Model Of Allergic Airway Inflammation Research Articles

Interaction of Interleukin-17A with a Th2 Response in a Mouse Model of Allergic Airway Inflammation.

A total of 262 million people worldwide suffer from asthma and 461000 people died from it in 2019. Asthma is a disease with different endotypes defined by the granulocytes found in the asthmatic lung. In allergic asthma, the eosinophilic endotype is present, driven by a TH2 response. A TH17 immune response leads to the neutrophil endotype. This often causes uncontrolled asthma and is triggered by pollutants, microbes, and oxidative stress. It has been described that a significant number of patients with eosinophilic asthma develop mixed granulocytic asthma over time. The severity of asthma in the mixed endotype is related to the proportion of neutrophils in the lungs. In this report, we address the question of how a TH2 response interacts with IL-17A in allergic asthma. To this end, we used a mouse model to induce allergic asthma followed by an aerosol challenge with ovalbumin. To investigate the role of IL-17A, we administered IL-17A intranasally during the challenge phase. IL-17A alone did not elicit an immune response, whereas in combination with allergic asthma, it resulted in a shift of the asthmatic endotype from eosinophilic to neutrophilic. TGFβ1 was increased in these lungs compared to asthmatic lungs without IL-17A, as was the expression of the IL-17A receptor subunits IL-17RA and IL-17RC. In cultures with human cells, we also found that IL-17A increased the expression of its receptors only in combination with IL-13. We also found this effect for IL-8, which attracts neutrophils in humans. The TH2 response increased the sensitivity to IL-17A in a mouse asthma model as well as in human cell lines.

Beneficial Effects of Astragalus membranaceus (Fisch.) Bunge Extract in Controlling Inflammatory Response and Preventing Asthma Features.

Astragalus membranaceus (Fisch.) Bunge root is used as herbal medicine for its immunomodulating activities in Chinese medicine. Recently, beneficial properties of A. membranaceus on allergic diseases have been proposed. Here we investigated the role of a commercial extract of A. membranaceus, standardized to 16% polysaccharides, in regulating the immune-inflammatory response in vitro and in vivo and its therapeutic application in asthma. A. membranaceus extract inhibited prostaglandin E2 and leukotriene C4 production in stimulated J774 and peritoneal macrophages, respectively. The extract also reduced interlukin-1β, tumor necrosis factor-α, and nitrite production, affecting inducible nitric oxide synthase expression. In vivo experiments confirmed the anti-inflammatory properties of A. membranaceus, as evident by a reduction in zymosan-induced peritoneal cellular infiltration and pro-inflammatory mediator production. The efficacy of A. membranaceus extract in modulating the immune response was confirmed in a model of allergic airway inflammation. Extracts improve lung function by inhibiting airway hyperresponsiveness, airway remodeling, and fibrosis. Its anti-asthmatic effects were further sustained by inhibition of the sensitization process, as indicated by a reduction of ovalbumin-induced IgE levels and the mounting of a Th2 immune response. In conclusion, our data demonstrate the anti-inflammatory properties of the commercial extract of A. membranaceus and its beneficial effects on asthma feature development.

Spatial characteristics of neutrophils and eosinophils in conducting airway mucosa of mice with induced allergic airway inflammation

Daily inhaled antigens induce cellular immune response in the airways. In case of allergens, allergic airway inflammation is usually represented by eosinophils, however, neutrophil infiltration is also observed during severe asthma. Animal models contribute to investigation of the mechanisms that involve the switching to eosinophil- or neutrophil-mediated inflammation. Data about the spatial location of eosinophils and neutrophils in the airways are necessary for both the understanding of allergic airway inflammation mechanisms and the drag potential estimation, however, not completely investigated. In the present study, we characterized the model of Aspergillus fumigatus extract-induced allergic airway inflammation that allowed investigating the early stage of inflammation development. The model adequacy was confirmed according to the blood and bronchoalveolar lavage eosinophilia. Using immunohistochemical staining of conducting airway as a whole-mount and confocal laser scanning microscopy, we estimated neutrophil and eosinophil spatial location: in the luminal side of the epithelium, in the airway wall or in the submucosal compartment close to the smooth muscle layer. An allergic airway response activation was detected upon significant elevation of blood eosinophil percentage compared to intact mice. Simultaneously, the number of eosinophils in the bronchoalveolar lavage was also significantly increased compared to the intact mice. At this time point, eosinophils predominated both in bronchoalveolar lavages and in conducting airway mucosa compared to neutrophils. Spatial location of conducting airway mucosal cell analysis demonstrated that eosinophils mostly located in the submucosal compartment, in a lesser extent in the airway wall, and a few eosinophils were detected in the luminal side of the epithelium. Neutrophils mainly infiltrated the luminal side of the epithelium, and a few neutrophils were detected in the submucosal compartment, while no neutrophils were detected in the airway wall. The data suggests that in response to the further allergen challenge, evidently eosinophils but not neutrophils will migrate through the airway wall to the airway lumen. Thus, eosinophils can be expected to damage airway epithelium in allergic airway inflammation development. Simultaneously, neutrophils located in close proximity to the smooth muscle layer together with eosinophils can contribute to bronchoconstriction induction.

Interleukin-9 promotes mast cell progenitor proliferation and CCR2-dependent mast cell migration in allergic airway inflammation

Allergic asthma is a chronic lung disease characterized by airway hyperresponsiveness and cellular infiltration that is exacerbated by immunoglobulin E-dependent mast cell (MC) activation. Interleukin-9 (IL-9) promotes MC expansion during allergic inflammation but precisely how IL-9 expands tissue MCs and promotes MC function is unclear. In this report, using multiple models of allergic airway inflammation, we show that both mature MCs (mMCs) and MC progenitors (MCp) express IL-9R and respond to IL-9 during allergic inflammation. IL-9 acts on MCp in the bone marrow and lungs to enhance proliferative capacity. Furthermore, IL-9 in the lung stimulates the mobilization of CCR2+ mMC from the bone marrow and recruitment to the allergic lung. Mixed bone marrow chimeras demonstrate that these are intrinsic effects in the MCp and mMC populations. IL-9-producing T cells are both necessary and sufficient to increase MC numbers in the lung in the context of allergic inflammation. Importantly, T cell IL-9-mediated MC expansion is required for the development of antigen-induced and MC-dependent airway hyperreactivity. Collectively, these data demonstrate that T cell IL-9 induces lung MC expansion and migration by direct effects on the proliferation of MCp and the migration of mMC to mediate airway hyperreactivity.

Prophylactic and therapeutic use of synthetically glycosylated antigens to limit allergic airway disease

Abstract Asthma is a disease involving chronic airway inflammation affecting more than 300 million people worldwide. There is currently no cure for asthma. While effective, corticosteroids cause broad immune suppression and long-term debilitating disease. Novel immune modulatory therapeutics leave patients vulnerable to infections. Therefore, there is a current need for new therapeutics that target the underlying causes of the disease without triggering detrimental side effects. Through synthetic glycosylation, our platform targets hepatic antigen presenting cells and leverages the liver’s tolerance-inducing mechanisms to limit inflammatory T cell responses, while promoting regulatory T cell (Treg) responses, thus preventing broad immunosuppression. In a model of experimental allergic airway inflammation, prophylactic treatment with synthetically mannosylated OVA (pMan OVA) ameliorated the allergic response to inhaled OVA. Our treatment reduced lung and airway eosinophilia, systemic levels of IgE and OVA-specific IgG1, and airway mucus. Furthermore, pMan OVAtreatment reduced OVA specific lung T H2 cells, and exhibited reduced production of IL-4, IL-5 and IL-13 upon antigen specific restimulation. Treatment with pMan OVAwas accompanied by induction of OVA-specific Tregs, which negatively correlated with features of allergic airway disease. In previously sensitized mice, therapeutic intervention with pMan OVAreduced airway and lung eosinophilia, B cell and CD4 +T cell inflammation. Altogether, these data suggest a potential role for prophylactic and therapeutic intervention with synthetically glycosylated allergens in ameliorating disease severity in a model of allergic airway inflammation.

Sex-dependent influence of LMAN1 on lung function and allergen-induced airway hyperresponsiveness

Abstract We recently reported LMAN1 as a regulatory receptor capable of downregulating NF-kB signaling in response to house dust mite (HDM) in vitro. In this follow up work, we have subjected WT and LMAN1 KO mice to a HDM model of allergic airway inflammation and assessed lung function and airway hyperreactivity (AHR). Given our previous in vitro findings, we had expected worsened disease in the absence of LMAN1. Interestingly, when mice were stratified by sex, we observed that while female, HDM-treated LMAN1 KO mice exhibited signs of enhanced airway narrowing and closure and enhanced AHR compared to their WT counterparts, male, HDM-treated LMAN1 KO mice showed the opposite trend. These sex-dependent effects appeared to be localized to the peripheral airways. We additionally characterized the type and extent of immune cell infiltration into the airway and highlight those features which might account for the gender-biased effects of LMAN1 on lung function in the setting of allergic asthma.

TLR2-hif1α-mediated glycolysis contributes to pyroptosis and oxidative stress in allergic airway inflammation.

As a pattern recognition receptor which activates innate immune system, toll-like receptor 2 (TLR2) has been reportedly mediates allergic airway inflammation (AAI), yet the underlying mechanism remains elusive. Here, in a murine AAI model, TLR2-/- mice showed decreased airway inflammation, pyroptosis and oxidative stress. RNA-sequencing revealed that allergen-induced hif1 signaling pathway and glycolysis were significantly downregulated when TLR2 was deficient, which were confirmed by lung protein immunoblots. Glycolysis inhibitor 2-Deoxy-d-glucose (2-DG) inhibited allergen-induced airway inflammation, pyroptosis, oxidative stress and glycolysis in wild type (WT) mice, while hif1α stabilizer ethyl 3,4-dihydroxybenzoate (EDHB) restored theses allergen-induced changes in TLR2-/- mice, indicating TLR2-hif1α-mediated glycolysis contributes to pyroptosis and oxidative stress in AAI. Moreover, upon allergen challenge, lung macrophages were highly activated in WT mice but were less activated in TLR2-/- mice, 2-DG replicated while EDHB reversed such effect of TLR2 deficiency on lung macrophages. Likewise, both in vivo and ex vivo WT alveolar macrophages (AMs) exhibited higher TLR2/hif1α expression, glycolysis and polarization activation in response to ovalbumin (OVA), which were all inhibited in TLR2-/- AMs, suggesting AMs activation and metabolic switch are dependent on TLR2. Finally, depletion of resident AMs in TLR2-/- mice abolished while transfer of TLR2-/- resident AMs to WT mice replicated the protective effect of TLR2 deficiency on AAI when administered before allergen challenge. Collectively, we suggested that loss of TLR2-hif1α-mediated glycolysis in resident AMs ameliorates allergic airway inflammation that inhibits pyroptosis and oxidative stress, therefore the TLR2-hif1α-glycolysis axis in resident AMs may be a novel therapeutic target for AAI.

The small molecule inhibitor BX-795 uncouples IL-2 production from inhibition of Th2 inflammation and induces CD4+ T cells resembling iTreg.

Treg cells have been shown to be an important part of immune-homeostasis and IL-2 which is produced upon T cell receptor (TCR)-dependent activation of T lymphocytes has been demonstrated to critically participate in Treg development. To evaluate small molecule inhibitors (SMI) for the identification of novel IL-2/Treg enhancing compounds. We used TCR-dependent and allergen-specific cytokine secretion of human and mouse T cells, next generation messenger ribonucleic acid sequencing (RNA-Seq) and two different models of allergic airway inflammation to examine lead SMI-compounds. We show here that the reported 3-phosphoinositide dependent kinase-1 (PDK1) SMI BX-795 increased IL-2 in culture supernatants of Jurkat E6-1 T cells, human peripheral blood mononuclear cells (hPBMC) and allergen-specific mouse T cells upon TCR-dependent and allergen-specific stimulation while concomitantly inhibiting Th2 cytokine secretion. RNA-Seq revealed that the presence of BX-795 during allergen-specific activation of T cells induces a bona fide Treg cell type highly similar to iTreg but lacking Foxp3 expression. When applied in mugwort pollen and house dust mite extract-based models of airway inflammation, BX-795 significantly inhibited Th2 inflammation including expression of Th2 signature transcription factors and cytokines and influx into the lungs of type 2-associated inflammatory cells such as eosinophils. BX-795 potently uncouples IL-2 production from Th2 inflammation and induces Th-IL-2 cells, which highly resemble induced (i)Tregs. Thus, BX-795 may be a useful new compound for the treatment of allergic diseases.

The Allergenic Activity of Blo t 2, a Blomia tropicalis IgE-Binding Molecule

Only few allergens derived from house dust mite (HDM) species have been evaluated in terms of their potential to induce allergic inflammation. In this study, we aimed to evaluate different aspects of the allergenicity and allergenic activity of Blo t 2, a Blomia tropicalis allergen. Blo t 2 was produced as a recombinant protein in Escherichia coli. Its allergenic activity was tested in humans by skin prick test and basophil activation assays, and in mice, by passive cutaneous anaphylaxis and a model of allergic airway inflammation. Sensitization rate to Blo t 2 (54.3%) was similar to that found to Blo t 21 (57.2%) and higher than to Der p 2 (37.5%). Most Blo t 2-sensitized patients showed a low intensity response (99.5%). Blo t 2 elicited CD203c upregulation and allergen induced skin inflammation. Additionally, immunized animals produced anti-Blo t 2 IgE antibodies and passive transfer of their serum to non-immunized animals induced skin inflammation after allergen exposure. Immunized animals developed bronchial hyperreactivity and a strong inflammatory lung reaction (eosinophils and neutrophils). These results confirm the allergenic activity of Blo t 2 and supports its clinical relevance.

Itaconate Suppresses the Activation of Mitochondrial NLRP3 Inflammasome and Oxidative Stress in Allergic Airway Inflammation.

Itaconate has emerged as a novel anti-inflammatory and antioxidative endogenous metabolite, yet its role in allergic airway inflammation (AAI) and the underlying mechanism remains elusive. Here, the itaconate level in the lung was assessed by High Performance Liquid Chromatography (HPLC), and the effects of the Irg1/itaconate pathway on AAI and alveolar macrophage (AM) immune responses were evaluated using an ovalbumin (OVA)-induced AAI model established by wild type (WT) and Irg1-/- mice, while the mechanism of this process was investigated by metabolomics analysis, mitochondrial/cytosolic protein fractionation and transmission electron microscopy in the lung tissues. The results demonstrated that the Irg1 mRNA/protein expression and itaconate production in the lung were significantly induced by OVA. Itaconate ameliorated while Irg1 deficiency augmented AAI, and this may be attributed to the fact that itaconate suppressed mitochondrial events such as NLRP3 inflammasome activation, oxidative stress and metabolic dysfunction. Furthermore, we identified that the Irg1/itaconate pathway impacted the NLRP3 inflammasome activation and oxidative stress in AMs. Collectively, our findings provide evidence for the first time, supporting the conclusion that in the allergic lung, the itaconate level is markedly increased, which directly regulates AMs' immune responses. We therefore propose that the Irg1/itaconate pathway in AMs is a potential anti-inflammatory and anti-oxidative therapeutic target for AAI.

Dietary digestible carbohydrates are associated with higher prevalence of asthma in humans and with aggravated lung allergic inflammation in mice.

Dietary carbohydrates and fats are intrinsically correlated within the habitual diet. We aimed to disentangle the associations of starch and sucrose from those of fat, in relation to allergic sensitization, asthma and rhinoconjuctivitis prevalence in humans, and to investigate underlying mechanisms using murine models. Epidemiological data from participants of two German birth cohorts (age 15) were used in logistic regression analyses testing cross-sectional associations of starch and sucrose (and their main dietary sources) with aeroallergen sensitization, asthma and rhinoconjunctivitis, adjusting for correlated fats (saturated, monounsaturated, omega-6 and omega-3 polyunsaturated) and other covariates. For mechanistic insights, murine models of aeroallergen-induced allergic airway inflammation (AAI) fed with a low-fat-high-sucrose or -high-starch versus a high-fat diet were used to characterize and quantify disease development. Metabolic and physiologic parameters were used to track outcomes of dietary interventions and cellular and molecular responses to monitor the development of AAI. Oxidative stress biomarkers were measured in murine sera or lung homogenates. We demonstrate a direct association of dietary sucrose with asthma prevalence in males, while starch was associated with higher asthma prevalence in females. In mice, high-carbohydrate feeding, despite scant metabolic effects, aggravated AAI compared to high-fat in both sexes, as displayed by humoral response, mucus hypersecretion, lung inflammatory cell infiltration and TH 2-TH 17 profiles. Compared to high-fat, high-carbohydrate intake was associated with increased pulmonary oxidative stress, signals of metabolic switch to glycolysis and decreased systemic anti-oxidative capacity. High consumption of digestible carbohydrates is associated with an increased prevalence of asthma in humans and aggravated lung allergic inflammation in mice, involving oxidative stress-related mechanisms.

Mucosal-associated invariant T cells repress group 2 innate lymphoid cells in Alternaria alternata-induced model of allergic airway inflammation.

Mucosal-associated invariant T (MAIT) cells, a blossoming member of the innate-like T cells, play a pivotal role in host defense through engaging the mucosal immunity. Although it has been suggested that MAIT cells are somehow implicated in the allergic airway inflammation mediated by group 2 innate lymphoid cells (ILC2s) such as asthma, the precise role(s) of MAIT cells in such inflammation has remained elusive. To explore the possible roles of MAIT cells in the inflammation, we examined whether MAIT cells suppressed the production of T helper (Th) 2 and inflammatory cytokines from ILC2s, and constrained the proliferation of ILC2s, both of which are prerequisite for airway inflammation. Given that laboratory mice are poor at MAIT cells, a novel mouse line rich in MAIT cells was used. We found that mice rich in MAIT cells showed alleviated airway inflammation as evidenced by reduced infiltration of the immune cells and hyperplasia in goblet cells in the lung concomitant with compromised production of Th2 and inflammatory cytokines, while wild type mice exhibited severe inflammation upon challenge with the fungal extracts. In vitro coculture experiments using purified ILC2s and MAIT cells unrevealed that cytokine-stimulated MAIT cells suppressed ILC2s to produce the cytokines as well as to proliferate most likely via production of IFN-γ. Furthermore, reconstitution of the allergic airway inflammation in the highly immunocompromised mice showed that ILC2-mediated inflammation was alleviated in mice that received MAIT cells along with ILC2s. We concluded that MAIT cells played a crucial role in suppressing the cytokine-producing capacity of ILC2s and ILC2 proliferation, that ultimately led to decrease in the allergic airway inflammation. The results open up a novel therapeutic horizon in ILC2-mediated inflammatory diseases by modulating MAIT cell activity.

Prostacyclin Regulation of Allergic Inflammation.

Prostacyclin is a metabolic product of the cyclooxygenase pathway that is constitutively expressed and can be induced during inflammatory conditions. While prostacyclin and its analogs have historically been considered effective vasodilators and used in treating pulmonary hypertension, prostacyclin has demonstrated potent anti-inflammatory effects in animal models of allergic airway inflammation. In vitro studies reveal that prostacyclin directly inhibits type 2 cytokine production from CD4+ Th2 cells and ILC2 and reduces the ability of dendritic cells to generate Th2 cytokine production from CD4+ T cells in an antigen-specific manner. Thus, there is strong evidence that prostacyclin may be an additional therapeutic target for treating allergic inflammation and asthma in human subjects.

Pyrroloquinoline Quinone Administration Alleviates Allergic Airway Inflammation in Mice by Regulating the JAK-STAT Signaling Pathway.

The current asthma therapies are inadequate for many patients with severe asthma. Pyrroloquinoline quinone (PQQ) is a naturally-occurring redox cofactor and nutrient that can exert a multitude of physiological effects, including anti-inflammatory and antioxidative effects. We sought to explore the effects of PQQ on allergic airway inflammation and reveal the underlying mechanisms. In vitro, the effects of PQQ on the secretion of epithelial-derived cytokines by house dust mite- (HDM-) incubated 16-HBE cells and on the differentiation potential of CD4+ T cells were investigated. In vivo, PQQ was administered to mice with ovalbumin- (OVA-) induced asthma, and lung pathology and inflammatory cell infiltration were assessed. The changes in T cell subsets and signal transducers and activators of transcription (STATs) were evaluated by flow cytometry. Pretreatment with PQQ significantly decreased HDM-stimulated thymic stromal lymphopoietin (TSLP) production in a dose-dependent manner in 16-HBE cells and inhibited Th2 cell differentiation in vitro. Treatment with PQQ significantly reduced bronchoalveolar lavage fluid (BALF) inflammatory cell counts in the OVA-induced mouse model. PQQ administration also changed the secretion of IFN-γ and IL-4 as well as the percentages of Th1, Th2, Th17, and Treg cells in the peripheral blood and lung tissues, along with inhibition the phosphorylation of STAT1, STAT3, and STAT6 while promoting that of STAT4 in allergic airway inflammation model mice. PQQ can alleviate allergic airway inflammation in mice by improving the immune microenvironment and regulating the JAK-STAT signaling pathway. Our findings suggest that PQQ has great potential as a novel therapeutic agent for inflammatory diseases, including asthma.

Allergic airway inflammation delays glioblastoma progression and reinvigorates systemic and local immunity in mice.

Numerous patient-based studies have highlighted the protective role of immunoglobulin E-mediated allergic diseases on glioblastoma (GBM) susceptibility and prognosis. However, the mechanisms behind this observation remain elusive. Our objective was to establish a preclinical model able to recapitulate this phenomenon and investigate the role of immunity underlying such protection. An immunocompetent mouse model of allergic airway inflammation (AAI) was initiated before intracranial implantation of mouse GBM cells (GL261). RAG1-KO mice served to assess tumor growth in a model deficient for adaptive immunity. Tumor development was monitored by MRI. Microglia were isolated for functional analyses and RNA-sequencing. Peripheral as well as tumor-associated immune cells were characterized by flow cytometry. The impact of allergy-related microglial genes on patient survival was analyzed by Cox regression using publicly available datasets. We found that allergy establishment in mice delayed tumor engraftment in the brain and reduced tumor growth resulting in increased mouse survival. AAI induced a transcriptional reprogramming of microglia towards a pro-inflammatory-like state, uncovering a microglia gene signature, which correlated with limited local immunosuppression in glioma patients. AAI increased effector memory T-cells in the circulation as well as tumor-infiltrating CD4+ T-cells. The survival benefit conferred by AAI was lost in mice devoid of adaptive immunity. Our results demonstrate that AAI limits both tumor take and progression in mice, providing a preclinical model to study the impact of allergy on GBM susceptibility and prognosis, respectively. We identify a potentiation of local and adaptive systemic immunity, suggesting a reciprocal crosstalk that orchestrates allergy-induced immune protection against GBM.

Pharmacological OGG1 inhibition decreases murine allergic airway inflammation.

Background and aim: Allergic asthma is a complex inflammatory disease involving type 2 innate lymphoid cells, type 2T helper cells, macrophages, and eosinophils. The disease is characterized by wheezing, dyspnea, coughing, chest tightness and variable airflow limitation for which there is no cure and is symptomatically treated with inhaled corticosteroids and β2-agonists. Molecular mechanisms underlying its complex pathogenesis are not fully understood. However, 8-oxoguanine DNA glycosylase-1 (OGG1), a DNA repair protein may play a central role, as OGG1 deficiency decreases both innate and allergic inflammation. Methods: Using a murine ovalbumin (OVA) model of allergic airway inflammation we assessed the utility of an inhibitor of OGG1 (TH5487) in this disease context. Cytokines and chemokines, promoting immune cell recruitment were measured using a 23-multiplex assay and Western blotting. Additionally, immune cell recruitment to bronchi was measured using flow cytometry. Histological analyses and immunofluorescent staining were used to confirm immune cell influx and goblet cell hyperplasia of the airways. A PCR array was used to assess asthma-related genes in murine lung tissue following TH5487 treatment. Finally, airway hyperresponsiveness was determined using in vivo lung function measurement. Results: In this study, administration of TH5487 to mice with OVA-induced allergic airway inflammation significantly decreased goblet cell hyperplasia and mucus production. TH5487 treatment also decreased levels of activated NF-κB and expression of proinflammatory cytokines and chemokines resulting in significantly lower recruitment of eosinophils and other immune cells to the lungs. Gene expression profiling of asthma and allergy-related proteins after TH5487 treatment revealed differences in several important regulators, including down regulation of Tnfrsf4, Arg1, Ccl12 and Ccl11, and upregulation of the negative regulator of type 2 inflammation, Bcl6. Furthermore, the gene Clca1 was upregulated following TH5487 treatment, which should be explored further due to its ambiguous role in allergic asthma. In addition, the OVA-induced airway hyperresponsiveness was significantly reduced by TH5487 treatment. Conclusion: Taken together, the data presented in this study suggest OGG1 as a clinically relevant pharmacological target for the treatment of allergic inflammation.

Lactobacillus delbrueckii UFV-H2b20 increases IFN-γ production and CD39+CD73+ Treg cell numbers in lungs, and protects mice against experimental allergic asthma

Asthma is a disorder characterized by airflow obstruction, inflammation, declining airway function, bronchial hyperresponsiveness and tissue remodelling. Probiotics are defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”. The use of probiotics is becoming increasingly studied and recent evidence has suggested that it may provide therapeutic benefits in asthma and other diseases. Lactobacillus delbrueckii UFV-H2b20 fulfils all the requirements to be classified as probiotic. Previous studies have already shown the ability of L. delbrueckii UFV-H2b20 to stimulate the immune system. Our objective was to evaluate the protective effects of L. delbrueckii UFV-H2b20 in experimental allergic asthma. We used a murine model of ovalbumin-induced allergic airway inflammation to mimic allergic asthma. Oral treatment with L. delbrueckii UFV-H2b20 improves respiratory parameters and inhibits the inflammatory response in the lungs by decreasing the numbers of inflammatory monocytes, eosinophils and alveolar macrophages, as well as IgE levels. Treatment increased the IFN-γ/IL-4 cytokine ratio. Levels of IL-10 in the lungs were also increased in treated animals. Our results also showed that the probiotic administration increases the number of CD39+CD73+ T regulatory lymphocytes in the lung, suggesting a role for purinergic signals in the regulation of inflammation promoted by the treatment. Understanding the mechanisms of modulation of the immune system by probiotics could allow the development of probiotic preparations that are safe and have a direct action. Our results suggest that oral administration of L. delbrueckii UFV-H2b20 could be helpful to treat chronic inflammatory airway diseases, such as asthma.

Low Dose Rate Radiation Regulates M2-like Macrophages in an Allergic Airway Inflammation Mouse Model.

We investigated the effects of low dose rate radiation (LDR) on M1 and M2 macrophages in an ovalbumin-induced mouse model of allergic airway inflammation and asthma. After exposure to LDR (1 Gy, 1.818 mGy/h) for 24 days, mice were euthanized and the changes in the number of M1 and M2 macrophages in the bronchoalveolar lavage fluid and lung, and M2-associated cytokine levels, were assessed. LDR treatment not only restored the M2-rich microenvironment but also ameliorated asthma-related progression in a macrophage-dependent manner. In an ovalbumin-induced mouse model, LDR treatment significantly inhibited M2, but not M1, macrophage infiltration. M2-specific changes in macrophage polarization during chronic lung disease reversed the positive effects of LDR. Moreover, the levels of cytokines, including chemokine (C-C motif) ligand (CCL) 24, CCL17, transforming growth factor beta 1, and matrix metalloproteinase-9, decreased in ovalbumin-sensitized/challenged mice upon exposure to LDR. Collectively, our results indicate that LDR exposure suppressed asthmatic progression, including mucin accumulation, inflammation, and Type 2 T helper (Th2) cytokine (interleukin (IL)-4 and IL-13) production. In conclusion, LDR exposure decreased Th2 cytokine secretion in M2 macrophages, resulting in a reduction in eosinophilic inflammation in ovalbumin-sensitized/challenged mice.

Effect of Agmatine on a mouse model of allergic airway inflammation: A comparative study

Introduction Asthma is a chronic lung disease that injures and constricts the airways. This study evaluates the effects of agmatine on ovalbumin (OVA)-induced allergic inflammation of the airways. Methods OVA sensitization by intraperitoneal injection was used to induce airway inflammation in mice on days 0 and 7; then the mice were challenged using beclomethasone (150 µg/kg, inhalation), a standard anti-asthmatic drug, from day 14 to day 16. Furthermore, agmatine (200 mg/kg) was intraperitoneally injected on day 0 and then daily for 16 days, followed by OVA challenge. The lung weight ratio, total and differential cell counts, TNF-α, interleukin-5 (IL-5) and IL-13 in bronchoalveolar lavage fluid (BALF), lung nitrite/nitrate (NO), and oxidative parameters were determined. Moreover, histopathological and immunohistochemical staining was employed. Results Injection of agmatine (200 mg/kg) for 16 days significantly attenuated inflammation of the airways. The levels of BALF inflammatory cells, TNF-α, IL-5, IL-13, lung NO, and malondialdehyde (MDA), significantly decreased with concomitant elevation of superoxide dismutase (SOD) levels. Histological and immunohistochemical analyses of mast cells paralleled to biochemical improvements. Conclusion Finally, this study illustrated that agmatine attenuates the allergic inflammation of airways caused by OVA by mitigating cytokines release, NO expression, and oxidative stress.

Treatment with Distinct Antibiotic Classes Causes Different Pulmonary Outcomes on Allergic Airway Inflammation Associated with Modulation of Symbiotic Microbiota

Background Asthma is a chronic pulmonary disease that affects about 300 million people worldwide. Previous studies have associated antimicrobial use with allergies, but the real impact of antibiotics on asthma is still elusive. We investigated the potential impact of amoxicillin (Amox), trimethoprim/sulfamethoxazole (TMP/SMX), and metronidazole (Metro) in a murine model of OVA-induced allergic airway inflammation. Methods BALB/c mice received three cycles of 7 days of antibiotics in drinking water followed by 7 days washout and were sensitized i.p. with OVA/Alum at days 0 and 14. After the end of the last antibiotic washout, the mice were challenged with aerosolized OVA. Pulmonary parameters were evaluated, and serum, BAL, and feces were collected for analysis. Results Amox- and TMP/SMX-treated animals displayed more severe allergic airway inflammation parameters with increased airway hyperresponsiveness, reduced lung alveolar volume, and increased levels in BAL of IL-4 and IL-6. In contrast, Metro-treated mice showed preserved FEV-50, decreased lung inflammation, and higher levels of butyrate and propionate in their feces. Metro treatment was associated with increased OVA-specific IgA in serum. BAL microbiota was abundant in allergic groups but not in nonallergic controls with the Amox-treated group displaying the increased frequency of Proteobacteria, while Metro and TMP/SMX showed increased levels of Firmicutes. In the gut, we observed the enrichment of Akkermansia muciniphila associated with reduced airway inflammation phenotype in the Metro group, even after the recovery period. Conclusion Our data suggest that different antibiotic treatments may impact the course of experimental allergic airway inflammation in diverse ways by several mechanisms, including modulation of short-chain fat acids production by intestinal microbiota.