Survey the Immuno-pharmacology Effect of Botulinum Toxin in Cell Signaling of Bronchial Smooth Muscle Cells of the Allergic Asthma

Abstract BackgroundAsthma is the lung disease that influenced more than 350 million people in worldwide. ASM spasm leads to AHR and bronchial obstruction that are acute symptoms of asthma attack. BTX is bacteria toxin that acts as muscle relaxant and may have therapeutic effect on AHR and asthma. Therefore, the effect of BTX on the AHR and related gene expression was evaluated.MethodsAfter producing of asthma mice model, which were treated with BTX in two ways; IN and N (0.01, 0.1, 1 and 10 U/ml). AHR was measured on day 24, 26, 28, 30 and gene expression of TrkA, TrkB, M1-M5, α7nAChR, TNF-α and ERK2 were evaluated. At least, in lung histopathology, perivascular and peribronchial inflammation, mucus production and goblet cell hyperplasia were studied. ResultsOn day 24, treatment with BTX for all dosages had no significant effect on AHR but, on day 26 and 28, AHR was decreased and it was continued on day 30 for all treated groups. Treatment with BTX had no significant effect on the expressions of TrkA, TrkB, M1, M2, M3, M4, M5, α7nAChR, TNF-α and ERK2 genes, perivascular inflammation, peribronchial inflammation, hyperplasia of the goblet cell and production of mucus. Also, the mice have been received BTX 10 mg/ml, were died. ConclusionsBTX therapy controlled asthma attacks via decreasing of AHR and induction of relaxation in the ASMs. But, it has no significant effect on inflammation and mucus production. In using of BTX, attention to the safe dose and prevention of dangerous side effects are necessary.

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A50 MODULATION OF GOBLET CELL ACTIVITY DURING GIARDIA DUODENALIS INFECTION: A ROLE FOR PAR2

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwab002.048 ◽

2021 ◽

Vol 4 (Supplement_1) ◽

pp. 6-7

Author(s):

E Fekete ◽

C B Amat ◽

T Allain ◽

M Hollenberg ◽

K Mihara ◽

...

Keyword(s):

Gene Expression ◽

Goblet Cell ◽

Cysteine Protease ◽

Protease Activity ◽

Calcium Release ◽

Cell Activity ◽

Goblet Cells ◽

Giardia Infection ◽

Mucus Production ◽

Mucin Gene

Abstract Background Giardia duodenalis has been shown to alter the structure of the intestinal mucus layers during infection via obscure mechanisms. We hypothesize that goblet cell activity may be disrupted in part due to proteolytic activation of protease-activated receptor 2 (PAR2) by Giardia proteases, resulting in disruption of mucus production and secretion by intestinal goblet cells. Aims Characterize alterations in goblet cell activity during Giardia infection, focusing on the roles of Giardia protease activity and PAR2. Methods Chinese hamster ovary cells transfected with nano-luciferase tagged PAR2 were incubated with Giardia NF or GSM trophozoites. Cleavage within the activation domain results in release of enzymes into the supernatant. Luminescence in the supernatant was measured as an indication of PAR cleavage by Giardia. LS174T, a human colonic mucus-producing cell line, was infected with Giardia trophozoites (isolates NF, WB, S2, and GSM). Prior to infection, trophozoites were treated with E64, a broad-spectrum cysteine protease inhibitor, and LS174T were treated with a PAR2 antagonist, a calcium chelator, or an ERK1/2 inhibitor. Quantitative PCR (qPCR) was performed for the MUC2 mucin gene. Wild-type (WT) and PAR2 knockout (KO) mice were infected with Giardia. Colonic mucus was stained using fluorescein-coupled wheat-germ agglutinin (WGA), and qPCR was performed for Muc2 and Muc5ac. Results Giardia trophozoites cleaved PAR2 within the N-terminal activation domain in a cysteine protease-dependent manner. Cleavage was isolate dependent, with isolates that show higher protease activity cleaving at a higher rate. High protease activity Giardia isolates increased MUC2 gene expression in LS714T. This increase was attenuated by inhibition of Giardia cysteine protease activity, and by antagonism of PAR2, inhibition of calcium release, or inhibition of ERK1/2 activity in LS174T cells. Both Muc2 and Muc5ac expression were upregulated in the colons of WT mice in response to Giardia infection, while in the jejunum Muc2 expression decreased and Muc5ac expression increased. In KO, no changes in gene expression were seen in the colon in response to Giardia infection, while in the jejunum, Muc2 expression was unchanged and Muc5ac expression decreased. Both WT infected and KO noninfected mice showed thinning of the colonic mucus layer compared to WT controls. There was some recovery in thickness in KO infected mice. Conclusions PAR2 plays a significant role in the regulation of mucin gene expression in mice and in a human colonic cell line. Results suggest that Giardia cysteine proteases cleave and activate PAR2, leading to calcium release and activation of the MAPK pathway in goblet cells, ultimately leading to altered mucin gene expression. Findings identify a novel regulatory pathway for mucus production by intestinal goblet cells. Funding Agencies CAG, CCC

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ILC2s mediate systemic innate protection by priming mucus production at distal mucosal sites

Journal of Experimental Medicine ◽

10.1084/jem.20180610 ◽

2019 ◽

Vol 216 (12) ◽

pp. 2714-2723 ◽

Cited By ~ 10

Author(s):

Laura Campbell ◽

Matthew R. Hepworth ◽

Jayde Whittingham-Dowd ◽

Seona Thompson ◽

Allison J. Bancroft ◽

...

Keyword(s):

Goblet Cell ◽

Helminth Infection ◽

Host Immunity ◽

Mucosal Barrier ◽

Parasitic Nematodes ◽

Cell Hyperplasia ◽

Mucus Production ◽

Mucin Production ◽

Helminth Infections

Host immunity to parasitic nematodes requires the generation of a robust type 2 cytokine response, characterized by the production of interleukin 13 (IL-13), which drives expulsion. Here, we show that infection with helminths in the intestine also induces an ILC2-driven, IL-13–dependent goblet cell hyperplasia and increased production of mucins (Muc5b and Muc5ac) at distal sites, including the lungs and other mucosal barrier sites. Critically, we show that type 2 priming of lung tissue through increased mucin production inhibits the progression of a subsequent lung migratory helminth infection and limits its transit through the airways. These data show that infection by gastrointestinal-dwelling helminths induces a systemic innate mucin response that primes peripheral barrier sites for protection against subsequent secondary helminth infections. These data suggest that innate-driven priming of mucus barriers may have evolved to protect from subsequent infections with multiple helminth species, which occur naturally in endemic areas.

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A Novel, Orally Active CXCR1/2 Receptor Antagonist, Sch527123, Inhibits Neutrophil Recruitment, Mucus Production, and Goblet Cell Hyperplasia in Animal Models of Pulmonary Inflammation

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.106.119040 ◽

2007 ◽

Vol 322 (2) ◽

pp. 486-493 ◽

Cited By ~ 89

Author(s):

Richard W. Chapman ◽

Michael Minnicozzi ◽

Chander S. Celly ◽

Jonathan E. Phillips ◽

Ted T. Kung ◽

...

Keyword(s):

Animal Models ◽

Receptor Antagonist ◽

Goblet Cell ◽

Pulmonary Inflammation ◽

Neutrophil Recruitment ◽

Cell Hyperplasia ◽

Mucus Production ◽

Goblet Cell Hyperplasia ◽

Orally Active

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Scopolamine-induced Delirium Promotes Neuroinflammation and Neuropsychiatric Disorder in Mice

10.21203/rs.3.rs-126768/v1 ◽

2020 ◽

Author(s):

So Yeong Cheon ◽

Bon-Nyeo Koo ◽

So Yeon Kim ◽

Eun Hee Kam ◽

Junhyun Nam ◽

...

Keyword(s):

Gene Expression ◽

Inflammatory Cytokines ◽

Expression Profiles ◽

Expression Patterns ◽

Gene Expression Profiles ◽

Brain Regions ◽

Mice Model ◽

Tnf Α ◽

Compare Gene Expression ◽

Pro Inflammatory Cytokines

Abstract BackgroundPostoperative delirium is a common neuropsychiatric syndrome resulting in a high postsurgical mortality rate and decline in postdischarge function. Extensive research has been performed on both human and animal delirium models due to their clinical significance, focusing on systemic inflammation and consequent neuroinflammation playing a key in the pathogenesis of postoperative cognitive dysfunctions. Since animal models are widely utilized for pathophysiological study of neuropsychiatric disorders, this study aimed at examining the validity of the scopolamine-induced delirium mice model with respect to the neuroinflammatory hypothesis of delirium. MethodsMale C57BL/6 mice were treated with intraperitoneal scopolamine (2 mg/kg). Neurobehavioural tests were performed to evaluate the changes in cognitive functions, including learning and memory, and the level of anxiety after surgery or scopolamine treatment. The levels of pro-inflammatory cytokines (IL-1ꞵ, IL-18, and TNF-α) and inflammasome components (NLRP3, ASC, and caspase-1) in different brain regions were measured. Gene expression profiles were also examined using whole-genome RNA sequencing analyses to compare gene expression patterns of different mice models.Results Scopolamine treatment showed significant increase in the level of anxiety and impairments in memory and cognitive function associated with increased level of pro-inflammatory cytokines and NLRP3 inflammasome components. Genetic analysis confirmed the different expression patterns of the genes involved in immune response and inflammation and those related with the development of the nervous system in both surgery and scopolamine-induced mice models. Conclusions The scopolamine-induced delirium mice model successfully showed that analogous neuropsychiatric changes coincide with the neuroinflammatory hypothesis for pathogenesis of delirium.

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Study effect of Ocimum basilicum seeds on mucus production and cytokine gene expression in allergic asthma mice model

Revue Française d Allergologie ◽

10.1016/j.reval.2018.08.003 ◽

2018 ◽

Vol 58 (7) ◽

pp. 489-493 ◽

Cited By ~ 3

Author(s):

S. Masoume Athari ◽

E. Mehrabi Nasab ◽

S. Shamsadin Athari

Keyword(s):

Gene Expression ◽

Allergic Asthma ◽

Ocimum Basilicum ◽

Cytokine Gene Expression ◽

Cytokine Gene ◽

Mice Model ◽

Mucus Production

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Scopolamine promotes neuroinflammation and delirium-like neuropsychiatric disorder in mice

Scientific Reports ◽

10.1038/s41598-021-87790-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

So Yeong Cheon ◽

Bon-Nyeo Koo ◽

So Yeon Kim ◽

Eun Hee Kam ◽

Junhyun Nam ◽

...

Keyword(s):

Gene Expression ◽

Inflammatory Cytokines ◽

Expression Profiles ◽

Expression Patterns ◽

Gene Expression Profiles ◽

Brain Regions ◽

Mice Model ◽

Tnf Α ◽

Compare Gene Expression ◽

Pro Inflammatory Cytokines

AbstractPostoperative delirium is a common neuropsychiatric syndrome resulting a high postsurgical mortality rate and decline in postdischarge function. Extensive research has been performed on both human and animal delirium-like models due to their clinical significance, focusing on systematic inflammation and consequent neuroinflammation playing a key role in the pathogenesis of postoperative cognitive dysfunctions. Since animal models are widely utilized for pathophysiological study of neuropsychiatric disorders, this study aimed at examining the validity of the scopolamine-induced delirium-like mice model with respect to the neuroinflammatory hypothesis of delirium. Male C57BL/6 mice were treated with intraperitoneal scopolamine (2 mg/kg). Neurobehavioral tests were performed to evaluate the changes in cognitive functions, including learning and memory, and the level of anxiety after surgery or scopolamine treatment. The levels of pro-inflammatory cytokines (IL-1β, IL-18, and TNF-α) and inflammasome components (NLRP3, ASC, and caspase-1) in different brain regions were measured. Gene expression profiles were also examined using whole-genome RNA sequencing analyses to compare gene expression patterns of different mice models. Scopolamine treatment showed significant increase in the level of anxiety and impairments in memory and cognitive function associated with increased level of pro-inflammatory cytokines and NLRP3 inflammasome components. Genetic analysis confirmed the different expression patterns of genes involved in immune response and inflammation and those related with the development of the nervous system in both surgery and scopolamine-induced mice models. The scopolamine-induced delirium-like mice model successfully showed that analogous neuropsychiatric changes coincides with the neuroinflammatory hypothesis for pathogenesis of delirium.

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Intestinal phenotype of variable-weight cystic fibrosis knockout mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00405.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. G222-G229 ◽

Cited By ~ 19

Author(s):

Juan C. Canale-Zambrano ◽

Maya C. Poffenberger ◽

Sean M. Cory ◽

Daryl G. Humes ◽

Christina K. Haston

Keyword(s):

Gene Expression ◽

Cystic Fibrosis ◽

Cell Proliferation ◽

Mast Cell ◽

Body Weight ◽

Goblet Cell ◽

Knockout Mice ◽

Expression Profiling ◽

Cell Hyperplasia ◽

Goblet Cell Hyperplasia

Cystic fibrosis (CF) transmembrane conductance regulator ( Cftr) knockout mice present the clinical features of low body weight and intestinal disease permitting an assessment of the interrelatedness of these phenotypes in a controlled environment. To identify intestinal alterations that are affected by body weight in CF mice, the histological phenotypes of crypt-villus axis height, goblet cell hyperplasia, mast cell infiltrate, crypt cell proliferation, and apoptosis were measured in a population of 12-wk-old (C57BL/6 × BALB/cJ) F2 Cftrtm1UNC and non-CF mice presenting a range of body weight. In addition, cardiac blood samples were assessed, and gene expression profiling of the ileum was completed. Crypt-villus axis height decreased with increasing body weight in CF but not control mice. Intestinal crypts from CF mice had fewer apoptotic cells, per unit length, than did non-CF mice, and normalized cell proliferation was similar to control levels. Goblet cell hyperplasia and mast cell infiltration were increased in the CF intestine and identified to be independent of body weight. Blood triglyceride levels were found to be significantly lower in CF mice than in control mice but were not dependent on CF mouse weight. By expression profiling, genes of DNA replication and lipid metabolism were among those altered in CF mice relative to non-CF controls, and no differences in gene expression were measured between samples from CF mice in the 25th and 75th percentile for weight. In this CF mouse model, crypt elongation, due to an expanded proliferative zone and decreased apoptosis, was identified to be dependent on body weight.

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NOTCH3 contributes to rhinovirus-induced goblet cell hyperplasia in COPD airway epithelial cells

Thorax ◽

10.1136/thoraxjnl-2017-210593 ◽

2018 ◽

Vol 74 (1) ◽

pp. 18-32 ◽

Cited By ~ 14

Author(s):

Yaxun Jing ◽

Joao Antonio Gimenes ◽

Rahul Mishra ◽

Duc Pham ◽

Adam T Comstock ◽

...

Keyword(s):

Gene Expression ◽

Cell Cultures ◽

Goblet Cell ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Cell Hyperplasia ◽

Goblet Cell Hyperplasia ◽

Mucin Gene ◽

Airways Obstruction ◽

Secretase Inhibitor

RationaleGoblet cell hyperplasia (GCH) is one of the cardinal features of chronic obstructive pulmonary disease (COPD) and contributes to airways obstruction. Rhinovirus (RV), which causes acute exacerbations in patients with COPD, also causes prolonged airways obstruction. Previously, we showed that RV enhances mucin gene expression and increases goblet cell number in a COPD mouse model. This study examines whether RV causes sustained GCH in relevant models of COPD.MethodsMucociliary-differentiated COPD and normal airway epithelial cell cultures and mice with normal or COPD phenotype were infected with RV or sham and examined for GCH by immunofluorescence and/or mucin gene expression. In some experiments, RV-infected COPD cells and mice with COPD phenotype were treated with γ-secretase inhibitor or interleukin-13 neutralising antibody and assessed for GCH. To determine the contribution of NOTCH1/3 in RV-induced GCH, COPD cells transduced with NOTCH1/3 shRNA were used.ResultsRV-infected COPD, but not normal cell cultures, showed sustained GCH and increased mucin genes expression. Microarray analysis indicated increased expression of NOTCH1, NOTCH3 and HEY1 only in RV-infected COPD cells. Blocking NOTCH3, but not NOTCH1, attenuated RV-induced GCH in vitro. Inhibition of NOTCH signalling by γ-secretase inhibitor, but not neutralising antibody to IL-13, abrogated RV-induced GCH and mucin gene expression.ConclusionsRV induces sustained GCH via NOTCH3 particularly in COPD cells or mice with COPD phenotype. This may be one of the mechanisms that may contribute to RV-induced prolonged airways obstruction in COPD.

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