Mcl-1 protects eosinophils from apoptosis and exacerbates allergic airway inflammation

Eosinophils are key effector cells in allergic diseases. Here we investigated Mcl-1 (an anti-apoptotic protein) in experimental allergic airway inflammation using transgenic overexpressing human Mcl-1 mice (hMcl-1) and reducing Mcl-1 by a cyclin-dependent kinase inhibitor. Overexpression of Mcl-1 exacerbated allergic airway inflammation, with increased bronchoalveolar lavage fluid cellularity, eosinophil numbers and total protein, and an increase in airway mucus production. Eosinophil apoptosis was suppressed by Mcl-1 overexpression, with this resistance to apoptosis attenuated by cyclin-dependent kinase inhibition which also rescued Mcl-1-exacerbated allergic airway inflammation. We propose that targeting Mcl-1 may be beneficial in treatment of allergic airway disease.

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Diabetes Downregulates Allergen-Induced Airway Inflammation in Mice

Mediators of Inflammation ◽

10.1155/2018/6150843 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Vinicius F. Carvalho ◽

Emiliano O. Barreto ◽

Ana Carolina S. Arantes ◽

Magda F. Serra ◽

Tatiana Paula T. Ferreira ◽

...

Keyword(s):

Airway Inflammation ◽

Bronchoalveolar Lavage Fluid ◽

Allergic Airway Inflammation ◽

Allergic Diseases ◽

Lavage Fluid ◽

Airway Hyperreactivity ◽

Eosinophil Infiltration ◽

Mucus Production ◽

Diabetes Induction

Previous studies described that allergic diseases, including asthma, occur less often than expected in patients with type 1 diabetes. Here, we investigated the influence of diabetes on allergic airway inflammation in a model of experimental asthma in mice. Diabetes was induced by intravenous injection of alloxan into 12 h-fasted A/J mice, followed by subcutaneous sensitization with ovalbumin (OVA) and aluminum hydroxide (Al(OH)3), on days 5 and 19 after diabetes induction. Animals were intranasally challenged with OVA (25 μg), from day 24 to day 26. Alloxan-induced diabetes significantly attenuated airway inflammation as attested by the lower number of total leukocytes in the bronchoalveolar lavage fluid, mainly neutrophils and eosinophils. Suppression of eosinophil infiltration in the peribronchiolar space and generation of eosinophilotactic mediators, such as CCL-11/eotaxin, CCL-3/MIP-1α, and IL-5, were noted in the lungs of diabetic sensitized mice. In parallel, reduction of airway hyperreactivity (AHR) to methacholine, mucus production, and serum IgE levels was also noted under diabetic conditions. Our findings show that alloxan diabetes caused attenuation of lung allergic inflammatory response in A/J mice, by a mechanism possibly associated with downregulation of IgE antibody production.

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Bacillus clausii, a Foreshore-Derived Probiotic, Attenuates Allergic Airway Inflammation Through Downregulation of Hypoxia Signaling

Journal of Rhinology ◽

10.18787/jr.2020.00325 ◽

2020 ◽

Vol 27 (2) ◽

pp. 108-116

Author(s):

Hyelim Park ◽

Ah-Yeoun Jung ◽

Chung-Soon Chang ◽

Young Hyo Kim

Keyword(s):

Pulmonary Inflammation ◽

Allergic Airway Inflammation ◽

Lung Parenchyma ◽

Airway Disease ◽

Lavage Fluid ◽

Specific Ige ◽

Allergic Airway Disease ◽

Eosinophil Infiltration ◽

Bacillus Clausii ◽

Lung Histopathology

Background and Objectives: The immunomodulatory effects and mechanism of probiotics in allergic airway disease are largely unknown. We studied whether Bacillus clausii (BC), a probiotic derived from mudflats, had anti-allergic effects and compared the results with those of Lactobacillus paracasei (LP). We also examined whether the anti-allergic mechanisms of probiotics are associated with hypoxia signaling.Materials and Method: Forty-two BALB/c mice were randomly assigned to six experimental groups: controls, ovalbumin (OVA)-induced mice for inducing asthma, and OVA-induced mice that were orally administered LP or BC, at 1×109 or 5×109 CFU/mL each. We performed differential cell count testing on bronchoalveolar lavage fluid (BALF), lung histopathology, serum totals and OVA-specific IgE and IgG1 assessments, Th2 cytokine titers (IL-4, IL-5) in BALF and pulmonary parenchyma, quantitative PCR for heme oxygenase (HO)-1 and Hif-1α, and immunohistochemistry.Results: Compared to the OVA group mice, OVA-sensitized mice treated with LP or BC showed significantly reduced numbers of eosinophils and neutrophils in the BALF (p<0.05). Both probiotics also significantly reduced pulmonary inflammation and eosinophil infiltration. Mice in the LP or BC group had a substantially lower titer of IL-4 and IL-5 in BALF, and decreased IL-4 and IL-5 expression in the lung parenchyma. Real-time PCR and immunohistochemistry showed that both LP and BC could significantly suppress HO-1 and Hif-1α expression in asthmatic mice (p<0.05).Conclusion: BC can attenuate murine allergic asthma by regulating HIF-1α signaling, and its anti-allergic effect is comparable to that of LP.

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Changes in Pulmonary Function and Parasite Burden in Rats Infected with Strongyloides venezuelensis Concomitant with Induction of Allergic Airway Inflammation

Infection and Immunity ◽

10.1128/iai.71.5.2607-2614.2003 ◽

2003 ◽

Vol 71 (5) ◽

pp. 2607-2614 ◽

Cited By ~ 39

Author(s):

Deborah Negrão-Corrêa ◽

Micheline R. Silveira ◽

Cynthia M. Borges ◽

Danielle G. Souza ◽

Mauro M. Teixeira

Keyword(s):

Airway Inflammation ◽

Mutual Influence ◽

Pulmonary Inflammation ◽

Allergic Airway Inflammation ◽

Parasite Burden ◽

Allergic Diseases ◽

Lavage Fluid ◽

Eosinophil Infiltration ◽

Asthmatic Patients ◽

Strongyloides Venezuelensis

ABSTRACT The prevalence of allergic diseases such as asthma has increased markedly over the past few decades. To evaluate the possible mutual influence of helminth infection and allergy, the combined effects of experimental allergic airway inflammation and infection with Strongyloides venezuelensis on various parasitological and inflammatory indices were evaluated in the rat. A challenge of immunized rats with aerosolized ovalbumin (OVA) resulted in eosinophilic inflammation that peaked 48 h after the challenge and was accompanied by airway hyperresponsiveness (AHR) to an intravenous acetylcholine challenge. S. venezuelensis infection concomitant with an OVA challenge of immunized rats resulted in prolonged pulmonary inflammation with increased eosinophil infiltration in bronchoalveolar lavage fluid but not in the lung tissue. These rats also showed a significant parasite burden reduction, especially during parasite migration through the lungs. However, the fecundity rates of worms that reached the intestine were similar in allergic and nonallergic animals. Despite airway inflammation, the increased responsiveness of the airways in the experimental asthma model was suppressed during parasite migration through the lungs (2 days). In contrast, parasite-induced AHR was unchanged 5 days after infection in immunized and challenged rats. In conclusion, infection with S. venezuelensis interfered with the onset of AHR following an antigen challenge of immunized rats. The ability of parasites to switch off functional airway responses is therapeutically relevant because we may learn from parasites how to modulate lung function and, hence, the AHR characteristic of asthmatic patients.

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The Fermented Soy Product ImmuBalanceTM Suppresses Airway Inflammation in a Murine Model of Asthma

Nutrients ◽

10.3390/nu13103380 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3380

Author(s):

Hideaki Kadotani ◽

Kazuhisa Asai ◽

Atsushi Miyamoto ◽

Kohei Iwasaki ◽

Takahiro Kawai ◽

...

Keyword(s):

Bronchoalveolar Lavage ◽

Airway Inflammation ◽

Murine Model ◽

Bronchoalveolar Lavage Fluid ◽

Inflammatory Cell ◽

Allergic Airway Inflammation ◽

Lavage Fluid ◽

Cell Infiltration ◽

Mucus Production ◽

Cell Counts

The fermented soy product ImmuBalance contains many active ingredients and its beneficial effects on some allergic diseases have been reported. We hypothesized that ImmuBalance could have potential effects on airway inflammation in a murine model of asthma. Mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was assessed for inflammatory cell counts and levels of cytokines. Lung tissues were examined for cell infiltration and mucus hypersecretion. Oral administration of ImmuBalance significantly inhibited ovalbumin-induced eosinophilic inflammation and decreased Th2 cytokine levels in bronchoalveolar lavage fluid (p < 0.05). In addition, lung histological analysis showed that ImmuBalance inhibited inflammatory cell infiltration and airway mucus production. Our findings suggest that supplementation with ImmuBalance may provide a novel strategy for the prevention or treatment of allergic airway inflammation.

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Sevoflurane Inhibits the Th2 Response and NLRP3 Expression in Murine Allergic Airway Inflammation

Journal of Immunology Research ◽

10.1155/2018/9021037 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

Lixia Wang ◽

Binshan Zha ◽

Qiying Shen ◽

Hongyun Zou ◽

Cheng Cheng ◽

...

Keyword(s):

Airway Inflammation ◽

Inflammatory Cell ◽

Allergic Airway Inflammation ◽

Inflammatory Cells ◽

Lavage Fluid ◽

Th2 Response ◽

Cell Hyperplasia ◽

Mucus Production ◽

Caspase 1 ◽

Nlrp3 Expression

Background. Our colleagues have demonstrated an impressive therapeutic role of sevoflurane in a murine allergic airway inflammation model, but the mechanisms underlying this effect remain undefined. In this study, we tried to investigate the effect of sevoflurane on the resolution of allergic airway inflammation and to assess whether NLRP3 or the NLRP3 inflammasome is involved in this process. Methods. Female (C57BL/6) mice were sensitized and challenged with ovalbumin (OVA). Then, some of the mice received MCC950 (10 mg/kg; i.p.) or 3% sevoflurane. Total and differential inflammatory cell numbers, proinflammatory cytokines in bronchoalveolar lavage fluid (BALF), the peribronchial inflammation density, and mucus production were evaluated. In addition, we analysed the protein levels of NLRP3, the apoptosis-associated speck-like protein containing the caspase activation and recruitment domain (ASC), pro-caspase-1, and caspase-1 in the lung tissue. Results. We found that OVA-induced inflammatory cell recruitment to peribronchial regions, goblet cell hyperplasia, the serum levels of IgE, inflammatory cells, and the Th2 cytokine secretion in BALF was potently suppressed by sevoflurane with an efficacy comparable with that suppressed by MCC950 treatment. Furthermore, sevoflurane, similar to MCC950, clearly inhibited the OVA-induced activity of NLRP3 in the lungs. In addition, we found that OVA challenge failed to increase the expression of ASC, pro-caspase-1, and caspase-1 in the lungs and the levels of IL-18 and IL-1β in BALF. Conclusion. Taken together, our data showed that sevoflurane ameliorated allergic airway inflammation by inhibiting Th2 responses and NLRP3 expression. The NLRP3 independent of inflammasomes participated in the pathogenesis of allergic asthma in this model.

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Prophylactic Bifidobacterium adolescentis ATTCC 15703 supplementation reduces partially allergic airway disease in Balb/c but not in C57BL/6 mice

Beneficial Microbes ◽

10.3920/bm2017.0073 ◽

2018 ◽

Vol 9 (3) ◽

pp. 465-476 ◽

Cited By ~ 2

Author(s):

M.C. Casaro ◽

A.R. Crisma ◽

A.T. Vieira ◽

G.H.M. Silva ◽

E. Mendes ◽

...

Keyword(s):

Airway Inflammation ◽

Allergic Asthma ◽

Therapeutic Potential ◽

Allergic Airway Inflammation ◽

Airway Disease ◽

Allergic Airway Disease ◽

Mouse Strains ◽

Genetic Profile ◽

Bifidobacterium Adolescentis ◽

Experimental Allergic

Allergic asthma is a chronic disease mainly characterised by eosinophil inflammation and airway remodelling. Many studies have shown that the gut microbiota of allergic individuals differs from that of non-allergic individuals. Although high levels of bifidobacteria have been associated with healthy persons, Bifidobacterium adolescentis ATCC 15703, a gut bacteria, has been associated with allergic individuals in some clinical studies. The relationship between B. adolescentis ATCC 15703 and asthma or allergies has not been well elucidated, and its effect may be dependent on the host’s genetic profile or disease state. To elucidate this question, we evaluated the role of preventive B. adolescentis ATCC 15703 treatment on experimental allergic airway inflammation in two genetically different mouse strains, Balb/c and C57BL/6 (B6). Balb/c mice display a greater predisposition to develop allergic responses than B6 mice. Oral preventive treatment with B. adolescentis ATCC 15703 modulated experimental allergic airway inflammation, specifically in Balb/c mice, which showed decreased levels of eosinophils in the airway. B6 mice did not exhibit any significant alterations in eosinophils but showed an increased influx of total leukocytes and neutrophils into the airway. The mechanism underlying the beneficial effects of these bacteria in experimental allergic mice may involve products of bacteria metabolism, as dead bacteria did not mimic the ability of live B. adolescentis ATCC 15703 to attenuate the influx of eosinophils into the airway. To conclude, preventive oral B. adolescentis ATCC 15703 treatment can attenuate the major characteristic of allergic asthma, eosinophil airway influx, in Balb/c but not B6 mice. These results suggest that oral treatment with this specific live bacterial strain may have therapeutic potential for the treatment of allergic airway disease, although its effect is mouse-strain-dependent.

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Nitrogen dioxide enhances allergic airway inflammation and hyperresponsiveness in the mouse

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00131.2005 ◽

2006 ◽

Vol 290 (1) ◽

pp. L144-L152 ◽

Cited By ~ 33

Author(s):

Matthew E. Poynter ◽

Rebecca L. Persinger ◽

Charles G. Irvin ◽

Kelly J. Butnor ◽

Hans van Hirtum ◽

...

Keyword(s):

Airway Inflammation ◽

Recovery Period ◽

Allergic Airway Inflammation ◽

Airway Disease ◽

Air Pollutant ◽

Allergic Airway Disease ◽

Eosinophilic Inflammation ◽

Neutrophilic Inflammation ◽

Inflammatory Changes ◽

Cardinal Feature

In addition to being an air pollutant, NO2 is a potent inflammatory oxidant generated endogenously by myeloperoxidase and eosinophil peroxidase. In these studies, we sought to determine the effects of NO2 exposure on mice with ongoing allergic airway disease pathology. Mice were sensitized and challenged with the antigen ovalbumin (OVA) to generate airway inflammation and subsequently exposed to 5 or 25 ppm NO2 for 3 days or 5 days followed by a 20-day recovery period. Whereas 5 ppm NO2 elicited no pathological changes, inhalation of 25 ppm NO2 alone induced acute lung injury, which peaked after 3 days and was characterized by increases in protein, LDH, and neutrophils recovered by BAL, as well as lesions within terminal bronchioles. Importantly, 25 ppm NO2 was also sufficient to cause AHR in mice, a cardinal feature of asthma. The inflammatory changes were ameliorated after 5 days of inhalation and completely resolved after 20 days of recovery after the 5-day inhalation. In contrast, in mice immunized and challenged with OVA, inhalation of 25 ppm NO2 caused a marked augmentation of eosinophilic inflammation and terminal bronchiolar lesions, which extended significantly into the alveoli. Moreover, 20 days postcessation of the 5-day 25 ppm NO2 inhalation regimen, eosinophilic and neutrophilic inflammation, pulmonary lesions, and AHR were still present in mice immunized and challenged with OVA. Collectively, these observations suggest an important role for NO2 in airway pathologies associated with asthma, both in modulation of degree and duration of inflammatory response, as well as in induction of AHR.

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Neutrophils restrain allergic airway inflammation by limiting ILC2 function and monocyte–dendritic cell antigen presentation

Science Immunology ◽

10.1126/sciimmunol.aax7006 ◽

2019 ◽

Vol 4 (41) ◽

pp. eaax7006 ◽

Cited By ~ 11

Author(s):

Dhiren F. Patel ◽

Teresa Peiró ◽

Nicoletta Bruno ◽

Juho Vuononvirta ◽

Samia Akthar ◽

...

Keyword(s):

Dendritic Cell ◽

Antigen Presentation ◽

Airway Inflammation ◽

Allergic Sensitization ◽

Allergic Airway Inflammation ◽

Airway Disease ◽

Lymphoid Cells ◽

Allergic Airway Disease ◽

Regulatory Pathways ◽

Neutrophil Depletion

Neutrophil mobilization, recruitment, and clearance must be tightly regulated as overexuberant neutrophilic inflammation is implicated in the pathology of chronic diseases, including asthma. Efforts to target neutrophils therapeutically have failed to consider their pleiotropic functions and the implications of disrupting fundamental regulatory pathways that govern their turnover during homeostasis and inflammation. Using the house dust mite (HDM) model of allergic airway disease, we demonstrate that neutrophil depletion unexpectedly resulted in exacerbated T helper 2 (TH2) inflammation, epithelial remodeling, and airway resistance. Mechanistically, this was attributable to a marked increase in systemic granulocyte colony-stimulating factor (G-CSF) concentrations, which are ordinarily negatively regulated in the periphery by transmigrated lung neutrophils. Intriguingly, we found that increased G-CSF augmented allergic sensitization in HDM-exposed animals by directly acting on airway type 2 innate lymphoid cells (ILC2s) to elicit cytokine production. Moreover, increased systemic G-CSF promoted expansion of bone marrow monocyte progenitor populations, which resulted in enhanced antigen presentation by an augmented peripheral monocyte-derived dendritic cell pool. By modeling the effects of neutrophil depletion, our studies have uncovered previously unappreciated roles for G-CSF in modulating ILC2 function and antigen presentation. More broadly, they highlight an unexpected regulatory role for neutrophils in limiting TH2 allergic airway inflammation.

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Strain-dependent activation of NF-κB in the airway epithelium and its role in allergic airway inflammation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00037.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. L57-L66 ◽

Cited By ~ 13

Author(s):

John F. Alcorn ◽

Karina Ckless ◽

Amy L. Brown ◽

Amy S. Guala ◽

Jay K. Kolls ◽

...

Keyword(s):

Transgenic Mice ◽

Airway Inflammation ◽

Nuclear Localization ◽

Airway Epithelium ◽

Allergic Airway Inflammation ◽

Airway Disease ◽

Dominant Negative ◽

Allergic Airway Disease ◽

Tnf Α ◽

Strain Dependent

NF-κB activation in the airway epithelium has been established as a critical pathway in ovalbumin (Ova)-induced airway inflammation in BALB/c mice (Poynter ME, Cloots R, van Woerkom T, Butnor KJ, Vacek P, Taatjes DJ, Irvin CG, Janssen-Heininger YM. J Immunol 173: 7003–7009, 2004). BALB/c mice are susceptible to the development of allergic airway disease, whereas other strains of mice, such as C57BL/6, are considered more resistant. The goal of the present study was to determine the proximal signals required for NF-κB activation in the airway epithelium in allergic airway disease and to unravel whether these signals are strain-dependent. Our previous studies, conducted in the BALB/c mouse background, demonstrated that transgenic mice expressing a dominant-negative version of IκBα in the airway epithelium (CC10-IκBαSR) were protected from Ova-induced inflammation. In contrast to these earlier observations, we demonstrate here that CC10-IκBαSR transgenic mice on the C57BL/6 background were not protected from Ova-induced allergic airway inflammation. Consistent with this finding, Ova-induced nuclear localization of the RelA subunit of NF-κB was not observed in C57BL/6 mice, in contrast to the marked nuclear presence of RelA in BALB/c mice. Evaluation of cytokine profiles in bronchoalveolar lavage demonstrated elevated expression of TNF-α in BALB/c mice compared with C57BL/6 mice after an acute challenge with Ova. Finally, neutralization of TNF-α by a blocking antibody prevented nuclear localization of RelA in BALB/c mice after Ova challenge. These data suggest that the mechanism of response of the airway epithelium of immunized C57BL/6 mice to antigen challenge is fundamentally different from that of immunized BALB/c mice and highlight the potential importance of TNF-α in regulating epithelial NF-κB activation in allergic airway disease.

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Role of multidrug resistance-associated protein 1 in the pathogenesis of allergic airway inflammation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00026.2008 ◽

2009 ◽

Vol 296 (1) ◽

pp. L30-L36 ◽

Cited By ~ 10

Author(s):

Masakata Yoshioka ◽

Hironori Sagara ◽

Fumiyuki Takahashi ◽

Norihiro Harada ◽

Kazuto Nishio ◽

...

Keyword(s):

Multidrug Resistance ◽

Mast Cells ◽

Airway Inflammation ◽

Biological Significance ◽

Allergic Airway Inflammation ◽

Lavage Fluid ◽

Allergic Airway Disease ◽

Cell Hyperplasia ◽

Murine Bone Marrow ◽

Ige Mediated

Multidrug resistance-associated protein 1 (MRP1) is a cysteinyl leukotriene (CysLT) export pump expressed on mast cells. CysLTs are crucial mediators in allergic airway disease. However, biological significance of MRP1 in allergic airway inflammation has not yet been elucidated. In this study, we sensitized wild-type control mice ( mrp1+/+) and MRP1-deficient mice ( mrp1−/−) to ovalbumin (OVA) and challenged them with OVA by aerosol. Airway inflammation and goblet cell hyperplasia after OVA exposure were reduced in mrp1−/− mice compared with mrp1+/+ mice. Furthermore, CysLT levels in bronchoalveolar lavage fluid (BALF) from OVA-exposed mrp1−/− mice were significantly lower than those from OVA-exposed mrp1+/+ mice. Levels of OVA-specific IgE, IL-4, and IL-13 in BALF were also decreased in OVA-exposed mrp1−/− mice. IgE-mediated release of CysLTs from murine bone marrow-derived mast cells was markedly impaired by MRP1 deficiency. Our results indicate that MRP1 plays an important role in the development of allergic airway inflammation through regulation of IgE-mediated CysLT export from mast cells.

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