scholarly journals Empagliflozin and Dulaglutide are Effective against Obesity-induced Airway Hyperresponsiveness and Fibrosis in A Murine Model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hye Jung Park ◽  
Heejae Han ◽  
Eun-Yi Oh ◽  
Sung Ryeol Kim ◽  
Kyung Hee Park ◽  
...  
Keyword(s):  
Murine Model ◽  
Airway Hyperresponsiveness ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Serum Levels ◽  
Lavage Fluid ◽  
Additive Effects ◽  
Abnormal Glucose Metabolism ◽  
Th17 Cell Differentiation ◽  
Weight Decrease

Abstract Patients with asthma with obesity experience severe symptoms, are unresponsive to conventional asthma treatment, and lack proper pharmacotherapy. Empagliflozin and dulaglutide, developed for diabetes, reduce weight, decrease insulin resistance, and exert additive effects. We evaluated the efficacy of empagliflozin, dulaglutide, and their combination on obesity-induced airway hyperresponsiveness (AHR) and lung fibrosis using a murine model. We assigned C57BL/6J mice to five groups: control, high-fat diet (HFD), and HFD with empagliflozin, dulaglutide, or both. Mice received a 12-week HFD, empagliflozin (5 days/week, oral gavage), and dulaglutide (once weekly, intraperitoneally). Both drugs significantly attenuated HFD-induced weight increase, abnormal glucose metabolism, and abnormal serum levels of leptin and insulin, and co-treatment was more effective. Both drugs significantly alleviated HFD-induced AHR, increased macrophages in bronchoalveolar lavage fluid (BALF), and co-treatment was more effective on AHR. HFD-induced lung fibrosis was decreased by both drugs alone and combined. HFD induced interleukin (IL)-17, transforming growth factor (TGF)-β1, and IL-1β mRNA and protein expression, which was significantly reduced by empagliflozin, dulaglutide, and their combination. Tumour necrosis factor (TNF)-α and IL-6 showed similar patterns without significant differences. HFD-enhanced T helper (Th) 1 and Th17 cell differentiation was improved by both drugs. Empagliflozin and dulaglutide could be a promising therapy for obesity-induced asthma and showed additive effects in combination.

Inhibitory effects of astragaloside IV on ovalbumin-induced chronic experimental asthma

2008 ◽  
Vol 86 (7) ◽  
pp. 449-457 ◽  
Author(s):  
Qiang Du ◽  
Zhen Chen ◽  
Lin-fu Zhou ◽  
Qian Zhang ◽  
Mao Huang ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Airway Hyperresponsiveness ◽  
Transforming Growth Factor ◽  
Immunoglobulin E ◽  
Airway Remodeling ◽  
Lavage Fluid ◽  
Transforming Growth Factor Β1 ◽  
Astragaloside Iv ◽  
Cell Hyperplasia ◽  
Characteristic Features

Astragaloside IV, a new cycloartane-type triterpene glycoside extract of Astragalus membranaceus Bunge, has been identified for its potent immunoregulatory, antiinflammatory, and antifibrotic actions. Here we investigated whether astragaloside IV could suppress the progression of airway inflammation, airway hyperresponsiveness, and airway remodeling in a murine model of chronic asthma. BALB/c mice sensitized to ovalbumin (OVA) were chronically challenged with aerosolized OVA for 8 weeks. Astragaloside IV was orally administered at a dose of 50 mg·kg–1·day–1 during each OVA challenge. Astragaloside IV treatment resulted in significant reduction of eosinophilic airway inflammation, airway hyperresponsiveness, interleukin (IL)-4 and IL-13 levels in bronchoalveolar lavage fluid, and total immunoglobulin E levels in serum. Furthermore, astragaloside IV treatment markedly inhibited airway remodeling, including subepithelial fibrosis, smooth muscle hypertrophy, and goblet cell hyperplasia. In addition, the expression of transforming growth factor-β1 in the lung was also reduced by astragaloside IV. These data indicate that astragaloside IV may mitigate the development of characteristic features in chronic experimental asthma.

Upregulated miR-29c suppresses silica-induced lung fibrosis through the Wnt/β-catenin pathway in mice

2017 ◽  
Vol 37 (9) ◽  
pp. 944-952 ◽  
Author(s):  
X Wang ◽  
K Xu ◽  
XY Yang ◽  
J Liu ◽  
Q Zeng ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Lentiviral Vector ◽  
Lavage Fluid ◽  
Candidate Target ◽  
Tgf Β1

Silicosis is an irreversible lung disease resulting from long-term inhalation of occupational dust containing silicon dioxide. However, the pathogenesis of silicosis has not been clearly understood yet. Accumulating evidence suggests that miR-29 may have a significant anti-fibrotic capacity, meanwhile it may relate to Wnt/β-catenin pathway. The purpose of this study was to discuss the role of miR-29 in the progression of silicosis. A lentiviral vector was constructed, named Lv-miR-29c, which was overexpressing miR-29c. In vivo, intratracheal treatment with Lv-miR-29c significantly increased expression of miR-29c, and reduced expression of β-catenin, matrix metalloproteinase (MMP)-2, and MMP-9 in the lung and levels of transforming growth factor-beta 1 (TGF-β1) and interleukin-6 (IL-6) in bronchoalveolar lavage fluid, and notably attenuated pulmonary fibrosis as evidenced by hydroxyproline content in silica-administered mice. These results indicated that miR-29c inhibited the development of silica-induced lung fibrosis. Thus, miR-29c may be a candidate target for silicosis treatment via its regulation of the Wnt/β-catenin pathway.

scholarly journals The importance of leukotrienes in airway inflammation in a mouse model of asthma.

1996 ◽  
Vol 184 (4) ◽  
pp. 1483-1494 ◽  
Author(s):  
W R Henderson ◽  
D B Lewis ◽  
R K Albert ◽  
Y Zhang ◽  
W J Lamm ◽  
...  
Keyword(s):  
Mouse Model ◽  
Murine Model ◽  
Airway Hyperresponsiveness ◽  
Pulmonary Inflammation ◽  
Late Phase ◽  
Lavage Fluid ◽  
Bronchial Hyperreactivity ◽  
Leukocytic Infiltration ◽  
Specific Inhibitors

Inhalation of antigen in immunized mice induces an infiltration of eosinophils into the airways and increased bronchial hyperreactivity as are observed in human asthma. We employed a model of late-phase allergic pulmonary inflammation in mice to address the role of leukotrienes (LT) in mediating airway eosinophilia and hyperreactivity to methacholine. Allergen intranasal challenge in OVA-sensitized mice induced LTB4 and LTC4 release into the airspace, widespread mucus occlusion of the airways, leukocytic infiltration of the airway tissue and broncho-alveolar lavage fluid that was predominantly eosinophils, and bronchial hyperreactivity to methacholine. Specific inhibitors of 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP) blocked airway mucus release and infiltration by eosinophils indicating a key role for leukotrienes in these features of allergic pulmonary inflammation. The role of leukotrienes or eosinophils in mediating airway hyperresponsiveness to aeroallergen could not be established, however, in this murine model.

Nociceptin/orphanin FQ receptor activation decreases the airway hyperresponsiveness induced by allergen in sensitized mice

2013 ◽  
Vol 304 (10) ◽  
pp. L657-L664 ◽  
Author(s):  
Nikol Sullo ◽  
Fiorentina Roviezzo ◽  
Maria Matteis ◽  
Angela Ianaro ◽  
Girolamo Calò ◽  
...  
Keyword(s):  
Airway Hyperresponsiveness ◽  
Serum Levels ◽  
Lavage Fluid ◽  
Receptor Activation ◽  
Nop Receptor ◽  
Orphanin Fq ◽  
Sensitization Process ◽  
Sensitization Phase ◽  
Airway Physiology

Several studies suggest that the N/OFQ (nociceptin/orphanin FQ)-NOP (N/OFQ peptide) receptor pathway is involved in airway physiology. We previously demonstrated a modulation of the endogenous N/OFQ levels in allergen-sensitized mice. Here, we investigated the effects of NOP receptor activation in allergen sensitization using a murine model of allergen-induced airway hyperresponsiveness (AHR). BALB/c mice were intraperitoneally treated with the NOP receptor agonist UFP-112, either during the sensitization phase (30 min before ovalbumin administration) or at the end of sensitization process (15 min before bronchopulmonary reactivity evaluation). At day 21 from the first allergen exposure, bronchopulmonary reactivity and total and differential cell count in bronchoalveolar lavage fluid were evaluated. In a separate set of experiments cell proliferation in lymphocytes, cytokine levels, IgE serum levels, and the effect of UFP-112 on IL-13-induced AHR were evaluated. Pretreatment with UFP-112, during the sensitization phase, caused a significant reduction in allergen-induced AHR and total cell lung infiltration. No effect on allergen-induced AHR was observed when the treatment was performed at the end of sensitization process, on tissues harvested from OVA-sensitized mice and on IL-13-induced AHR. The in vitro proliferative response of lymphocytes was significantly reduced by pretreatment during the sensitization phase with UFP-112. This effect was paralleled by a significant modulation of cytokine secretion in pulmonary tissues and lymphocytes. In conclusion, we demonstrated a role for the NOP receptor and N/OFQ pathway in the AHR induced by allergen, probably through a modulation of the immune response that triggers the development of AHR that involves pro- and anti-inflammatory cytokines.

scholarly journals CD8+ Tregs Ameliorate Inflammatory Reactions in a Murine Model of Allergic Rhinitis

2021 ◽  
Author(s):  
Lin Lin ◽  
Fei Dai ◽  
Jinjin Wei ◽  
Zheng Chen
Keyword(s):  
Allergic Rhinitis ◽  
Cell Cultures ◽  
Murine Model ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Lavage Fluid ◽  
Inflammatory Reactions ◽  
Inflammatory Conditions ◽  
Nasal Lavage Fluid

Abstract Background CD8+CD25+fork-head box transcription factor (Foxp3)+ regulatory T cells (CD8+ Tregs) play a role in immune tolerance. However, the role of these cells in allergic rhinitis (AR) has not been elucidated. The study aimed to evaluate influences of CD8+ Tregs on inflammatory conditions in a murine model of AR. Methods A murine model of AR was established. CD8+ Tregs were isolated from mice nasal mucosa and cultured in vitro. We examined interleukin (IL)-10 and transforming growth factor (TGF)-β in cell cultures. Then, we administered CD8+ Tregs into mice nasal mucosal cultures, and examined eosinophil cation protein (ECP), IL-4, IL-5 and IL-13 in these cultures. Finally, we adoptively transferred CD8+ Tregs into mice models, and evaluated percentages of CD8+ Tregs, numbers of sneezing and nasal rubbing, and counts of eosinophils and contents of ECP, IL-4, IL-5, IL-13, IL-10 and TGF-β in nasal lavage fluid (NLF) in mice. Results The percentage of CD8+ Tregs from AR mice was reduced. IL-10 and TGF-β were increased in cell cultures from AR mice. ECP, IL-4, IL-5 and IL-13 were decreased after the AR mice CD8+ Tregs administration in mucosal cultures. However, their contents were not changed after normal CD8+ Tregs treatment. Additionally, the adoptive transfer of AR CD8+ Tregs enhanced the percentage of CD8+ Tregs and levels of IL-10 and TGF-β in NLF, reduced numbers of sneezing and nasal rubbing, and counts of eosinophils and concentrations of ECP, IL-4, IL-5 and IL-13 in NLF. However, normal CD8+ Tregs could not change above parameters. Conclusion These findings show that CD8+ Tregs may inhibit inflammatory responses in the AR condition.

Pulmonary overexpression of IL-10 augments lung fibrosis and Th2 responses induced by silica particles

2005 ◽  
Vol 288 (5) ◽  
pp. L841-L848 ◽  
Author(s):  
Virginie Barbarin ◽  
Zhou Xing ◽  
Monique Delos ◽  
Dominique Lison ◽  
Francois Huaux
Keyword(s):  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Lavage Fluid ◽  
Th2 Cytokines ◽  
T Helper ◽  
Th2 Response ◽  
Adenoviral Gene Transfer

Chronic inflammation and proinflammatory cytokines as well as T helper type 2 (Th2) cytokines have been involved in the pathogenesis of pulmonary injury and lung fibrosis. The actual role of IL-10 in lung fibrosis is still unclear because this cytokine has been identified as Th2 but possesses strong anti-inflammatory properties. To better dissect the potential role of IL-10 in silica-induced lung fibrosis, IL-10 was overexpressed in the lung of mice by adenoviral gene transfer during the inflammatory (administered at day − 1) or the fibrotic (administered at day + 30) stages of the disease. Pulmonary overexpression of IL-10 during both silica-induced lung inflammation and fibrosis exacerbated the fibrotic lesions as estimated by the measurement of hydroxyproline and other biochemical and histological markers. Increased expression of IL-10 significantly enhanced the number of lung lymphocytes and bronchoalveolar lavage fluid IgG1 but not IgG2a levels, indicating the induction of a Th2-like immune response. In addition, the production of the profibrotic Th2 cytokines IL-4 and IL-13 was also significantly increased upon IL-10 overexpression. No difference in transforming growth factor-β or PGE2 production was noted after adenoviral IL-10 treatment of silica-treated mice. Together, these data indicate that the increased expression of IL-10 significantly contributed to silica-induced lung fibrosis by exacerbating the Th2 response and the production of the profibrotic cytokines IL-4 and IL-13.

scholarly journals CD8+ Tregs ameliorate inflammatory reactions in a murine model of allergic rhinitis

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Lin Lin ◽  
Fei Dai ◽  
Jinjin Wei ◽  
Zheng Chen
Keyword(s):  
Allergic Rhinitis ◽  
Cell Cultures ◽  
Murine Model ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Lavage Fluid ◽  
Inflammatory Reactions ◽  
Inflammatory Conditions ◽  
Nasal Lavage Fluid

Abstract Background CD8+CD25+fork-head box transcription factor (Foxp3)+ regulatory T cells (CD8+ Tregs) play a role in immune tolerance. However, the role of these cells in allergic rhinitis (AR) has not been elucidated. The study aimed to evaluate influences of CD8+ Tregs on inflammatory conditions in a murine model of AR. Methods A murine model of AR was established. CD8+ Tregs were isolated from mice nasal mucosa and cultured in vitro. We examined interleukin (IL)-10 and transforming growth factor (TGF)-β in cell cultures. Then, we administered CD8+ Tregs into mice nasal mucosal cultures, and examined eosinophil cation protein (ECP), IL-4, IL-5 and IL-13 in these cultures. Finally, we adoptively transferred CD8+ Tregs into mice models, and evaluated percentages of CD8+ Tregs, numbers of sneezing and nasal rubbing, and counts of eosinophils and contents of ECP, IL-4, IL-5, IL-13, IL-10 and TGF-β in nasal lavage fluid (NLF) in mice. Results The percentage of CD8+ Tregs from AR mice was reduced. IL-10 and TGF-β were increased in cell cultures from AR mice. ECP, IL-4, IL-5 and IL-13 were decreased after the AR mice CD8+ Tregs administration in mucosal cultures. However, their contents were not changed after normal CD8+ Tregs treatment. Additionally, the adoptive transfer of AR CD8+ Tregs enhanced the percentage of CD8+ Tregs and levels of IL-10 and TGF-β in NLF, reduced numbers of sneezing and nasal rubbing, and counts of eosinophils and concentrations of ECP, IL-4, IL-5 and IL-13 in NLF. However, normal CD8+ Tregs could not change above parameters. Conclusion These findings show that CD8+ Tregs may inhibit inflammatory responses in the AR condition.

Surfactant alterations and lung fibrosis in a murine model of amiodarone-induced pulmonary fibrosis

Pneumologie ◽  
2008 ◽  
Vol 62 (S 2) ◽  
Author(s):  
P Mahavadi ◽  
L Schwertner ◽  
T Morky ◽  
I Henneke ◽  
M Korfei ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Murine Model ◽  
Lung Fibrosis
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