Mepacrine inhibits subepithelial fibrosis by reducing the expression of arginase and TGF-β1 in an extended subacute mouse model of allergic asthma

Asthma is a dynamic disorder of airway inflammation and airway remodeling with an imbalance in T helper type 1 (Th1)/Th2 immune response. Increased Th2 cytokines such as IL-4 and IL-13 induce arginase either directly or indirectly through transforming growth factor-β1 (TGF-β1) and lead to subepithelial fibrosis, which is a crucial component of airway remodeling. Synthetic antimalarials have been reported to have immunomodulatory properties. Mepacrine is known for its reduction of airway inflammation in short-term allergen challenge model by reducing Th2 cytokines and cysteinyl leukotrienes, which has an important role in the development of airway remodeling features. Therefore, we hypothesized that mepacrine may reduce airway remodeling. For this, extended subacute ovalbumin mice model of asthma was developed; these mice showed an increased expression of profibrotic mediators, subepithelial fibrosis, and goblet cell metaplasia along with airway inflammation, increased Th2 cytokines, allergen-specific IgE, IgG1, increased cytosolic PLA2 (cPLA2), and airway hyperresponsiveness. Presence of intraepithelial eosinophils and significant TGF-β1 expression in subepithelial mesenchymal regions by repeated allergen exposures indicate that asthmatic mice of this study have developed human mimicking as well as late stages of asthma. However, mepacrine treatment decreased Th2 cytokines and subepithelial fibrosis and alleviated asthma features. These reductions by mepacrine were associated with a decrease in levels and expression of TGF-β1 and the reduction in activity, expression of arginase in lung cytosol, and immunolocalization in inflammatory cells present in perivascular and peribronchial regions. These results suggest that mepacrine might reduce the development of subepithelial fibrosis by reducing the arginase and TGF-β1. These effects of mepacrine likely underlie its antiairway remodeling action in asthma.

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Amelioration of ovalbumin induced allergic symptoms in Balb/c mice by potentially probiotic strains of lactobacilli

Beneficial Microbes ◽

10.3920/bm2014.0141 ◽

2015 ◽

Vol 6 (5) ◽

pp. 669-678 ◽

Cited By ~ 5

Author(s):

M. Nawaz ◽

C. Ma ◽

M.A.R Basra ◽

J. Wang ◽

J. Xu

Keyword(s):

Mrna Expression ◽

Transforming Growth Factor ◽

Immunoglobulin E ◽

Lactobacillus Rhamnosus ◽

Inflammatory Cells ◽

Transforming Growth Factor Β ◽

Lavage Fluid ◽

Specific Ige ◽

Control Group ◽

Probiotic Strains

To evaluate the antiallergic effect of newly characterised probiotic strains, Lactobacillus fermentum NWS29, Lactobacillus casei NWP08 and Lactobacillus rhamnosus NWP13, mice were divided into six experimental groups: control, ovalbumin (OVA), NWS29, NWP08, NWP13 and L. rhamnosus GG (LGG). Mice were immunised and probiotics were administered via oral gavage followed by challenge with OVA. After last challenge with OVA, inflammatory cells in bronchoalveolar lavage fluid (BALF), recruitment of inflammatory cells in airways and OVA-specific immunoglobulin E (IgE) in serum were determined by Giemsa, haematoxylin and eosin (HE) staining, and ELISA, respectively. Relative mRNA expression of interleukins (IL-4, IL-5, IL-10, IL-13 and IL-17), transforming growth factor-β (TGF-β) and interferon-γ (IFN-γ) in lung and spleen tissue was determined by real time RT-PCR. OVA-specific IgE levels, recruitment of eosinophils and mRNA expressions of inflammatory cytokines were remarkably increased in OVA-exposed mice compared with the control group. Administration of NWS29 and NWP13 suppressed inflammatory cell infiltration in airways and BALF, and level of OVA-specific IgE in serum of OVA-exposed mice. Furthermore, NWS29 and NWP13 also abrogated the mRNA expression of 1L-4, IL-5, IL-13 and TGF-β in mice immunised and exposed to OVA. Our findings suggest that NWS29 and NWP13 might be good candidates for the prevention of allergic airway inflammation.

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Transforming Growth Factor-β Regulates House Dust Mite–induced Allergic Airway Inflammation but Not Airway Remodeling

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/rccm.200706-958oc ◽

2008 ◽

Vol 177 (6) ◽

pp. 593-603 ◽

Cited By ~ 68

Author(s):

Ramzi Fattouh ◽

N. Gabriela Midence ◽

Katherine Arias ◽

Jill R. Johnson ◽

Tina D. Walker ◽

...

Keyword(s):

Growth Factor ◽

Airway Inflammation ◽

House Dust ◽

House Dust Mite ◽

Transforming Growth Factor ◽

Airway Remodeling ◽

Allergic Airway Inflammation ◽

Transforming Growth Factor Β ◽

Dust Mite

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Effect of the Fungal Immunomodulatory Protein FIP-fve in the Neutrophilic Asthma Animal Model

International Archives of Allergy and Immunology ◽

10.1159/000517184 ◽

2021 ◽

pp. 1-12

Author(s):

Hui-Hsien Pan ◽

Jiunn-Liang Ko ◽

Chia-Ta Wu ◽

Hai-Lun Sun ◽

Yeak-Wun Quek ◽

...

Keyword(s):

Airway Inflammation ◽

Transforming Growth Factor ◽

Inflammatory Cells ◽

Neutrophil Infiltration ◽

Transforming Growth Factor Β ◽

Lavage Fluid ◽

Fungal Immunomodulatory Protein ◽

Hematoxylin And Eosin ◽

Ifn Γ ◽

Hematoxylin And Eosin Stain

Background: Asthma animal models provide valuable information about the pathogenesis and the treatment of asthma. An ovalbumin (OVA)/complete Freund’s adjuvant (CFA)-sensitized model was developed to induce neutrophil-dominant asthma and to investigate whether fungal immunomodulatory peptide-fve (FIP-fve) could improve asthma features in the OVA/CFA-sensitized model. Methods: We used female BALB/c mice and sensitized them intraperitoneally with OVA/CFA on days 1, 2, and 3. On days 14, 17, 21, 24, and 27, they were challenged with intranasal OVA. The airway hyper-responsiveness (AHR) was detected by BUXCO, inflammatory cells were stained with Liu’s stain, the cytokines were detected using ELISA, and the airway inflammation was analyzed with hematoxylin and eosin stain. Results: According to the results, OVA/CFA sensitization could induce AHR, high levels of IgE, and inflammatory cells especially neutrophils infiltration in the lung and airway inflammation. IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-17, IL-25, IL-33, and transforming growth factor-β (TGF-β) increased in the OVA/CFA-sensitized mice. OVA/CFA-sensitized mice treated with FIP-fve not only increased IL-12 and IFN-γ but also decreased IL-4, IL-5, IL-6, IL-8, IL-13, IL-17, IL-25, IL-33, and TGF-β in the bronchoalveolar lavage fluid. Moreover, FIP-fve significantly decreased neutrophil infiltration in the lung. Conclusion: The OVA/CFA model induced neutrophilic asthma successfully, and FIP-fve improved neutrophil-dominant asthma.

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Lactobacillus gasseri suppresses Th17 pro-inflammatory response and attenuates allergen-induced airway inflammation in a mouse model of allergic asthma

British Journal Of Nutrition ◽

10.1017/s0007114511005265 ◽

2011 ◽

Vol 108 (1) ◽

pp. 130-139 ◽

Cited By ~ 32

Author(s):

Ren-Long Jan ◽

Kung-Chih Yeh ◽

Miao-Hsi Hsieh ◽

Yen-Lin Lin ◽

Hui-Fang Kao ◽

...

Keyword(s):

Mouse Model ◽

Oral Administration ◽

Airway Inflammation ◽

Allergic Asthma ◽

Transforming Growth Factor ◽

Allergen Challenge ◽

Inflammatory Cells ◽

Airway Responsiveness ◽

High Dose ◽

Lactobacillus Gasseri

Probiotics are normal inhabitants of the gastrointestinal tract of man and are widely considered to exert a number of beneficial effects in many diseases. But the mechanism by which they modulate the immune system is poorly understood. The present study was planned to explore the anti-allergic effect of Lactobacillus gasseri on a mouse model of allergic asthma. Dermatophoides pteronyssinus (Der p) sensitised and challenged BALB/c mice were orally administered via oral administration with three different doses of L. gasseri (low, 1 × 106 colony-forming units (CFU); medium, 2 × 106 CFU; high, 4 × 106 CFU), in 700 μl of PBS daily, starting from 2 weeks before Der p sensitisation for 4 weeks. After the allergen challenge, airway responsiveness to methacholine, influx of inflammatory cells to the lung, and cytokine levels in bronchoalveolar lavage (BAL) fluids and splenocytes culture were assessed. Our results showed that oral administration of a high dose of L. gasseri (4 × 106 CFU) decreased airway responsiveness to methacholine, attenuated the influx of inflammatory cells to the airways and reduced the levels of TNF-α, thymus and activation-regulated chemokine (TARC) and IL-17A in BAL fluids of Der p-sensitised and -challenged mice. Moreover, L. gasseri decreased IL-17A production in transforming growth factor-α and IL-6 stimulated splenocytes and cell numbers of IL-17 producing alveolar macrophages in L. gasseri-treated mice as compared to non-treated, Der p-sensitised and -challenged mice. In conclusion, oral administration with L. gasseri can attenuate major characteristics of allergen-induced airway inflammation and IL-17 pro-inflammatory immune response in a mouse model of allergic asthma, which may have clinical implication in the preventive or therapeutic potential in allergic asthma.

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Attenuation of allergen-induced airway hyperresponsiveness is mediated by airway regulatory T cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00521.2007 ◽

2009 ◽

Vol 296 (3) ◽

pp. L307-L319 ◽

Cited By ~ 38

Author(s):

Jennifer T. Burchell ◽

Matthew E. Wikstrom ◽

Philip A. Stumbles ◽

Peter D. Sly ◽

Debra J. Turner

Keyword(s):

Airway Hyperresponsiveness ◽

Transforming Growth Factor ◽

Airway Remodeling ◽

Allergic Diseases ◽

Transforming Growth Factor Β ◽

Specific Ige ◽

Treg Cells ◽

Th2 Cytokines ◽

Cell Counts

Understanding the mechanisms involved in respiratory tolerance to inhaled allergens could potentially result in improved therapies for asthma and allergic diseases. Airway hyperresponsiveness (AHR) is a major feature of allergic asthma, thus the aim of the current study was to investigate mechanisms underlying suppression of allergen-induced AHR during chronic allergen exposure. Adult BALB/c mice were systemically sensitized with ovalbumin (OVA) in adjuvant and then challenged with a single 3 or 6 wk of OVA aerosols. Airway and parenchymal responses to inhaled methacholine (MCh), inflammatory cell counts, cytokines, OVA-specific IgE and IgG1, parenchymal histology, and numbers of airway CD4+69+ activated and CD4+25+FoxP3+ regulatory T (Treg) cells were assessed 24 h after the final aerosol. Single OVA challenge resulted in AHR, eosinophilia, increased serum OVA-specific IgE, and T helper 2 (Th2) cytokines in bronchoalveolar lavage (BAL) but no difference in numbers of Treg compared with control mice. Three weeks of OVA challenges resulted in suppression of AHR and greater numbers of airway Treg cells and increased transforming growth factor-β1 (TGFβ1) compared with control mice despite the presence of increased eosinophilia, OVA-specific IgE and IgG1, and airway remodeling. Six weeks of OVA challenges restored AHR, whereas airway Treg numbers, TGFβ1, BAL eosinophilia, and Th2 cytokines returned to control levels. Partial in vivo depletion or adoptive transfer of Treg cells restored or inhibited AHR, respectively, but did not affect TGFβ1 or Th2 cytokine production. In conclusion, AHR suppression is mediated by airway Treg cells and potentially via a paracrine induction of TGFβ1 in the airways.

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Exhaled nitric oxide estimation by a simple and efficient noninvasive technique and its utility as a marker of airway inflammation in mice

Journal of Applied Physiology ◽

10.1152/japplphysiol.00235.2009 ◽

2009 ◽

Vol 107 (1) ◽

pp. 295-301 ◽

Cited By ~ 16

Author(s):

Tanveer Ahmad ◽

Ulaganathan Mabalirajan ◽

Duraisamy Arul Joseph ◽

Lokesh Makhija ◽

Vijay Pal Singh ◽

...

Keyword(s):

Nitric Oxide ◽

Airway Inflammation ◽

Airway Remodeling ◽

Allergen Challenge ◽

Allergic Airway Inflammation ◽

Ambient Air ◽

Exhaled Nitric Oxide ◽

Noninvasive Technique ◽

Modified Method ◽

Chronic Models

Allergic airway inflammation (AI) is commonly associated with enhanced exhaled nitric oxide (ENO) in both humans and mice. Since mouse models are being used to understand various mechanisms of asthma, a noninvasive, simple, and reproducible method to determine ENO in mice is required for serial nonterminal assessment that can be used independent of environmental situations in which the ambient air contains substantial amounts of NO as a contaminant. The aim of this study was to noninvasively measure ENO in individual mice and to test its utility as a marker of AI in different models of allergic AI. We modified the existing ENO measuring methods by incorporating flushing and washout steps that allowed simple but reliable measurements under highly variable ambient NO conditions (1–100 ppb). This method was used to serially follow ENO in acute and chronic models of allergic AI in mice. ENO was reproducibly measured by this modified method and was positively correlated to AI in both acute and chronic models of asthma but was not independently related to airway remodeling. Resolution of AI and other related parameters in dexamethasone-treated mice resulted in reduction of ENO, further confirming this association. Restriction of allergen challenge to pulmonary but not nasal airways was associated with a smaller increase in ENO compared with allergen challenge to both. Hence, ENO can now be reliably measured in mice independent of ambient NO levels and is a valid biomarker for AI. However, nasal and pulmonary airways are likely to be independent sources of ENO, and any results must be interpreted as such.

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Metalloproteinase and growth factor interactions: do they play a role in pulmonary fibrosis?

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00489.2001 ◽

2002 ◽

Vol 283 (1) ◽

pp. L1-L11 ◽

Cited By ~ 26

Author(s):

Margaret K. Winkler ◽

John L. Fowlkes

Keyword(s):

Acute Lung Injury ◽

Growth Factors ◽

Growth Factor ◽

Pulmonary Fibrosis ◽

Lung Injury ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Inflammatory Cells ◽

Transforming Growth Factor Β ◽

Target Cells

Chronic lung disease due to interstitial fibrosis can be a consequence of acute lung injury and inflammation. The inflammatory response is mediated through the migration of inflammatory cells, actions of proinflammatory cytokines, and the secretion of matrix-degrading proteinases. After the initial inflammatory insult, successful healing of the lung may occur, or alternatively, dysregulated tissue repair can result in scarring and fibrosis. On the basis of recent insights into the mechanisms underlying acute lung injury and its long-term consequences, data suggest that proteinases, such as the matrix metalloproteinases (MMPs), may not only be involved in the breakdown and remodeling that occurs during the injury but may also cause the release of growth factors and cytokines known to influence growth and differentiation of target cells within the lung. Through the release of and activation of fibrosis-promoting cytokines and growth factors such as transforming growth factor-β1, tumor necrosis factor-α, and insulin-like growth factors by MMPs, we propose that these metalloproteinases may be integral to the initiation and progression of pulmonary fibrosis.

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CD4+ cells are required for chronic eosinophilic lung inflammation but not airway remodeling

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.90543.2008 ◽

2009 ◽

Vol 296 (2) ◽

pp. L229-L235 ◽

Cited By ~ 38

Author(s):

Taylor A. Doherty ◽

Pejman Soroosh ◽

David H. Broide ◽

Michael Croft

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Lung Inflammation ◽

Chronic Exposure ◽

Acute Inflammation ◽

Airway Remodeling ◽

Allergen Challenge ◽

Cd4 Cells ◽

Inkt Cells ◽

Subepithelial Fibrosis

The contribution of CD4 T cells and other CD4+ cells to lung inflammation and airway remodeling remains unclear during bouts of chronic exposure to airborne allergen. Previously, murine models have shown that CD4 T cells are required for initiation of acute inflammation and the remodeling process. However, it is unknown whether CD4 T cells or other CD4+ cells continue to be required for remodeling during ongoing allergen challenges after the development of acute eosinophilic lung inflammation. To test this, mice were sensitized and challenged with ovalbumin (OVA). After acute airway inflammation was established, a CD4 depleting antibody was administered for 4 wk during a period of chronic exposure to intranasal OVA, resulting in effective depletion of CD4+ cells from all organs, including the lung, lung-draining lymph nodes, and spleen. In these mice, levels of peribronchial inflammation, bronchoalveolar (BAL) eosinophils, and lung CD11c+, CD8+, and Siglec-F+CD11c- cells were significantly reduced. However, mucus metaplasia, peribronchial subepithelial fibrosis, and smooth muscle mass were not affected. Additionally, depletion of CD4+ cells before the last week of chronic allergen challenges also led to significant reductions in BAL eosinophils, peribronchial inflammation, and lung CD11c+, CD8+, and Siglec-F+CD11c- cells. These results show that CD4 T cells, and other CD4+ cells including subsets of dendritic cells, iNKT cells, and LTi cells, play a role in ongoing eosinophilic lung inflammation during periods of chronic allergen challenge, but are not required for progressive airway remodeling that develops after initial acute inflammation.

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Characterization of Growth-Differentiation Factor 15, a Transforming Growth Factor β Superfamily Member Induced following Liver Injury

Molecular and Cellular Biology ◽

10.1128/mcb.20.10.3742-3751.2000 ◽

2000 ◽

Vol 20 (10) ◽

pp. 3742-3751 ◽

Cited By ~ 173

Author(s):

Edward C. Hsiao ◽

Leonidas G. Koniaris ◽

Teresa Zimmers-Koniaris ◽

Suzanne M. Sebald ◽

Thanh V. Huynh ◽

...

Keyword(s):

Carbon Tetrachloride ◽

Growth Factor ◽

Liver Injury ◽

Transforming Growth Factor ◽

Experimental Treatment ◽

Inflammatory Cells ◽

Transforming Growth Factor Β ◽

Northern Analysis ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor

ABSTRACT We have identified a new murine transforming growth factor β superfamily member, growth-differentiation factor 15 (Gdf15), that is expressed at highest levels in adult liver. As determined by Northern analysis, the expression ofGdf15 in liver was rapidly and dramatically up-regulated following various surgical and chemical treatments that cause acute liver injury and regeneration. In situ hybridization analysis revealed distinct patterns of Gdf15 mRNA localization that appeared to reflect the known patterns of hepatocyte injury in each experimental treatment. In addition, treatment of two hepatocyte-like cell lines with either carbon tetrachloride or heat shock inducedGdf15 mRNA expression, indicating that direct cellular injury can induce Gdf15 expression in the absence of other cell types, such as inflammatory cells. In order to investigate the potential functions of Gdf15, we created Gdf15 null mice by gene targeting. Homozygous null mice were viable and fertile. Despite the dramatic regulation of Gdf15 expression observed in the partial-hepatectomy and carbon tetrachloride injury models, we found no differences in the injury responses between homozygous null mutants and wild-type mice. Our findings suggest either that Gdf15 does not have a regulatory role in liver injury and regeneration or that Gdf15 function within the liver is redundant with that of other signaling molecules.

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