung was not affected by simvastatin administration. Conclusions Simvastatin attenuates airway mucus hypersecretion and pulmonary inflammatory damage induced by LPS. The inhibitory effect of simvastatin on airway mucus hypersecretion may be through, at least in part, the suppression of neutrophil accumulation and inflammatory cytokine release via inactivation of RhoA and p38 signaling pathway.
基金This study was supported by the grants from National Natural Science Foundation of China and China Medical Board of New York to Dr. Wen （No. 30425007, 30370627, 00-722, 00-384）.
文摘Mucus hypersecretion is a distinguishing feature of chronic inflammation diseases, such as asthma,chronic bronchitis, bronchiectasis and cystic fibrosis Mucus hypersecretion leads to impairment of mucociliary clearance, abnormal bacterial plantation, mucus plug in the airway, and dysfunction of gas exchange.5 To block this vicious cycle, chronic inflammation in the airway must be controlled and mucus hypersecretion must be reduced.
基金This study was supported by a grant from China Postdoctoral Science Foundation （No. 37508）.
文摘Background Airway mucus hypersecretion is an important pathophysiological feature of chronic obstructive pulmonary disease, which is closely associated with cigarette smoking. However, the signal transduction pathway from the cell surface to the nucleus through which cigarette smoke causes upregulation of mucin gene expression is not well known. This study was designed to investigate the role of extracellular signal-regulated Kinase 1/2 （ERK 1/2） in airway mucus hypersecretion induced by cigarette smoke in rats. Methods A rat model of airway mucus hypersecretion was induced by exposure to cigarette smoke for 4 weeks. Rats exposed to inhalation of cigarette smoke or normal saline were given an intraperitoneal injection of U0126, a specific MEK1 kinase inhibitor, at doses of 0.25 mg/kg, 0.5 mg/kg and 1 mg/kg for 14 days. Expression of MUC5AC mRNA and protein, ERK 1/2 and phosphorylated-ERK 1/2 （p-ERK 1/2） were detected by RT-PCR, immunohistochemistry and Western blotting. Results Cigarette smoke significantly increased airway goblet cells metaplasia, induced the overexpression of MUC5AC mRNA and protein in bronchial epithelia, and increased the ratio of p-ERK 1/2 and ERK 1/2. U0126 significantly attentuated the expression of MUC5AC mRNA and protein induced by cigarette smoke （P 〈0.05）. Moreover, there was a significant positive correlation between the ratio of p-ERK1/2 to ERK1/2 and the expression of MUC5AC mRNA and protein （P 〈0.05）. Conclusions Inhibition of ERK 1/2 by U0126 decreased the ratio of p-ERK 1/2 to ERK 1/2 and expression of MUC5AC mRNA and protein. ERK 1/2 may play an essential role in cigarette smoke-induced mucus hypersecretion in vivo.
基金supported by grants from the National Natural Science Foundation of China for Young Scholar(No.81801484)China Postdoctoral Science Foundation(No.2014M552369)+1 种基金Natural Science Foundation of Guangdong Province(No.2017A030310286)Scientific Research Project of Guangzhou(No.201707010282)。
文摘Background:Mounting evidence,consistent with our previous study,showed thatγ-aminobutyric acid type A receptor(GABAAR)played an indispensable role in airway inflammation and mucus hypersecretion in asthma.Monocyte chemotactic protein-inducing protein 1(MCPIP1)was a key negative regulator of inflammation.Recent studies showed that inflammation was largely suppressed by enhanced MCPIP1 expression in many inflammatory diseases.However,the role and potential mechanism of MCPIP1 in airway inflammation and mucus hypersecretion in asthma were still not well studied.This study was to explore the role of MCPIP1 in asthmatic airway inflammation and mucus hypersecretion in both mice and BEAS-2B cells,and its potential mechanism.Methods:In vivo,mice were sensitized and challenged by ovalbumin(OVA)to induce asthma.Airway inflammation and mucus secretion were analyzed.In vitro,BEAS-2B cells were chosen.Interleukin(IL)-13 was used to stimulate inflammation and mucus hypersecretion in cells.MCPIP1 Lentiviral vector(LA-MCPIP1)and plasmid-MCPIP1 were used to up-regulate MCPIP1 in lung and cells,respectively.MCP-1,thymic stromal lymphopoietin(TSLP),mucin 5AC(MUC5AC),MCPIP1,and GABAARβ2 expressions were measured in both lung and BEAS-2B cells.Immunofluorescence staining was performed to observe the expression of GABAARβ2 in cells.Results:MCPIP1 was up-regulated by LA-MCPIP1(P<0.001)and plasmid-MCPIP1(P<0.001)in lung and cells,respectively.OVA-induced airway inflammation and mucus hypersecretion,OVA-enhanced MCP-1,TSLP,MUC5AC,and GABAARβ2 expressions,and OVA-reduced MCPIP1 were significantly blunted by LA-MCPIP1 in mice(all P<0.001).IL-13-enhanced MCP-1,TSLP,MUC5AC,and GABAARβ2 expressions,and IL-13-reduced MCPIP1 were markedly abrogated by plasmid-MCPIP1 in BEAS-2B cells(all P<0.001).Conclusion:The results of this study suggested that OVA and IL-13-induced airway inflammation and mucus hypersecretion were negatively regulated by MCPIP1 in both lung and BEAS-2B cells,involving GABAAR signaling pathway.
基金the National Natural Science Foundation of China(82201501)the Natural Science Foundation of Sichuan Province(2023NSFC1581,China)+1 种基金1·3.5 projects for disciplines of excellence-Clinical Research Incubation Project,West China Hospital,Sichuan University(No.2020HXFH013,China)Sichuan Science and Technology Program(22ZDYF2619,China)for financial support.
文摘The choroid plexus(ChP)serves as the principal origin of cerebrospinal fluid(CSF).CSF hypersecretion due to ChP inflammation has emerged as an important pathogenesis of hydrocephalus recently.Nevertheless,the precise mechanisms of ChP inflammation and the ensuing CSF hypersecretion in hydrocephalus remain ill-defined.In the present study,we elucidate the critical role of macrophages in the pathogenesis of ChP inflammation.Specifically,we identify the chemokine CCL2,released by ChP epithelial cells,recruits CCR2+monocytes to the ChP thereby inciting hydrocephalus pathogenesis.The accumulated ChP macrophages increase the inflammation in ChP epithelial cells through TNF-α/TNFR1/NF-κB signaling cascade,thereby leading to CSF hypersecretion.Strikingly,augmentation of ChP‒CCL2 using an adeno-associated viral approach(AAV)exacerbates macrophage recruitment,activation,and ventriculomegaly in rat PHH models.Systemic application of Bindarit,a specific CCL2 inhibitor,significantly inhibits ChP macrophage infiltration and activation and reduces CSF secretion rate.Furthermore,the administration of CCR2 antagonist(INCB 3284)reduces ChP macrophage accumulation and ventriculomegaly.This study not only unveils the ChP CCL2‒CCR2 signaling in the pathophysiology of hydrocephalus but also unveils Bindarit as a promising therapeutic choice for the management of posthemorrhagic hydrocephalus.
基金Supported by a Wellcome Trust IRDA Grant to P.H. (No. 022618)Hungarian Scientific Research Funds to P.H. and J.L. (No. D42188,T43066)a Wellcome Trust Travelling Fellowship to Z.R. (No. 069470)a Bolyai Postdoctoral Fellowship to P.H. (No. 00276/04)a National Fund for Scientific Research (OTKA) to Z.B. (No. T049171)
文摘AIM： To examine the effect of acute infection caused by herpesvirus （pseudorabies virus, PRV） on pancreatic ductal secretion. METHODS： The virulent Ba-DupGreen （BDG） and non- virulent Ka-RREp01acgfp （KEG） genetically modified strains of PRV were used in this study and both of them contain the gene for green fluorescent protein （GFP）. Small intra/ interlobular ducts were infected with BDG virus （10^7 PFU/mL for 6 h） or with KEG virus （10^10 PFU/mL for 6 h）, while non-infected ducts were incubated only with the culture media. The ducts were then cultured for a further 18 h. The rate of HCO3 secretion [base efflux -λ（B）] was determined from the buffering capacity of the cells and the initial rate of intracellular acidification （1） after sudden blockage of basolateral base loaders with dihydro-4,4,- diisothiocyanatostilbene-2,2,-disulfonic acid （500 μmol/L） and amiloride （200 μmol/L）, and （2） after alkali loading the ducts by exposure to NH4Cl. All the experiments were performed in HCO3-buffered Ringer solution at 37 ℃ （n = 5 ducts for each experimental condition）. Viral structural proteins were visualized by immunohistochemistry. Virallyencoded GFP and immunofluorescence signals were recorded by a confocal laser scanning microscope.RESULTS： The BDG virus infected the majority of accessible cells of the duct as judged by the appearance of GFP and viral anUgens in the ductal cells. KEG virus caused a similarly high efficiency of infection. After blockage of basolateral base loaders, BDG infection significantly elevated -λB-） 24 h after the infection, compared to the non-infected group. However, KEG infection did not modify -λB-）. After alkali loading the ducts, -λB-） was significantly elevated in the BDG group compared to the control group 24 h after the infection. As we found with the inhibitor stop method, no change was observed in the group KEG compared to the non-infected group. CONCLUSION： Incubation with the BDG or KEG strains of PRV results in an effective infection of ductal epithelial cells. The BDG strain of PRV, which is able to initiate a lytic viral cycle, stimulates HCO3 secretion in guinea pig pancreatic duct by about fourto fivefold, 24 h after the infection. However, the KEG strain of PRV, which can infect, but fails to replicate, has no effect on HCO3 secretion. We suggest that this response of pancreatic ducts to virulent PRV infection may represent a defense mechanism against invasive pathogens to avoid pancreatic injury.
文摘Gastric acid plays an important role in digesting food （especially protein）, iron absorption, and destroying swallowed micro-organisms. H＋ is secreted by the oxyntic parietal cells and its secretion is regulated by endocrine, neurocrine and paracrine mechanisms. Gastrin released from the antral G cell is the principal physiological stimulus of gastric acid secretion. Activation of the enterochromaffin-like （ECL） cell is accepted as the main source of histamine participating in the regulation of acid secretion and is functionally and trophically controlled by gastrin, which is mediated by gastrin/CCK-2 receptors expressed on the ECL cell. However, longterm hypergastrinemia will induce ECL cell hyperplasia and probably carcinoids. Clinically, potent inhibitors of acid secretion have been prescribed widely to patients with acid-related disorders. Long-term potent acid inhibition evokes a marked increase in plasma gastdn levels, leading to enlargement of oxyntic mucosa with ECL cell hyperplasia. Accordingly, the induction of ECL cell hyperplasia and carcinoids remains a topic of considerable concern, especially in long-term use. In addition, the activation of ECL cells also induces another clinical concem, i.e., rebound acid hypersecretion after acid inhibition. Recent experimental and clinical findings indicate that the activation of ECL cells plays a critical role both physiologically and dinically in the regulation of gastric acid secretion.
基金National Natural Science Foundation of China(No.81660010,31660329,8191101552)。
文摘Objective:To observe the effect of Elephantopus scaber Linn on chronic obstructive pulmonary disease(COPD),to investigate its effect on the MUC5AC hypersecretion of airway mucus mediated by neutrophil elastin in patients with acute exacerbation of COPD,and to observe its effect on lung function(FEV1,FEV1/FVC),so as to provide new ideas and theoretical basis for the prevention and treatment of COPD.Methods:160 patients with acute exacerbation of COPD were randomly divided into observation group and control group with 80 cases each according to the numerical table method.The observation group was treated with aerosol inhalation of Elephantopus scaber Linn on the basis of conventional treatment.Both groups were treated for 2 weeks.During the same period,80 healthy patients were selected as the healthy control group.The expression of NE and MUC5AC in serum of observation group,control group and healthy control group before and after treatment was detected by enzymelinked immunosorbent assay(ELISA).The changes of lung function(FEV1,FEV1/FVC)after treatment in the observation group and the control group were compared and analyzed,and the efficacy of Elephantopus scaber Linn in patients with acute exacerbation of copd was observed.Results:Compared with the control group,the total effective rate of the observation group was significantly better than that of the control group,with statistical significance(P<0.05).Compared with the healthy control group,there were significant differences in serum NE and MUC5AC between the observation group and the control group(P<0.05).Serum NE,MUC5AC,FEV1 and FEV1/FVC were significantly different in the observation group before and after treatment(P<0.05).Serum NE,MUC5AC,FEV1 and FEV1/FVC were significantly different in the observation group before and after treatment(P<0.05).Compared with the control group after treatment,there were significant differences in serum NE and MUC5AC in the observation group after treatment(P<0.05),and the increase of FEV1/FVC and FEV1 was significantly better than that of the control group after treatment(P<0.05).Conclusion:Elephantopus scaber Linn can significantly improve the clinical treatment effect of patients with acute exacerbation of COPD,improve lung function and airway mucus hypersecretion.It can effectively inhibit the expression of NE and MUC5AC in the blood.There were significant differences in serum NE and MUC5AC between the observation group and the control group after treatment(P<0.05),showing a positive correlation,suggesting that inhibition of MUC5AC secretion by Elephantopus scaber Linn in patients with COPD may be related to NE-mediated pathways.
基金This work was supported by Xi’an Science and Technology Plan Project(22YXYJ0136).
文摘Objective:To explore the role of NLRP3 in mucus hypersecretion in asthmatic patients.Methods:From January 2020 to June 2022,90 patients with asthma and 60 healthy patients under the Department of Pulmonary and Critical Care Medicine of the First Affiliated Hospital of Xi’an Medical University were selected.Immunohistochemistry and enzyme-linked immunosorbent assay were performed.NLRP3 inflammasome and mucins MUC5AC and MUC5B levels in lung tissue and sputum were detected.Results:Compared to the healthy control group,the asthma group had significantly higher sputum MUC5A(20.12±5.07 versus 36.21±6.13)and NLRP3(72.31±15.13 versus 119.21±31.21)levels(P<0.05)but lower MUC5B levels(1.35±0.12 versus 0.53±0.11,P<0.05).Immunohistochemistry showed that NLRP3,MUC5AC,and MUC5B expressions were consistent with the sputum results.Conclusion:NLRP3 and MUC5AC levels are significantly increased in asthmatic patients,whereas MUC5B levels are reduced in these patients.They can be used as targets for the diagnosis and treatment of asthma.
文摘While the skin is among the most commonly affected organ systems in systemic lupus erythematosus(SLE),the role of the skin in driving disease onset remains unresolved.In their recent work,Tian et al.reported that PPARy deficiency in keratinocytes(KCs)leads to epidermal hypersecretion of type I IFN.The resulting IFNrich environment activates local dendritic cells(DCs),which in turn activate autoreactive T cells to precipitate SLE-like autoimmune disease[1].
文摘Background Chronic obstructive pulmonary disease （COPD） is associated not only with airway inflammation characterized by mucin hypersecretion but also with systemic inflammation. Tumor necrosis factor alpha （TNF-α） is found to take part in systemic inflammation, and ErbB3 plays an important role in mucin hypersecretion of COPD. Since TNF-α converting enzyme （TACE） is involved in the activation of both TNF-α and ErbB3, we established rat models of COPD to investigate the expressions of TACE, TNF-α and ErbB3 and to explore the correlations among TACE,TNF-α and ErbB3 respectively. Methods Thirty Wistar male rats were randomly divided into COPD group （group C, n=10）, saline solution parallel group （group P, n=-8）, and normal control group （group N, n=-8）. Group C was challenged with passive cigarette smoking and intratracheal instillation of lipopolysaccharide. Six weeks later pulmonary functions were tested, bronchoalveolar fluid and arterial blood gases were assayed, and histopathological evaluations were performed in turn. The expressions of TACE, TNF-α and ErbB3 in lungs of all rats were determined histochemically. Results The expressions of TACE, TNF-α and ErbB3 were significantly higher in group C than in group N （P〈0.01）. The contents of TNF-α in serum （P〈0.01） and bronchoalveolar lavage fluid （BALF） （P〈0.01） were elevated more significantly in group C than in group N. A positive correlation existed between TACE and TNF-α （r=0.784, P〈0.01） and between TACE and ErbB3 （r=0.526, P〈0.01） respectively. Conclusions TNF-α and ErbB3 are involved in the pathogenesis of COPD. TACE contributes to the progress of COPD indirectly through the function of TNF-α and ErbB3.
基金supported by research grants from the National Natural Science Foundation of China(81420108007 and 81830024 to X.H.,82270844,82070843,and 81870531 to Y.Zhu).
文摘Brain-specific serine/threonine-protein kinase 2(BRSK2)plays critical roles in insulin secretion andβ-cell biology.However,whether BRSK2 is associated with human type 2 diabetes mellitus(T2DM)has not been determined.Here,we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population.BRSK2 protein levels are significantly elevated inβcells from T2DM patients and high-fat diet(HFD)-fed mice due to enhanced protein stability.Mice with inducibleβ-cell-specific Brsk2 knockout(βKO)exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions.Moreover,βKO mice are protected from HFD-induced hyperinsulinemia,obesity,insulin resistance,and glucose intolerance.Conversely,gain-of-function BRSK2 in matureβcells reversibly triggers hyperglycemia due toβ-cell hypersecretion-coupled insulin resistance.Mechanistically,BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner.The enhanced basal insulin secretion drives insulin resistance andβ-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 inβcells.These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay betweenβcells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.
