Chronic Allergic Airway Disease Research Articles

Therapeutic properties of Helicobacter pylori-derived vacuolating cytotoxin A in an animal model of chronic allergic airway disease

BackgroundIt has previously been shown that the Helicobacter pylori (H. pylori)-derived molecule vacuolating cytotoxin A (VacA) could be suitable for the treatment of allergic airway disease. The therapeutic activity of the protein, which acts through modulation of dendritic cells (DC) and regulatory T cells (Tregs), was demonstrated in murine short-term acute models. The aim of this study is to further evaluate the therapeutic potential of VacA by determining the effectiveness of different application routes and the suitability of the protein for treating the chronic phase of allergic airway disease.MethodsVacA was administered by the intraperitoneal (i.p.), oral (p.o.) or intratracheal (i.t.) routes, and long-term therapeutic effectiveness, allergic airway disease hallmarks, and immune phenotype were analyzed in murine models of acute and chronic allergic airway disease.ResultsAdministration of VacA via the i.p., p.o or i.t. routes was associated with a reduction in airway inflammation. The i.p. route showed the most consistent effect in reducing airway inflammation and i.p. treatment with VacA was the only treatment that significantly reduced mucus cell hyperplasia. In a murine model of chronic allergic airway disease, both short- and long-term treatment with VacA showed a therapeutic effect, with a reduction in a variety of asthma hallmarks, including bronchoalveolar lavage eosinophilia, lung inflammation and goblet cell metaplasia. Short-term treatment was associated with induction of Tregs, while repetitive long-term administration of VacA influenced immunological memory in the lung.ConclusionsIn addition to showing therapeutic efficacy in short-term models, treatment with VacA also appeared to be effective in suppressing inflammation in a chronic airway disease model. The observation that treatment was effective after administration via several different routes highlights the potential of VacA as a therapeutic agent with different routes of administration in humans.

ERG Functionally Overlaps with Other Ets Proteins in Promoting TH9 Cell Expression of Il9 during Allergic Lung Inflammation.

CD4+ TH cells develop into subsets that are specialized in the secretion of particular cytokines to mediate restricted types of inflammation and immune responses. Among the subsets that promote development of allergic inflammatory responses, IL-9-producing TH9 cells are regulated by a number of transcription factors. We have previously shown that the E26 transformation-specific (Ets) family members PU.1 and Ets translocation variant 5 (ETV5) function in parallel to regulate IL-9. In this study we identified a third member of the Ets family of transcription factors, Ets-related gene (ERG), that mediates IL-9 production in TH9 cells in the absence of PU.1 and ETV5. Chromatin immunoprecipitation assays revealed that ERG interaction at the Il9 promoter region is restricted to the TH9 lineage and is sustained during murine TH9 polarization. Knockdown or knockout of ERG during murine or human TH9 polarization in vitro led to a decrease in IL-9 production in TH9 cells. Deletion of ERG in vivo had modest effects on IL-9 production in vitro or in vivo. However, in the absence of PU.1 and ETV5, ERG was required for residual IL-9 production in vitro and for IL-9 production by lung-derived CD4 T cells in a mouse model of chronic allergic airway disease. Thus, ERG contributes to IL-9 regulation in TH9 cells.

Chemokine CXCL12 drives pericyte accumulation and airway remodeling in allergic airway disease

BackgroundAirway remodeling is a significant contributor to impaired lung function in chronic allergic airway disease. Currently, no therapy exists that is capable of targeting these structural changes and the consequent loss of function. In the context of chronic allergic inflammation, pericytes have been shown to uncouple from the pulmonary microvasculature, migrate to areas of inflammation, and significantly contribute to airway wall remodeling and lung dysfunction. This study aimed to elucidate the mechanism by which pulmonary pericytes accumulate in the airway wall in a model of chronic allergic airway inflammation.MethodsMice were subjected to a protocol of chronic airway inflammation driven by the common environmental aeroallergen house dust mite. Phenotypic changes to lung pericytes were assessed by flow cytometry and immunostaining, and the functional capacity of these cells was evaluated using in vitro migration assays. The molecular mechanisms driving these processes were targeted pharmacologically in vivo and in vitro.ResultsPericytes demonstrated increased CXCR4 expression in response to chronic allergic inflammation and migrated more readily to its cognate chemokine, CXCL12. This increase in migratory capacity was accompanied by pericyte accumulation in the airway wall, increased smooth muscle thickness, and symptoms of respiratory distress. Pericyte uncoupling from pulmonary vessels and subsequent migration to the airway wall were abrogated following topical treatment with the CXCL12 neutraligand LIT-927.ConclusionThese results provide new insight into the role of the CXCL12/CXCR4 signaling axis in promoting pulmonary pericyte accumulation and airway remodeling and validate a novel target to address tissue remodeling associated with chronic inflammation.

Exogenous leptin enhances markers of airway fibrosis in a mouse model of chronic allergic airways disease

BackgroundAsthma patients with comorbid obesity exhibit increased disease severity, in part, due to airway remodeling, which is also observed in mouse models of asthma and obesity. A mediator of remodeling that is increased in obesity is leptin. We hypothesized that in a mouse model of allergic airways disease, mice receiving exogenous leptin would display increased airway inflammation and fibrosis.MethodsFive-week-old male and female C57BL/6J mice were challenged with intranasal house dust mite (HDM) allergen or saline 5 days per week for 6 weeks (n = 6–9 per sex, per group). Following each HDM exposure, mice received subcutaneous recombinant human leptin or saline. At 48 h after the final HDM challenge, lung mechanics were evaluated and the mice were sacrificed. Bronchoalveolar lavage was performed and differential cell counts were determined. Lung tissue was stained with Masson’s trichrome, periodic acid-Schiff, and hematoxylin and eosin stains. Mouse lung fibroblasts were cultured, and whole lung mRNA was isolated.ResultsLeptin did not affect mouse body weight, but HDM+leptin increased baseline blood glucose. In mixed-sex groups, leptin increased mouse lung fibroblast invasiveness and increased lung Col1a1 mRNA expression. Total lung resistance and tissue damping were increased with HDM+leptin treatment, but not leptin or HDM alone. Female mice exhibited enhanced airway responsiveness to methacholine with HDM+leptin treatment, while leptin alone decreased total respiratory system resistance in male mice.ConclusionsIn HDM-induced allergic airways disease, administration of exogenous leptin to mice enhanced lung resistance and increased markers of fibrosis, with differing effects between males and females.

Macrophage-Intrinsic DUOX1 Contributes to Type 2 Inflammation and Mucus Metaplasia During Chronic Allergic Airway Disease

Macrophage-Intrinsic DUOX1 Contributes to Type 2 Inflammation and Mucus Metaplasia During Chronic Allergic Airway Disease

Intranasal delivery of allergen in a nanoemulsion adjuvant inhibits allergen-specific reactions in mouse models of allergic airway disease.

Atopic diseases are an increasing problem that involve both immediate hypersensitivity reactions mediated by IgE and unique cellular inflammation. Many forms of specific immunotherapy involve the administration of allergen to suppress allergic immune responses but are focused on IgE-mediated reactions. In contrast, the effect of allergen-specific immunotherapy on allergic inflammation is complex, not entirely consistent and not well understood. We have previously demonstrated the ability of allergen administered in a nanoemulsion (NE) mucosal adjuvant to suppress IgE-mediated allergic responses and protect from allergen challenge in murine food allergy models. This activity was associated with decreases in allergen-specific IL-10 and reductions in allergic cytokines and increases in regulatory T cells. Here, we extend these studies to using 2 distinct models, the ovalbumin (OVA) and cockroach (CRA) models of allergic airway disease, which are based predominantly on allergic inflammation. Acute or chronic allergic airway disease was induced in mice using ovalbumin and cockroach allergen models. Mice received three therapeutic immunizations with allergen in NE, and reactivity to airway challenge was determined. Therapeutic immunization with cockroach or OVA allergen in NE markedly reduced pathology after airway challenge. The 2 models demonstrated protection from allergen challenge-induced pathology that was associated with suppression of Th2-polarized immune responses in the lung. In addition, the reduction in ILC2 numbers in the lungs of allergic mice along with reduction in epithelial cell alarmins, IL-25 and IL-33, suggests an overall change in the lung immune environment induced by the NE immunization protocol. These results demonstrate that suppression of allergic airway inflammation and bronchial hyper-reactivity can be achieved using allergen-specific immunotherapy without significant reductions in allergen-specific IgE and suggest that ILC2 cells may be critical targets for this activity.

Pulmonary myeloid cell uptake of biodegradable nanoparticles conjugated with an anti-fibrotic agent provides a novel strategy for treating chronic allergic airways disease

Asthma (chronic allergic airways disease, AAD) is characterized by airway inflammation (AI), airway remodeling (AWR) and airway hyperresponsiveness (AHR). Current treatments for AAD mainly focus on targeting AI and its contribution AHR, with the use of corticosteroids. However, there are no therapies for the direct treatment of AWR, which can contribute to airway obstruction, AHR and corticosteroid resistance independently of AI. The acute heart failure drug, serelaxin (recombinant human gene-2 relaxin, RLX), has potential anti-remodeling and anti-fibrotic effects but only when continuously infused or injected to overcome its short half-life. To alleviate this limitation, we conjugated serelaxin to biodegradable and noninflammatory nanoparticles (NP-RLX) and evaluated their therapeutic potential on measures of AI, AWR and AHR, when intranasally delivered to a preclinical rodent model of chronic AAD and TGF-β1-stimulated collagen gel contraction from asthma patient-derived myofibroblasts. NP-RLX was preferentially taken-up by CD206+-infiltrating and CD68+-tissue resident alveolar macrophages. Furthermore, NP-RLX ameliorated the chronic AAD-induced AI, pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), chemokines (CCL2, CCL11) and the pro-fibrotic TGF-β1/IL-1β axis on AWR and resulting AHR, as well as human myofibroblast-induced collagen gel contraction, to a similar extent as unconjugated RLX. Hence, NP-RLX represents a novel strategy for treating the central features of asthma.

Multidisciplinary Care for Severe or Uncontrolled Chronic Upper Airway Diseases.

A multidisciplinary approach is regarded as the best practice for many chronic diseases, such as cancer and asthma, with well-documented value. There is also evidence that it may be beneficial to patients with chronic rhinosinusitis (CRS) and/or allergic airway disease presenting to tertiary referral centres. We discuss here whether and how organizing this kind of healthcare transition into a more integrated care pathway would benefit severe chronic upper airways disease (SCUAD) management. Based on a recent related EUFOREA panel discussion, literature search, and review of the best overseas practices, an appropriate implementation strategy of multidisciplinary care and its potential results are presented. Organizational principles, hurdles, and challenges of the process, as well as envisaged solutions and results, are being reported. The efficiency of care and the quality control assessment are concepts that are currently gaining importance. At the same time, novel treatment options based on molecular and precision medicine advancements, such as biologics, are being increasingly prescribed. Appropriately organized multidisciplinary care teams can adapt to new demands, data, and discoveries to assure maximum benefit for both patients and healthcare professionals.

Investigation of molecular mechanisms of experimental compounds in murine models of chronic allergic airways disease using synchrotron Fourier-transform infrared microspectroscopy

The ovalbumin-induced (OVA) chronic allergic airways murine model is a well-established model for investigating pre-clinical therapies for chronic allergic airways diseases, such as asthma. Here, we examined the effects of several experimental compounds with potential anti-asthmatic effects including resveratrol (RV), relaxin (RLN), l-sulforaphane (LSF), valproic acid (VPA), and trichostatin A (TSA) using both a prevention and reversal model of chronic allergic airways disease. We undertook a novel analytical approach using focal plane array (FPA) and synchrotron Fourier-transform infrared (S-FTIR) microspectroscopic techniques to provide new insights into the mechanisms of action of these experimental compounds. Apart from the typical biological effects, S-FTIR microspectroscopy was able to detect changes in nucleic acids and protein acetylation. Further, we validated the reduction in collagen deposition induced by each experimental compound evaluated. Although this has previously been observed with conventional histological methods, the S-FTIR technique has the advantage of allowing identification of the type of collagen present. More generally, our findings highlight the potential utility of S-FTIR and FPA-FTIR imaging techniques in enabling a better mechanistic understanding of novel asthma therapeutics.

Biochemical and electrophoretic study for diagnosis of the disease stage in patients with asthmatic bronchitis

BackgroundAsthmatic bronchitis is a chronic allergic airway disease diagnosed after development of chronic obstructive pulmonary disease symptoms. This study was designed to reveal relation of the different electrophoretic patterns to impairment of the lung functions in patients with asthmatic bronchitis.Materials and methodsPatients were categorized into patients at mild stage (n = 10) and those at severe stage (n = 12) in comparison to healthy group (n = 21). The major blood components, arterial blood gases and electrolytes were immediately assayed in addition to assessment of liver enzymes and kidney functions. The pulmonary indices including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), ratio of FEV1 to FVC and maximal expiratory pressure (MEP) were assayed. Furthermore, protein, lipid and calcium moieties of native protein patterns in addition to isoenzemes were electrophoretically detected.ResultsIt was found that liver and kidney functions were significantly (P < 0.05) elevated in asthmatic bronchitis patients. Ca2+ is the only electrolyte that decreased significantly (P < 0.05) at the severe stage. Electrophoretic patterns showed that asthmatic bronchitis disease at mild and severe stages were physiologically similar to control by 54.5 and 75.6% (protein), 73.1 and 41.6% (lipid moiety), 66.4 and 30.6% (calcium moiety), respectively. As regards to electrophoretic isoenzymes, the disease at mild and severe stages were similar to control by 95.2 and 35.4% (catalase (CAT)), 40.1 and 50.5% (peroxidase (POX)), 67.9 and 69.6% (α-esterase (α-EST)), 83.1 and 73.1% (β-esterase (β-EST)), respectively.ConclusionThe native electrophoretic patterns used as diagnostic tool for determining the stage at which the patients with asthmatic bronchitis exist.

IL-9 promotes allergic lung inflammation by differentially affecting macrophage populations

Abstract IL-9 promotes to the development of allergic lung disease through several responsive populations including mast cells, lymphocytes and eosinophils. However, it is not known if these represent the entire IL-9-responsive cell repertoire. In this study, we detected high IL-9R expression on macrophages and these cells occupied a large proportion of IL-9R+ cells in allergic lung. Allergic inflammation leads to a decrease in the number of alveolar macrophages (AM) in wild type mice. However, in Il9r−/− mice, the AM population is not diminished as greatly, suggesting that IL-9 represses AM self-renewal. The level of the IL-9R expression on blood monocyte is corelated with CCR2 expression, which is required for blood monocyte migration to the inflammatory site. In the chronic allergic airway disease model, the circulating monocyte population decreased coincident with an increase in the number of interstitial macrophages in the control mice compared to the Il9r−/− mice, suggesting IL-9 promotes monocyte migration and differentiation in the lung. Interestingly, IL-9 also induces a CD11c+ interstitial macrophage population in the allergic lung. Adoptive transfer of CD11c+ wild type macrophages to the Il9r−/− mice increased the inflammatory response. Thus, our study demonstrated that macrophages are important IL-9-responsive populations in allergic lung disease, and that IL-9 inhibits AM numbers as it promotes the development of pro-inflammatory CD11c+ and CD11c− interstitial macrophages. This balance is important in determining the level of allergic inflammation in the lung.

Diacylglycerol kinase ζ promotes allergic airway inflammation and airway hyperresponsiveness through distinct mechanisms.

Asthma is a chronic allergic inflammatory airway disease caused by aberrant immune responses to inhaled allergens, which leads to airway hyperresponsiveness (AHR) to contractile stimuli and airway obstruction. Blocking T helper 2 (TH2) differentiation represents a viable therapeutic strategy for allergic asthma, and strong TCR-mediated ERK activation blocks TH2 differentiation. Here, we report that targeting diacylglycerol (DAG) kinase zeta (DGKζ), a negative regulator of DAG-mediated cell signaling, protected against allergic asthma by simultaneously reducing airway inflammation and AHR though independent mechanisms. Targeted deletion of DGKζ in T cells decreased type 2 inflammation without reducing AHR. In contrast, loss of DGKζ in airway smooth muscle cells decreased AHR but not airway inflammation. T cell-specific enhancement of ERK signaling was only sufficient to limit type 2 airway inflammation, not AHR. Pharmacological inhibition of DGK diminished both airway inflammation and AHR in mice and also reduced bronchoconstriction of human airway samples in vitro. These data suggest that DGK is a previously unrecognized therapeutic target for asthma and reveal that the inflammatory and AHR components of asthma are not as interdependent as generally believed.

Orally administered fisetin as an immuno-modulatory and therapeutic agent in a mouse model of chronic allergic airway disease

Introduction: Allergic asthma is a prevalent disorder, in which eosinophilic inflammation is involved in the lungs. Asthma affects people all over the world, regardless of the country's level of development. Chronic allergen-induced fibrotic damage of the lungs is stimulated in 55 days, which results in significant tissue destruction constitutive to pulmonary tissues, in addition to extensive oxidative &amp; inflammation-induced damage of small and large airways. To date, there is no cure for asthma, and symptoms are controlled using corticosteroids, which may cause systemic side effects. Flavonoids, like fisetin, are a class of secondary metabolites produced by plants, which are known to have numerous beneficial effects. Previous report demonstrated that fisetin has beneficial effects against various diseases such as cancers, tumors, diabetes, and alcohol-induced liver injury.&#x0D; Methods: In the present study, chronic allergic disease (asthma) was developed in C57BL/6J mice, using intraperitoneal injection of ovalbumin for 54 days together with orally administered fisetin as a treatment strategy. Fisetin was administered 1 hour before intratracheal treatment. On day 55, treated animals were sacrificed, and tissues were collected for various assays.&#x0D; Results: Fisetin was found to reduce the symptoms of asthma significantly. Reduction in total cell infiltration, eosinophil count, and the levels of serum IgE were observed. There was a down regulation in CD3+CD4+ TH cells, and a decrease in the deposition of collagen in the lung and airways.&#x0D; Conclusion: From these observations, we conclude that fisetin is effective in the treatment of asthma, and a pathway by which fisetin acts was hypothesized.&#x0D;

Serelaxin enhances the therapeutic effects of human amnion epithelial cell-derived exosomes in experimental models of lung disease.

There is growing interest in stem cell-derived exosomes for their therapeutic and regenerative benefits given their manufacturing and regulatory advantages over cell-based therapies. As existing fibrosis impedes the viability and efficacy of stem cell/exosome-based strategies for treating chronic diseases, here we tested the effects of the anti-fibrotic drug, serelaxin, on the therapeutic efficacy of human amnion epithelial cell (AEC)-derived exosomes in experimental lung disease. Female Balb/c mice were subjected to either the 9.5-week model of ovalbumin and naphthalene (OVA/NA)-induced chronic allergic airway disease (AAD) or 3-week model of bleomycin (BLM)-induced pulmonary fibrosis; then administered increasing concentrations of AEC-exosomes (5μg or 25μg), with or without serelaxin (0.5mg/kg/day) for 7-days. 1x106 AECs co-administered with serelaxin over the corresponding time-period were included for comparison in both models, as was pirfenidone-treatment of the BLM model. Control groups received saline/corn oil or saline, respectively. Both experimental models presented with significant tissue inflammation, remodelling, fibrosis and airway/lung dysfunction at the time-points studied. While AEC-exosome (5μg or 25μg)-administration alone demonstrated some benefits in each model, serelaxin was required for AEC-exosomes (25μg) to rapidly normalise chronic AAD-induced airway fibrosis and airway reactivity, and BLM-induced lung inflammation, epithelial damage and subepithelial/basement membrane fibrosis. Combining serelaxin with AEC-exosomes (25μg) also demonstrated broader protection compared to co-administration of serelaxin with 1x106 AECs or pirfenidone. Serelaxin enhanced the therapeutic efficacy of AEC-exosomes in treating basement membrane-induced fibrosis and related airway dysfunction.

FoxO1 is a critical regulator of M2-like macrophage activation in allergic asthma.

The pathogenesis of asthma and airway obstruction is the result of an abnormal response to different environmental exposures. The scientific premise of our study was based on the finding that FoxO1 expression is increased in lung macrophages of mice after allergen exposure and human asthmatic patients. Macrophages are capable of switching from one functional phenotype to another, and it is important to understand the mechanisms involved in the transformation of macrophages and how their cellular function affects the peribronchial stromal microenvironment. We employed a murine asthma model, in which mice were treated by intranasal insufflation with allergens for 2-8weeks. We used both a pharmacologic approach using a highly specific FoxO1 inhibitor and genetic approaches using FoxO1 knockout mice (FoxO1fl/fl LysMcre). Cytokine level in biological fluids was measured by ELISA and the expression of encoding molecules by NanoString assay and qRT-PCR. We show that the levels of FoxO1 gene are significantly elevated in the airway macrophages of patients with mild asthma in response to subsegmental bronchial allergen challenge. Transcription factor FoxO1 regulates a pro-asthmatic phenotype of lung macrophages that is involved in the development and progression of chronic allergic airway disease. We have shown that inhibition of FoxO1 induced phenotypic conversion of lung macrophages and downregulates pro-asthmatic and pro-fibrotic gene expression by macrophages, which contribute to airway inflammation and airway remodeling in allergic asthma. Targeting FoxO1 with its downstream regulator IRF4 is a novel therapeutic target for controlling allergic inflammation and potentially reversing fibrotic airway remodeling.

The loss of DGK protects against allergic airway inflammation and airway hyperresponsiveness

Abstract Asthma is a chronic allergic inflammatory airway disease that is caused by aberrant immune responses to inhaled allergens, which leads to airflow obstruction driven in part by increased sensitivity of airway smooth muscle to contractile agonists, a process known as airway hyperresponsiveness (AHR). The inflammation of allergic asthma is driven by type 2 cytokines released by Th2 CD4+ T cells and group 2 innate lymphoid cells (ILC2) in the lung. Here, we report that targeting DAG kinase zeta (DGKζ), a negative regulator of DAG-mediated cell signaling, protects against allergic asthma. DGKζ knockout (KO) mice exhibited reduced type 2 airway inflammation and were completely resistant to AHR induction in a mouse model of allergic asthma. Surprisingly, the mechanism by which DGKζ protected against airway inflammation and AHR were separable. Targeted deletion of DGKζ in T cells led to decreased type 2 inflammation with no attenuation of AHR. In contrast, conditional deletion of DGKζ in airway smooth muscle cells led to decreased AHR despite no changes in airway inflammation. Importantly, the pharmacological inhibition of DGK provided protection against airway inflammation and AHR in mice, and also reduced bronchoconstriction of human airways. Together, our data suggest that DGKζ is potentially a novel therapeutic target for allergic asthma. Moreover, the targeted deletion of DGKζ reveals that the inflammatory and AHR components of allergic asthma are not as interdependent, as generally believed.

Development of allergic airway inflammation inearly life - interaction of early viral infections and allergic sensitization.

Airway inflammation is a key feature of upper and lower respiratory allergic diseases, such as allergic rhinitis and asthma. Characteristically, histological alterations such as goblet cell hyperplasia, mucus hypersecretion, loss of epithelial barrier function, airway infiltration and structural changes such as basal membrane thickening and airway smooth muscle hyperplasia. These inflammatory signs are often obvious already early in life and may be accompanied by structural changes (remodeling) occurring in early lifetime. This review focusses on the main mechanisms underlying the development of airway inflammation and remodeling and discusses the question which factors contribute to the persistence of airway inflammation in chronic allergic airway disease.

Targeted HAS2 Expression Lessens Airway Responsiveness in Chronic Murine Allergic Airway Disease.

Hyaluronan (HA), a major component of the extracellular matrix, is secreted by airway structural cells. Airway fibroblasts in allergic asthma secrete elevated levels of HA in association with increased HA synthase 2 (HAS2) expression. Thus, we hypothesized that HA accumulation in the airway wall may contribute to airway remodeling and hyperresponsiveness in allergic airways disease. To examine this hypothesis, transgenic mice in which the α-smooth muscle actin (α-SMA) promoter drives HAS2 expression were generated. Mixed male and female α-SMA-HAS2 mice (HAS2+ mice, n = 16; HAS2- mice, n = 13) were sensitized via intraperitoneal injection and then chronically challenged with aerosolized ovalbumin (OVA) for 6 weeks. To test airway responsiveness, increasing doses of methacholine were delivered intravenously and airway resistance was measured using the forced oscillation technique. HA, cytokines, and cell types were analyzed in bronchoalveolar lavage fluid, serum, and whole lung homogenates. Lung sections were stained using antibodies specific for HA-binding protein (HABP) and α-SMA, as well as Masson's trichrome stain. Staining of lung tissue demonstrated significantly increased peribronchial HA, α-SMA, and collagen deposition in OVA-challenged α-SMA-HAS2+ mice compared with α-SMA-HAS2- mice. Unexpectedly, OVA-challenged α-SMA-HAS2+ mice displayed significantly reduced airway responsiveness to methacholine compared with similarly treated α-SMA-HAS2- mice. The total numbers of inflammatory cell types in the bronchoalveolar lavage fluid did not differ significantly between OVA-challenged α-SMA-HAS2+ mice and α-SMA-HAS2- mice. We conclude that allergen-challenged mice that overexpress HAS2 in myofibroblasts and smooth muscle cells develop increased airway fibrosis, which lessens airway hyperresponsiveness to bronchoconstrictors.

Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c.

Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin-1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)-induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c-deficient (Fbln1c-/- ) mice had reduced mucin (MUC) 5 AC levels, but not MUC5B levels, in the airways as compared with wild-type (WT) mice. Fbln1c interacted with fibronectin and periostin that was linked to collagen deposition around the small airways. Fbln1c-/- mice with AAD also had reduced numbers of α-smooth muscle actin-positive cells around the airways and reduced airway contractility as compared with WT mice. After HDM challenge, these mice also had fewer airway inflammatory cells, reduced interleukin (IL)-5, IL-13, IL-33, tumour necrosis factor (TNF) and CXCL1 levels in the lungs, and reduced IL-5, IL-33 and TNF levels in lung-draining lymph nodes. Therapeutic targeting of Fbln1c reduced the numbers of GATA3-positive Th2 cells in the lymph nodes and lungs after chronic HDM challenge. Treatment also reduced the secretion of IL-5 and IL-13 from co-cultured dendritic cells and T cells restimulated with HDM extract. Human epithelial cells cultured with Fbln1c peptide produced more CXCL1 mRNA than medium-treated controls. Our data show that Fbln1c may be a therapeutic target in chronic asthma. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Downregulation of semaphorin 3E promotes hallmarks of experimental chronic allergic asthma.

Guidance cues such as semaphorins are attractive novel therapeutic targets for allergic disorders. We have previously described an inhibitory effect of semaphorin 3E (Sema3E) on human airway smooth muscle cell function. We have further addressed a canonical role for Sema3E in acute model of allergic asthma in vivo. Considering the chronic nature of the disease, the potential implication of Sema3E to alleviate long-lasting deficits should be investigated. Expression of Sema3E in a chronic model of allergic asthma was assessed after exposure to house dust mite (HDM) as a clinically relevant allergen. Chronic features of allergic asthma including airway hyper-responsiveness (AHR), inflammation, and remodeling were studied in Sema3E-deficient mice. Additionally, the effect of exogenous Sema3E treatment was evaluated in prophylactic and therapeutic experimental models. We have demonstrated that expression of Sema3E is robustly suppressed in the airways upon chronic HDM exposure. Chronic allergic airway disease was significantly augmented in Sema3E-deficient mouse model which was associated with an increased AHR, remodeling, and Th2/Th17 inflammation. Intranasal Sema3E administration restored chronic deficits of allergic asthma in mice. Data from this study unveil a key regulatory role of Sema3E in chronic course of asthma via orchestration of impaired inflammatory and remodeling responses.