The multi-faceted role of allergen exposure to the local airway mucosa.

PubMed

Golebski, K; Röschmann, K I L; Toppila-Salmi, S; Hammad, H; Lambrecht, B N; Renkonen, R; Fokkens, W J; van Drunen, C M

2013-02-01

Airway epithelial cells are the first to encounter aeroallergens and therefore have recently become an interesting target of many studies investigating their involvement in the modulation of allergic inflammatory responses. Disruption of a passive structural barrier composed of epithelial cells by intrinsic proteolytic activity of allergens may facilitate allergen penetration into local tissues and additionally affect chronic and ongoing inflammatory processes in respiratory tissues. Furthermore, the ability of rhinoviruses to disrupt and interfere with epithelial tight junctions may alter the barrier integrity and enable a passive passage of inhaled allergens through the airway epithelium. On the other hand, epithelial cells are no longer considered to act only as a physical barrier toward inhaled allergens, but also to actively contribute to airway inflammation by detecting and responding to environmental factors. Epithelial cells can produce mediators, which may affect the recruitment and activation of more specialized immune cells to the local tissue and also create a microenvironment in which these activated immune cells may function and propagate the inflammatory processes. This review presents the dual role of epithelium acting as a passive and active barrier when encountering an inhaled allergen and how this double role contributes to the start of local immune responses. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

Allergic asthma is distinguished by sensitivity of allergen-specific CD4+ T cells and airway structural cells to type 2 inflammation.

PubMed

Cho, Josalyn L; Ling, Morris F; Adams, David C; Faustino, Lucas; Islam, Sabina A; Afshar, Roshi; Griffith, Jason W; Harris, Robert S; Ng, Aylwin; Radicioni, Giorgia; Ford, Amina A; Han, Andre K; Xavier, Ramnik; Kwok, William W; Boucher, Richard; Moon, James J; Hamilos, Daniel L; Kesimer, Mehmet; Suter, Melissa J; Medoff, Benjamin D; Luster, Andrew D

2016-10-05

Despite systemic sensitization, not all allergic individuals develop asthma symptoms upon airborne allergen exposure. Determination of the factors that lead to the asthma phenotype in allergic individuals could guide treatment and identify novel therapeutic targets. We used segmental allergen challenge of allergic asthmatics (AA) and allergic nonasthmatic controls (AC) to determine whether there are differences in the airway immune response or airway structural cells that could drive the development of asthma. Both groups developed prominent allergic airway inflammation in response to allergen. However, asthmatic subjects had markedly higher levels of innate type 2 receptors on allergen-specific CD4 + T cells recruited into the airway. There were also increased levels of type 2 cytokines, increased total mucin, and increased mucin MUC5AC in response to allergen in the airways of AA subjects. Furthermore, type 2 cytokine levels correlated with the mucin response in AA but not AC subjects, suggesting differences in the airway epithelial response to inflammation. Finally, AA subjects had increased airway smooth muscle mass at baseline measured in vivo using novel orientation-resolved optical coherence tomography. Our data demonstrate that the development of allergic asthma is dependent on the responsiveness of allergen-specific CD4 + T cells to innate type 2 mediators as well as increased sensitivity of airway epithelial cells and smooth muscle to type 2 inflammation. Copyright © 2016, American Association for the Advancement of Science.

Allergic Sensitization through the Airway Primes Th17-dependent Neutrophilia and Airway Hyperresponsiveness

PubMed Central

Wilson, Rhonda H.; Whitehead, Gregory S.; Nakano, Hideki; Free, Meghan E.; Kolls, Jay K.; Cook, Donald N.

2009-01-01

Rationale: In humans, immune responses to inhaled aeroallergens develop in the lung and draining lymph nodes. Many animal models of asthma bypass this route and instead use intraperitoneal injections of allergen using aluminum hydroxide as an adjuvant. Objectives: We investigated whether allergic sensitization through the airway elicits immune responses qualitatively different than those arising in the peritoneum. Methods: Mice were sensitized to allergen through the airway using low-dose LPS as an adjuvant, or through the peritoneum using aluminum hydroxide as an adjuvant. After a single allergen challenge, ELISA and flow cytometry were used to measure cytokines and leukocyte subsets. Invasive measurements of airway resistance were used to measure allergen-induced airway hyperreactivity (AHR). Measurements and Main Results: Sensitization through the peritoneum primed strong Th2 responses and eosinophilia, but not AHR, after a single allergen challenge. By contrast, allergic sensitization through the airway primed only modest Th2 responses, but strong Th17 responses. Th17 cells homed to the lung and released IL-17 into the airway on subsequent encounter with inhaled allergen. As a result, these mice developed IL-17–dependent airway neutrophilia and AHR. This AHR was neutrophil-dependent because it was abrogated in CXCR2-deficient mice and also in wild-type mice receiving a neutrophil-depleting antibody. Individually, neither IL-17 nor ongoing Th2 responses were sufficient to confer AHR, but together they acted synergistically to promote neutrophil recruitment, eosinophil recruitment and AHR. Conclusions: Allergic sensitization through the airway primes modest Th2 responses but strong Th17 responses that promote airway neutrophilia and acute AHR. These findings support a causal role for neutrophils in severe asthma. PMID:19661246

Interferon response factor 3 is essential for house dust mite-induced airway allergy.

PubMed

Marichal, Thomas; Bedoret, Denis; Mesnil, Claire; Pichavant, Muriel; Goriely, Stanislas; Trottein, François; Cataldo, Didier; Goldman, Michel; Lekeux, Pierre; Bureau, Fabrice; Desmet, Christophe J

2010-10-01

Pattern-recognition receptors (PRRs) are critically involved in the pathophysiology of airway allergy, yet most of the signaling pathways downstream of PRRs implicated in allergic airway sensitization remain unknown. We sought to study the effects of genetic depletion of interferon response factor (IRF) 3 and IRF7, important transcription factors downstream of various PRRs, in a murine model of house dust mite (HDM)-induced allergic asthma. We compared HDM-induced allergic immune responses in IRF3-deficient (IRF3(-/-)), IRF7(-/-), and wild-type mice. Parameters of airway allergy caused by HDM exposure were strongly attenuated in IRF3(-/-), but not IRF7(-/-), mice compared with those in wild-type mice. Indeed, in HDM-exposed IRF3(-/-) mice HDM-specific T(H)2 cell responses did not develop. This correlated with impaired maturation and migration of IRF3(-/-) lung dendritic cells (DCs) on HDM treatment. Furthermore, adoptive transfer of HDM-loaded DCs indicated that IRF3(-/-) DCs had an intrinsic defect rendering them unable to migrate and to prime HDM-specific T(H)2 responses. Intriguingly, we also show that DC function and allergic airway sensitization in response to HDM were independent of signaling by type I interferons, the main target genes of IRF3. Through its role in DC function, IRF3, mainly known as a central activator of antiviral immunity, is essential for the development of T(H)2-type responses to airway allergens. Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Adoptive transfer of induced-Treg cells effectively attenuates murine airway allergic inflammation.

PubMed

Xu, Wei; Lan, Qin; Chen, Maogen; Chen, Hui; Zhu, Ning; Zhou, Xiaohui; Wang, Julie; Fan, Huimin; Yan, Chun-Song; Kuang, Jiu-Long; Warburton, David; Togbe, Dieudonnée; Ryffel, Bernhard; Zheng, Song-Guo; Shi, Wei

2012-01-01

Both nature and induced regulatory T (Treg) lymphocytes are potent regulators of autoimmune and allergic disorders. Defects in endogenous Treg cells have been reported in patients with allergic asthma, suggesting that disrupted Treg cell-mediated immunological regulation may play an important role in airway allergic inflammation. In order to determine whether adoptive transfer of induced Treg cells generated in vitro can be used as an effective therapeutic approach to suppress airway allergic inflammation, exogenously induced Treg cells were infused into ovalbumin-sensitized mice prior to or during intranasal ovalbumin challenge. The results showed that adoptive transfer of induced Treg cells prior to allergen challenge markedly reduced airway hyperresponsiveness, eosinophil recruitment, mucus hyper-production, airway remodeling, and IgE levels. This effect was associated with increase of Treg cells (CD4(+)FoxP3(+)) and decrease of dendritic cells in the draining lymph nodes, and with reduction of Th1, Th2, and Th17 cell response as compared to the controls. Moreover, adoptive transfer of induced Treg cells during allergen challenge also effectively attenuate airway inflammation and improve airway function, which are comparable to those by natural Treg cell infusion. Therefore, adoptive transfer of in vitro induced Treg cells may be a promising therapeutic approach to prevent and treat severe asthma.

Adoptive Transfer of Induced-Treg Cells Effectively Attenuates Murine Airway Allergic Inflammation

PubMed Central

Chen, Maogen; Chen, Hui; Zhu, Ning; Zhou, Xiaohui; Wang, Julie; Fan, Huimin; Yan, Chun-Song; Kuang, Jiu-Long; Warburton, David; Togbe, Dieudonnée; Ryffel, Bernhard; Zheng, Song-Guo; Shi, Wei

2012-01-01

Both nature and induced regulatory T (Treg) lymphocytes are potent regulators of autoimmune and allergic disorders. Defects in endogenous Treg cells have been reported in patients with allergic asthma, suggesting that disrupted Treg cell-mediated immunological regulation may play an important role in airway allergic inflammation. In order to determine whether adoptive transfer of induced Treg cells generated in vitro can be used as an effective therapeutic approach to suppress airway allergic inflammation, exogenously induced Treg cells were infused into ovalbumin-sensitized mice prior to or during intranasal ovalbumin challenge. The results showed that adoptive transfer of induced Treg cells prior to allergen challenge markedly reduced airway hyperresponsiveness, eosinophil recruitment, mucus hyper-production, airway remodeling, and IgE levels. This effect was associated with increase of Treg cells (CD4+FoxP3+) and decrease of dendritic cells in the draining lymph nodes, and with reduction of Th1, Th2, and Th17 cell response as compared to the controls. Moreover, adoptive transfer of induced Treg cells during allergen challenge also effectively attenuate airway inflammation and improve airway function, which are comparable to those by natural Treg cell infusion. Therefore, adoptive transfer of in vitro induced Treg cells may be a promising therapeutic approach to prevent and treat severe asthma. PMID:22792275

IL-15-deficient mice develop enhanced allergic responses to airway allergen exposure

PubMed Central

Mathias, Clinton B.; Schramm, Craig M.; Guernsey, Linda A.; Wu, Carol A.; Polukort, Stephanie H.; Rovatti, Jeffrey; Ser-Dolansky, Jennifer; Secor, Eric; Schneider, Sallie S.; Thrall, Roger S.; Aguila, Hector L.

2017-01-01

Background Interleukin-15 is a pleiotropic cytokine that is critical for the development and survival of multiple hematopoietic lineages. Mice lacking IL-15 have selective defects in populations of several pro-allergic immune cells including natural killer (NK) cells, NKT cells, and memory CD8+T cells. We therefore hypothesized that IL-15−/− mice will have reduced inflammatory responses during the development of allergic airway disease (AAD). Objective To determine whether IL-15−/− mice have attenuated allergic responses in a mouse model of AAD. Methods C57BL/6 wild-type (WT) and IL-15−/− mice were sensitized and challenged with ovalbumin (OVA) and the development of AAD was ascertained by examining changes in airway inflammatory responses, Th2 responses, and lung histopathology. Results Here we report that IL-15−/− mice developed enhanced allergic responses in an OVA-induced model of AAD. In the absence of IL-15, OVA-challenged mice exhibited enhanced bronchial eosinophilic inflammation, elevated IL-13 production, and severe lung histopathology in comparison with WT mice. In addition, increased numbers of CD4+T and B cells in the spleens and broncholaveolar lavage (BAL) were also observed. Examination of OVA-challenged IL-15Rα−/− animals revealed a similar phenotype resulting in enhanced airway eosinophilia compared to WT mice. Adoptive transfer of splenic CD8+T cells from OVA-sensitized WT mice suppressed the enhancement of eosinophilia in IL-15−/− animals to levels observed in WT mice, but had no further effects. Conclusion and Clinical Relevance These data demonstrate that mice with an endogenous IL-15 deficiency are susceptible to the development of severe, enhanced Th2-mediated AAD, which can be regulated by CD8+T cells. Furthermore, the development of disease as well as allergen-specific Th2 responses occurs despite deficiencies in several IL-15-dependent cell types including NK, NKT, and γδ T cells, suggesting that these cells or

Myeloid hypoxia-inducible factor 1α prevents airway allergy in mice through macrophage-mediated immunoregulation.

PubMed

Toussaint, M; Fievez, L; Drion, P-V; Cataldo, D; Bureau, F; Lekeux, P; Desmet, C J

2013-05-01

Hypoxia-inducible factor (HIF) has important roles in promoting pro-inflammatory and bactericidal functions in myeloid cells. Conditional genetic ablation of its major subunit Hif1α in the myeloid lineage consequently results in decreased inflammatory responses in classical models of acute inflammation in mice. By contrast, we report here that mice conditionally deficient for Hif1α in myeloid cells display enhanced sensitivity to the development of airway allergy to experimental allergens and house-dust mite antigens. We support that upon allergen exposure, MyD88-dependent upregulation of Hif1α boosts the expression of the immunosuppressive cytokine interleukin (IL)-10 by lung interstitial macrophages (IMs). Hif1α-dependent IL-10 secretion is required for IMs to block allergen-induced dendritic cell activation and consequently for preventing the development of allergen-specific T-helper cell responses upon allergen exposure. Thus, this study supports that, in addition to its known pro-inflammatory activities, myeloid Hif1α possesses immunoregulatory functions implicated in the prevention of airway allergy.

Chitin-Induced Airway Epithelial Cell Innate Immune Responses Are Inhibited by Carvacrol/Thymol

PubMed Central

Erle, David J.

2016-01-01

Chitin is produced in large amounts by fungi, insects, and other organisms and has been implicated in the pathogenesis of asthma. Airway epithelial cells are in direct contact with environmental particles and serve as the first line of defense against inhaled allergens and pathogens. The potential contributions of airway epithelial cells to chitin-induced asthma remain poorly understood. We hypothesized that chitin directly stimulates airway epithelial cells to release cytokines that promote type 2 immune responses and to induce expression of molecules which are important in innate immune responses. We found that chitin exposure rapidly induced the expression of three key type 2-promoting cytokines, IL-25, IL-33 and TSLP, in BEAS-2B transformed human bronchial epithelial cells and in A549 and H292 lung carcinoma cells. Chitin also induced the expression of the key pattern recognition receptors TLR2 and TLR4. Chitin induced the expression of miR-155, miR-146a and miR-21, each of which is known to up-regulate the expression of pro-inflammatory cytokines. Also the expression of SOCS1 and SHIP1 which are known targets of miR-155 was repressed by chitin treatment. The monoterpene phenol carvacrol (Car) and its isomer thymol (Thy) are found in herbal essential oils and have been shown to inhibit allergic inflammation in asthma models. We found that Car/Thy inhibited the effects of chitin on type 2-promoting cytokine release and on the expression of TLRs, SOCS1, SHIP1, and miRNAs. Car/Thy could also efficiently reduce the protein levels of TLR4, inhibit the increase in TLR2 protein levels in chitin plus Car/Thy-treated cells and increase the protein levels of SHIP1 and SOCS1, which are negative regulators of TLR-mediated inflammatory responses. We conclude that direct effects of chitin on airway epithelial cells are likely to contribute to allergic airway diseases like asthma, and that Car/Thy directly inhibits epithelial cell pro-inflammatory responses to chitin. PMID

Toll-like receptor-2 agonist-allergen coupling efficiently redirects Th2 cell responses and inhibits allergic airway eosinophilia.

PubMed

Krishnaswamy, Jayendra Kumar; Jirmo, Adan Chari; Baru, Abdul Mannan; Ebensen, Thomas; Guzmán, Carlos A; Sparwasser, Tim; Behrens, Georg M N

2012-12-01

Toll-like receptor (TLR) agonists beneficially modulate allergic airway inflammation. However, the efficiency of TLR agonists varies considerably, and their exact cellular mechanisms (especially of TLR 2/6 agonists) are incompletely understood. We investigated at a cellular level whether the administration of the pharmacologically improved TLR2/6 agonist S-[2,3-bispalmitoyiloxy-(2R)-propyl]-R-cysteinyl-amido-monomethoxy polyethylene glycol (BPP) conjugated to antigenic peptide (BPP-OVA) could divert an existing Th2 response and influence airway eosinophilia. The effects of BPP-OVA on airway inflammation were assessed in a classic murine sensitization/challenge model and an adoptive transfer model, which involved the adoptive transfer of in vitro differentiated ovalbumin (OVA)-specific Th2 cells. Functional T-cell stimulation by lung dendritic cells (DCs) was determined both in vitro and in vivo, combined with a cytokine secretion analysis. A single mucosal application of BPP-OVA efficiently delivered antigen, led to TLR2-mediated DC activation, and resulted in OVA-specific T-cell proliferation via lung DCs in vivo. In alternative models of allergic airway disease, a single administration of BPP-OVA before OVA challenge (but not BPP alone) significantly reduced airway eosinophilia, most likely through altered antigen-specific T-cell stimulation via DCs. Analyses of adoptively transferred Th2-biased cells after BPP-OVA administration in vivo suggested that BPP-OVA guides antigen-specific Th2 cells to produce significantly higher amounts of IFN-γ upon allergen challenge. In conclusion, our data show for the first time that a single mucosal administration of a TLR 2/6 agonist-allergen conjugate can provoke IFN-γ responses in Th2-biased cells and alleviate allergic airway inflammation.

Endotoxin Exposure during Sensitization to Blomia tropicalis Allergens Shifts TH2 Immunity Towards a TH17-Mediated Airway Neutrophilic Inflammation: Role of TLR4 and TLR2

PubMed Central

Barboza, Renato; Câmara, Niels Olsen Saraiva; Gomes, Eliane; Sá-Nunes, Anderson; Florsheim, Esther; Mirotti, Luciana; Labrada, Alexis; Alcântara-Neves, Neuza Maria; Russo, Momtchilo

2013-01-01

Experimental evidence and epidemiological studies indicate that exposure to endotoxin lipopolysaccharide (eLPS) or other TLR agonists prevent asthma. We have previously shown in the OVA-model of asthma that eLPS administration during alum-based allergen sensitization blocked the development of lung TH2 immune responses via MyD88 pathway and IL-12/IFN-γ axis. In the present work we determined the effect of eLPS exposure during sensitization to a natural airborne allergen extract derived from the house dust mite Blomia tropicalis (Bt). Mice were subcutaneously sensitized with Bt allergens co-adsorbed onto alum with or without eLPS and challenged twice intranasally with Bt. Cellular and molecular parameters of allergic lung inflammation were evaluated 24 h after the last Bt challenge. Exposure to eLPS but not to ultrapure LPS (upLPS) preparation during sensitization to Bt allergens decreased the influx of eosinophils and increased the influx of neutrophils to the airways. Inhibition of airway eosinophilia was not observed in IFN-γdeficient mice while airway neutrophilia was not observed in IL-17RA-deficient mice as well in mice lacking MyD88, CD14, TLR4 and, surprisingly, TLR2 molecules. Notably, exposure to a synthetic TLR2 agonist (PamCSK4) also induced airway neutrophilia that was dependent on TLR2 and TLR4 molecules. In the OVA model, exposure to eLPS or PamCSK4 suppressed OVA-induced airway inflammation. Our results suggest that B. tropicalis allergens engage TLR4 that potentiates TLR2 signaling. This dual TLR activation during sensitization results in airway neutrophilic inflammation associated with increased frequency of lung TH17 cells. Our work highlight the complex interplay between bacterial products, house dust mite allergens and TLR signaling in the induction of different phenotypes of airway inflammation. PMID:23805294

Purified Timothy grass pollen major allergen Phl p 1 may contribute to the modulation of allergic responses through a pleiotropic induction of cytokines and chemokines from airway epithelial cells

PubMed Central

Röschmann, K I L; van Kuijen, A-M; Luiten, S; Jonker, M J; Breit, T M; Fokkens, W J; Petersen, A; van Drunen, C M

2012-01-01

By definition, allergens are proteins with the ability to elicit powerful T helper lymphocyte type 2 (Th2) responses, culminating in immunoglobulin (Ig)E antibody production. Why specific proteins cause aberrant immune responses has remained largely unanswered. Recent data suggest that there may be several molecular paths that may affect allergenicity of proteins. The focus of this study is the response of airway epithelium to a major allergen from Phleum pratense Phl p 1. Instead of focusing on a few genes and proteins that might be affected by the major allergen, our aim was to obtain a broader view on the immune stimulatory capacity of Phl p 1. We therefore performed detailed analysis on mRNA and protein level by using a microarray approach to define Phl p 1-induced gene expression. We found that this allergen induces modulation and release of a broad range of mediators, indicating it to be a powerful trigger of the immune system. We were able to show that genes belonging to the GO cluster ‘cell communication’ were among the most prominent functional groups, which is also reflected in cytokines and chemokines building centres in a computational model of direct gene interaction. Further detailed comparison of grass pollen extract (GPE)- and Phl p 1-induced gene expression might be beneficial with regard to the application of single components within diagnosis and immunotherapy. PMID:22288584

Exposure-response relationships of occupational inhalative allergens.

PubMed

Baur, X; Chen, Z; Liebers, V

1998-05-01

Only a few threshold limit values exist at present for allergens in the workplace known to cause bronchial asthma. This contrasts with the great number of occupational asthma cases observed in industrialized countries. Recently published studies provide clear evidence for exposure intensity response relationships of occupational allergens of plant, microbiological, animal or man-made origin. If allergen exposure levels fall short of determined limit values, they are not associated with an increased risk of occupational asthma. Corresponding data are available for wheat flour (1-2.4 mg/m3), fungal alpha-amylase (0.25 ng/m3), natural rubber latex (0.6 ng/m3), western red cedar (0.4 mg/m3) and rat allergens (0.7 microg/m3). It is suggested to stipulate legally binding threshold limit values (TLV/TWA) on this basis in order to induce more effective primary preventive measures. If no reliable data on the health risk of an occupational airborne noxa exist, the lowest reasonably practicable exposure level has to be achieved. Appropriate secondary preventive measures have to be initiated in all workplaces contaminated with airborne allergens. Verified exposure-response relationships provide the basis for risk assessment and for targeted interventions to reduce the incidence of occupational asthma also in consideration of cost benefit aspects. 'Occupational asthma is a disease characterized by variable airflow limitation and/or airway hyperresponsiveness due to causes in a working environment. These causes can give rise to asthma through immunological or non-immunological mechanisms. Up to 15% of all asthma cases are of occupational origin or have at least a significant causal occupational factor. According to the New Zealand part of the European Respiratory Health Survey, an increased risk of asthma prevalence was found for several occupations such as laboratory technicians, food producers, chemical workers, plastic and rubber workers. The Spain part of this study

dNP2-ctCTLA-4 inhibits German cockroach extract-induced allergic airway inflammation and hyper-responsiveness via inhibition of Th2 responses

PubMed Central

Lim, Sangho; Ho Sohn, Jung; Koo, Ja-Hyun; Park, Jung-Won; Choi, Je-Min

2017-01-01

German cockroaches are major household allergens that can trigger allergic airway inflammatory diseases with sensitive T-cell responses. Although the use of immune modulatory biologics, such as antibodies, to mediate allergic responses has recently been examined, only systemic administration is available because of the size limitations on intranasal administration. Here we utilized a cell-permeable peptide, dNP2, to deliver the cytoplasmic domain of cytotoxic T-lymphocyte antigen-4 (ctCTLA-4) through the airway epithelium to modulate Th2 responses in a German cockroach extract (GCE)-induced allergic airway inflammation model. The intranasal delivery efficiency of the dNP2-dTomato protein to the lungs was higher in GCE-induced asthmatic lung parenchymal cells compared to the sham cells. Intranasal administration of the dNP2-ctCTLA-4 protein inhibited airway hyper-responsiveness and reduced airway inflammation and remodeling, including goblet cell metaplasia and collagen deposition around the bronchi. The number of infiltrated cells, including eosinophils, and the levels of IL-4, IL-5, IL-13 and IFN-γ in the lungs were significantly reduced, presumably owing to inhibition of Th2 differentiation. However, intranasal administration of CTLA4-Ig did not inhibit airway inflammation. These results collectively suggest that dNP2-ctCTLA-4 is an efficient intranasally applicable candidate biologic for treating allergic asthma. PMID:28775364

dNP2-ctCTLA-4 inhibits German cockroach extract-induced allergic airway inflammation and hyper-responsiveness via inhibition of Th2 responses.

PubMed

Lim, Sangho; Ho Sohn, Jung; Koo, Ja-Hyun; Park, Jung-Won; Choi, Je-Min

2017-08-04

German cockroaches are major household allergens that can trigger allergic airway inflammatory diseases with sensitive T-cell responses. Although the use of immune modulatory biologics, such as antibodies, to mediate allergic responses has recently been examined, only systemic administration is available because of the size limitations on intranasal administration. Here we utilized a cell-permeable peptide, dNP2, to deliver the cytoplasmic domain of cytotoxic T-lymphocyte antigen-4 (ctCTLA-4) through the airway epithelium to modulate Th2 responses in a German cockroach extract (GCE)-induced allergic airway inflammation model. The intranasal delivery efficiency of the dNP2-dTomato protein to the lungs was higher in GCE-induced asthmatic lung parenchymal cells compared to the sham cells. Intranasal administration of the dNP2-ctCTLA-4 protein inhibited airway hyper-responsiveness and reduced airway inflammation and remodeling, including goblet cell metaplasia and collagen deposition around the bronchi. The number of infiltrated cells, including eosinophils, and the levels of IL-4, IL-5, IL-13 and IFN-γ in the lungs were significantly reduced, presumably owing to inhibition of Th2 differentiation. However, intranasal administration of CTLA4-Ig did not inhibit airway inflammation. These results collectively suggest that dNP2-ctCTLA-4 is an efficient intranasally applicable candidate biologic for treating allergic asthma.

Allergen and ozone exacerbate serotonin-induced increases in airway smooth muscle contraction in a model of childhood asthma.

PubMed

Moore, Brian D; Hyde, Dallas; Miller, Lisa; Wong, Emily; Frelinger, Jessica; Schelegle, Edward S

2012-01-01

Serotonin (5-HT) modulates cholinergic neurotransmission and exacerbates airway smooth muscle (ASM) contraction in normal animal and nonasthmatic human tissue. Exposure to house dust mite allergen (HDMA) and ozone (O(3)) leads to airway hyperreactivity and 5-HT-positive cells in the airway epithelium of infant rhesus monkeys. Research shows that concomitant exposure in allergic animals has an additive effect on airway hyperreactivity. In this study, the hypothesis is that the exposure of allergic infant rhesus monkeys to HDMA, O(3) and in combination, acting through 5-HT receptors, enhances 5-HT modulation of postganglionic cholinergic ASM contraction. Twenty-four HDMA-sensitized infant monkeys were split into 4 groups at the age of 1 month, and were exposed to filtered air (FA), HDMA, O(3) or in combination (HDMA+O(3)). At the age of 6 months, airway rings were harvested and postganglionic, and parasympathetic-mediated ASM contraction was evaluated using electrical-field stimulation (EFS). 5-HT exacerbated the EFS response within all exposure groups, but had no effect in the FA group. 5-HT(2), 5-HT(3) and 5-HT(4) receptor agonists exacerbated the response. 5-HT concentration-response curves performed after incubation with specific receptor antagonists confirmed the involvement of 5-HT(2), 5-HT(3) and 5-HT(4) receptors. Conversely, a 5-HT(1) receptor agonist attenuated the tension across all groups during EFS, and in ASM contracted via exogenous acetylcholine. HDMA, O(3) and HDMA+O(3) exposure in a model of childhood allergic asthma enhances 5-HT exacerbation of EFS-induced ASM contraction through 5-HT(2), 5-HT(3) and 5-HT(4) receptors. A nonneurogenic inhibitory pathway exists, unaffected by exposure, mediated by 5-HT(1) receptors located on ASM. Copyright © 2012 S. Karger AG, Basel.

Primary Prevention of Asthma: Age and Sex Influence Sensitivity to Allergen-Induced Airway Inflammation and Contribute to Asthma Heterogeneity in Guinea Pigs

PubMed Central

Regal, Jean F.; Regal, Ronald R.; Meehan, Jessica L.; Mohrman, Margaret E.

2010-01-01

Background Limiting allergen exposure in the sensitization phase has been proposed as a means of primary prevention of asthma, but its effectiveness is debated. Hypothesis Primary prevention of asthma is more effective in limiting asthma symptoms in young guinea pigs compared with adults, whether males or females. Methods The following experimental groups were used: young/young, sensitized and challenged before sexual maturity; young/adult, sensitized young and challenged after sexual maturity; adult/adult, sensitized and challenged after sexual maturity. Males and females were sensitized intraperitoneally with varying doses of ovalbumin (OVA) and challenged intratracheally with a constant OVA dose. Cellular infiltration into lung and lavage fluid as well as airway hyperresponsiveness to intravenous methacholine was determined 24 h later. Results In unsensitized animals, density of resident inflammatory cells as well as baseline pulmonary function differed with age and sex. Maximum OVA-induced eosinophilia in females occurred at a lower sensitizing dose of OVA than in males, and the slopes of the dose-response relationship differed significantly between sexes. Young females had more pronounced increases in eosinophils compared with some adult treatment groups. The concentrations of OVA-specific antibodies were not directly related to differences in cellular infiltration. Airway hyperresponsiveness to methacholine challenge was observed in all treatment groups. Conclusion Young animals require major reductions in allergen exposure compared with adults to effectively limit airway inflammation in primary prevention. Heterogeneity of asthma symptoms seen with age and sex suggests that primary prevention by limiting allergen exposure or treatment with anti-inflammatory or bronchodilator drugs may be more effective strategies for specific age and gender populations. PMID:16931886

Immunosuppression in Early Postnatal Days Induces Persistent and Allergen-Specific Immune Tolerance to Asthma in Adult Mice

PubMed Central

Chen, Yan; Zhang, Jin; Lu, Yong; Wang, Libo

2015-01-01

Bronchial asthma is a chronic airway inflammatory condition with high morbidity, and effective treatments for asthma are limited. Allergen-specific immunotherapy can only induce peripheral immune tolerance and is not sustainable. Exploring new therapeutic strategies is of great clinical importance. Recombinant adenovirus (rAdV) was used as a vector to make cells expressing cytotoxic T lymphocyte-associated antigen-4-immunoglobulin (CTLA4Ig) a soluble CTLA4 immunoglobulin fusion protein. Dendritic cells (DCs) were modified using the rAdVs together with allergens. Then these modified DCs were transplanted to mice before allergen sensitization. The persistence and specificity of immune tolerance were evaluated in mice challenged with asthma allergens at 3 and 7 months. DCs modified by CTLA4Ig showed increased IL-10 secretion, decreased IL-12 secretion, and T cell stimulation in vitro. Mice treated with these DCs in the early neonatal period developed tolerance against the allergens that were used to induce asthma in the adult stage. Asthma symptoms, lung damage, airway reactivity, and inflammatory response all improved. Humoral immunity indices showed that this therapeutic strategy strongly suppressed mice immune responses and was maintained for as long as 7 months. Furthermore, allergen cross-sensitization and challenge experiments demonstrated that this immune tolerance was allergen-specific. Treatment with CTLA4Ig modified DCs in the early neonatal period, inducing persistent and allergen-specific immune tolerance to asthma in adult mice. Our results suggest that it may be possible to develop a vaccine for asthma. PMID:25860995

The plant extract Isatis tinctoria L. extract (ITE) inhibits allergen-induced airway inflammation and hyperreactivity in mice.

PubMed

Brattström, A; Schapowal, A; Kamal, M A; Maillet, I; Ryffel, B; Moser, R

2010-07-01

The herbal Isatis tinctoria extract (ITE) inhibits the inducible isoform of cyclooxygenase (COX-2) as well as lipoxygenase (5-LOX) and therefore possesses anti-inflammatory properties. The extract might also be useful in allergic airway diseases which are characterized by chronic inflammation. ITE obtained from leaves by supercritical carbon dioxide extraction was investigated in ovalbumin (OVA) immunised BALB/c mice given intranasally together with antigen challenge in the murine model of allergic airway disease (asthma) with the analysis of the inflammatory and immune parameters in the lung. ITE given with the antigen challenge inhibited in a dose related manner the allergic response. ITE diminished airway hyperresponsiveness (AHR) and eosinophil recruitment into the bronchoalveolar lavage (BAL) fluid upon allergen challenge, but had no effect in the saline control mice. Eosinophil recruitment was further assessed in the lung by eosinophil peroxidase (EPO) activity at a dose of 30 microg ITE per mouse. Microscopic investigations revealed less inflammation, eosinophil recruitment and mucus hyperproduction in the lung in a dose related manner. Diminution of AHR and inflammation was associated with reduced IL-4, IL-5, and RANTES production in the BAL fluid at the 30 microg ITE dose, while OVA specific IgE and eotaxin serum levels remained unchanged. ITE, which has been reported inhibiting COX-2 and 5-LOX, reduced allergic airway inflammation and AHR by inhibiting the production of the Th2 cytokines IL-4 and IL-5, and RANTES. (c) 2009 Elsevier GmbH. All rights reserved.

Purified Timothy grass pollen major allergen Phl p 1 may contribute to the modulation of allergic responses through a pleiotropic induction of cytokines and chemokines from airway epithelial cells.

PubMed

Röschmann, K I L; van Kuijen, A-M; Luiten, S; Jonker, M J; Breit, T M; Fokkens, W J; Petersen, A; van Drunen, C M

2012-03-01

By definition, allergens are proteins with the ability to elicit powerful T helper lymphocyte type 2 (Th2) responses, culminating in immunoglobulin (Ig)E antibody production. Why specific proteins cause aberrant immune responses has remained largely unanswered. Recent data suggest that there may be several molecular paths that may affect allergenicity of proteins. The focus of this study is the response of airway epithelium to a major allergen from Phleum pratense Phl p 1. Instead of focusing on a few genes and proteins that might be affected by the major allergen, our aim was to obtain a broader view on the immune stimulatory capacity of Phl p 1. We therefore performed detailed analysis on mRNA and protein level by using a microarray approach to define Phl p 1-induced gene expression. We found that this allergen induces modulation and release of a broad range of mediators, indicating it to be a powerful trigger of the immune system. We were able to show that genes belonging to the GO cluster 'cell communication' were among the most prominent functional groups, which is also reflected in cytokines and chemokines building centres in a computational model of direct gene interaction. Further detailed comparison of grass pollen extract (GPE)- and Phl p 1-induced gene expression might be beneficial with regard to the application of single components within diagnosis and immunotherapy. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.

Macrophages induce an allergen-specific and long-term suppression in a mouse asthma model.

PubMed

Vissers, J L M; van Esch, B C A M; Hofman, G A; van Oosterhout, A J M

2005-12-01

Increasing evidence suggests that macrophages (Mphi) play a crucial downregulatory role in the initiation and progression of allergic asthma. Recently, the current authors demonstrated that ovalbumin (OVA)-loaded Mphi (OVA-Mphi) suppress subsequent OVA-induced airway manifestations of asthma and that this effect could be potentiated upon selective activation. In the present study, the authors further delineated the underlying pathway by which Mphi exert this immunosuppressive effect. To examine the migration of OVA-Mphi, cells were labelled with 5'chloromethylfluorescein diacetate (CMFDA) and were administered (i.v.) into OVA-sensitised BALB/c mice. After 20 h, the relevant organs were dissected and analysed using fluorescent microscopy. Allergen-specificity was investigated by treating OVA-sensitised mice with keyhole limpet haemocyanin (KLH)-Mphi activated with immunostimulatory sequence oligodeoxynucleotide (ISS-ODN). By lengthening the period between treatment and challenge to 4 weeks it was examined whether OVA-Mphi exerted an immunosuppressive memory response. Strikingly, CMFDA-labelled Mphi were not trapped in the lungs, but migrated to the spleen. ISS-ODN-stimulated KLH-Mphi failed to suppress OVA-induced airway manifestations of asthma. Moreover, treatment with ISS-ODN-stimulated OVA-Mphi was still effective after lengthening the period between treatment and challenge. These data demonstrate that allergen-loaded macrophages can induce an indirect immunosuppressive response that is allergen-specific and long lasting, which are both hallmarks of a memory lymphocyte response.

Animal models of allergen-induced tolerance in asthma: are T-regulatory-1 cells (Tr-1) the solution for T-helper-2 cells (Th-2) in asthma?

PubMed

Tournoy, K G; Hove, C; Grooten, J; Moerloose, K; Brusselle, G G; Joos, G F

2006-01-01

Non-specific anti-inflammatory medication is actually the treatment of choice for controlling the T-helper type 2 (Th-2) cell-driven airway inflammation in asthma. The induction of counterbalancing Th-1 cell clones, long considered a promising approach for immunotherapy, has failed to fulfil its promise because of potentially detrimental side-effects. This is therefore probably not a valid option for the treatment of asthma. With the increasing awareness that active immune mechanisms exist to control inflammatory responses, interest rises to investigate whether these can be exploited to control allergen-induced airway disease. The induction of antigen-specific T cells with suppressive characteristics (regulatory T cells) is therefore a potentially interesting approach. These regulatory T cells mediate tolerance in healthy, non-atopic individuals and have the potential of becoming an effective means of preventing allergen-induced airway inflammation and possibly of suppressing ongoing allergic immune responses. Here we review the available knowledge about allergen-induced suppressive immunity obtained from animal models taking into account the different developmental stages of allergic airway disease.

Evidence for autocrine and paracrine regulation of allergen-induced mast cell mediator release in the guinea pig airways.

PubMed

Yu, Li; Liu, Qi; Canning, Brendan J

2018-03-05

Mast cells play an essential role in immediate type hypersensitivity reactions and in chronic allergic diseases of the airways, including asthma. Mast cell mediator release can be modulated by locally released autacoids and circulating hormones, but surprisingly little is known about the autocrine effects of mediators released upon mast cell activation. We thus set out to characterize the autocrine and paracrine effects of mast cell mediators on mast cell activation in the guinea pig airways. By direct measures of histamine, cysteinyl-leukotriene and thromboxane release and with studies of allergen-evoked contractions of airway smooth muscle, we describe a complex interplay amongst these autacoids. Notably, we observed an autocrine effect of the cysteinyl-leukotrienes acting through cysLT 1 receptors on mast cell leukotriene release. We confirmed the results of previous studies demonstrating a marked enhancement of mast cell mediator release following cyclooxygenase inhibition, but we have extended these results by showing that COX-2 derived eicosanoids inhibit cysteinyl-leukotriene release and yet are without effect on histamine release. Given the prominent role of COX-1 inhibition in aspirin-sensitive asthma, these data implicate preformed mediators stored in granules as the initial drivers of these adverse reactions. Finally, we describe the paracrine signaling cascade leading to thromboxane synthesis in the guinea pig airways following allergen challenge, which occurs indirectly, secondary to cysLT 1 receptor activation on structural cells and/ or leukocytes within the airway wall, and a COX-2 dependent synthesis of the eicosanoid. The results highlight the importance of cell-cell and autocrine interactions in regulating allergic responses in the airways. Copyright © 2017. Published by Elsevier B.V.

Characteristics of antibody responses induced in mice by protein allergens.

PubMed

Hilton, J; Dearman, R J; Sattar, N; Basketter, D A; Kimber, I

1997-12-01

Whereas many foreign proteins are immunogenic, only a proportion is also allergenic, having the capacity to induce the quality of immune response necessary to support the production of IgE antibody. We have demonstrated previously that intraperitoneal administration to mice of proteins such as ovalbumin (OVA) or the industrial enzyme A. oryzae lipase, which possess significant allergenic potential, stimulates the production of both IgG and IgE antibody. Identical exposure to bovine serum albumin (BSA), a protein with limited potential to cause immediate respiratory or gastrointestinal hypersensitivity reactions, induced IgG responses only. In the current investigations, the quality of immune responses induced following exposure to these proteins via mucosal tissue (intranasal) has been compared with those provoked following administration via a non-mucosal (intraperitoneal) route of exposure. Intranasal or intraperitoneal administration of BSA, OVA or A. oryzae lipase elicited in each case vigorous IgG and IgG1 antibody responses. For all three proteins, at every concentration tested, and via both routes of exposure, IgG1 antibody titres paralleled closely IgG titres. However, the three materials displayed a differential potential to provoke IgE responses and this correlated with their known allergenic potential in humans. Thus, OVA and A. oryzae lipase stimulated strong IgE antibody responses, whereas BSA provoked low titre IgE only at the highest concentration tested (5% administered intraperitoneally). The quality of induced responses was not affected by the route of exposure. It would appear, therefore, that the stimulation of IgG and IgG1 antibody responses is a reflection of protein immunogenicity whereas protein allergenicity is associated with the induction of strong IgE responses.

Motorcycle exhaust particles induce airway inflammation and airway hyperresponsiveness in BALB/C mice.

PubMed

Lee, Chen-Chen; Liao, Jiunn-Wang; Kang, Jaw-Jou

2004-06-01

A number of large studies have reported that environmental pollutants from fossil fuel combustion can cause deleterious effects to the immune system, resulting in an allergic reaction leading to respiratory tract damage. In this study, we investigated the effect of motorcycle exhaust particles (MEP), a major pollutant in the Taiwan urban area, on airway inflammation and airway hyperresponsiveness in laboratory animals. BALB/c mice were instilled intratracheally (i.t.) with 1.2 mg/kg and 12 mg/kg of MEP, which was collected from two-stroke motorcycle engines. The mice were exposed 3 times i.t. with MEP, and various parameters for airway inflammation and hyperresponsiveness were sequentially analyzed. We found that MEP would induce airway and pulmonary inflammation characterized by infiltration of eosinophils, neutrophils, lymphocytes, and macrophages in bronchoalveolar lavage fluid (BALF) and inflammatory cell infiltration in lung. In addition, MEP treatment enhanced BALF interleukin-4 (IL-4), IL-5, and interferon-gamma (IFN-gamma) cytokine levels and serum IgE production. Bronchial response measured by unrestrained plethysmography with methacholine challenge showed that MEP treatment induced airway hyperresponsiveness (AHR) in BALB/c mice. The chemical components in MEP were further fractionated with organic solvents, and we found that the benzene-extracted fraction exerts a similar biological effect as seen with MEP, including airway inflammation, increased BALF IL-4, serum IgE production, and induction of AHR. In conclusion, we present evidence showing that the filter-trapped particles emitted from the unleaded-gasoline-fueled two-stroke motorcycle engine may induce proinflammatory and proallergic response profiles in the absence of exposure to allergen.

Cockroach protease allergen induces allergic airway inflammation via epithelial cell activation

PubMed Central

Kale, Sagar L.; Agrawal, Komal; Gaur, Shailendra Nath; Arora, Naveen

2017-01-01

Protease allergens are known to enhance allergic inflammation but their exact role in initiation of allergic reactions at mucosal surfaces still remains elusive. This study was aimed at deciphering the role of serine protease activity of Per a 10, a major cockroach allergen in initiation of allergic inflammation at mucosal surfaces. We demonstrate that Per a 10 increases epithelial permeability by disruption of tight junction proteins, ZO-1 and occludin, and enhances the migration of Monocyte derived dendritic cell precursors towards epithelial layer as exhibited by trans-well studies. Per a 10 exposure also leads to secretion of IL-33, TSLP and intracellular Ca2+ dependent increase in ATP levels. Further, in vivo experiments revealed that Per a 10 administration in mice elevated allergic inflammatory parameters along with high levels of IL-33, TSLP, IL-1α and uric acid in the mice lungs. We next demonstrated that Per a 10 cleaves CD23 (low affinity IgE receptor) from the surface of PBMCs and purified B cells and CD25 (IL-2 receptor) from the surface of PBMCs and purified T cells in an activity dependent manner, which might favour Th2 responses. In conclusion, protease activity of Per a 10 plays a significant role in initiation of allergic airway inflammation at the mucosal surfaces. PMID:28198394

IκBNS induces Muc5ac expression in epithelial cells and causes airway hyper-responsiveness in murine asthma models.

PubMed

Yokota, M; Tamachi, T; Yokoyama, Y; Maezawa, Y; Takatori, H; Suto, A; Suzuki, K; Hirose, K; Takeda, K; Nakajima, H

2017-07-01

In allergic asthma, environmental allergens including house dust mite (HDM) trigger pattern recognition receptors and activate downstream signaling pathways including NF-κB pathways not only in immune cells but also in airway epithelial cells. Recent studies have shown that NF-κB activation is regulated positively or negatively depending on the cellular context by IκBNS (encoded by the gene Nfkbid), one of atypical IκB proteins, in the nucleus. Therefore, we hypothesized that IκBNS expressed in immune cells or epithelial cells is involved in the regulation of asthmatic responses. To determine the roles of IκBNS in HDM-induced asthmatic responses. Roles of IκBNS in HDM-induced airway inflammation and airway hyper-responsiveness (AHR) were examined by using IκBNS-deficient (Nfkbid -/- ) mice. Roles of IκBNS expressed in hematopoietic cells and nonhematopoietic cells were separately evaluated by bone marrow chimeric mice. Roles of IκBNS expressed in murine tracheal epithelial cells (mTECs) were examined by air-liquid interface culture. House dust mite-induced airway inflammation and AHR were exacerbated in mice lacking IκBNS in hematopoietic cells. In contrast, HDM-induced airway inflammation was exacerbated, but AHR was attenuated in mice lacking IκBNS in nonhematopoietic cells. The induction of Muc5ac, a representative mucin in asthmatic airways, was reduced in Nfkbid -/- mTEC, whereas the induction of Spdef, a master regulator of goblet cell metaplasia, was not impaired in Nfkbid -/- mTEC. Moreover, IκBNS bound to and activated the MUC5AC distal promoter in epithelial cells. IκBNS is involved in inducing Muc5ac expression in lung epithelial cells and causing AHR in HDM-induced asthma models. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Polyclonal and allergen-induced cytokine responses in children with elevated immunoglobulin E but no atopic disease.

PubMed

Smart, J M; Tang, M L K; Kemp, A S

2002-11-01

Reduced Th1 and elevated Th2 cytokine responses are considered to be a principal mechanism in the generation of the inflammation leading to the manifestations of atopic disease in the skin of atopic dermatitis and in the airways of asthma. If reduced Th1 and elevated Th2 responses are principal determinants of the manifestation of atopic disease it might be expected that subjects with established disease would exhibit differences in their cytokine profiles as compared with atopic patients without clinical disease. To determine whether asymptomatic atopic children exhibit a cytokine imbalance similar to that seen in patients with established atopic disease or if they behave like non-atopic controls. Cytokine responses in a group of children with elevated IgE but no clinical manifestations of disease, atopic children with established disease and non-atopic controls were compared. We examined allergen-induced (house dust mite, HDM, rye grass pollen and RYE) cytokine responses in parallel with polyclonal (staphylococcal enterotoxin B, SEB) cytokine responses in a group of children with elevated serum IgE levels without current or past evidence of atopic disease (median age 6.6 years) and compared these with a non-atopic control group (median age 6.5 years) and a group of children with atopic disease (median age 6.7 years). Symptomatic atopic children had reduced SEB-induced IFN-gamma and increased SEB-induced IL-4 and IL-5 as compared with non-atopic controls. In contrast, SEB-induced IFN-gamma, IL-4 and IL-5 production in asymptomatic atopics was not significantly different from the non-atopic control subjects. Allergen-induced Th1 (IFN-gamma) and Th2 (IL-5 and IL-13) cytokine production was increased in both symptomatic atopics and asymptomatic atopics when compared with non-atopic controls. The defect in polyclonally induced IFN-gamma production was associated with the clinical manifestation of atopic disease but not the atopic stateper se. This suggests that the

Asthma progression to airway remodeling and bone marrow eosinophil responses in genetically distinct strains of mice.

PubMed

Hogan, Mary Beth; Piktel, Debra; Hubbs, Ann F; McPherson, Leslie E; Landreth, Kenneth S

2008-12-01

Patient factors that cause long-term airway remodeling are largely unidentified. This suggests that genetic differences may determine which asthmatic patients develop airway remodeling. A murine model with repeated allergen exposure leading to peribronchial fibrosis in complement factor 5 (C5)-deficient A/J mice has been used to study asthma progression. No studies have addressed the systemic effects of allergen sensitization or chronic allergen exposure on bone marrow eosinophilopoiesis in this mouse strain. To investigate bone marrow eosinophil responses during acute sensitization and chronic allergen exposure using genetically distinct mouse strains differing in persistent airway reactivity and remodeling. The C5-sufficient BALB/c and C5-deficient A/J mice were repetitively exposed to intranasal ovalbumin for 12 weeks. Subsequently, the mice were evaluated for airway eosinophilia, mucus-containing goblet cells, and peribronchial fibrosis. Both strains of mice were also acutely sensitized to ovalbumin. Bone marrow eosinophil progenitor cells and mature eosinophils were enumerated. BALB/c and A/J mice have similar bone marrow responses after acute allergen exposure, with elevations in bone marrow eosinophil progenitor cell and eosinophil numbers. After chronic allergen exposure, only C5-deficient A/J mice that developed peribronchial fibrosis exhibited bone marrow eosinophilia. BALB/c mice lacked peribronchial fibrosis and extinguished accelerated eosinophil production after long-term allergen challenge. Chronic airway remodeling after repeated allergen exposure in genetically different mice correlated with differences in long-term bone marrow eosinophilopoiesis. Preventing asthma from progressing to chronic airway remodeling with fibrosis may involve identifying genetically determined influences on bone marrow responses to chronic allergen exposure.

Increased Th1 and Th2 allergen-induced cytokine responses in children with atopic disease.

PubMed

Smart, J M; Kemp, A S

2002-05-01

Polyclonal cytokine responses following stimulation of T cells with mitogens or superantigens provides information on cytokine production from a wide range of T cells. Alternatively allergen-induced T cell responses can provide information on cytokine production by allergen-reactive T cells. While there is evidence of increased Th2 and reduced Th1 cytokine production following T cell stimulation with non-specific mitogens and superantigens, the evidence that Th1 cytokine production to allergens is decreased in line with a postulated imbalance in Th1/Th2 responses is unclear, with studies finding decreased, no difference or increased IFN-gamma responses to allergens in atopic subjects. To examine childhood polyclonal and allergen-induced cytokine responses in parallel to evaluate cytokine imbalances in childhood atopic disease. PBMC cytokine responses were examined in response to a polyclonal stimulus, staphylococcal superantigen (SEB), in parallel with two inhalant allergens, house dust mite (HDM) and rye grass pollen (RYE), and an ingested allergen, ovalbumin (OVA), in (a) 35 healthy children (non-atopic) and (b) 36 children with atopic disease (asthma, eczema and/or rhinitis) (atopic). Atopic children had significantly reduced IFN-gamma and increased IL-4 and IL-5 but not IL13 production to SEB superantigen stimulation when compared with non-atopic children. HDM and RYE allergens stimulated significantly increased IFN-gamma, IL-5 and IL-13, while OVA stimulated significantly increased IFN-gamma production in atopic children. We show that a polyclonal stimulus induces a reduced Th1 (IFN-gamma) and increased Th2 (IL-4 and IL-5) cytokine pattern. In contrast, the allergen-induced cytokine responses in atopic children were associated with both increased Th1 (INF-gamma) and Th2 (IL-5 and IL-13) cytokine production. The increased Th1 response to allergen is likely to reflect prior sensitization and indicates that increases in both Th1 and Th2 cytokine production to

Airway and serum adipokines after allergen and diesel exposure in a controlled human crossover study of atopic adults.

PubMed

Kramer, Marabeth M; Hirota, Jeremy A; Sood, Akshay; Teschke, Kay; Carlsten, Christopher

2017-04-01

Adipokines are mediators released from adipose tissue. These proteins are regarded as active elements of systemic and pulmonary inflammation, whose dysregulation can alter an individual's risk of developing allergic lung diseases. Despite this knowledge, adipokine responses to inhaled stimuli are poorly understood. We sought to measure serum and lung adiponectin, leptin, and resistin in an atopic adult study population following exposure to allergen and diesel exhaust (DE). Two types of lung samples including bronchoalveolar lavage (BAL) and bronchial wash (BW), and a time course of serum samples, were collected from the 18 subjects who participated in the randomized, double-blinded controlled human study. The two crossover exposure triads in this study were inhaled DE and filtered air each followed by instilled allergen or saline. Serum and lung adipokine responses to these exposures were quantified using enzyme-linked immunosorbent assay. Allergen significantly increased adiponectin and leptin in BAL, and adiponectin in the BW 48 hours after exposure. Serum leptin and resistin responses were not differentially affected by exposure, but varied over time. Coexposure with DE and allergen revealed significant correlations between the adiponectin/leptin ratio and FEV 1 changes and airway responsiveness measures. Changes in lung and serum adipokines in response to allergen exposure were identified in the context of a controlled exposure study. Coexposure identified a potentially protective role of adiponectin in the lung. This response was not observed in those with baseline airway hyper-responsiveness, or after allergen exposure alone. The clinical relevance of this potentially adaptive adipokine pattern warrants further study. Copyright © 2016 Elsevier Inc. All rights reserved.

House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection.

PubMed

Fujimura, Kei E; Demoor, Tine; Rauch, Marcus; Faruqi, Ali A; Jang, Sihyug; Johnson, Christine C; Boushey, Homer A; Zoratti, Edward; Ownby, Dennis; Lukacs, Nicholas W; Lynch, Susan V

2014-01-14

Exposure to dogs in early infancy has been shown to reduce the risk of childhood allergic disease development, and dog ownership is associated with a distinct house dust microbial exposure. Here, we demonstrate, using murine models, that exposure of mice to dog-associated house dust protects against ovalbumin or cockroach allergen-mediated airway pathology. Protected animals exhibited significant reduction in the total number of airway T cells, down-regulation of Th2-related airway responses, as well as mucin secretion. Following dog-associated dust exposure, the cecal microbiome of protected animals was extensively restructured with significant enrichment of, amongst others, Lactobacillus johnsonii. Supplementation of wild-type animals with L. johnsonii protected them against both airway allergen challenge or infection with respiratory syncytial virus. L. johnsonii-mediated protection was associated with significant reductions in the total number and proportion of activated CD11c(+)/CD11b(+) and CD11c(+)/CD8(+) cells, as well as significantly reduced airway Th2 cytokine expression. Our results reveal that exposure to dog-associated household dust results in protection against airway allergen challenge and a distinct gastrointestinal microbiome composition. Moreover, the study identifies L. johnsonii as a pivotal species within the gastrointestinal tract capable of influencing adaptive immunity at remote mucosal surfaces in a manner that is protective against a variety of respiratory insults.

House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection

PubMed Central

Fujimura, Kei E.; Demoor, Tine; Rauch, Marcus; Faruqi, Ali A.; Jang, Sihyug; Johnson, Christine C.; Boushey, Homer A.; Zoratti, Edward; Ownby, Dennis; Lukacs, Nicholas W.; Lynch, Susan V.

2014-01-01

Exposure to dogs in early infancy has been shown to reduce the risk of childhood allergic disease development, and dog ownership is associated with a distinct house dust microbial exposure. Here, we demonstrate, using murine models, that exposure of mice to dog-associated house dust protects against ovalbumin or cockroach allergen-mediated airway pathology. Protected animals exhibited significant reduction in the total number of airway T cells, down-regulation of Th2-related airway responses, as well as mucin secretion. Following dog-associated dust exposure, the cecal microbiome of protected animals was extensively restructured with significant enrichment of, amongst others, Lactobacillus johnsonii. Supplementation of wild-type animals with L. johnsonii protected them against both airway allergen challenge or infection with respiratory syncytial virus. L. johnsonii-mediated protection was associated with significant reductions in the total number and proportion of activated CD11c+/CD11b+ and CD11c+/CD8+ cells, as well as significantly reduced airway Th2 cytokine expression. Our results reveal that exposure to dog-associated household dust results in protection against airway allergen challenge and a distinct gastrointestinal microbiome composition. Moreover, the study identifies L. johnsonii as a pivotal species within the gastrointestinal tract capable of influencing adaptive immunity at remote mucosal surfaces in a manner that is protective against a variety of respiratory insults. PMID:24344318

High Degree of Overlap between Responses to a Virus and to the House Dust Mite Allergen in Airway Epithelial Cells

PubMed Central

Golebski, Korneliusz; Luiten, Silvia; van Egmond, Danielle; de Groot, Esther; Röschmann, Kristina Irene Lisolette; Fokkens, Wytske Johanna; van Drunen, Cornelis Maria

2014-01-01

Background Airway epithelium is widely considered to play an active role in immune responses through its ability to detect changes in the environment and to generate a microenvironment for immune competent cells. Therefore, besides its role as a physical barrier, epithelium affects the outcome of the immune response by the production of various pro-inflammatory mediators. Methods We stimulated airway epithelial cells with viral double stranded RNA analogue poly(I:C) or with house dust mite in a time course of 24 hours. In order to determine cytokines production by stimulated cells, we performed multiplex enzyme linked immunosorbant assay (ELISA). Results We demonstrate that the temporal pattern of the genes that respond to virus exposure in airway epithelium resembles to a significant degree their pattern of response to HDM. The gene expression pattern of EGR1, DUSP1, FOSL1, JUN, MYC, and IL6 is rather similar after viral (poly(I:C)) and HDM exposure. However, both triggers also induce a specific response (e.g. ATF3, FOS, and NFKB1). We confirmed these data by showing that epithelial cells produce a variety of similar mediators in response to both poly(I:C) and HDM challenge (IL1-RA, IL-17, IFN-α and MIP1-α), sometimes with a quantitative difference in response (IL2-R, IL-6, IL-8, MCP-1, MIG, and HGF). Interestingly, only four mediators (IL-12, IP-10, RANTES and VEGF) where up-regulated specifically by poly(I:C) and not by HDM. Additionally, we report that pre-exposure to HDM deregulates production of cytokines and mediators in response to poly(I:C). Conclusions Epithelial cells responses to the HDM-allergen and a virus strongly resemble both in gene expression and in protein level explaining why these two responses may affect each other. PMID:24498371

High degree of overlap between responses to a virus and to the house dust mite allergen in airway epithelial cells.

PubMed

Golebski, Korneliusz; Luiten, Silvia; van Egmond, Danielle; de Groot, Esther; Röschmann, Kristina Irene Lisolette; Fokkens, Wytske Johanna; van Drunen, Cornelis Maria

2014-01-01

Airway epithelium is widely considered to play an active role in immune responses through its ability to detect changes in the environment and to generate a microenvironment for immune competent cells. Therefore, besides its role as a physical barrier, epithelium affects the outcome of the immune response by the production of various pro-inflammatory mediators. We stimulated airway epithelial cells with viral double stranded RNA analogue poly(I:C) or with house dust mite in a time course of 24 hours. In order to determine cytokines production by stimulated cells, we performed multiplex enzyme linked immunosorbant assay (ELISA). We demonstrate that the temporal pattern of the genes that respond to virus exposure in airway epithelium resembles to a significant degree their pattern of response to HDM. The gene expression pattern of EGR1, DUSP1, FOSL1, JUN, MYC, and IL6 is rather similar after viral (poly(I:C)) and HDM exposure. However, both triggers also induce a specific response (e.g. ATF3, FOS, and NFKB1). We confirmed these data by showing that epithelial cells produce a variety of similar mediators in response to both poly(I:C) and HDM challenge (IL1-RA, IL-17, IFN-α and MIP1-α), sometimes with a quantitative difference in response (IL2-R, IL-6, IL-8, MCP-1, MIG, and HGF). Interestingly, only four mediators (IL-12, IP-10, RANTES and VEGF) where up-regulated specifically by poly(I:C) and not by HDM. Additionally, we report that pre-exposure to HDM deregulates production of cytokines and mediators in response to poly(I:C). Epithelial cells responses to the HDM-allergen and a virus strongly resemble both in gene expression and in protein level explaining why these two responses may affect each other.

Tumor necrosis factor regulates NMDA receptor-mediated airway smooth muscle contractile function and airway responsiveness.

PubMed

Anaparti, Vidyanand; Pascoe, Christopher D; Jha, Aruni; Mahood, Thomas H; Ilarraza, Ramses; Unruh, Helmut; Moqbel, Redwan; Halayko, Andrew J

2016-08-01

We have shown that N-methyl-d-aspartate receptors (NMDA-Rs) are receptor-operated calcium entry channels in human airway smooth muscle (HASM) during contraction. Tumor necrosis factor (TNF) augments smooth muscle contractility by influencing pathways that regulate intracellular calcium flux and can alter NMDA-R expression and activity in cortical neurons and glial cells. We hypothesized that NMDA-R-mediated Ca(2+) and contractile responses of ASM can be altered by inflammatory mediators, including TNF. In cultured HASM cells, we assessed TNF (10 ng/ml, 48 h) effect on NMDA-R subunit abundance by quantitative PCR, confocal imaging, and immunoblotting. We observed dose- and time-dependent changes in NMDA-R composition: increased obligatory NR1 subunit expression and altered regulatory NR2 and inhibitory NR3 subunits. Measuring intracellular Ca(2+) flux in Fura-2-loaded HASM cultures, we observed that TNF exposure enhanced cytosolic Ca(2+) mobilization and changed the temporal pattern of Ca(2+) flux in individual myocytes induced by NMDA, an NMDA-R selective analog of glutamate. We measured airway responses to NMDA in murine thin-cut lung slices (TCLS) from allergen-naive animals and observed significant airway contraction. However, NMDA acted as a bronchodilator in TCLS from house dust mice-challenged mice and in allergen-naive TCLS subjected to TNF exposure. All contractile or bronchodilator responses were blocked by a selective NMDA-R antagonist, (2R)-amino-5-phosphonopentanoate, and bronchodilator responses were prevented by N(G)-nitro-l-arginine methyl ester (nitric oxide synthase inhibitor) or indomethacin (cyclooxygenase inhibitor). Collectively, we show that TNF augments NMDA-R-mediated Ca(2+) mobilization in HASM cells, whereas in multicellular TCLSs allergic inflammation and TNF exposure leads to NMDA-R-mediated bronchodilation. These findings reveal the unique contribution of ionotrophic NMDA-R to airway hyperreactivity. Copyright © 2016 the American

Effect of TEI-9874, an inhibitor of immunoglobulin E production, on allergen-induced asthmatic model in rats.

PubMed

Nonaka, T; Mitsuhashi, H; Takahashi, K; Sugiyama, H; Kishimoto, T

2000-08-25

As TEI-9874, 2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)ben zoic acid reduces allergen-specific immunoglobulin E (IgE) production by human peripheral blood mononuclear cells in vitro, we evaluated its potency on an allergen-induced asthmatic model in Brown-Norway rats. Inhaled ovalbumin induced the immediate-phase asthmatic response, the late-phase asthmatic response, the infiltration of leukocytes into bronchoalveolar lavage fluid, and an increase of serum anti-ovalbumin IgE. These parameters were suppressed by the treatment with TEI-9874 (3, 10, and 30 mg/kg p.o.). The ovalbumin-induced airway hyperresponsiveness was prevented by TEI-9874 (30 mg/kg p.o.). Furthermore, the suppression of the immediate-phase asthmatic response and the late-phase asthmatic response by TEI-9874 was almost completely extinguished by the exogenous administration of rat anti-ovalbumin antiserum. These results indicate that the efficacy of TEI-9874 on the asthmatic response is mainly mediated by the suppression of allergen-specific IgE production and TEI-9874 appears to be a good candidate as therapy for IgE-mediated allergic asthma.

Increased CCL24/eotaxin-2 with postnatal ozone exposure in allergen-sensitized infant monkeys is not associated with recruitment of eosinophils to airway mucosa

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chou, Debbie L.; Gerriets, Joan E.; Schelegle, Edward S.

Epidemiology supports a causal link between air pollutant exposure and childhood asthma, but the mechanisms are unknown. We have previously reported that ozone exposure can alter the anatomic distribution of CD25+ lymphocytes in airways of allergen-sensitized infant rhesus monkeys. Here, we hypothesized that ozone may also affect eosinophil trafficking to allergen-sensitized infant airways. To test this hypothesis, we measured blood, lavage, and airway mucosa eosinophils in 3-month old monkeys following cyclical ozone and house dust mite (HDM) aerosol exposures. We also determined if eotaxin family members (CCL11, CCL24, CCL26) are associated with eosinophil location in response to exposures. In lavage,more » eosinophil numbers increased in animals exposed to ozone and/or HDM. Ozone + HDM animals showed significantly increased CCL24 and CCL26 protein in lavage, but the concentration of CCL11, CCL24, and CCL26 was independent of eosinophil number for all exposure groups. In airway mucosa, eosinophils increased with exposure to HDM alone; comparatively, ozone and ozone + HDM resulted in reduced eosinophils. CCL26 mRNA and immunofluorescence staining increased in airway mucosa of HDM alone animals and correlated with eosinophil volume. In ozone + HDM animal groups, CCL24 mRNA and immunofluorescence increased along with CCR3 mRNA, but did not correlate with airway mucosa eosinophils. Cumulatively, our data indicate that ozone exposure results in a profile of airway eosinophil migration that is distinct from HDM mediated pathways. CCL24 was found to be induced only by combined ozone and HDM exposure, however expression was not associated with the presence of eosinophils within the airway mucosa. -- Highlights: Black-Right-Pointing-Pointer Ozone can modulate the localization of eosinophils in infant allergic airways. Black-Right-Pointing-Pointer Expression of eotaxins within the lung is affected by ozone and allergen exposure. Black-Right-Pointing-Pointer CCL24

A limited CpG-containing oligodeoxynucleotide therapy regimen induces sustained suppression of allergic airway inflammation in mice

PubMed Central

Kozy, Heather M.; Lum, Jeremy A.; Sweetwood, Rosemary; Chu, Mabel; Cunningham, Cameron R.; Salamon, Hugh; Lloyd, Clare M.; Coffman, Robert L.; Hessel, Edith M.

2015-01-01

Background CpG-containing oligodeoxynucleotides (CpG-ODN) are potent inhibitors of Th2-mediated allergic airway disease in sensitized mice challenged with allergen. A single treatment has transient effects but a limited series of treatments has potential to achieve clinically meaningful sustained inhibition of allergic airway disease. Objective To optimize the treatment regimen and determine the mechanisms of action in mice of an inhaled form of CpG-ODN being developed for human asthma treatment. Methods A limited series of weekly intranasal 1018 ISS (CpG-ODN; B-class) treatments were given to ragweed allergen-sensitized mice chronically exposed to allergen during and after the 1018 ISS treatment regimen. Treatment effects were evaluated by measuring effect on lung Th2 cytokines and eosinophilia as well as lung dendritic cell function and T cell responses. Results Twelve intranasal 1018 ISS treatments induced significant suppression of BAL eosinophilia and IL-4, IL-5, and IL-13 levels and suppression was maintained through 13 weekly ragweed exposures administered after treatment cessation. At least 5 treatments were required for lasting Th2 suppression. CpG-ODN induced moderate Th1 responses but Th2 suppression did not require IFN-γ. Th2 suppression was associated with induction of a regulatory T cell response. Conclusion A short series of CpG-ODN treatments results in sustained suppression of allergic lung inflammation induced by a clinically relevant allergen. PMID:24464743

Reduced immune responses in chimeric mice engrafted with bone marrow cells from mice with airways inflammation.

PubMed

Scott, Naomi M; Ng, Royce L X; McGonigle, Terence A; Gorman, Shelley; Hart, Prue H

2015-11-01

During respiratory inflammation, it is generally assumed that dendritic cells differentiating from the bone marrow are immunogenic rather than immunoregulatory. Using chimeric mice, the outcomes of airways inflammation on bone marrow progenitor cells were studied. Immune responses were analyzed in chimeric mice engrafted for >16 weeks with bone marrow cells from mice with experimental allergic airways disease (EAAD). Responses to sensitization and challenge with the allergen causing inflammation in the bone marrow-donor mice were significantly reduced in the chimeric mice engrafted with bone marrow cells from mice with EAAD (EAAD-chimeric). Responses to intranasal LPS and topical fluorescein isothiocyanate (non-specific challenges) were significantly attenuated. Fewer activated dendritic cells from the airways and skin of the EAAD-chimeric mice could be tracked to the draining lymph nodes, and may contribute to the significantly reduced antigen/chemical-induced hypertrophy in the draining nodes, and the reduced immune responses to sensitizing allergens. Dendritic cells differentiating in vitro from the bone marrow of >16 weeks reconstituted EAAD-chimeric mice retained an ability to poorly prime immune responses when transferred into naïve mice. Dendritic cells developing from bone marrow progenitors during airways inflammation are altered such that daughter cells have reduced antigen priming capabilities.

MyD88-dependent dendritic and epithelial cell crosstalk orchestrates immune responses to allergens.

PubMed

Thomas, S Y; Whitehead, G S; Takaku, M; Ward, J M; Xu, X; Nakano, K; Lyons-Cohen, M R; Nakano, H; Gowdy, K M; Wade, P A; Cook, D N

2018-05-01

Sensitization to inhaled allergens is dependent on activation of conventional dendritic cells (cDCs) and on the adaptor molecule, MyD88. However, many cell types in the lung express Myd88, and it is unclear how signaling in these different cell types reprograms cDCs and leads to allergic inflammation of the airway. By combining ATAC-seq with RNA profiling, we found that MyD88 signaling in cDCs maintained open chromatin at select loci even at steady state, allowing genes to be rapidly induced during allergic sensitization. A distinct set of genes related to metabolism was indirectly controlled in cDCs through MyD88 signaling in airway epithelial cells (ECs). In mouse models of asthma, Myd88 expression in ECs was critical for eosinophilic inflammation, whereas Myd88 expression in cDCs was required for Th17 cell differentiation and consequent airway neutrophilia. Thus, both cell-intrinsic and cell-extrinsic MyD88 signaling controls gene expression in cDCs and orchestrates immune responses to inhaled allergens.

Eotaxin, but not IL-8, is increased in upper and lower airways of allergic rhinitis subjects after nasal allergen challenge.

PubMed

Semik-Orzech, Aleksandra; Barczyk, Adam; Wiaderkiewicz, Ryszard; Pierzchała, Władysław

2011-01-01

The aim of this study was to assess the impact of a single nasal allergen challenge (NAC) on levels of eotaxin and IL-8 and the inflammatory cells in upper and lower airways of allergic rhinitis (AR) patients. Twenty-four AR patients and 12 control subjects entered a sequential nasal placebo challenge and NAC study, out of the pollen season. Nasal lavage fluid (NLF) was obtained at baseline, 15 minutes, and 1, 5, and 24 hours postchallenge. Before and 24 hours after placebo/allergen challenge induced sputum was performed. NLF and induced sputum were evaluated for total cell count (TCC) and differential cell count and analyzed for concentrations of eotaxin and IL-8 using ELISA method. NAC in AR subjects was associated with significantly increased sputum (p = 0.008) and NLF (p < 0.001) eotaxin levels. Post-NAC IL-8 levels were significantly increased in NLF (p < 00001) but not in sputum (p = 0.080) of AR subjects. Increased eotaxin levels in NLF positively correlated with the increased TCC and eosinophils. Positive correlations were also found between NLF increased eotaxin level and sputum TCC, eosinophils, and macrophages. NAC is associated with the increased levels of eotaxin in lower airways of AR subjects. Allergen-induced secretion of eotaxin in nasal mucosa of AR subjects is involved in determining the cellular character of both upper and lower airway inflammation.

Immune Modulatory Effects of IL-22 on Allergen-Induced Pulmonary Inflammation

PubMed Central

Fang, Ping; Zhou, Li; Zhou, Yuqi; Kolls, Jay K.; Zheng, Tao; Zhu, Zhou

2014-01-01

IL-22 is a Th17/Th22 cytokine that is increased in asthma. However, recent animal studies showed controversial findings in the effects of IL-22 in allergic asthma. To determine the role of IL-22 in ovalbumin-induced allergic inflammation we generated inducible lung-specific IL-22 transgenic mice. Transgenic IL-22 expression and signaling activity in the lung were determined. Ovalbumin (OVA)-induced pulmonary inflammation, immune responses, and airway hyperresponsiveness (AHR) were examined and compared between IL-22 transgenic mice and wild type controls. Following doxycycline (Dox) induction, IL-22 protein was readily detected in the large (CC10 promoter) and small (SPC promoter) airway epithelial cells. IL-22 signaling was evidenced by phosphorylated STAT3. After OVA sensitization and challenge, compared to wild type littermates, IL-22 transgenic mice showed decreased eosinophils in the bronchoalveolar lavage (BAL), and in lung tissue, decreased mucus metaplasia in the airways, and reduced AHR. Among the cytokines and chemokines examined, IL-13 levels were reduced in the BAL fluid as well as in lymphocytes from local draining lymph nodes of IL-22 transgenic mice. No effect was seen on the levels of serum total or OVA-specific IgE or IgG. These findings indicate that IL-22 has immune modulatory effects on pulmonary inflammatory responses in allergen-induced asthma. PMID:25254361

Comparison of Airway Responses Induced in a Mouse Model by the Gas and Particulate Fractions of Gasoline Direct Injection Engine Exhaust.

PubMed

Maikawa, Caitlin L; Zimmerman, Naomi; Ramos, Manuel; Shah, Mittal; Wallace, James S; Pollitt, Krystal J Godri

2018-03-01

Diesel exhaust has been associated with asthma, but its response to other engine emissions is not clear. The increasing prevalence of vehicles with gasoline direct injection (GDI) engines motivated this study, and the objective was to evaluate pulmonary responses induced by acute exposure to GDI engine exhaust in an allergic asthma murine model. Mice were sensitized with an allergen to induce airway hyperresponsiveness or treated with saline (non-allergic group). Animals were challenged for 2-h to exhaust from a laboratory GDI engine operated at conditions equivalent to a highway cruise. Exhaust was filtered to assess responses induced by the particulate and gas fractions. Short-term exposure to particulate matter from GDI engine exhaust induced upregulation of genes related to polycyclic aromatic hydrocarbon (PAH) metabolism ( Cyp1b1 ) and inflammation ( TNFα ) in the lungs of non-allergic mice. High molecular weight PAHs dominated the particulate fraction of the exhaust, and this response was therefore likely attributable to the presence of these PAHs. The particle fraction of GDI engine exhaust further contributed to enhanced methacholine responsiveness in the central and peripheral tissues in animals with airway hyperresponsiveness. As GDI engines gain prevalence in the vehicle fleet, understanding the health impacts of their emissions becomes increasingly important.

Comparison of Airway Responses Induced in a Mouse Model by the Gas and Particulate Fractions of Gasoline Direct Injection Engine Exhaust

PubMed Central

Maikawa, Caitlin L.; Zimmerman, Naomi; Ramos, Manuel; Wallace, James S.; Pollitt, Krystal J. Godri

2018-01-01

Diesel exhaust has been associated with asthma, but its response to other engine emissions is not clear. The increasing prevalence of vehicles with gasoline direct injection (GDI) engines motivated this study, and the objective was to evaluate pulmonary responses induced by acute exposure to GDI engine exhaust in an allergic asthma murine model. Mice were sensitized with an allergen to induce airway hyperresponsiveness or treated with saline (non-allergic group). Animals were challenged for 2-h to exhaust from a laboratory GDI engine operated at conditions equivalent to a highway cruise. Exhaust was filtered to assess responses induced by the particulate and gas fractions. Short-term exposure to particulate matter from GDI engine exhaust induced upregulation of genes related to polycyclic aromatic hydrocarbon (PAH) metabolism (Cyp1b1) and inflammation (TNFα) in the lungs of non-allergic mice. High molecular weight PAHs dominated the particulate fraction of the exhaust, and this response was therefore likely attributable to the presence of these PAHs. The particle fraction of GDI engine exhaust further contributed to enhanced methacholine responsiveness in the central and peripheral tissues in animals with airway hyperresponsiveness. As GDI engines gain prevalence in the vehicle fleet, understanding the health impacts of their emissions becomes increasingly important. PMID:29494515

Dysregulation of type 2 innate lymphoid cells and TH2 cells impairs pollutant-induced allergic airway responses.

PubMed

De Grove, Katrien C; Provoost, Sharen; Hendriks, Rudi W; McKenzie, Andrew N J; Seys, Leen J M; Kumar, Smitha; Maes, Tania; Brusselle, Guy G; Joos, Guy F

2017-01-01

Although the prominent role of T H 2 cells in type 2 immune responses is well established, the newly identified type 2 innate lymphoid cells (ILC2s) can also contribute to orchestration of allergic responses. Several experimental and epidemiologic studies have provided evidence that allergen-induced airway responses can be further enhanced on exposure to environmental pollutants, such as diesel exhaust particles (DEPs). However, the components and pathways responsible remain incompletely known. We sought to investigate the relative contribution of ILC2 and adaptive T H 2 cell responses in a murine model of DEP-enhanced allergic airway inflammation. Wild-type, Gata-3 +/nlslacZ (Gata-3-haploinsufficient), RAR-related orphan receptor α (RORα) fl/fl IL7R Cre (ILC2-deficient), and recombination-activating gene (Rag) 2 -/- mice were challenged with saline, DEPs, or house dust mite (HDM) or DEP+HDM. Airway hyperresponsiveness, as well as inflammation, and intracellular cytokine expression in ILC2s and T H 2 cells in the bronchoalveolar lavage fluid and lung tissue were assessed. Concomitant DEP+HDM exposure significantly enhanced allergic airway inflammation, as characterized by increased airway eosinophilia, goblet cell metaplasia, accumulation of ILC2s and T H 2 cells, type 2 cytokine production, and airway hyperresponsiveness compared with sole DEPs or HDM. Reduced Gata-3 expression decreased the number of functional ILC2s and T H 2 cells in DEP+HDM-exposed mice, resulting in an impaired DEP-enhanced allergic airway inflammation. Interestingly, although the DEP-enhanced allergic inflammation was marginally reduced in ILC2-deficient mice that received combined DEP+HDM, it was abolished in DEP+HDM-exposed Rag2 -/- mice. These data indicate that dysregulation of ILC2s and T H 2 cells attenuates DEP-enhanced allergic airway inflammation. In addition, a crucial role for the adaptive immune system was shown on concomitant DEP+HDM exposure. Copyright © 2016 American

Do individuals with asthma experience airway hyper-responsiveness after exposure to nitrogen dioxide?

PubMed

Goodman, Julie E; Kennedy, Erin M; Seeley, Mara

2017-10-01

The current 100 ppb short-term National Ambient Air Quality Standard for NO 2 , and EPA's determination of a causal association for respiratory effects, are based in part on controlled human exposure studies evaluating airway hyper-responsiveness (AHR). A meta-analysis by Goodman et al. (2009) found increased AHR at 100 ppb NO 2 but no clear concentration-response relationship up to 600 ppb, and an overall lack of an AHR effect for studies involving exercise or exposure to allergens. Several factors have been suggested to explain why effects on AHR are observed while people are at rest, but not during exercise or after exposure to allergens. These include an exercise-induced refractory period; partial reversal of bronchospasm from use of forced expiration maneuvers; and greater airway responsiveness of participants exposed to NO 2 at rest. We reviewed the scientific evidence to determine whether there is biological support for these factors and found that none sufficiently explained the lack of an effect during exercise or after exposure to allergens. In the absence of either a consistent concentration-response or a plausible explanation for the paradoxical AHR findings, the biological significance of these findings is uncertain and provides equivocal support for NO 2 as a causal factor of AHR at these exposure levels. Copyright © 2017 Gradient. Published by Elsevier Inc. All rights reserved.

Role of M2 Muscarinic Receptor in the Airway Response to Methacholine of Mice Selected for Minimal or Maximal Acute Inflammatory Response

PubMed Central

Castro, Juciane Maria de Andrade; Resende, Rodrigo R.; Florsheim, Esther; Albuquerque, Layra Lucy; Lino-dos-Santos-Franco, Adriana; Gomes, Eliane; Tavares de Lima, Wothan; de Franco, Marcelo; Ribeiro, Orlando Garcia

2013-01-01

Airway smooth muscle constriction induced by cholinergic agonists such as methacholine (MCh), which is typically increased in asthmatic patients, is regulated mainly by muscle muscarinic M3 receptors and negatively by vagal muscarinic M2 receptors. Here we evaluated basal (intrinsic) and allergen-induced (extrinsic) airway responses to MCh. We used two mouse lines selected to respond maximally (AIRmax) or minimally (AIRmin) to innate inflammatory stimuli. We found that in basal condition AIRmin mice responded more vigorously to MCh than AIRmax. Treatment with a specific M2 antagonist increased airway response of AIRmax but not of AIRmin mice. The expression of M2 receptors in the lung was significantly lower in AIRmin compared to AIRmax animals. AIRmax mice developed a more intense allergic inflammation than AIRmin, and both allergic mouse lines increased airway responses to MCh. However, gallamine treatment of allergic groups did not affect the responses to MCh. Our results confirm that low or dysfunctional M2 receptor activity is associated with increased airway responsiveness to MCh and that this trait was inherited during the selective breeding of AIRmin mice and was acquired by AIRmax mice during allergic lung inflammation. PMID:23691511

A Jagged 1-Notch 4 molecular switch mediates airway inflammation induced by ultrafine particles.

PubMed

Xia, Mingcan; Harb, Hani; Saffari, Arian; Sioutas, Constantinos; Chatila, Talal A

2018-04-05

Exposure to traffic-related particulate matter promotes asthma and allergic diseases. However, the precise cellular and molecular mechanisms by which particulate matter exposure acts to mediate these effects remain unclear. We sought to elucidate the cellular targets and signaling pathways critical for augmentation of allergic airway inflammation induced by ambient ultrafine particles (UFP). We used in vitro cell-culture assays with lung-derived antigen-presenting cells and allergen-specific T cells and in vivo mouse models of allergic airway inflammation with myeloid lineage-specific gene deletions, cellular reconstitution approaches, and antibody inhibition studies. We identified lung alveolar macrophages (AM) as the key cellular target of UFP in promoting airway inflammation. Aryl hydrocarbon receptor-dependent induction of Jagged 1 (Jag1) expression in AM was necessary and sufficient for augmentation of allergic airway inflammation by UFP. UFP promoted T H 2 and T H 17 cell differentiation of allergen-specific T cells in a Jag1- and Notch 4-dependent manner. Treatment of mice with an anti-Notch 4 antibody abrogated exacerbation of allergic airway inflammation induced by UFP. UFP exacerbate allergic airway inflammation by promoting a Jag1-Notch 4-dependent interaction between AM and allergen-specific T cells, leading to augmented T H cell differentiation. Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

A 4-Week Model of House Dust Mite (HDM) Induced Allergic Airways Inflammation with Airway Remodeling.

PubMed

Woo, L N; Guo, W Y; Wang, X; Young, A; Salehi, S; Hin, A; Zhang, Y; Scott, J A; Chow, C W

2018-05-02

Animal models of allergic airways inflammation are useful tools in studying the pathogenesis of asthma and potential therapeutic interventions. The different allergic airways inflammation models available to date employ varying doses, frequency, duration and types of allergen, which lead to the development of different features of asthma; showing varying degrees of airways inflammation and hyper-responsiveness (AHR) and airways remodeling. Models that also exhibit airway remodeling, a key feature of asthma, in addition to AHR and airway inflammation typically require 5-12 weeks to develop. In this report, we describe a 4-week mouse model of house dust mite (HDM)-induced allergic airways inflammation, and compare the phenotypic features of two different doses of HDM exposures (10 µg and 25 µg) for 5 days/week with a well-characterized 8-week chronic HDM model. We found that 4 weeks of intranasal HDM (25 µg in 35 µl saline; 5 days/week) resulted in AHR, airway inflammation and airway remodeling that were comparable to the 8-week model. We conclude that this new 4-week HDM model is another useful tool in studies of human asthma that offers advantages of shorter duration for development and decreased costs when compared to other models that require longer durations of exposure (5-12 weeks) to develop.

Innate Immune Responses to Engineered Nanomaterials During Allergic Airway Inflammation

NASA Astrophysics Data System (ADS)

Shipkowski, Kelly Anne

The field of nanotechnology is continually advancing, and increasing amounts of consumer goods are being produced using engineered nanomaterials (ENMs). The health risks of occupational and/or consumer exposure to ENMs are not completely understood, although significant research indicates that pulmonary exposure to nanomaterials induces toxic effects in the lungs of exposed animals. Multi-walled carbon nanotubes (MWCNTs) are a specific category of ENMs and consist of sheets of graphene rolled into cylinders that are multiple layers thick in order to strengthen their rigidity. MWCNTs have a fiber-like shape, similar to that of asbestos, which allows for a high aspect ratio and makes them difficult to clear from the lung. Studies with rodent models have demonstrated that pulmonary exposure to ENMs, in particular MWCNTs, results in acute lung inflammation and the subsequent development of chronic fibrosis, suggesting a potential human health risk to individuals involved in the manufacturing of products utilizing these nanomaterials. Induction of IL-1beta secretion via activation of the inflammasome is a prime mechanism of MWCNT-induced inflammation. The inflammasome is a multi-protein scaffold found in a variety of cell types that forms in response to a variety of immune signals, including particulates. Sensitization with allergens, such as house dust mite (HDM), increases levels of the T helper 2 (Th2) cytokines IL-4 and IL-13 in mice and in humans, and there is particular cause for concern in cases of MWCNT exposure in individuals with pre-existing allergic airway disease, such as asthma. MWCNT exposure exacerbates airway inflammation and fibrosis in animal models of pre-existing allergic asthma, suggesting that individuals suffering from asthma are more susceptible to the toxic pulmonary effects of MWCNT exposure. Asthma is an exceptionally prominent human disease, and therefore the goal of this research was to better understand how pre-existing allergic airway

Contributions of direct versus indirect mechanisms for regulatory dendritic cell suppression of asthmatic allergen-specific IgG1 antibody responses

PubMed Central

Ma, Yanna; Dawicki, Wojciech; Zhang, Xiaobei

2018-01-01

IL-10-differentiated dendritic cells (DC10) can reverse the asthma phenotype in mice, but how they suppress the asthmatic B cell response is unclear. Herein we assessed the mechanism(s) by which DC10 and DC10-induced Treg affect IgG1 production in asthma. We observed a rapid decline in lung-resident OVA-specific IgG1-secreting B cells on cessation of airway allergen challenge, and intraperitoneal DC10 therapy did not amplify that (p>0.05). It did however increase the loss of IgG1-B cells from the bone marrow (by 45+/-7.2%; p≤0.01) and spleen (by 65+/-17.8%; p≤0.05) over 2 wk. Delivery of OVA-loaded DC10 directly into the airways of asthmatic mice decreased the lung IgG1 B cell response assessed 2 dy later by 33+/-9.7% (p≤0.01), while their co-culture with asthmatic lung cell suspensions reduced the numbers of IgG1-secreting cells by 56.5+/-9.7% (p≤0.01). This effect was dependent on the DC10 carrying intact allergen on their cell surface; DC10 that had phagocytosed and fully processed their allergen were unable to suppress B cell responses, although they did suppress asthmatic Th2 cell responses. We had shown that therapeutic delivery of DC10-induced Treg can effectively suppress asthmatic T and B cell (IgE and IgG1) responses; herein CD4+ cells or Treg from the lungs of DC10-treated OVA-asthmatic mice suppressed in vitro B cell IgG1 production by 52.2+/-8.7% (p≤0.001) or 44.6+/-12.2% (p≤0.05), respectively, but delivery of DC10-induced Treg directly into the airways of asthmatic mice had no discernible impact over 2 dy on the numbers of lung IgG1-secreting cells (p≥0.05). In summary, DC10 treatment down-regulates OVA-specific B cell responses of asthmatic mice. While DC10 that carry intact allergen on their cell surface can dampen this response, DC10-induced Treg are critical for full realization of this outcome. This suggests that infectious tolerance is an essential element in regulatory DC control of the B cell response in allergic asthma. PMID

Saccharomyces cerevisiae-Derived Mannan Does Not Alter Immune Responses to Aspergillus Allergens.

PubMed

Lew, D Betty; LeMessurier, Kim S; Palipane, Maneesha; Lin, Yanyan; Samarasinghe, Amali E

2018-01-01

Severe asthma with fungal sensitization predominates in the population suffering from allergic asthma, to which there is no cure. While corticosteroids are the mainstay in current treatment, other means of controlling inflammation may be beneficial. Herein, we hypothesized that mannan from Saccharomyces cerevisiae would dampen the characteristics of fungal allergic asthma by altering the pulmonary immune responses. Using wild-type and transgenic mice expressing the human mannose receptor on smooth muscle cells, we explored the outcome of mannan administration during allergen exposure on the pathogenesis of fungal asthma through measurement of cardinal features of disease such as inflammation, goblet cell number, and airway hyperresponsiveness. Mannan treatment did not alter most hallmarks of allergic airways disease in wild-type mice. Transgenic mice treated with mannan during allergen exposure had an equivalent response to non-mannan-treated allergic mice except for a prominent granulocytic influx into airways and cytokine availability. Our studies suggest no role for mannan as an inflammatory regulator during fungal allergy.

Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism.

PubMed

Levy, Bruce D; Lukacs, Nicholas W; Berlin, Aaron A; Schmidt, Birgitta; Guilford, William J; Serhan, Charles N; Parkinson, John F

2007-12-01

Cellular recruitment during inflammatory/immune responses is tightly regulated. The ability to dampen inflammation is imperative for prevention of chronic immune responses, as in asthma. Here we investigated the ability of lipoxin A4 (LXA4) stable analogs to regulate airway responses in two allergen-driven models of inflammation. A 15-epi-LXA4 analog (ATLa) and a 3-oxa-15-epi-LXA4 analog (ZK-994) prevented excessive eosinophil and T lymphocyte accumulation and activation after mice were sensitized and aerosol-challenged with ovalbumin. At <0.5 mg/kg, these LXA4 analogs reduced leukocyte trafficking into the lung by >50% and to a greater extent than equivalent doses of the CysLT1 receptor antagonist montelukast. Distinct from montelukast, ATLa treatment led to marked reductions in cysteinyl leukotrienes, interleukin-4 (IL-4), and IL-10, and both ATLa and ZK-994 inhibited levels of IL-13. In cockroach allergen-induced airway responses, both intraperitoneal and oral administration of ZK-994 significantly reduced parameters of airway inflammation and hyper-responsiveness in a dose-dependent manner. ZK-994 also significantly changed the balance of Th1/Th2-specific cytokine levels. Thus, the ATLa/LXA4 analog actions are distinct from CysLT1 antagonism and potently block both allergic airway inflammation and hyper-reactivity. Moreover, these results demonstrate these analogs' therapeutic potential as new agonists for the resolution of inflammation.

Aspergillus fumigatus proteases, Asp f 5 and Asp f 13, are essential for airway inflammation and remodelling in a murine inhalation model.

PubMed

Namvar, S; Warn, P; Farnell, E; Bromley, M; Fraczek, M; Bowyer, P; Herrick, S

2015-05-01

In susceptible individuals, exposure to Aspergillus fumigatus can lead to the development of atopic lung diseases such as allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS). Protease allergens including Asp f 5 and Asp f 13 from Aspergillus fumigatus are thought to be important for initiation and progression of allergic asthma. To assess the importance of secreted protease allergens Asp f 5 (matrix metalloprotease) and Asp f 13 (serine protease) in Aspergillus fumigatus-induced inflammation, airway hyperactivity, atopy and airway wall remodelling in a murine model following chronic exposure to secreted allergens. BALB/c mice were repeatedly intranasally dosed over the course of 5 weeks with culture filtrate from wild-type (WT), Asp f 5 null (∆5) or Asp f 13 null (∆13) strains of Aspergillus fumigatus. Airway hyper-reactivity was measured by non-invasive whole-body plethysmography, Th2 response and airway inflammation by ELISA and cell counts, whilst airway remodelling was assessed by histological analysis. Parent WT and ∆5 culture filtrates showed high protease activity, whilst protease activity in ∆13 culture filtrate was low. Chronic intranasal exposure to the three different filtrates led to comparable airway hyper-reactivity and Th2 response. However, protease allergen deleted strains, in particular ∆13 culture filtrate, induced significantly less airway inflammation and remodelling compared to WT culture filtrate. Aspergillus fumigatus-secreted allergen proteases, Asp f 5 and Asp f 13, are important for recruitment of inflammatory cells and remodelling of the airways in this murine model. However, deletion of a single allergen protease fails to alleviate airway hyper-reactivity and allergic immune response. Targeting protease activity of Aspergillus fumigatus in conditions such as SAFS or ABPA may have beneficial effects in preventing key aspects of airway pathology. © 2014 John Wiley & Sons Ltd.

Exploring the context of the lung proteome within the airway mucosa following allergen challenge.

PubMed

Fehniger, Thomas E; Sato-Folatre, José-Gabriel; Malmström, Johan; Berglund, Magnus; Lindberg, Claes; Brange, Charlotte; Lindberg, Henrik; Marko-Varga, György

2004-01-01

The lung proteome is a dynamic collection of specialized proteins related to pulmonary function. Many cells of different derivations, activation states, and levels of maturity contribute to the changing environment, which produces the lung proteome. Inflammatory cells reacting to environmental challenge, for example from allergens, produce and secrete proteins which have profound effects on both resident and nonresident cells located in airways, alveoli, and the vascular tree which provides blood cells to the parenchyma alveolar bed for gas exchange. In an experimental model of allergic airway inflammation, we have compared control and allergen challenged lung compartments to determine global protein expression patterns using 2D-gel electrophoresis and subsequent spot identification by MS/MS mass spectrometry. We have then specifically isolated the epithelial mucosal layer, which lines conducting airways, from control and allergen challenged lungs, using laser capture technology and performed proteome identification on these selected cell samples. A central component of our investigations has been to contextually relate the histological features of the dynamic pulmonary environment to the changes in protein expression observed following challenge. Our results provide new information of the complexity of the submucosa/epithelium interface and the mechanisms behind the transformation of airway epithelium from normal steady states to functionally activated states.

Effect of controlled human exposure to diesel exhaust and allergen on airway surfactant protein D, myeloperoxidase and club (Clara) cell secretory protein 16.

PubMed

Biagioni, B J; Tam, S; Chen, Y-W R; Sin, D D; Carlsten, C

2016-09-01

Air pollution is a major cause of global morbidity and mortality. Air pollution and aeroallergens aggravate respiratory illness, but the variable effects of air pollutants and allergens in the lung are poorly understood. To determine the effects of diesel exhaust (DE) and bronchial allergen challenge as single and dual exposures on aspects of innate immunity in the airway as reflected by surfactant protein D (SPD), myeloperoxidase (MPO) and club (Clara) cell secretory protein 16 (CC16) in 18 atopic individuals. In this double-blind, randomized crossover study, atopic individuals were exposed to DE or filtered air, followed by endobronchial allergen or saline 1 hour after inhalational exposure. Bronchoalveolar lavage, bronchial washings, nasal lavage and blood samples were obtained 48 hours after exposures and assayed for CC16, MPO and SPD by ELISA. In bronchial samples, the concentration of SPD increased from 53.3 to 91.8 ng/mL after endobronchial allergen, with no additional contribution from DE. MPO also increased significantly in response to allergen (6.8 to 14.7 ng/mL), and there was a small additional contribution from exposure to DE. The concentration of CC16 decreased from 340.7 to 151.0 ng/mL in response to DE, with minor contribution from allergen. These changes were not reflected in nasal lavage fluid or plasma samples. These findings suggest that allergen and DE variably influence different aspects of the innate immune response of the lung. SPD and MPO, known markers of allergic inflammation in the lung, are strongly increased by allergen while DE has a minor effect therein. DE induces a loss of CC16, a protective protein, while allergen has a minor effect therein. Results support site- and exposure-specific responses in the human lung upon multiple exposures. © 2016 John Wiley & Sons Ltd.

Rebamipide suppresses mite-induced asthmatic responses in NC/Nga mice.

PubMed

Murakami, Ikuo; Zhang, Ran; Kubo, Masayuki; Nagaoka, Kenjiro; Eguchi, Eri; Ogino, Keiki

2015-10-15

Allergic asthma caused by continuous allergen exposure evokes allergen-specific Th2 responses and is characterized by chronic airway inflammation and hyperresponsiveness. A previous report showed that rebamipide improved asthmatic symptoms in an ovalbumin/trypsin mice model. However, it is still unclear how rebamipide exerts its effects in asthma. In this study, rebamipide improved the asthmatic responses induced by mite exposure in NC/Nga mice, revealing the mechanism of this therapeutic effect. Rebamipide suppressed the infiltration of eosinophils into the airways and lung as well as attenuating the production of reactive oxygen species in tissues. In addition to these anti-inflammatory effects, rebamipide inhibited the production of IL-33, a member of the IL-1 family that drives the subsequent production of Th2-associated cytokines. These observations identify the point where rebamipide exerts its suppressive action on asthma and suggest that rebamipide has therapeutic potential in preventing mite-induced asthma. Copyright © 2015 the American Physiological Society.

Counterbalancing of TH2-driven allergic airway inflammation by IL-12 does not require IL-10.

PubMed

Tournoy, K G; Kips, J C; Pauwels, R A

2001-03-01

Asthma is characterized by allergen-induced airway inflammation orchestrated by TH2 cells. The TH1-promoting cytokine IL-12 is capable of inhibiting the TH2-driven allergen-induced airway changes in mice and is therefore regarded as an interesting strategy for treating asthma. The antiallergic effects of IL-12 are only partially dependent of IFN-gamma. Because IL-12 is a potent inducer of the anti-inflammatory cytokine IL-10, the aim of the present study was to investigate in vivo whether the antiallergic effects of IL-12 are mediated through IL-10. C57BL/6J-IL-10 knock-out (IL-10(-/-)) mice were sensitized intraperitoneally to ovalbumin (OVA) and subsequently exposed from day 14 to day 21 to aerosolized OVA (1%). IL-12 was administered intraperitoneally during sensitization, subsequent OVA exposure, or both. IL-12 inhibited the OVA-induced airway eosinophilia, despite the absence of IL-10. Moreover, a shift from a TH2 inflammatory pattern toward a TH1 reaction was observed, with concomitant pronounced mononuclear peribronchial inflammation after IL-12 treatment. Allergen-specific IgE synthesis was completely suppressed only when IL-12 was administered along with the allergen sensitization. Furthermore, treating the animals with IL-12 at the time of the secondary allergen challenge resulted not only in a significant suppression of the airway responsiveness but also in an important IFN-gamma-associated toxicity. These results indicate that IL-12 is able to inhibit allergen-induced airway changes, even in the absence of IL-10. In addition, our results raise concerns regarding the redirection of TH2 inflammation by TH1-inducing therapies because treatment with IL-12 resulted not only in a disappearance of the TH2 inflammation but also in a TH1-driven inflammatory pulmonary pathology.

Allergenic proteases cleave the chemokine CX3CL1 directly from the surface of airway epithelium and augment the effect of rhinovirus.

PubMed

Loxham, M; Smart, D E; Bedke, N J; Smithers, N P; Filippi, I; Blume, C; Swindle, E J; Tariq, K; Howarth, P H; Holgate, S T; Davies, D E

2018-03-01

CX3CL1 has been implicated in allergen-induced airway CD4 + T-lymphocyte recruitment in asthma. As epidemiological evidence supports a viral infection-allergen synergy in asthma exacerbations, we postulated that rhinovirus (RV) infection in the presence of allergen augments epithelial CX3CL1 release. Fully differentiated primary bronchial epithelial cultures were pretreated apically with house dust mite (HDM) extract and infected with rhinovirus-16 (RV16). CX3CL1 was measured by enzyme-linked immunosorbent assay and western blotting, and shedding mechanisms assessed using inhibitors, protease-activated receptor-2 (PAR-2) agonist, and recombinant CX3CL1-expressing HEK293T cells. Basolateral CX3CL1 release was unaffected by HDM but stimulated by RV16; inhibition by fluticasone or GM6001 implicated nuclear factor-κB and ADAM (A Disintegrin and Metalloproteinase) sheddases. Conversely, apical CX3CL1 shedding was stimulated by HDM and augmented by RV16. Although fluticasone or GM6001 reduced RV16+HDM-induced apical CX3CL1 release, heat inactivation or cysteine protease inhibition completely blocked CX3CL1 shedding. The HDM effect was via enzymatic cleavage of CX3CL1, not PAR-2 activation, yielding a product mitogenic for smooth muscle cells. Extracts of Alternaria fungus caused similar CX3CL1 shedding. We have identified a novel mechanism whereby allergenic proteases cleave CX3CL1 from the apical epithelial surface to yield a biologically active product. RV16 infection augmented HDM-induced CX3CL1 shedding-this may contribute to synergy between allergen exposure and RV infection in triggering asthma exacerbations and airway remodeling.

Neutrophil recruitment by allergens contribute to allergic sensitization and allergic inflammation.

PubMed

Hosoki, Koa; Itazawa, Toshiko; Boldogh, Istvan; Sur, Sanjiv

2016-02-01

To discuss the presence and role of neutrophils in asthma and allergic diseases, and outline the importance of pollen and cat dander-induced innate neutrophil recruitment in induction of allergic sensitization and allergic inflammation. Uncontrolled asthma is associated with elevated numbers of neutrophils, and levels of neutrophil-attracting chemokine IL-8 and IL-17 in bronchoalveolar lavage fluids. These parameters negatively correlate with lung function. Pollen allergens and cat dander recruit neutrophils to the airways in a toll-like receptor 4, myeloid differentiation protein-2, and chemokine (C-X-C motif) receptor (CXCR) 2-dependent manner. Repeated recruitment of activated neutrophils by these allergens facilitates allergic sensitization and airway inflammation. Inhibition of neutrophil recruitment with CXCR2 inhibitor, disruption of toll-like receptor 4, or small interfering RNA against myeloid differentiation protein-2 also inhibits allergic inflammation. The molecular mechanisms by which innately recruited neutrophils contribute to shifting the airway inflammatory response induced by allergens from neutrophilic to an eosinophilic-allergic is an area of active research. Recent studies have revealed that neutrophil recruitment is important in the development of allergic sensitization and inflammation. Inhibition of neutrophils recruitment may be a strategy to control allergic inflammation.

Peripheral erythrocytes decrease upon specific respiratory challenge with grass pollen allergen in sensitized mice and in human subjects.

PubMed

Jordakieva, Galateja; Wallmann, Julia; Schmutz, René; Lemell, Patrick; Wegmann, Michael; Nittke, Thomas; Mittlböck, Martina; Fehrenbach, Heinz; Godnic-Cvar, Jasminka; Zieglmayer, René; Jensen-Jarolim, Erika

2014-01-01

Specific hyper-responsiveness towards an allergen and non-specific airway hyperreactivity both impair quality of life in patients with respiratory allergic diseases. We aimed to investigate cellular responses following specific and non-specific airway challenges locally and systemically in i) sensitized BALB/c mice challenged with grass pollen allergen Phl p 5, and in ii) grass pollen sensitized allergic rhinitis subjects undergoing specific airway challenge in the Vienna Challenge Chamber (VCC). BALB/c mice (n = 20) were intraperitoneally immunized with grass pollen allergen Phl p 5 and afterwards aerosol challenged with either the specific allergen Phl p 5 (n = 10) or the non-specific antigen ovalbumin (OVA) (n = 10). A protocol for inducing allergic asthma as well as allergic rhinitis, according to the united airway concept, was used. Both groups of exposed mice showed significantly reduced physical activity after airway challenge. Specific airway challenge further resulted in goblet cell hyperplasia, enhanced mucous secretion, intrapulmonary leukocyte infiltration and lymphoid follicle formation, associated with significant expression of IL-4, IL-5 and IL-13 in splenocytes and also partially in lung tissue. Concerning circulating blood cell dynamics, we observed a significant drop of erythrocyte counts, hemoglobin and hematocrit levels in both mouse groups, challenged with allergen or OVA. A significant decrease in circulating erythrocytes and hematocrit levels after airway challenges with grass pollen allergen was also found in grass pollen sensitized human rhinitis subjects (n = 42) at the VCC. The effects on peripheral leukocyte counts in mice and humans however were opposed, possibly due to the different primary inflammation sites. Our data revealed that, besides significant leukocyte dynamics, particularly erythrocytes are involved in acute hypersensitivity reactions to respiratory allergens. A rapid recruitment of erythrocytes to the lungs to compensate

Pathways of airway oxidant formation by house dust mite allergens and viral RNA converge through myosin motors, pannexons and Toll-like receptor 4.

PubMed

Zhang, Jihui; Chen, Jie; Mangat, Shannon C; Perera Baruhupolage, Chathuri; Garrod, David R; Robinson, Clive

2018-06-01

Intracellular reactive oxidant species (ROS) are generated in human airway epithelial cells by the prothrombinase action of Group 1 house dust mite (HDM) allergens and by ligation of viral RNA sensor Toll-like receptors (TLRs). We explored signaling convergence between HDM allergens and TLRs in ROS generation because epithelial cells form the primary barrier against inhaled substances and dictate host responses to allergens and viruses. ROS formation by Calu-3 human airway cells was studied by measuring dihydrorhodamine 123 oxidation after activation by polyinosinic:polycytidylic acid (to activate TLR3), CL097 (to activate TLR7), a natural mixture of HDM allergens, or BzATP. TLR4 activation was identified as an indispensable response element for all stimuli, operating downstream from myosin motor activation, pannexon gating for ATP release and the endogenous activation of prothrombin. Exogenous prothrombin activation by HDM allergens was prevented by SGUL 1733, a novel inhibitor of the proteolytic activity of Group 1 HDM allergens, which thus prevented TLR4 from being activated at source. Our data identify for the first time that endogenously-generated prothrombin and TLR4 form a shared effector mechanism essential to intracellular ROS generation activated by a group 1 HDM allergen (itself a prothrombinase) or by ligation of viral RNA-sensing TLRs. These stimuli operate a confluent signaling pathway in which myosin motors, gating of pannexons, and ADAM 10 lead to prothrombin-dependent activation of TLR4 with a recycling activation of pannexons. © 2018 The Authors. Immunity, Inflammation and Disease Published by John Wiley & Sons Ltd.

Age-related T cell responses to allergens in childhood.

PubMed

Smart, J M; Suphioglu, C; Kemp, A S

2003-03-01

T cell priming, as determined by allergen-induced proliferative responses, is believed to occur principally in early childhood in both atopic and non-atopic infants under the influence of multiple factors including environmental allergen exposure. It is considered that T cell priming with expansion of Th2 cells is a crucial factor in the development of atopic disease. To examine T cell priming to commonly encountered allergens in childhood in relation to age. In a cross-sectional study T cell proliferation in relation to age was examined for three common allergens, ovalbumin (OVA), house dust mite (HDM) and rye grass pollen (RYE), in atopic and non-atopic children. The effect of age on Th1 (IFN-gamma) and Th2 (IL-5 and IL-13) cytokine production in response to these allergens was investigated to examine the possibility of immune deviation with time. A significant increase in T cell proliferation with age was observed with RYE among atopic children only. However, the same was not observed with the two other allergens studied (i.e. OVA and HDM). In addition, RYE-induced (but not HDM or OVA) cytokine production showed an increased Th2 deviation with age as reflected in the increasing IL-5/IFN-gamma and IL-13/IFN-gamma ratios only among the atopic subjects with rye grass pollen sensitivity. These findings suggest that grass pollen sensitivity in childhood is accompanied by a progressive accumulation of allergen-primed T cells and progressive deviation of the allergen-induced cytokine response towards a Th2 response in atopic subjects throughout childhood.

Safety and benefits of inhaled hypertonic saline following airway challenges with endotoxin and allergen in asthmatics.

PubMed

Alexis, Neil E; Bennett, William; Peden, David Blaine

2017-11-01

To determine whether induced sputum (IS) with hypertonic saline inhalation is safe to use in asthmatics within 24 hours of two commonly used airway challenges, namely endotoxin and dust mite allergen, and to assess whether IS can enhance mucociliary clearance (MCC) rates in asthmatics. IS (three 7-minute inhalation periods of 3%, 4%, and 5% hypertonic saline) was employed before (N = 29) and within 24 hours of inhaled challenges with endotoxin (N = 13) and dust mite allergen (N = 12) in a cohort of mild to moderate asthmatics. Safety was assessed by lung function (Forced Expiratory Volume in 1 second; FEV1) and MCC was measured using a radiolabeled gamma scintigraphy method (Tcm99 sulfur colloid). IS was performed pre and post MCC. No significant lung function decrement was observed before or after inhaled challenges with endotoxin or dust mite allergen. IS significantly enhanced MCC rates before and after inhaled endotoxin challenge. Based on a small cohort, IS is safe to use in mild to moderate asthmatics before and within 24 hours of inhaled challenges with endotoxin and dust mite allergen. Furthermore, IS has beneficial effects on host defense function in asthmatics by enhancing MCC rates.

Comparison of non-invasive measures of cholinergic and allergic airway responsiveness in rats.

PubMed

Glaab, T; Hecker, H; Stephan, M; Baelder, R; Braun, A; Korolewitz, R; Krug, N; Hoymann, H G

2006-04-01

Non-invasive analysis of tidal expiratory flow parameters such as Tme/TE (time needed to reach peak expiratory flow divided by total expiratory time) or midexpiratory tidal flow (EF50) has been shown useful for phenotypic characterization of lung function in humans and animal models. In this study, we aimed to compare the utility of two non-invasive measures, EF50 and Tme/TE, to monitor bronchoconstriction to inhaled cholinergic and allergic challenges in Brown-Norway rats. Non-invasive measurements of Tme/TE and EF50 were paralleled by invasive recordings of Tme/TE, EF50 and pulmonary conductance (GL). First, dose-response studies with acetylcholine were performed in naive rats, showing that EF50 better than Tme/TE reflected the dose-related changes as observed with the classical invasive outcome parameter GL. The subsequent determination of allergen-specific early airway responsiveness (EAR) showed that ovalbumin-sensitized and -challenged rats exhibited airway inflammation and allergen-specific EAR. Again, EF50 was more sensitive than Tme/TE in detecting the allergen-specific EAR recorded with invasive and non-invasive lung function methods and agreed well with classical GL measurements. We conclude that non-invasive assessment of EF50 is significantly superior to Tme/TE and serves as a suitable and valid tool for phenotypic screening of cholinergic and allergic airway responsiveness in rats.

Allergen immunotherapy with heat-killed Listeria monocytogenes alleviates peanut and food-induced anaphylaxis in dogs.

PubMed

Frick, O L; Teuber, S S; Buchanan, B B; Morigasaki, S; Umetsu, D T

2005-02-01

Heat-killed Listeria monocytogenes (HKL) potently stimulates interferon (IFN)-gamma production in CD4 T-lymphocytes, and when used as adjuvant for immunotherapy, reduces immunoglobulin (Ig)E production and reverses established allergen-induced airway hyperreactivity (AHR) in a murine model of asthma. We asked if such treatment could decrease established peanut-induced anaphylaxis or cow's milk-induced food allergy in highly food-allergic dogs. We therefore studied four 4-year-old atopic colony dogs extremely allergic to peanut (Group I), as well as five 7-year-old dogs very allergic to wheat, milk and other foods (Group II). All dogs experienced marked allergic symptoms, including vomiting and diarrhea on oral challenge with the relevant foods. The dogs were then vaccinated once subcutaneously with peanut or milk and wheat with HKL emulsified in incomplete Freund's adjuvant. Following vaccination of the allergic dogs with HKL and allergen, oral challenges with peanut (Group I) or milk (Group II) elicited only minor or no symptoms. In addition, skin test end-point titrations showed marked reductions for >10 weeks after treatment, and levels of Ara h 1-specific IgE in serum of peanut sensitive dogs, as demonstrated by immunoblotting, were greatly reduced by treatment with HKL plus peanut allergen. Thus, HKL plus allergen treatment markedly improved established food allergic responses in dogs, suggesting that such an immunotherapy strategy in humans might greatly improve individuals with food allergy and anaphylaxis.

Plethysmography Phenotype QTL in Mice Before and After Allergen Sensitization and Challenge.

PubMed

Kelada, Samir N P

2016-09-08

Allergic asthma is common airway disease that is characterized in part by enhanced airway constriction in response to nonspecific stimuli. Genome-wide association studies have identified multiple loci associated with asthma risk in humans, but these studies have not accounted for gene-environment interactions, which are thought to be important factors in asthma. To identify quantitative trait loci (QTL) that regulate responses to a common human allergen, we applied a house dust mite mouse (HDM) model of allergic airway disease (AAD) to 146 incipient lines of the Collaborative Cross (CC) and the CC founder strains. We employed a longitudinal study design in which mice were phenotyped for response to the bronchoconstrictor methacholine both before and after HDM sensitization and challenge using whole body plethysmography (WBP). There was significant variation in methacholine responsiveness due to both strain and HDM treatment, as reflected by changes in the WBP parameter enhanced pause. We also found that distinct QTL regulate baseline [chromosome (Chr) 18] and post-HDM (Chr 19) methacholine responsiveness and that post-HDM airway responsiveness was correlated with other features of AAD. Finally, using invasive measurements of airway mechanics, we tested whether the Chr 19 QTL affects lung resistance per se using C57BL/6J mice and a consomic strain but found that QTL haplotype did not affect lung resistance. We conclude that aspects of baseline and allergen-induced methacholine responsiveness are associated with genetic variation, and that robust detection of airway resistance QTL in genetically diverse mice will be facilitated by direct measurement of airway mechanics. Copyright © 2016 Kelada.

Plethysmography Phenotype QTL in Mice Before and After Allergen Sensitization and Challenge

DOE PAGES

Kelada, Samir N. P.

2016-07-22

Allergic asthma is common airway disease that is characterized in part by enhanced airway constriction in response to nonspecific stimuli. Genome-wide association studies have identified multiple loci associated with asthma risk in humans, but these studies have not accounted for gene–environment interactions, which are thought to be important factors in asthma. To identify quantitative trait loci (QTL) that regulate responses to a common human allergen, we applied a house dust mite mouse (HDM) model of allergic airway disease (AAD) to 146 incipient lines of the Collaborative Cross (CC) and the CC founder strains. We employed a longitudinal study design inmore » which mice were phenotyped for response to the bronchoconstrictor methacholine both before and after HDM sensitization and challenge using whole body plethysmography (WBP). There was significant variation in methacholine responsiveness due to both strain and HDM treatment, as reflected by changes in the WBP parameter enhanced pause. We also found that distinct QTL regulate baseline [chromosome (Chr) 18] and post-HDM (Chr 19) methacholine responsiveness and that post-HDM airway responsiveness was correlated with other features of AAD. Finally, using invasive measurements of airway mechanics, we tested whether the Chr 19 QTL affects lung resistance per se using C57BL/6J mice and a consomic strain but found that QTL haplotype did not affect lung resistance. We conclude that aspects of baseline and allergen-induced methacholine responsiveness are associated with genetic variation, and that robust detection of airway resistance QTL in genetically diverse mice will be facilitated by direct measurement of airway mechanics.« less

Plethysmography Phenotype QTL in Mice Before and After Allergen Sensitization and Challenge

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kelada, Samir N. P.

Allergic asthma is common airway disease that is characterized in part by enhanced airway constriction in response to nonspecific stimuli. Genome-wide association studies have identified multiple loci associated with asthma risk in humans, but these studies have not accounted for gene–environment interactions, which are thought to be important factors in asthma. To identify quantitative trait loci (QTL) that regulate responses to a common human allergen, we applied a house dust mite mouse (HDM) model of allergic airway disease (AAD) to 146 incipient lines of the Collaborative Cross (CC) and the CC founder strains. We employed a longitudinal study design inmore » which mice were phenotyped for response to the bronchoconstrictor methacholine both before and after HDM sensitization and challenge using whole body plethysmography (WBP). There was significant variation in methacholine responsiveness due to both strain and HDM treatment, as reflected by changes in the WBP parameter enhanced pause. We also found that distinct QTL regulate baseline [chromosome (Chr) 18] and post-HDM (Chr 19) methacholine responsiveness and that post-HDM airway responsiveness was correlated with other features of AAD. Finally, using invasive measurements of airway mechanics, we tested whether the Chr 19 QTL affects lung resistance per se using C57BL/6J mice and a consomic strain but found that QTL haplotype did not affect lung resistance. We conclude that aspects of baseline and allergen-induced methacholine responsiveness are associated with genetic variation, and that robust detection of airway resistance QTL in genetically diverse mice will be facilitated by direct measurement of airway mechanics.« less

Secreted products of Fasciola hepatica inhibit the induction of T cell responses that mediate allergy.

PubMed

Finlay, C M; Stefanska, A M; Coleman, M M; Jahns, H; Cassidy, J P; McLoughlin, R M; Mills, K H G

2017-10-01

There is evidence from epidemiology studies of a negative association between infection with helminth parasites and the development of allergy and asthma. Here, we demonstrate that the excretory/secretory products of the helminth Fasciola hepatica (FHES) protected mice against ovalbumin (OVA)-induced allergic asthma when administered at time of allergen sensitization. FHES reduced the accumulation of mucus, eosinophils and lymphocytes into the airways of allergen-challenged mice. Furthermore, FHES treatment suppressed Th2 responses in the airways. Interestingly, systemic administration of FHES at allergen challenge had no effect on airway inflammation, demonstrating that alum-induced Th2 response is set following initial allergen sensitization. Our findings highlight the immunomodulatory potential of molecules secreted by F. hepatica. © 2017 John Wiley & Sons Ltd.

In vivo and in vitro immunomodulation of Der p 1 allergen-specific response by Lactobacillus plantarum bacteria.

PubMed

Hisbergues, M; Magi, M; Rigaux, P; Steuve, J; Garcia, L; Goudercourt, D; Pot, B; Pestel, J; Jacquet, A

2007-09-01

Lactic acid bacteria (LAB) were reported to reduce some allergic manifestations in mice and humans but their impact on the aeroallergen-dependent immune mechanisms is still debated. The potential capacities of Lactobacillus plantarum NCIMB8826 to reduce the allergic response induced by Der p 1, the major house dust mite allergen of Dermatophagoides pteronyssinus, were evaluated in vivo and in vitro. Methods First, the effect of the intranasal co-administration of LAB and purified Der p 1 allergen before a sensitization protocol was evaluated. The allergen-specific antibody and cellular responses as well as airway inflammation were measured. Second, the impact of LAB on the cytokine profile of spleens cells from Der p 1-sensitized mice was assessed. Third, upon stimulation with LAB, the levels of cytokine produced by dendritic cells derived from the bone marrow (BMDCs) of wild-type, Toll-like receptor 2 (TLR2)-, TLR4- and MyD88-KO mice were compared. Results The co-application of L. plantarum and Der p 1 induced a T-helper type 1 (Th1)-biased allergen-specific IgG response, the absence of specific IgE response and favoured the production of INF-gamma upon allergen re-stimulation. Moreover, the previous LAB administration reduced the development of bronchoalveolar lavage eosinophilia usually induced by aerosol exposure. Additionally, the studied LAB strain was shown to modify in vitro the cytokine level produced by Der p 1-sensitized spleen cells mainly towards a Th1 profile. Finally, L. plantarum stimulated high IL-12 and moderate IL-10 production in mouse BMDCs notably through the TLR2-, MyD88-dependent and TLR4-independent pathway. In vivo co-administration of probiotic LAB with Der p 1 might prevent the development of the mite allergic response. The probiotic L. plantarum was shown to display in vitro therapeutic potentials for the treatment of allergy and to trigger the immune system by a TLR2- and MyD88-dependent signalling pathway.

Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells

PubMed Central

Longphre, M.; Li, D.; Gallup, M.; Drori, E.; Ordoñez, C.L.; Redman, T.; Wenzel, S.; Bice, D. E.; Fahy, J.V.; Basbaum, C.

1999-01-01

A hallmark of asthma is mucin overproduction, a condition that contributes to airway obstruction. The events responsible for mucin overproduction are not known but are thought to be associated with mediators of chronic inflammation. Others have shown that T-helper 2 (Th2) lymphocytes are required for mucous cell metaplasia, which then leads to mucin overproduction in animal models of allergy. We hypothesized that Th2 cell mediators are present in asthmatic airway fluid and directly stimulate mucin synthesis in airway epithelial cells. Results in cultured airway epithelial cells showed that samples of asthmatic fluid stimulated mucin (MUC5AC) synthesis severalfold more potently than non-asthmatic fluid. Consistent with this, lavage fluid from the airways of allergen-challenged dogs stimulated mucin synthesis severalfold more potently than that from non–allergen-challenged dogs. Fractionation of dog samples revealed 2 active fractions at <10 kDa and 30–100 kDa. Th2 cytokines in these molecular weight ranges are IL-9 (36 kDa), IL-5 (56 kDa), and IL-13 (10 kDa). Antibody blockade of ligand-receptor interaction for IL-9 (but not IL-5 or IL-13) inhibited mucin stimulation by dog airway fluid. Furthermore, recombinant IL-9, but not IL-5 or IL-13, stimulated mucin synthesis. These results indicate that IL-9 may account for as much as 50–60% of the mucin-stimulating activity of lung fluids in allergic airway disease. J. Clin. Invest. 104:1375–1382 (1999). PMID:10562299

Role of substance P and neurokinin A in toluene diisocyanate-induced increased airway responsiveness in rabbits.

PubMed

Marek, W; Potthast, J J; Marcynski, B; Baur, X

1996-01-01

The aim of the present study was to examine the role of neuropeptides, especially substance P (SP) and neurokinin A (NKA), in toluene diisocyanate (TDI)-induced airway hyperresponsiveness (AHR) to acetylcholine aerosols. Thirty parts per billion of TDI in air administered over 4 hours caused a significant increase in the airway constrictive response to acetylcholine (ACH) aerosols in rabbits (DeltaRI: 245 +/- 30%, p < 0.005) without altering basic values of respiratory, cardiovascular or blood gas parameters. Inhalation of the aerosolized neuropeptides SP and NKA resulted in a similar increase in airway responsiveness (AR) to ACH as exposure to 30 ppb TDI. To determine whether neuropeptides contribute to TDI-induced AHR, we studied their effects after systemic treatment with capsaicin as well as after infusion of specific synthetic antagonists for SP and NK2 (NKA) receptors. CAPS treatment performed on 4 consecutive days as well as antagonists' infusion only moderately (p > 0.05) decreased airway responses to ACH. CAPS application prevented the TDI-induced increase in AR to ACH in all rabbits. The increase in airway resistance to ACH did not significantly change after TDI exposure (98 +/- 22% of the control response before TDI, p > 0.05). Simultaneous infusion of specific synthetic SP and NK2 receptor antagonists also abolished the TDI-induced increase in airway responses to ACH in all animals investigated (p > 0.05). The results of this study demonstrate that neuropeptides, especially the tachykinins SP and NKA, are important mediators in TDI-induced AHR in rabbits.

Unrepaired DNA damage in macrophages causes elevation of particulate matter- induced airway inflammatory response.

PubMed

Luo, Man; Bao, Zhengqiang; Xu, Feng; Wang, Xiaohui; Li, Fei; Li, Wen; Chen, Zhihua; Ying, Songmin; Shen, Huahao

2018-04-14

The inflammatory cascade can be initiated with the recognition of damaged DNA. Macrophages play an essential role in particulate matter (PM)-induced airway inflammation. In this study, we aim to explore the PM induced DNA damage response of macrophages and its function in airway inflammation. The DNA damage response and inflammatory response were assessed using bone marrow-derived macrophages following PM treatment and mouse model instilled intratracheally with PM. We found that PM induced significant DNA damage both in vitro and in vivo and simultaneously triggered a rapid DNA damage response, represented by nuclear RPA, 53BP1 and γH2AX foci formation. Genetic ablation or chemical inhibition of the DNA damage response sensor amplified the production of cytokines including Cxcl1, Cxcl2 and Ifn-γ after PM stimulation in bone marrow-derived macrophages. Similar to that seen in vitro , mice with myeloid-specific deletion of RAD50 showed higher levels of airway inflammation in response to the PM challenge, suggesting a protective role of DNA damage sensor during inflammation. These data demonstrate that PM exposure induces DNA damage and activation of DNA damage response sensor MRN complex in macrophages. Disruption of MRN complex lead to persistent, unrepaired DNA damage that causes elevated inflammatory response.

Protease-Activated Receptor-2 Activation Contributes to House Dust Mite-Induced IgE Responses in Mice

PubMed Central

Post, Sijranke; Heijink, Irene H.; Petersen, Arjen H.; de Bruin, Harold G.; van Oosterhout, Antoon J. M.; Nawijn, Martijn C.

2014-01-01

Aeroallergens such as house dust mite (HDM), cockroach, and grass or tree pollen are innocuous substances that can induce allergic sensitization upon inhalation. The serine proteases present in these allergens are thought to activate the protease-activated receptor (PAR)-2, on the airway epithelium, thereby potentially inducing allergic sensitization at the expense of inhalation tolerance. We hypothesized that the proteolytic activity of allergens may play an important factor in the allergenicity to house dust mite and is essential to overcome airway tolerance. Here, we aimed to investigate the role of PAR-2 activation in allergic sensitization and HDM-induced allergic airway inflammation. In our study, Par-2 deficient mice were treated with two different HDM extracts containing high and low serine protease activities twice a week for a period of 5 weeks. We determined airway inflammation through quantification of percentages of mononuclear cells, eosinophils and neutrophils in the bronchial alveolar lavage fluid and measured total IgE and HDM-specific IgE and IgG1 levels in serum. Furthermore, Th2 and pro-inflammatory cytokines including IL-5, IL-13, Eotaxin-1, IL-17, KC, Chemokine (C-C motif) ligand 17 (CCL17) and thymic stromal lymphopoietin (TSLP), were measured in lung tissue homogenates. We observed that independent of the serine protease content, HDM was able to induce elevated levels of eosinophils and neutrophils in the airways of both wild-type (WT) and Par-2 deficient mice. Furthermore, we show that induction of pro-inflammatory cytokines by HDM exposure is independent of Par-2 activation. In contrast, serine protease activity of HDM does contribute to enhanced levels of total IgE, but not HDM-specific IgE. We conclude that, while Par-2 activation contributes to the development of IgE responses, it is largely dispensable for the HDM-induced induction of pro-inflammatory cytokines and airway inflammation in an experimental mouse model of HDM

Functional Effects of TGF-beta1 on Mesenchymal Stem Cell Mobilization in Cockroach Allergen Induced Asthma

PubMed Central

Xian, Lingling; Li, Changjun; Xu, Ting; Plunkett, Beverly; Huang, Shau-Ku; Wan, Mei; Cao, Xu

2014-01-01

Mesenchymal stem cells (MSCs) have been suggested to participate in immune regulation and airway repair/remodeling. Transforming growth factor β1 (TGFβ1) is critical in the recruitment of stem/progenitor cells for tissue repair, remodeling and cell differentiation. In this study, we sought to investigate the role of TGFβ1 in MSC migration in allergic asthma. We examined nestin expression (a marker for MSCs) and TGFβ1 signaling activation in airways in cockroach allergen (CRE) induced mouse models. Compared with control mice, there were increased nestin+ cells in airways, and higher levels of active TGFβ1 in serum and p-Smad2/3 expression in lungs of CRE-treated mice. Increased activation of TGFβ1 signaling was also found in CRE-treated MSCs. We then assessed MSC migration induced by conditioned medium (ECM) from CRE-challenged human epithelium in air/liquid interface (ALI) culture in Transwell assays. MSC migration was stimulated by ECM, but was significantly inhibited by either TGFβ1 neutralizing antibody or TβR1 inhibitor. Intriguingly, increased migration of MSCs from blood and bone marrow to the airway was also observed after systemic injection of GFP+-MSCs, and from bone marrow of Nes-GFP mice following CRE challenge. Furthermore, TGFβ1 neutralizing antibody inhibited the CRE-induced MSC recruitment, but promoted airway inflammation. Finally, we investigated the role of MSCs in modulating CRE induced T cell response, and found that MSCs significantly inhibited CRE-induced inflammatory cytokine secretion (IL-4, IL13, IL17 and IFN-γ) by CD4+ T cells. These results suggest that TGFβ1 may be a key pro-migratory factor in recruiting MSCs to the airways in mouse models of asthma. PMID:24711618

The impact of food allergens on airway responsiveness in schoolchildren with asthma: A DBPCFC study.

PubMed

Krogulska, Aneta; Dynowski, Jarosław; Jędrzejczyk, Magdalena; Sardecka, Izabela; Małachowska, Beata; Wąsowska-Królikowska, Krystyna

2016-08-01

Despite the growing evidence of a possible link between asthma and food allergy (FA), so far, the involvement of food in inducing respiratory symptoms has not been fully evaluated. The objective of this study was to evaluate the impact of food allergens on respiratory symptoms and bronchial reactivity (BHR) in schoolchildren with asthma. The initial study group consisted of 362 children with asthma. In the end, 22 children with concomitant FA, and 18 without FA, were selected to participate in the study. Spirometry and Methacholine Inhalation Challenge (MIC) were conducted prior to and after the completion of a double blind placebo control food challenge (DBPCFC). The food-induced asthmatic reactions were observed in nine (2.5%) out of all 362 children with asthma. Mean FEV1 prior to and after allergen or placebo challenge did not differ between the groups studied. Increase of BHR after DBPCFC was seen in 17 (4.7%) children with asthma. The mean PC20 value in children with FA was 1.41 ± 1.12 mg/ml prior to the allergen challenge and 0.86 ± 0.71 mg/ml (P = 0.002) after the test, whereas these values were 1.93 ± 1.68 mg/ml and 2.02 ± 1.75 mg/ml, respectively, in children without FA (P > 0.05). Significant differences were noted after the allergen provocation in children with FA as compared to children without FA (P = 0.007). Although food allergens are a rare trigger of food-induced asthmatic reactions in schoolchildren with asthma, they could enhance BHR, despite a lack of evident clinical respiratory signs and decreased in FEV1 values after food challenge. Pediatr Pulmonol. 2016;51:787-795. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

20-HETE mediates ozone-induced, neutrophil-independent airway hyper-responsiveness in mice.

PubMed

Cooper, Philip R; Mesaros, A Clementina; Zhang, Jie; Christmas, Peter; Stark, Christopher M; Douaidy, Karim; Mittelman, Michael A; Soberman, Roy J; Blair, Ian A; Panettieri, Reynold A

2010-04-20

Ozone, a pollutant known to induce airway hyper-responsiveness (AHR), increases morbidity and mortality in patients with obstructive airway diseases and asthma. We postulate oxidized lipids mediate in vivo ozone-induced AHR in murine airways. Male BALB/c mice were exposed to ozone (3 or 6 ppm) or filtered air (controls) for 2 h. Precision cut lung slices (PCLS; 250 microm thickness) containing an intrapulmonary airway ( approximately 0.01 mm(2) lumen area) were prepared immediately after exposure or 16 h later. After 24 h, airways were contracted to carbachol (CCh). Log EC(50) and E(max) values were then calculated by measuring the airway lumen area with respect to baseline. In parallel studies, dexamethasone (2.5 mg/kg), or 1-aminobenzotriazol (ABT) (50 mg/kg) were given intraperitoneal injection to naïve mice 18 h prior to ozone exposure. Indomethacin (10 mg/kg) was administered 2 h prior. Cell counts, cytokine levels and liquid chromatography-mass spectrometry (LC-MS) for lipid analysis were assessed in bronchoalveolar lavage (BAL) fluid from ozone exposed and control mice. Ozone acutely induced AHR to CCh. Dexamethasone or indomethacin had little effect on the ozone-induced AHR; while, ABT, a cytochrome P450 inhibitor, markedly attenuated airway sensitivity. BAL fluid from ozone exposed animals, which did not contain an increase in neutrophils or interleukin (IL)-6 levels, increased airway sensitivity following in vitro incubation with a naïve PCLS. In parallel, significant increases in oxidized lipids were also identified using LC-MS with increases of 20-HETE that were decreased following ABT treatment. These data show that ozone acutely induces AHR to CCh independent of inflammation and is insensitive to steroid treatment or cyclooxygenase (COX) inhibition. BAL fluid from ozone exposed mice mimicked the effects of in vivo ozone exposure that were associated with marked increases in oxidized lipids. 20-HETE plays a pivotal role in mediating acute ozone-induced

Sulforaphane inhibits the Th2 immune response in ovalbumin-induced asthma.

PubMed

Park, Jun Ho; Kim, Jong Won; Lee, Chang-Min; Kim, Yeong Dae; Chung, Sung Woon; Jung, In Duk; Noh, Kyung Tae; Park, Jin Wook; Heo, Deok Rim; Shin, Yong Kyoo; Seo, Jong Keun; Park, Yeong-Min

2012-05-01

Sulforaphane (1-isothiocyanato-4-(methylsulfinyl)-butane), belonging to a family of natural compounds that are abundant in broccoli, has received significant therapeutic interest in recent years. However, the molecular basis of its effects remains to be elucidated. In this study, we attempt to determine whether sulforaphane regulates the inflammatory response in an ovalbumin (OVA)-induced murine asthma model. Mice were sensitized with OVA, treated with sulforaphane, and then challenged with OVA. Sulforaphane administration significantly alleviated the OVA-induced airway hyperresponsiveness to inhaled methacholine. Additionally, sulforaphane suppressed the increase in the levels of SOCS-3 and GATA-3 and IL-4 expression in the OVA-challenged mice. Collectively, our results demonstrate that sulforaphane regulates Th2 immune responses. This sutdy provides novel insights into the regulatory role of sulforaphane in allergen-induced Th2 inflammation and airway responses, which indicates its therapeutic potential for asthma and other allergic diseases.

Effect of thromboxane antagonists on ozone-induced airway responses in dogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jones, G.L.; Lane, C.G.; O'Byrne, P.M.

1990-09-01

Airway hyperresponsiveness after inhaled ozone in dogs may occur as a result of thromboxane release in the airway. In this study, two thromboxane receptor antagonists, L-655,240 and L-670,596, were used in doses that inhibit the response to an inhaled thromboxane mimetic, U-46619, to determine further the role of thromboxane in ozone-induced airway hyperresponsiveness. Dogs were studied on 2 days separated by 1 wk. On each day, the dogs inhaled ozone (3 ppm) for 30 min. On one randomly assigned day, 10 dogs received an infusion of L-655,240 (5 mg.kg-1.h-1) and 5 dogs received an infusion of L-670,596 (1 mg.kg-1.h-1); onmore » the other day dogs received a control infusion. Airway responses to doubling doses of acetylcholine were measured before and after inhalation of ozone and were expressed as the concentration of acetylcholine giving a rise in resistance of 5 cmH2O.l-1.s from baseline (acetylcholine provocation concentration). The development of airway hyperresponsiveness after ozone was not inhibited by the thromboxane antagonists. The mean log difference in the acetylcholine provocative concentration before and after ozone on the L-655,240 treatment day was 0.62 +/- 0.12 (SE) and on the control day was 0.71 +/- 0.12 (P = 0.48); on the L-670,596 treatment day the mean log difference was 0.68 +/- 0.15 (SE) and on the control day it was 0.75 +/- 0.19 (P = 0.45). These results do not support an important role for thromboxane in causing ozone-induced airway hyperresponsiveness.« less

Differential Activation of Airway Eosinophils Induces IL-13 Mediated Allergic Th2 Pulmonary Responses in Mice

PubMed Central

Jacobsen, EA; Doyle, AD; Colbert, DC; Zellner, KR; Protheroe, CA; LeSuer, WE; Lee, NA.; Lee, JJ

2015-01-01

Background Eosinophils are hallmark cells of allergic Th2 respiratory inflammation. However, the relative importance of eosinophil activation and the induction of effector functions such as the expression of IL-13 to allergic Th2 pulmonary disease remain to be defined. Methods Wild type or cytokine deficient (IL-13−/− or IL-4−/−) eosinophils treated with cytokines (GM-CSF, IL-4, IL-33) were adoptively transferred into eosinophil-deficient recipient mice subjected to allergen provocation using established models of respiratory inflammation. Allergen-induced pulmonary changes were assessed. Results In contrast to the transfer of untreated blood eosinophils to the lungs of recipient eosinophildeficient mice, which induced no immune/inflammatory changes either in the lung or lung draining lymph nodes (LDLNs), pretreatment of blood eosinophils with GM-CSF prior to transfer elicited trafficking of these eosinophils to LDLNs. In turn, these LDLN eosinophils elicited the accumulation of dendritic cells and CD4+ T cells to these same LDLNs without inducing pulmonary inflammation. However, exposure of eosinophils to GM-CSF, IL-4 and IL-33 prior to transfer induced not only immune events in the LDLN, but also allergen-mediated increases in airway Th2 cytokine/chemokine levels, the subsequent accumulation of CD4+ T cells as well as alternatively activated (M2) macrophages, and the induction of pulmonary histopathologies. Significantly, this allergic respiratory inflammation was dependent on eosinophil-derived IL-13 whereas IL-4 expression by eosinophils had no significant role. Conclusion The data demonstrate the differential activation of eosinophils as a function of cytokine exposure and suggest that eosinophil-specific IL-13 expression by activated cells is a necessary component of the subsequent allergic Th2 pulmonary pathologies. PMID:26009788

Differential activation of airway eosinophils induces IL-13-mediated allergic Th2 pulmonary responses in mice.

PubMed

Jacobsen, E A; Doyle, A D; Colbert, D C; Zellner, K R; Protheroe, C A; LeSuer, W E; Lee, N A; Lee, J J

2015-09-01

Eosinophils are hallmark cells of allergic Th2 respiratory inflammation. However, the relative importance of eosinophil activation and the induction of effector functions such as the expression of IL-13 to allergic Th2 pulmonary disease remain to be defined. Wild-type or cytokine-deficient (IL-13(-/-) or IL-4(-/-) ) eosinophils treated with cytokines (GM-CSF, IL-4, IL-33) were adoptively transferred into eosinophil-deficient recipient mice subjected to allergen provocation using established models of respiratory inflammation. Allergen-induced pulmonary changes were assessed. In contrast to the transfer of untreated blood eosinophils to the lungs of recipient eosinophil deficient mice, which induced no immune/inflammatory changes either in the lung or in the lung draining lymph nodes (LDLN), pretreatment of blood eosinophils with GM-CSF prior to transfer elicited trafficking of these eosinophils to LDLN. In turn, these LDLN eosinophils elicited the accumulation of dendritic cells and CD4(+) T cells to these same LDLNs without inducing pulmonary inflammation. However, exposure of eosinophils to GM-CSF, IL-4, and IL-33 prior to transfer induced not only immune events in the LDLN, but also allergen-mediated increases in airway Th2 cytokine/chemokine levels, the subsequent accumulation of CD4(+) T cells as well as alternatively activated (M2) macrophages, and the induction of pulmonary histopathologies. Significantly, this allergic respiratory inflammation was dependent on eosinophil-derived IL-13, whereas IL-4 expression by eosinophils had no significant role. The data demonstrate the differential activation of eosinophils as a function of cytokine exposure and suggest that eosinophil-specific IL-13 expression by activated cells is a necessary component of the subsequent allergic Th2 pulmonary pathologies. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Role of IL-4 receptor α-positive CD4(+) T cells in chronic airway hyperresponsiveness.

PubMed

Kirstein, Frank; Nieuwenhuizen, Natalie E; Jayakumar, Jaisubash; Horsnell, William G C; Brombacher, Frank

2016-06-01

TH2 cells and their cytokines are associated with allergic asthma in human subjects and with mouse models of allergic airway disease. IL-4 signaling through the IL-4 receptor α (IL-4Rα) chain on CD4(+) T cells leads to TH2 cell differentiation in vitro, implying that IL-4Rα-responsive CD4(+) T cells are critical for the induction of allergic asthma. However, mechanisms regulating acute and chronic allergen-specific TH2 responses in vivo remain incompletely understood. This study defines the requirements for IL-4Rα-responsive CD4(+) T cells and the IL-4Rα ligands IL-4 and IL-13 in the development of allergen-specific TH2 responses during the onset and chronic phase of experimental allergic airway disease. Development of acute and chronic ovalbumin (OVA)-induced allergic asthma was assessed weekly in CD4(+) T cell-specific IL-4Rα-deficient BALB/c mice (Lck(cre)IL-4Rα(-/lox)) and respective control mice in the presence or absence of IL-4 or IL-13. During acute allergic airway disease, IL-4 deficiency did not prevent the onset of TH2 immune responses and OVA-induced airway hyperresponsiveness or goblet cell hyperplasia, irrespective of the presence or absence of IL-4Rα-responsive CD4(+) T cells. In contrast, deficiency of IL-13 prevented allergic asthma, irrespective of the presence or absence of IL-4Rα-responsive CD4(+) T cells. Importantly, chronic allergic inflammation and airway hyperresponsiveness were dependent on IL-4Rα-responsive CD4(+) T cells. Deficiency in IL-4Rα-responsive CD4(+) T cells resulted in increased numbers of IL-17-producing T cells and, consequently, increased airway neutrophilia. IL-4-responsive T helper cells are dispensable for acute OVA-induced airway disease but crucial in maintaining chronic asthmatic pathology. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Comparison of Timothy grass pollen extract- and single major allergen-induced gene expression and mediator release in airway epithelial cells: a meta-analysis.

PubMed

Röschmann, K I L; van Kuijen, A-M; Luiten, S; Jonker, M J; Breit, T M; Fokkens, W J; Petersen, A; van Drunen, C M

2012-10-01

Seasonal allergic rhinitis (AR) is a global health problem and its prevalence has increased considerably in the last decades. As the allergic response with its clinical manifestations is triggered by only a few proteins within natural extracts, there is an increasing tendency for single-component-resolved diagnosis and immunotherapy. As natural exposure is not to single proteins, but to complex mixtures of molecules, we were interested in comparing the activation of respiratory epithelial cells induced by the purified major allergen Phl p 1 with the induction caused by a complete extract of Timothy grass pollen (GPE). NCI-H292 cells were exposed to GPE or Ph1 p 1 for 24 h, isolated RNA and cell culture supernatants were used for microarray analysis, multiplex enzyme-linked immunosorbant assay (ELISA) and subsequent analysis. We found 262 genes that showed a GPE-induced change of at least 3-fold, whereas Ph1 p 1-stimulation resulted in 71 genes with a fold induction of more than 3-fold. Besides genes that were regulated by both stimuli, we also detected genes displaying an opposite response after stimulation, suggesting that GPE might be more than purified major allergens with regard to induced immune responses. Additional components within GPE and the resulting modulation of general processes affecting gene transcription and signalling pathways might be crucial to maintain/overcome the diseased phenotype and to induce the influx of cells contributing to late-phase allergic responses. When the initial process of sensitization is the matter of interest or late-phase allergic responses, one might miss important immune modulatory molecules and their interaction with allergens by applying single components only. © 2012 Blackwell Publishing Ltd.

Role of nicotinic receptors and acetylcholine in mucous cell metaplasia, hyperplasia and airway mucus formation in vitro and in vivo

PubMed Central

Gundavarapu, Sravanthi; Wilder, Julie A.; Mishra, Neerad C.; Rir-sima-ah, Jules; Langley, Raymond J.; Singh, Shashi P.; Saeed, Ali Imran; Jaramillo, Richard J.; Gott, Katherine M.; Peña-Philippides, Juan Carlos; Harrod, Kevin S.; McIntosh, J. Michael; Buch, Shilpa; Sopori, Mohan L.

2012-01-01

Background Airway mucus hypersecretion is a key pathophysiological feature in number of lung diseases. Cigarette smoke/nicotine and allergens are strong stimulators of airway mucus; however, the mechanism of mucus modulation is unclear. Objectives Characterize the pathway by which cigarette smoke/nicotine regulates airway mucus and identify agents that decrease airway mucus. Methods IL-13 and gamma-aminobutyric acid receptors (GABAARs) are implicated in airway mucus. We examined the role of IL-13 and GABAARs in nicotine-induced mucus formation in normal human bronchial epithelial (NHBE) and A549 cells, and secondhand cigarette smoke and/or ovalbumin-induced mucus formation in vivo. Results Nicotine promotes mucus formation in NHBE cells; however, the nicotine-induced mucus formation is independent of IL-13 but sensitive to the GABAAR antagonist picrotoxin (PIC). Airway epithelial cells express α7/α9/α10 nicotinic acetylcholine receptors (nAChRs) and specific inhibition or knockdown of α7- but not α9/α10-nAChRs abrogates mucus formation in response to nicotine and IL-13. Moreover, addition of acetylcholine or inhibition of its degradation increases mucus in NHBE cells. Nicotinic but not muscarinic receptor antagonists block allergen or nicotine/cigarette smoke-induced airway mucus formation in NHBE cells and/or in mouse airways. Conclusions Nicotine-induced airway mucus formation is independent of IL-13 and α7-nAChRs are critical in airway mucous cell metaplasia/hyperplasia and mucus production in response to various pro-mucoid agents, including IL-13. In the absence of nicotine, acetylcholine may be the biological ligand for α7-nAChRs to trigger airway mucus formation. α7-nAChRs are downstream of IL-13 but upstream of GABAARα2 in the MUC5AC pathway. Acetylcholine and α-7-nAChRs may serve as therapeutic targets to control airway mucus. PMID:22578901

Secretory response induced by essential oils on airway surface fluid: a pharmacological MRI study.

PubMed

Nicolato, Elena; Boschi, Federico; Marzola, Pasquina; Sbarbati, Andrea

2009-07-30

Using pharmacological magnetic resonance imaging, we have performed an in vivo evaluation of the secretory response induced by essential oils in the rat airway. Aim of the work was to establish a computerized method to assess the efficacy of volatile compounds in spatially localized areas without the bias derived by subjective evaluation. Magnetic resonance experiments were carried out using a 4.7 T horizontal magnet. In the trachea, airway surface fluid was easily identified for its high intensity signal. The tracheal glands were also easily visible. The oesophageal lumen was usually collapsed and was identifiable only in the presence of intraluminal liquid. Scotch pine essential oil inhalation significantly increased the surface fluid in the middle portion of the trachea and the increase was visible at both 5 and 10 min. A lesser secretory response was detected after rosemary essential oil inhalation even though the response was significant with respect to the control in particular at 10 min. No secretory response was detected after peppermint essential oil inhalation both at 5 and 10 min. The data obtained in the present work demonstrate a chemically induced airway secretion. The availability of a pharmacological magnetic resonance imaging approach opens new perspectives to test the action of volatile compounds on the airway.

Baicalein Reduces Airway Injury in Allergen and IL-13 Induced Airway Inflammation

PubMed Central

Mabalirajan, Ulaganathan; Ahmad, Tanveer; Rehman, Rakhshinda; Leishangthem, Geeta Devi; Dinda, Amit Kumar; Agrawal, Anurag; Ghosh, Balaram; Sharma, Surendra Kumar

2013-01-01

Background Baicalein, a bioflavone present in the dry roots of Scutellaria baicalensis Georgi, is known to reduce eotaxin production in human fibroblasts. However, there are no reports of its anti-asthma activity or its effect on airway injury. Methodology/Principal Findings In a standard experimental asthma model, male Balb/c mice that were sensitized with ovalbumin (OVA), treated with baicalein (10 mg/kg, ip) or a vehicle control, either during (preventive use) or after OVA challenge (therapeutic use). In an alternate model, baicalein was administered to male Balb/c mice which were given either IL-4 or IL-13 intranasally. Features of asthma were determined by estimating airway hyperresponsiveness (AHR), histopathological changes and biochemical assays of key inflammatory molecules. Airway injury was determined with apoptotic assays, transmission electron microscopy and assessing key mitochondrial functions. Baicalein treatment reduced AHR and inflammation in both experimental models. TGF-β1, sub-epithelial fibrosis and goblet cell metaplasia, were also reduced. Furthermore, baicalein treatment significantly reduced 12/15-LOX activity, features of mitochondrial dysfunctions, and apoptosis of bronchial epithelia. Conclusion/Significance Our findings demonstrate that baicalein can attenuate important features of asthma, possibly through the reduction of airway injury and restoration of mitochondrial function. PMID:23646158

TNF is required for TLR ligand-mediated but not protease-mediated allergic airway inflammation.

PubMed

Whitehead, Gregory S; Thomas, Seddon Y; Shalaby, Karim H; Nakano, Keiko; Moran, Timothy P; Ward, James M; Flake, Gordon P; Nakano, Hideki; Cook, Donald N

2017-09-01

Asthma is associated with exposure to a wide variety of allergens and adjuvants. The extent to which overlap exists between the cellular and molecular mechanisms triggered by these various agents is poorly understood, but it might explain the differential responsiveness of patients to specific therapies. In particular, it is unclear why some, but not all, patients benefit from blockade of TNF. Here, we characterized signaling pathways triggered by distinct types of adjuvants during allergic sensitization. Mice sensitized to an innocuous protein using TLR ligands or house dust extracts as adjuvants developed mixed eosinophilic and neutrophilic airway inflammation and airway hyperresponsiveness (AHR) following allergen challenge, whereas mice sensitized using proteases as adjuvants developed predominantly eosinophilic inflammation and AHR. TLR ligands, but not proteases, induced TNF during allergic sensitization. TNF signaled through airway epithelial cells to reprogram them and promote Th2, but not Th17, development in lymph nodes. TNF was also required during the allergen challenge phase for neutrophilic and eosinophilic inflammation. In contrast, TNF was dispensable for allergic airway disease in a protease-mediated model of asthma. These findings might help to explain why TNF blockade improves lung function in only some patients with asthma.

TNF is required for TLR ligand–mediated but not protease-mediated allergic airway inflammation

PubMed Central

Whitehead, Gregory S.; Thomas, Seddon Y.; Shalaby, Karim H.; Nakano, Keiko; Moran, Timothy P.; Ward, James M.; Flake, Gordon P.; Cook, Donald N.

2017-01-01

Asthma is associated with exposure to a wide variety of allergens and adjuvants. The extent to which overlap exists between the cellular and molecular mechanisms triggered by these various agents is poorly understood, but it might explain the differential responsiveness of patients to specific therapies. In particular, it is unclear why some, but not all, patients benefit from blockade of TNF. Here, we characterized signaling pathways triggered by distinct types of adjuvants during allergic sensitization. Mice sensitized to an innocuous protein using TLR ligands or house dust extracts as adjuvants developed mixed eosinophilic and neutrophilic airway inflammation and airway hyperresponsiveness (AHR) following allergen challenge, whereas mice sensitized using proteases as adjuvants developed predominantly eosinophilic inflammation and AHR. TLR ligands, but not proteases, induced TNF during allergic sensitization. TNF signaled through airway epithelial cells to reprogram them and promote Th2, but not Th17, development in lymph nodes. TNF was also required during the allergen challenge phase for neutrophilic and eosinophilic inflammation. In contrast, TNF was dispensable for allergic airway disease in a protease-mediated model of asthma. These findings might help to explain why TNF blockade improves lung function in only some patients with asthma. PMID:28758900

Chronic cat allergen exposure induces a TH2 cell-dependent IgG4 response related to low sensitization.

PubMed

Renand, Amedee; Archila, Luis D; McGinty, John; Wambre, Erik; Robinson, David; Hales, Belinda J; Thomas, Wayne R; Kwok, William W

2015-12-01

In human subjects, allergen tolerance has been observed after high-dose allergen exposure or after completed allergen immunotherapy, which is related to the accumulation of anti-inflammatory IgG4. However, the specific T-cell response that leads to IgG4 induction during chronic allergen exposure remains poorly understood. We sought to evaluate the relationship between cat allergen-specific T-cell frequency, cat allergen-specific IgE and IgG4 titers, and clinical status in adults with cat allergy with and without cat ownership and the cellular mechanism by which IgG4 is produced. Fel d 1-, Fel d 4-, Fel d 7-, and Fel d 8-specific T-cell responses were characterized by CD154 expression after antigen stimulation. In allergic subjects without cat ownership, the frequency of cat allergen (Fel d 1 and Fel d 4)-specific TH2 (sTH2) cells correlates with higher IgE levels and is linked to asthma. Paradoxically, we observed that subjects with cat allergy and chronic cat exposure maintain a high frequency of sTH2 cells, which correlates with higher IgG4 levels and low sensitization. B cells from allergic, but not nonallergic subjects, are able to produce IgG4 after cognate interactions with sTH2 clones and Fel d 1 peptide or the Fel d 1 recombinant protein. These experiments suggest that (1) allergen-experienced B cells with the capacity to produce IgG4 are present in allergic subjects and (2) cat allergen exposure induces an IgG4 response in a TH2 cell-dependent manner. Thus IgG4 accumulation could be mediated by chronic activation of the TH2 response, which in turn drives desensitization. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. All rights reserved.

Inhibition of CD23-mediated IgE transcytosis suppresses the initiation and development of airway allergic inflammation

USDA-ARS?s Scientific Manuscript database

The epithelium lining the airway tract and allergen-specific IgE are considered essential controllers of inflammatory responses to allergens. The human IgE receptor, CD23 (Fc'RII), is capable of transporting IgE or IgE-allergen complexes across the polarized human airway epithelial cell (AEC) monola...

Corticosteroid-induced gene expression in allergen-challenged asthmatic subjects taking inhaled budesonide

PubMed Central

Kelly, MM; King, EM; Rider, CF; Gwozd, C; Holden, NS; Eddleston, J; Zuraw, B; Leigh, R; O'Byrne, PM; Newton, R

2012-01-01

BACKGROUND AND PURPOSE Inhaled corticosteroids (ICS) are the cornerstone of asthma pharmacotherapy and, acting via the glucocorticoid receptor (GR), reduce inflammatory gene expression. While this is often attributed to a direct inhibitory effect of the GR on inflammatory gene transcription, corticosteroids also induce the expression of anti-inflammatory genes in vitro. As there are no data to support this effect in asthmatic subjects taking ICS, we have assessed whether ICS induce anti-inflammatory gene expression in subjects with atopic asthma. EXPERIMENTAL APPROACH Bronchial biopsies from allergen-challenged atopic asthmatic subjects taking inhaled budesonide or placebo were subjected to gene expression analysis using real-time reverse transcriptase-PCR for the corticosteroid-inducible genes (official gene symbols with aliases in parentheses): TSC22D3 [glucocorticoid-induced leucine zipper (GILZ)], dual-specificity phosphatase-1 (MAPK phosphatase-1), both anti-inflammatory effectors, and FKBP5 [FK506-binding protein 51 (FKBP51)], a regulator of GR function. Cultured pulmonary epithelial and smooth muscle cells were also treated with corticosteroids before gene expression analysis. KEY RESULTS Compared with placebo, GILZ and FKBP51 mRNA expression was significantly elevated in budesonide-treated subjects. Budesonide also increased GILZ expression in human epithelial and smooth muscle cells in culture. Immunostaining of bronchial biopsies revealed GILZ expression in the airways epithelium and smooth muscle of asthmatic subjects. CONCLUSIONS AND IMPLICATIONS Expression of the corticosteroid-induced genes, GILZ and FKBP51, is up-regulated in the airways of allergen-challenged asthmatic subjects taking inhaled budesonide. Consequently, the biological effects of corticosteroid-induced genes should be considered when assessing the actions of ICS. Treatment modalities that increase or decrease GR-dependent transcription may correspondingly affect corticosteroid efficacy

Rapid allergen-induced interleukin-17 and interferon-γ secretion by skin-resident memory CD8+ T cells.

PubMed

Schmidt, Jonas D; Ahlström, Malin G; Johansen, Jeanne D; Dyring-Andersen, Beatrice; Agerbeck, Christina; Nielsen, Morten M; Poulsen, Steen S; Woetmann, Anders; Ødum, Niels; Thomsen, Allan R; Geisler, Carsten; Bonefeld, Charlotte M

2017-04-01

Skin-resident memory T (T RM ) cells are associated with immunological memory in the skin. Whether immunological memory responses to allergens in the skin are solely localized to previously allergen-exposed sites or are present globally in the skin is not clear. Furthermore, the mechanisms whereby T RM cells induce rapid recall responses need further investigation. To study whether contact allergens induce local and/or global memory, and to determine the mechanisms involved in memory responses in the skin. To address these questions, we analysed responses to contact allergens in mice and humans sensitized to 2,4-dinitrofluorobenzene and nickel, respectively. Challenge responses in both mice and humans were dramatically increased at sites previously exposed to allergens as compared with previously unexposed sites. Importantly, the magnitude of the challenge response correlated with the epidermal accumulation of interleukin (IL)-17A-producing and interferon (IFN)-γ-producing T RM cells. Moreover, IL-17A and IFN-γ enhanced allergen-induced IL-1β production in keratinocytes. We show that sensitization with contact allergens induces a strong, long-lasting local memory and a weaker, temporary global immunological memory response to the allergen that is mediated by IL-17A-producing and IFN-γ-producing CD8 + T RM cells. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Allergen-induced cytokine production, atopic disease, IgE, and wheeze in children.

PubMed

Contreras, J Paola; Ly, Ngoc P; Gold, Diane R; He, Hongzhen; Wand, Mathew; Weiss, Scott T; Perkins, David L; Platts-Mills, Thomas A E; Finn, Patricia W

2003-12-01

The early childhood allergen-induced immune responses associated with atopic disease and IgE production in early life are not well understood. We assessed the relationship of allergen-induced cytokine production by PBMCs to both atopic disease and to IgE increase in a cohort of children with a parental history of allergy or asthma (n = 112) at a median of 2 years of age. We examined cockroach (Bla g 1)-induced, house dust mite (Der f 1)-induced, and cat (Fel d 1)-induced cytokine secretion, including secretion of IFN-gamma, IL-13, IL-10, and TNF-alpha. We investigated whether distinct cytokine patterns associated with atopic disease can be detected in immune responses of children. PBMCs were isolated, and allergen-induced cytokine secretion was analyzed by means of ELISA. Atopic disease was defined as physician- or nurse-diagnosed eczema or hay fever. Increased IgE was defined as an IgE level of greater than 35 U/mL to dust mite, cockroach, cat, and egg white or a total IgE level of 60 U/mL or greater. Compared with children without atopic disease, children with atopic disease had lower Der f 1 (P =.005) and Bla g 2 (P =.03) allergen-induced IFN-gamma levels. Compared with children without increased IgE (n = 95), those with increased IgE (n = 16) had higher Der f 1-induced (P =.006) and Fel d 1-induced (P =.005) IL-13 levels and lower Bla g 2-induced (P =.03) IFN-gamma levels. Compared with children with neither atopic disease nor repeated wheeze, children with both atopic disease and repeated wheeze had lower levels of allergen-induced IFN-gamma (P =.01 for Der f 1 and P =.02 for Bla g 2) cytokine secretion. In young children at risk for asthma or allergy, decreased allergen-induced IFN-gamma secretion is associated with atopic disease and, in some cases, with increased IgE levels. Increased allergen-induced IL-13 secretion is most strongly associated with early life increase of IgE.

Modeling TH 2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma.

PubMed

Foster, Paul S; Maltby, Steven; Rosenberg, Helene F; Tay, Hock L; Hogan, Simon P; Collison, Adam M; Yang, Ming; Kaiko, Gerard E; Hansbro, Philip M; Kumar, Rakesh K; Mattes, Joerg

2017-07-01

In this review, we highlight experiments conducted in our laboratories that have elucidated functional roles for CD4 + T-helper type-2 lymphocytes (T H 2 cells), their associated cytokines, and eosinophils in the regulation of hallmark features of allergic asthma. Notably, we consider the complexity of type-2 responses and studies that have explored integrated signaling among classical T H 2 cytokines (IL-4, IL-5, and IL-13), which together with CCL11 (eotaxin-1) regulate critical aspects of eosinophil recruitment, allergic inflammation, and airway hyper-responsiveness (AHR). Among our most important findings, we have provided evidence that the initiation of T H 2 responses is regulated by airway epithelial cell-derived factors, including TRAIL and MID1, which promote T H 2 cell development via STAT6-dependent pathways. Further, we highlight studies demonstrating that microRNAs are key regulators of allergic inflammation and potential targets for anti-inflammatory therapy. On the background of T H 2 inflammation, we have demonstrated that innate immune cells (notably, airway macrophages) play essential roles in the generation of steroid-resistant inflammation and AHR secondary to allergen- and pathogen-induced exacerbations. Our work clearly indicates that understanding the diversity and spatiotemporal role of the inflammatory response and its interactions with resident airway cells is critical to advancing knowledge on asthma pathogenesis and the development of new therapeutic approaches. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Administration of SIN-1 induces guinea pig airway hyperresponsiveness through inactivation of airway neutral endopeptidase.

PubMed

Kanazawa, H; Hirata, K; Yoshikawa, J

1999-12-01

Peroxynitrite plays an important role in the pathogenesis of airway inflammation. We have already found that peroxynitrite may contribute to decreased beta(2)-adrenoceptor responses in airway smooth muscle. However, it is not known whether peroxynitrite can alter neutral endopeptidase (EC 3.4.24.11; NEP) activity in the airways. This study was designed to determine whether peroxynitrite induces airway hyperresponsiveness to substance P (SP) and endothelin-1 (ET-1) through the inactivation of airway NEP. We examined whether the administration of S-morpholinosydnonimine (SIN-1), a compound that releases peroxynitrite, increased bronchoconstrictor responses to SP and ET-1 in anesthetized guinea pigs. In addition, we assayed NEP activity in the airways of SIN-1-exposed guinea pigs. Though SIN-1 (10(-7) M) alone had no effect on pulmonary resistance, pretreatment with SIN-1 significantly enhanced SP- and ET-1-induced bronchoconstriction. Pretreatment with phosphoramidon, an NEP inhibitor, also enhanced SP- and ET-1-induced bronchoconstriction. However, simultaneous administration of phosphoramidon and SIN-1 had no additive effect on SP- and ET-1-induced bronchoconstriction. Peroxynitrite formation by SIN-1 was completely inhibited by N-acetylcysteine (NAC) and glutathione (GSH) in vitro, and pretreatment with NAC and GSH significantly reversed the potentiation by SIN-1 of SP-induced bronchoconstriction. In addition, the NEP activity of the trachea after SIN-1 exposure was significantly reduced compared to the level in control guinea pigs (solvent for SIN-1: 30.0+/-4.2 fmol.min(-1).mg tissue(-1); 10(-7) M SIN-1; 15.5+/-4.5 fmol.min(-1).mg tissue(-1), p<0.05). These findings suggest that peroxynitrite induces airway hyperresponsiveness to SP and ET-1 through the inactivation of airway NEP, and that peroxynitrite is an important mediator of the alterations in airway functions.

Sphingosine-1-phosphate induces pro-remodelling response in airway smooth muscle cells

PubMed Central

Fuerst, E; Foster, H R; Ward, J P T; Corrigan, C J; Cousins, D J; Woszczek, G

2014-01-01

Background Increased proliferation of airway smooth muscle (ASM) cells leading to hyperplasia and increased ASM mass is one of the most characteristic features of airway remodelling in asthma. A bioactive lipid, sphingosine-1-phosphate (S1P), has been suggested to affect airway remodelling by stimulation of human ASM cell proliferation. Objective To investigate the effect of S1P on signalling and regulation of gene expression in ASM cells from healthy and asthmatic individuals. Methods Airway smooth muscle cells grown from bronchial biopsies of healthy and asthmatic individuals were exposed to S1P. Gene expression was analysed using microarray, real-time PCR and Western blotting. Receptor signalling and function were determined by mRNA knockdown and intracellular calcium mobilization experiments. Results S1P potently regulated the expression of more than 80 genes in human ASM cells, including several genes known to be involved in the regulation of cell proliferation and airway remodelling (HBEGF, TGFB3, TXNIP, PLAUR, SERPINE1, RGS4). S1P acting through S1P2 and S1P3 receptors activated intracellular calcium mobilization and extracellular signal-regulated and Rho-associated kinases to regulate gene expression. S1P-induced responses were not inhibited by corticosteroids and did not differ significantly between ASM cells from healthy and asthmatic individuals. Conclusion S1P induces a steroid-resistant, pro-remodelling pathway in ASM cells. Targeting S1P or its receptors could be a novel treatment strategy for inhibiting airway remodelling in asthma. PMID:25041788

Exercise-induced dehydration alters pulmonary function but does not modify airway responsiveness to dry air in athletes with mild asthma

PubMed Central

Romer, L. M.

2017-01-01

Local airway water loss is the main physiological trigger for exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effects of whole body water loss on airway responsiveness and pulmonary function in athletes with mild asthma and/or EIB. Ten recreational athletes with a medical diagnosis of mild asthma and/or EIB completed a randomized, crossover study. Pulmonary function tests, including spirometry, whole body plethysmography, and diffusing capacity of the lung for carbon monoxide (DlCO), were conducted before and after three conditions: 1) 2 h of exercise in the heat with no fluid intake (dehydration), 2) 2 h of exercise with ad libitum fluid intake (control), and 3) a time-matched rest period (rest). Airway responsiveness was assessed 2 h postexercise/rest via eucapnic voluntary hyperpnea (EVH) to dry air. Exercise in the heat with no fluid intake induced a state of mild dehydration, with a body mass loss of 2.3 ± 0.8% (SD). After EVH, airway narrowing was not different between conditions: median (interquartile range) maximum fall in forced expiratory volume in 1 s was 13 (7–15)%, 11 (9–24)%, and 12 (7–20)% in dehydration, control, and rest conditions, respectively. Dehydration caused a significant reduction in forced vital capacity (300 ± 190 ml, P = 0.001) and concomitant increases in residual volume (260 ± 180 ml, P = 0.001) and functional residual capacity (260 ± 250 ml, P = 0.011), with no change in DlCO. Mild exercise-induced dehydration does not exaggerate airway responsiveness to dry air in athletes with mild asthma/EIB but may affect small airway function. NEW & NOTEWORTHY This study is the first to investigate the effect of whole body dehydration on airway responsiveness. Our data suggest that the airway response to dry air hyperpnea in athletes with mild asthma and/or exercise-induced bronchoconstriction is not exacerbated in a state of mild dehydration. On the basis of alterations in lung volumes, however, exercise-induced

Exercise-induced dehydration alters pulmonary function but does not modify airway responsiveness to dry air in athletes with mild asthma.

PubMed

Simpson, A J; Romer, L M; Kippelen, P

2017-05-01

Local airway water loss is the main physiological trigger for exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effects of whole body water loss on airway responsiveness and pulmonary function in athletes with mild asthma and/or EIB. Ten recreational athletes with a medical diagnosis of mild asthma and/or EIB completed a randomized, crossover study. Pulmonary function tests, including spirometry, whole body plethysmography, and diffusing capacity of the lung for carbon monoxide (Dl CO ), were conducted before and after three conditions: 1 ) 2 h of exercise in the heat with no fluid intake (dehydration), 2 ) 2 h of exercise with ad libitum fluid intake (control), and 3 ) a time-matched rest period (rest). Airway responsiveness was assessed 2 h postexercise/rest via eucapnic voluntary hyperpnea (EVH) to dry air. Exercise in the heat with no fluid intake induced a state of mild dehydration, with a body mass loss of 2.3 ± 0.8% (SD). After EVH, airway narrowing was not different between conditions: median (interquartile range) maximum fall in forced expiratory volume in 1 s was 13 (7-15)%, 11 (9-24)%, and 12 (7-20)% in dehydration, control, and rest conditions, respectively. Dehydration caused a significant reduction in forced vital capacity (300 ± 190 ml, P = 0.001) and concomitant increases in residual volume (260 ± 180 ml, P = 0.001) and functional residual capacity (260 ± 250 ml, P = 0.011), with no change in Dl CO Mild exercise-induced dehydration does not exaggerate airway responsiveness to dry air in athletes with mild asthma/EIB but may affect small airway function. NEW & NOTEWORTHY This study is the first to investigate the effect of whole body dehydration on airway responsiveness. Our data suggest that the airway response to dry air hyperpnea in athletes with mild asthma and/or exercise-induced bronchoconstriction is not exacerbated in a state of mild dehydration. On the basis of alterations in lung volumes, however, exercise-induced

The contribution of airway smooth muscle to airway narrowing and airway hyperresponsiveness in disease.

PubMed

Martin, J G; Duguet, A; Eidelman, D H

2000-08-01

Airway hyperresponsiveness (AHR), the exaggerated response to constrictor agonists in asthmatic subjects, is incompletely understood. Changes in either the quantity or properties of airway smooth muscle (ASM) are possible explanations for AHR. Morphometric analyses demonstrate structural changes in asthmatic airways, including subepithelial fibrosis, gland hyperplasia/hypertrophy, neovascularization and an increase in ASM mass. Mathematical modelling of airway narrowing suggests that, of all the changes in structure, the increase in ASM mass is the most probable cause of AHR. An increase in ASM mass in the large airways is more closely associated with a greater likelihood of dying from asthma than increases in ASM mass in other locations within the airway tree. ASM contraction is opposed by the elastic recoil of the lungs and airways, which appears to limit the degree of bronchoconstriction in vivo. The cyclical nature of tidal breathing applies stresses to the airway wall that enhance the bronchodilating influence of the lung tissues on the contracting ASM, in all probability by disrupting cross-bridges. However, the increase in ASM mass in asthma may overcome the limitation resulting from the impedances to ASM shortening imposed by the lung parenchyma and airway wall tissues. Additionally, ASM with the capacity to shorten rapidly may achieve shorter lengths and cause a greater degree of bronchoconstriction when stimulated to contract than slower ASM. Changes in ASM properties are induced by the process of sensitization and allergen-exposure such as enhancement of phospholipase C activity and inositol phosphate turnover, and increases in myosin light chain kinase activity. Whether changes in ASM mass or biochemical/biomechanical properties form the basis for asthma remains to be determined.

Effects of the tripeptide substance P antagonist, FR113680, on airway constriction and airway edema induced by neurokinins in guinea-pigs.

PubMed

Murai, M; Morimoto, H; Maeda, Y; Fujii, T

1992-06-24

FR113680 is a newly developed tripeptide substance P (SP) receptor antagonist. The effects of FR113680 on airway constriction and airway edema induced by neurokinins were investigated in guinea-pigs. In in vitro experiments, FR113680 inhibited the contraction of isolated guinea-pig trachea induced by SP and neurokinin A (NKA) in a dose-dependent manner with IC50 values of 2.3 x 10(-6) and 1.5 x 10(-5) M, respectively. The tracheal contraction induced by histamine and acetylcholine was not affected by FR113680. FR113680 (5 x 10(-5) M) also significantly inhibited the atropine-resistant contraction of isolated guinea-pig bronchi induced by electrical field stimulation. In in vivo experiments, FR113680 given i.v. inhibited SP-induced airway constriction in guinea-pigs at doses of 1 and 10 mg kg-1. However, FR113680 only inhibited NKA- and capsaicin-induced airway constriction by 40-50% even at a dose of 10 mg kg-1. FR113680 also inhibited SP-induced airway edema in guinea-pigs with the same potency as it inhibited SP-induced airway constriction. Histamine-induced airway constriction and airway edema were not affected at a dose of 10 mg kg-1. These results suggest that FR113680 preferentially inhibits responses induced by NK1 receptor activation (SP-induced airway constriction and airway edema), but is less effective on a NK2 receptor-induced response (airway constriction by NKA and neurogenic stimulation).

Decreased airway narrowing and smooth muscle contraction in hyperresponsive pigs.

PubMed

Turner, Debra J; Noble, Peter B; Lucas, Matthew P; Mitchell, Howard W

2002-10-01

Increased smooth muscle contractility or reduced smooth muscle mechanical loads could account for the excessive airway narrowing and hyperresponsiveness seen in asthma. These mechanisms were investigated by using an allergen-induced porcine model of airway hyperresponsiveness. Airway narrowing to electric field stimulation was measured in isolated bronchial segments, over a range of transmural pressures (0-20 cmH(2)O). Contractile responses to ACh were measured in bronchial segments and in isolated tracheal smooth muscle strips isolated from control and test (ovalbumin sensitized and challenged) pigs. Test airways narrowed less than controls (P < 0.0001). Test pigs showed reduced contractility to ACh, both in isolated bronchi (P < 0.01) and smooth muscle strips (P < 0.01). Thus isolated airways from pigs exhibiting airway hyperresponsiveness in vivo are hyporesponsive in vitro. The decreased narrowing in bronchi from hyperresponsive pigs may be related to decreased smooth muscle contractility. These data suggest that mechanisms external to the airway wall may be important to the hyperresponsive nature of sensitized lungs.

Airway extravasation induced by increasing airway temperature in ovalbumin-sensitized rats

PubMed Central

Hsu, Chun-Chun; Tapia, Reyno J.; Lee, Lu-Yuan

2015-01-01

This study was carried out to determine whether hyperventilation of humidified warm air (HWA) induced airway extravasation in ovalbumin (Ova)-sensitized rats. Our results showed: 1) After isocapnic hyperventilation with HWA for 2 min, tracheal temperature (Ttr) was increased to 40.3°C, and the Evans blue contents in major airways and lung tissue were elevated to 651% and 707%, respectively, of that after hyperventilation with humidified room air in Ova-sensitized rats; this striking effect of HWA was absent in control rats. 2) The HWA-induced increase in Evans blue content in sensitized rats was completely prevented by a pretreatment with either L-732138, a selective antagonist of neurokinin type 1 (NK-1) receptor, or formoterol, a selective agonist of β2 adrenoceptor. This study demonstrated that an increase in airway temperature induced protein extravasation in the major airways and lung tissue of sensitized rats, and an activation of the NK-1 receptor by tachykinins released from bronchopulmonary C-fiber nerve endings was primarily responsible. PMID:25864799

Receptor for advanced glycation end products and its ligand high-mobility group box-1 mediate allergic airway sensitization and airway inflammation.

PubMed

Ullah, Md Ashik; Loh, Zhixuan; Gan, Wan Jun; Zhang, Vivian; Yang, Huan; Li, Jian Hua; Yamamoto, Yasuhiko; Schmidt, Ann Marie; Armour, Carol L; Hughes, J Margaret; Phipps, Simon; Sukkar, Maria B

2014-08-01

The receptor for advanced glycation end products (RAGE) shares common ligands and signaling pathways with TLR4, a key mediator of house dust mite (Dermatophagoides pteronyssinus) (HDM) sensitization. We hypothesized that RAGE and its ligand high-mobility group box-1 (HMGB1) cooperate with TLR4 to mediate HDM sensitization. To determine the requirement for HMGB1 and RAGE, and their relationship with TLR4, in airway sensitization. TLR4(-/-), RAGE(-/-), and RAGE-TLR4(-/-) mice were intranasally exposed to HDM or cockroach (Blatella germanica) extracts, and features of allergic inflammation were measured during the sensitization or challenge phase. Anti-HMGB1 antibody and the IL-1 receptor antagonist Anakinra were used to inhibit HMGB1 and the IL-1 receptor, respectively. The magnitude of allergic airway inflammation in response to either HDM or cockroach sensitization and/or challenge was significantly reduced in the absence of RAGE but not further diminished in the absence of both RAGE and TLR4. HDM sensitization induced the release of HMGB1 from the airway epithelium in a biphasic manner, which corresponded to the sequential activation of TLR4 then RAGE. Release of HMGB1 in response to cockroach sensitization also was RAGE dependent. Significantly, HMGB1 release occurred downstream of TLR4-induced IL-1α, and upstream of IL-25 and IL-33 production. Adoptive transfer of HDM-pulsed RAGE(+/+)dendritic cells to RAGE(-/-) mice recapitulated the allergic responses after HDM challenge. Immunoneutralization of HMGB1 attenuated HDM-induced allergic airway inflammation. The HMGB1-RAGE axis mediates allergic airway sensitization and airway inflammation. Activation of this axis in response to different allergens acts to amplify the allergic inflammatory response, which exposes it as an attractive target for therapeutic intervention. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Acinetobacter baumannii Infection Inhibits Airway Eosinophilia and Lung Pathology in a Mouse Model of Allergic Asthma

PubMed Central

Qiu, Hongyu; KuoLee, Rhonda; Harris, Greg; Zhou, Hongyan; Miller, Harvey; Patel, Girishchandra B.; Chen, Wangxue

2011-01-01

Allergic asthma is a dysregulation of the immune system which leads to the development of Th2 responses to innocuous antigens (allergens). Some infections and microbial components can re-direct the immune response toward the Th1 response, or induce regulatory T cells to suppress the Th2 response, thereby inhibiting the development of allergic asthma. Since Acinetobacter baumannii infection can modulate lung cellular and cytokine responses, we studied the effect of A. baumannii in modulating airway eosinophilia in a mouse model of allergic asthma. Ovalbumin (OVA)-sensitized mice were treated with live A. baumannii or phosphate buffered saline (PBS), then intranasally challenged with OVA. Compared to PBS, A. baumannii treatment significantly reduced pulmonary Th2 cytokine and chemokine responses to OVA challenge. More importantly, the airway inflammation in A. baumannii-treated mice was strongly suppressed, as seen by the significant reduction of the proportion and the total number of eosinophils in the bronchoalveolar lavage fluid. In addition, A. baumannii-treated mice diminished lung mucus overproduction and pathology. However, A. baumannii treatment did not significantly alter systemic immune responses to OVA. Serum OVA-specific IgE, IgG1 and IgG2a levels were comparable between A. baumannii- and PBS-treated mice, and tracheobronchial lymph node cells from both treatment groups produced similar levels of Th1 and Th2 cytokines in response to in vitro OVA stimulation. Moreover, it appears that TLR-4 and IFN-γ were not directly involved in the A. baumannii-induced suppression of airway eosinophilia. Our results suggest that A. baumannii inhibits allergic airway inflammation by direct suppression of local pulmonary Th2 cytokine responses to the allergen. PMID:21789200

Interleukin-1beta-induced airway hyperresponsiveness enhances substance P in intrinsic neurons of ferret airway.

PubMed

Wu, Z-X; Satterfield, B E; Fedan, J S; Dey, R D

2002-11-01

Interleukin (IL)-1beta causes airway inflammation, enhances airway smooth muscle responsiveness, and alters neurotransmitter expression in sensory, sympathetic, and myenteric neurons. This study examines the role of intrinsic airway neurons in airway hyperresponsiveness (AHR) induced by IL-1beta. Ferrets were instilled intratracheally with IL-1beta (0.3 microg/0.3 ml) or saline (0.3 ml) once daily for 5 days. Tracheal smooth muscle contractility in vitro and substance P (SP) expression in tracheal neurons were assessed. Tracheal smooth muscle reactivity to acetylcholine (ACh) and methacholine (MCh) and smooth muscle contractions to electric field stimulation (EFS) both increased after IL-1beta. The IL-1beta-induced AHR was maintained in tracheal segments cultured for 24 h, a procedure that depletes SP from sensory nerves while maintaining viability of intrinsic airway neurons. Pretreatment with CP-99994, an antagonist of neurokinin 1 receptor, attenuated the IL-1beta-induced hyperreactivity to ACh and MCh and to EFS in cultured tracheal segments. SP-containing neurons in longitudinal trunk, SP innervation of superficial muscular plexus neurons, and SP nerve fiber density in tracheal smooth muscle all increased after treatment with IL-1beta. These results show that IL-1beta-enhanced cholinergic airway smooth muscle contractile responses are mediated by the actions of SP released from intrinsic airway neurons.

Control of epithelial immune-response genes and implications for airway immunity and inflammation.

PubMed

Holtzman, M J; Look, D C; Sampath, D; Castro, M; Koga, T; Walter, M J

1998-01-01

A major goal of our research is to understand how immune cells (especially T cells) infiltrate the pulmonary airway during host defense and inflammatory disease (especially asthma). In that context, we have proposed that epithelial cells lining the airway provide critical biochemical signals for immune-cell influx and activation and that this epithelial-immune cell interaction is a critical feature of airway inflammation and hyperreactivity. In this brief report, we describe our progress in defining a subset of epithelial immune-response genes the expression of which is coordinated for viral defense both directly in response to replicating virus and indirectly under the control of a specific interferon-gamma signal transduction pathway featuring the Stat1 transcription factor as a critical relay signal between cytoplasm and nucleus. Unexpectedly, the same pathway is also activated during asthmatic airway inflammation in a setting where there is no apparent infection and no increase in interferon-gamma levels. The findings provide the first evidence of an overactive Stat1-dependent gene network in asthmatic airways and a novel molecular link between mucosal immunity and inflammation. The findings also offer the possibility that overactivity of Stat1-dependent genes might augment a subsequent T helper cell (Th1)-type response to virus or might combine with a heightened Th2-type response to allergen to account for more severe exacerbations of asthma.

Risk factors associated with airway allergic diseases from exposure to laboratory animal allergens among veterinarians.

PubMed

Krakowiak, Anna; Wiszniewska, Marta; Krawczyk, Patrycja; Szulc, Bogdan; Wittczak, Tomasz; Walusiak, Jolanta; Pałczynski, Cezary

2007-05-01

Investigate the risk factors for the development of occupational airway allergy (OAA) from exposure to laboratory animal allergens (LAA) among Polish veterinarians. Two hundred veterinarians responded to the questionnaire and were subjected to skin prick test (SPT) to common allergens and LAA (rat, mouse, hamster, guinea pig, rabbit). Evaluation of total serum IgE level and specific IgE against occupational allergens was performed. In addition, bronchial hyperreactivity (BHR) and peak expiratory flow rate (PEFR) were measured before and after specific challenge testing (SCT) only in the subjects with work-related symptoms suggestive of occupational asthma (OA). The prevalence of asthmatic and ocular symptoms was statistically more prevalent in the group of veterinarians sensitised to LAA versus non-sensitised subjects. The most frequent occupational allergens of skin and serum reactivity were LAA (44.5 and 31.5%, respectively). In 41 (20.5%) and in 22 (11%) subjects out of 200 veterinarians, serum specific IgE to natural rubber latex (NRL) allergens and disinfectants was also found. Serum sensitisation to cat allergens and daily contact with laboratory animals (LA) increased the risk for developing isolated occupational rhinitis. Furthermore, working time of more than 10 years and daily contact with LA were also significant risk factors for the development of OAA. Measuring PEFR and BHR before and after SCT is a useful method to confirm the presence of OA. Allergy to LAA is an important health problem among veterinary medicine practitioners in Poland.

CARMA3 Is Critical for the Initiation of Allergic Airway Inflammation

PubMed Central

Causton, Benjamin; Ramadas, Ravisankar A.; Cho, Josalyn L.; Jones, Khristianna; Pardo-Saganta, Ana; Rajagopal, Jayaraj; Xavier, Ramnik J.

2015-01-01

Innate immune responses to allergens by airway epithelial cells (AECs) help initiate and propagate the adaptive immune response associated with allergic airway inflammation in asthma. Activation of the transcription factor NF-κB in AECs by allergens or secondary mediators via G protein–coupled receptors (GPCRs) is an important component of this multifaceted inflammatory cascade. Members of the caspase recruitment domain family of proteins display tissue-specific expression and help mediate NF-κB activity in response to numerous stimuli. We have previously shown that caspase recruitment domain–containing membrane-associated guanylate kinase protein (CARMA)3 is specifically expressed in AECs and mediates NF-κB activation in these cells in response to stimulation with the GPCR agonist lysophosphatidic acid. In this study, we demonstrate that reduced levels of CARMA3 in normal human bronchial epithelial cells decreases the production of proasthmatic mediators in response to a panel of asthma-relevant GPCR ligands such as lysophosphatidic acid, adenosine triphosphate, and allergens that activate GPCRs such as Alternaria alternata and house dust mite. We then show that genetically modified mice with CARMA3-deficient AECs have reduced airway eosinophilia and proinflammatory cytokine production in a murine model of allergic airway inflammation. Additionally, we demonstrate that these mice have impaired dendritic cell maturation in the lung and that dendritic cells from mice with CARMA3-deficient AECs have impaired Ag processing. In conclusion, we show that AEC CARMA3 helps mediate allergic airway inflammation, and that CARMA3 is a critical signaling molecule bridging the innate and adaptive immune responses in the lung. PMID:26041536

Modulation of the allergen-induced human IgE response in Hu-SCID mice: inhibitory effect of human recombinant IFN-gamma and allergen-derived lipopeptide.

PubMed

Duez, C; Gras-Masse, H; Hammad, H; Akoum, H; Didierlaurent, A; André, C; Tonnel, A B; Pestel, J

2001-01-01

We have previously established a model to study the in vivo human IgE response using humanized SCID mice. Allergic SCID mice were obtained following intraperitoneal injection with mononuclear cells from Dermatophagoides pteronyssinus (Dpt)-sensitive patients, and sensitization by Dpt allergen intraperitoneal injection (immunization) or Dpt aerosol (inhalation). Human serum IgE was measured in allergic SCID mice after administration of human recombinant IFN-gamma or the lipopeptide LP 52-71 (derived from peptide p52-71 from Der p 1, Dpt major allergen, coupled to a lipophilic moiety), during the immunization or the inhalation phase. IFN-gamma inhibited human IgE production when given at the time of immunization, but not during inhalation. This effect was long-lasting as Dpt aerosol, given one month after immunization and IFN-gamma administration, failed to increase IgE levels. Unlike Dpt or p52-71, LP 52-71 failed to induce human IgE production at day 14 and 21 after its injection, but did inhibit the development of the IgE response after a secondary Dpt-challenge. Moreover, LP 52-71 administration 14 days after Dpt inhalation decreased IgE levels, in contrast to peptide 52-71, which increased IgE levels. Thus, taken together these results indicate that the development of the human IgE response in allergic SCID mice can be modulated by modified allergen and a Th1 cytokine.

Early growth response gene 1 is essential for urban particulate matter-induced inflammation and mucus hyperproduction in airway epithelium.

PubMed

Xu, Feng; Cao, Jiaofei; Luo, Man; Che, Luanqing; Li, Wen; Ying, Songmin; Chen, Zhihua; Shen, Huahao

2018-05-19

Particulate matter (PM) has been implicated as a risk factor for human airway disorders. However, the biological mechanisms underlying the correlation between PM exposure and adverse airway effects have not yet been fully clarified. The objective of this study was to explore the possible role of early growth response gene 1 (Egr-1) in PM-induced toxic effects in pulmonary inflammation and mucus hyperproduction in vitro and in vivo. Particulate matter exposure induced a rapid Egr-1 expression in human bronchial epithelial (HBE) cells and in mouse lungs. Genetic blockage of Egr-1 markedly reduced PM-induced inflammatory cytokines, e.g., IL6 and IL8, and MUC5AC in HBE cells, and these effects were mechanistically mediated by the nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) pathways, respectively. Egr-1-knockout mice displayed significantly reduced airway inflammation and mucus hyperproduction in response to PM exposure in vivo. Moreover, polycyclic aromatic hydrocarbons (PAHs) contained in the PM also induced Egr-1 expression, and also played a role in the inflammatory responses and mucus production. Taken together, our data reveal novel Egr-1 signaling that mediates the NF-κB and AP-1 pathways to orchestrate PM-induced pulmonary inflammation and mucus hyperproduction, suggesting that Egr-1 inhibition could be an effective therapeutic approach for airway disorders or disease exacerbations induced by airborne particulate pollution. Copyright © 2018. Published by Elsevier B.V.

Directional secretory response of double stranded RNA-induced thymic stromal lymphopoetin (TSLP) and CCL11/eotaxin-1 in human asthmatic airways.

PubMed

Nino, Gustavo; Huseni, Shehlanoor; Perez, Geovanny F; Pancham, Krishna; Mubeen, Humaira; Abbasi, Aleeza; Wang, Justin; Eng, Stephen; Colberg-Poley, Anamaris M; Pillai, Dinesh K; Rose, Mary C

2014-01-01

Thymic stromal lymphoproetin (TSLP) is a cytokine secreted by the airway epithelium in response to respiratory viruses and it is known to promote allergic Th2 responses in asthma. This study investigated whether virally-induced secretion of TSLP is directional in nature (apical vs. basolateral) and/or if there are TSLP-mediated effects occurring at both sides of the bronchial epithelial barrier in the asthmatic state. Primary human bronchial epithelial cells (HBEC) from control (n = 3) and asthmatic (n = 3) donors were differentiated into polarized respiratory tract epithelium under air-liquid interface (ALI) conditions and treated apically with dsRNA (viral surrogate) or TSLP. Sub-epithelial effects of TSLP were examined in human airway smooth muscle cells (HASMC) from normal (n = 3) and asthmatic (n = 3) donors. Clinical experiments examined nasal airway secretions obtained from asthmatic children during naturally occurring rhinovirus-induced exacerbations (n = 20) vs. non-asthmatic uninfected controls (n = 20). Protein levels of TSLP, CCL11/eotaxin-1, CCL17/TARC, CCL22/MDC, TNF-α and CXCL8 were determined with a multiplex magnetic bead assay. Our data demonstrate that: 1) Asthmatic HBEC exhibit an exaggerated apical, but not basal, secretion of TSLP after dsRNA exposure; 2) TSLP exposure induces unidirectional (apical) secretion of CCL11/eotaxin-1 in asthmatic HBEC and enhanced CCL11/eotaxin-1 secretion in asthmatic HASMC; 3) Rhinovirus-induced asthma exacerbations in children are associated with in vivo airway secretion of TSLP and CCL11/eotaxin-1. There are virally-induced TSLP-driven secretory immune responses at both sides of the bronchial epithelial barrier characterized by enhanced CCL11/eotaxin-1 secretion in asthmatic airways. These results suggest a new model of TSLP-mediated eosinophilic responses in the asthmatic airway during viral-induced exacerbations.

Directional Secretory Response of Double Stranded RNA-Induced Thymic Stromal Lymphopoetin (TSLP) and CCL11/Eotaxin-1 in Human Asthmatic Airways

PubMed Central

Perez, Geovanny F.; Pancham, Krishna; Mubeen, Humaira; Abbasi, Aleeza; Wang, Justin; Eng, Stephen; Colberg-Poley, Anamaris M.; Pillai, Dinesh K.; Rose, Mary C.

2014-01-01

Background Thymic stromal lymphoproetin (TSLP) is a cytokine secreted by the airway epithelium in response to respiratory viruses and it is known to promote allergic Th2 responses in asthma. This study investigated whether virally-induced secretion of TSLP is directional in nature (apical vs. basolateral) and/or if there are TSLP-mediated effects occurring at both sides of the bronchial epithelial barrier in the asthmatic state. Methods Primary human bronchial epithelial cells (HBEC) from control (n = 3) and asthmatic (n = 3) donors were differentiated into polarized respiratory tract epithelium under air-liquid interface (ALI) conditions and treated apically with dsRNA (viral surrogate) or TSLP. Sub-epithelial effects of TSLP were examined in human airway smooth muscle cells (HASMC) from normal (n = 3) and asthmatic (n = 3) donors. Clinical experiments examined nasal airway secretions obtained from asthmatic children during naturally occurring rhinovirus-induced exacerbations (n = 20) vs. non-asthmatic uninfected controls (n = 20). Protein levels of TSLP, CCL11/eotaxin-1, CCL17/TARC, CCL22/MDC, TNF-α and CXCL8 were determined with a multiplex magnetic bead assay. Results Our data demonstrate that: 1) Asthmatic HBEC exhibit an exaggerated apical, but not basal, secretion of TSLP after dsRNA exposure; 2) TSLP exposure induces unidirectional (apical) secretion of CCL11/eotaxin-1 in asthmatic HBEC and enhanced CCL11/eotaxin-1 secretion in asthmatic HASMC; 3) Rhinovirus-induced asthma exacerbations in children are associated with in vivo airway secretion of TSLP and CCL11/eotaxin-1. Conclusions There are virally-induced TSLP-driven secretory immune responses at both sides of the bronchial epithelial barrier characterized by enhanced CCL11/eotaxin-1 secretion in asthmatic airways. These results suggest a new model of TSLP-mediated eosinophilic responses in the asthmatic airway during viral-induced exacerbations. PMID:25546419

Absence of Foxp3+ Regulatory T Cells during Allergen Provocation Does Not Exacerbate Murine Allergic Airway Inflammation

PubMed Central

Baru, Abdul Mannan; Ganesh, Venkateswaran; Krishnaswamy, Jayendra Kumar; Hesse, Christina; Untucht, Christopher; Glage, Silke; Behrens, Georg; Mayer, Christian Thomas; Puttur, Franz; Sparwasser, Tim

2012-01-01

Regulatory T cells (Tregs) play a non-redundant role in maintenance of immune homeostasis. This is achieved by suppressing both, priming of naïve cells and effector cell functions. Although Tregs have been implicated in modulating allergic immune responses, their influence on distinct phases of development of allergies remains unclear. In this study, by using bacterial artificial chromosome (BAC)-transgenic Foxp3-DTR (DEREG) mice we demonstrate that the absence of Foxp3+ Tregs during the allergen challenge surprisingly does not exacerbate allergic airway inflammation in BALB/c mice. As genetic disposition due to strain specificity may contribute significantly to development of allergies, we performed similar experiment in C57BL/6 mice, which are less susceptible to allergy in the model of sensitization used in this study. We report that the genetic background does not influence the consequence of this depletion regimen. These results signify the temporal regulation exerted by Foxp3+ Tregs in limiting allergic airway inflammation and may influence their application as potential therapeutics. PMID:23071726

The role of protease-activated receptor-2 on pulmonary neutrophils in the innate immune response to cockroach allergen

PubMed Central

2012-01-01

Background Serine proteases in German cockroach (GC) have been shown to mediate allergic airway inflammation through the activation of protease activated receptor (PAR)-2. Neutrophils play an important role in regulating the innate immune response, and are recruited into the airways following GC frass exposure. As such, we investigated the role of PAR-2 in airway neutrophil recruitment, activation and cytokine production following allergen exposure. Methods Wild type and PAR-2-deficient mice were administered a single intratracheal instillation of PBS or GC frass and neutrophil recruitment, expression of PAR-2, CD80, CD86, and MHC class II were assessed by flow cytometry and levels of tumor necrosis factor (TNF)α was assessed by ELISA. Uptake of AlexaFluor 405-labeled GC frass by neutrophils was performed by flow cytometry. Results Neutrophil recruitment in the lung and airways following GC frass exposure was significantly decreased in PAR-2-deficient mice compared to wild type mice. GC frass exposure increased the level of PAR-2 on pulmonary neutrophils and increased numbers of PAR-2-positive neutrophils were found in the lungs; however PAR-2 did not play a role in meditating allergen uptake. Comparing wild type and PAR-2-deficient mice, we found that a single exposure to GC frass increased levels of CD80 and CD86 on pulmonary neutrophils, an effect which was independent of PAR-2 expression. Neutrophils isolated from the whole lungs of naïve PAR-2-deficient mice treated ex vivo with GC frass produced significantly less TNFα than in similarly treated wild type neutrophils. Lastly, neutrophils were isolated from the bronchoalveolar lavage fluid of wild type and PAR-2-deficient mice following a single intratracheal exposure to GC frass. Airway neutrophils from PAR-2-deficient mice released substantially decreased levels of TNFα, suggesting a role for PAR-2 in neutrophil-derived cytokine production. Conclusions Together these data suggest PAR-2 expression can be

Site of Allergic Airway Narrowing and the Influence of Exogenous Surfactant in the Brown Norway Rat

PubMed Central

Risse, Paul-André; Bullimore, Sharon R.; Benedetti, Andrea; Martin, James G.

2012-01-01

Background The parameters RN (Newtonian resistance), G (tissue damping), and H (tissue elastance) of the constant phase model of respiratory mechanics provide information concerning the site of altered mechanical properties of the lung. The aims of this study were to compare the site of allergic airway narrowing implied from respiratory mechanics to a direct assessment by morphometry and to evaluate the effects of exogenous surfactant administration on the site and magnitude of airway narrowing. Methods We induced airway narrowing by ovalbumin sensitization and challenge and we tested the effects of a natural surfactant lacking surfactant proteins A and D (Infasurf®) on airway responses. Sensitized, mechanically ventilated Brown Norway rats underwent an aerosol challenge with 5% ovalbumin or vehicle. Other animals received nebulized surfactant prior to challenge. Three or 20 minutes after ovalbumin challenge, airway luminal areas were assessed on snap-frozen lungs by morphometry. Results At 3 minutes, RN and G detected large airway narrowing whereas at 20 minutes G and H detected small airway narrowing. Surfactant inhibited RN at the peak of the early allergic response and ovalbumin-induced increase in bronchoalveolar lavage fluid cysteinyl leukotrienes and amphiregulin but not IgE-induced mast cell activation in vitro. Conclusion Allergen challenge triggers the rapid onset of large airway narrowing, detected by RN and G, and subsequent peripheral airway narrowing detected by G and H. Surfactant inhibits airway narrowing and reduces mast cell-derived mediators. PMID:22276110

CARMA3 Is Critical for the Initiation of Allergic Airway Inflammation.

PubMed

Causton, Benjamin; Ramadas, Ravisankar A; Cho, Josalyn L; Jones, Khristianna; Pardo-Saganta, Ana; Rajagopal, Jayaraj; Xavier, Ramnik J; Medoff, Benjamin D

2015-07-15

Innate immune responses to allergens by airway epithelial cells (AECs) help initiate and propagate the adaptive immune response associated with allergic airway inflammation in asthma. Activation of the transcription factor NF-κB in AECs by allergens or secondary mediators via G protein-coupled receptors (GPCRs) is an important component of this multifaceted inflammatory cascade. Members of the caspase recruitment domain family of proteins display tissue-specific expression and help mediate NF-κB activity in response to numerous stimuli. We have previously shown that caspase recruitment domain-containing membrane-associated guanylate kinase protein (CARMA)3 is specifically expressed in AECs and mediates NF-κB activation in these cells in response to stimulation with the GPCR agonist lysophosphatidic acid. In this study, we demonstrate that reduced levels of CARMA3 in normal human bronchial epithelial cells decreases the production of proasthmatic mediators in response to a panel of asthma-relevant GPCR ligands such as lysophosphatidic acid, adenosine triphosphate, and allergens that activate GPCRs such as Alternaria alternata and house dust mite. We then show that genetically modified mice with CARMA3-deficient AECs have reduced airway eosinophilia and proinflammatory cytokine production in a murine model of allergic airway inflammation. Additionally, we demonstrate that these mice have impaired dendritic cell maturation in the lung and that dendritic cells from mice with CARMA3-deficient AECs have impaired Ag processing. In conclusion, we show that AEC CARMA3 helps mediate allergic airway inflammation, and that CARMA3 is a critical signaling molecule bridging the innate and adaptive immune responses in the lung. Copyright © 2015 by The American Association of Immunologists, Inc.

Multiple exposures to swine barn air induce lung inflammation and airway hyper-responsiveness

PubMed Central

Charavaryamath, Chandrashekhar; Janardhan, Kyathanahalli S; Townsend, Hugh G; Willson, Philip; Singh, Baljit

2005-01-01

Background Swine farmers repeatedly exposed to the barn air suffer from respiratory diseases. However the mechanisms of lung dysfunction following repeated exposures to the barn air are still largely unknown. Therefore, we tested a hypothesis in a rat model that multiple interrupted exposures to the barn air will cause chronic lung inflammation and decline in lung function. Methods Rats were exposed either to swine barn (8 hours/day for either one or five or 20 days) or ambient air. After the exposure periods, airway hyper-responsiveness (AHR) to methacholine (Mch) was measured and rats were euthanized to collect bronchoalveolar lavage fluid (BALF), blood and lung tissues. Barn air was sampled to determine endotoxin levels and microbial load. Results The air in the barn used in this study had a very high concentration of endotoxin (15361.75 ± 7712.16 EU/m3). Rats exposed to barn air for one and five days showed increase in AHR compared to the 20-day exposed and controls. Lungs from the exposed groups were inflamed as indicated by recruitment of neutrophils in all three exposed groups and eosinophils and an increase in numbers of airway epithelial goblet cells in 5- and 20-day exposure groups. Rats exposed to the barn air for one day or 20 days had more total leukocytes in the BALF and 20-day exposed rats had more airway epithelial goblet cells compared to the controls and those subjected to 1 and 5 exposures (P < 0.05). Bronchus-associated lymphoid tissue (BALT) in the lungs of rats exposed for 20 days contained germinal centers and mitotic cells suggesting activation. There were no differences in the airway smooth muscle cell volume or septal macrophage recruitment among the groups. Conclusion We conclude that multiple exposures to endotoxin-containing swine barn air induce AHR, increase in mucus-containing airway epithelial cells and lung inflammation. The data also show that prolonged multiple exposures may also induce adaptation in AHR response in the exposed

Effect of ozone exposure on antigen-induced airway hyperresponsiveness in guinea pigs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vargas, M.H.; Segura, P.; Campos, M.G.

1994-12-31

Airway hyperresponsiveness can be induced by several stimuli including antigen and ozone, both of which may be present in the air of polluted cities. Though the effect of ozone on the bronchoconstrictor response to antigen has been well described, the combined effect of these stimuli on airway hyperresponsiveness has not yet been studied. Sensitized guinea pigs with or without ozone exposure for 1 h at 3 ppm, 18 h prior to study, were challenged with a dose-response curve to histamine (0.01-1.8 {mu}g/kg, iv), and then by a second histamine dose-response curve 1 h later. Airway responses were measured as themore » increase in pulmonary insufflation pressure. In sensitized guinea pigs, the histamine ED50 significantly decreased after antigen challenge, demonstrating the development of airway hyperresponsiveness. Sensitized guinea pigs exposed to ozone showed airway hyperresponsiveness to histamine when compared with nonexposed animals, and such hyperresponsiveness was further enhanced after antigen challenge. We conclude that in this guinea pig model of acute allergic bronchoconstriction both antigen challenge and ozone induce airway hyperresponsiveness, while ozone exposure does not modify the development of antigen-induced hyperresponsiveness. 25 refs., 1 fig., 1 tab.« less

Mechanism for substance P-induced relaxation of precontracted airway smooth muscle during development.

PubMed

Mhanna, M J; Dreshaj, I A; Haxhiu, M A; Martin, R J

1999-01-01

Release of substance P (SP) from sensory nerve endings of the tracheobronchial system modulates airway smooth muscle contraction and may cause relaxation of precontracted airways. We sought to elucidate the effect of postnatal maturation on SP-induced relaxation of precontracted airways and determine the roles of endogenously generated nitric oxide (NO) and prostaglandins (PGs). Cylindrical airway segments were isolated from the midtrachea of rats at four different ages, 1, 2, and 4 wk and 3 mo, and contracted to 50-75% of the maximum response induced by bethanechol. SP was then administered in the absence and presence of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), the PG inhibitor indomethacin, or both. Relaxation of airways with SP decreased significantly with advancing postnatal age. SP-induced tracheal relaxation was consistently attenuated by pretreatment with L-NAME, indomethacin, or both. In a different group of animals, L-NAME significantly attenuated the relaxant response of airways to PGE2 exposure, but indomethacin had no significant effect on the relaxant response to exogenous NO. We conclude that SP induces a relaxant effect on precontracted airway smooth muscle, which decreases with advancing age and is mediated via SP-induced release of NO and/or PG.

Effects of local nasal immunotherapy in allergic airway inflammation: Using urea denatured Dermatophagoides pteronyssinus

PubMed Central

Yu, Sheng-Jie; Liao, En-Chih; Tsai, Jaw-Ji

2015-01-01

Despite improvements in anti-allergy medication, the prevalence of allergic airway inflammation remains high, affecting up to 40% of the population worldwide. Allergen immunotherapy is effective for inducing tolerance but has the adverse effect of severe allergic reaction. This can be avoided by denaturing with urea. In this study, we demonstrated that the serum level of allergen-specific IgE in mice sensitized with native Dermatophagoides pteronyssinus (Der p) crude extract after receiving local nasal immunotherapy (LNIT) with urea-denatured Der p crude extract (DN-Dp) significantly decreased compared to that in the normal saline (NS) treatment group. Expressions of IL-4 were significantly reduced in lung tissues after treatment. Inflammation around the bronchial epithelium improved and airway hypersensitivity was down-regulated. LNIT with DN-Dp can down-regulate IL-1b, IL-6 and TNF-a expression and then decrease Der p-induced allergic airway inflammation. This therapeutic modality may be used as an alternative treatment for airway allergic diseases. PMID:25933184

Modulation of allergic immune responses by mucosal application of recombinant lactic acid bacteria producing the major birch pollen allergen Bet v 1.

PubMed

Daniel, C; Repa, A; Wild, C; Pollak, A; Pot, B; Breiteneder, H; Wiedermann, U; Mercenier, A

2006-07-01

Probiotic lactic acid bacteria (LAB) are able to modulate the host immune system and clinical trials have demonstrated that specific strains have the capacity to reduce allergic symptoms. Therefore, we aimed to evaluate the potential of recombinant LAB producing the major birch pollen allergen Bet v 1 for mucosal vaccination against birch pollen allergy. Recombinant Bet v 1-producing Lactobacillus plantarum and Lactococcus lactis strains were constructed. Their immunogenicity was compared with purified Bet v 1 by subcutaneous immunization of mice. Intranasal application of the live recombinant strains was performed to test their immunomodulatory potency in a mouse model of birch pollen allergy. Bet v 1 produced by the LAB was recognized by monoclonal anti-Bet v 1 and IgE antibodies from birch pollen-allergic patients. Systemic immunization with the recombinant strains induced significantly lower IgG1/IgG2a ratios compared with purified Bet v 1. Intranasal pretreatment led to reduced allergen-specific IgE vs enhanced IgG2a levels and reduced interleukin (IL)-5 production of splenocytes in vitro, indicating a shift towards non-allergic T-helper-1 (Th1) responses. Airway inflammation, i.e. eosinophils and IL-5 in lung lavages, was reduced using either Bet v 1-producing or control strains. Allergen-specific secretory IgA responses were enhanced in lungs and intestines after pretreatment with only the Bet v 1-producing strains. Mucosal vaccination with live recombinant LAB, leading to a shift towards non-allergic immune responses along with enhanced allergen-specific mucosal IgA levels offers a promising approach to prevent systemic and local allergic immune responses.

Preexposure to ozone blocks the antigen-induced late asthmatic response of the canine peripheral airways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Turner, C.R.; Kleeberger, S.R.; Spannhake, E.W.

1989-01-01

The influence of exposure of the airways to ozone on acute allergic responsiveness has been investigated in several species. Little is known, however, about the effect of this environmental pollutant on the late asthmatic response (LAR) in animals in which it is exhibited. The purpose of this study was to evaluate this effect in the canine peripheral airways and to assess the potential role of mast cells in modulating the effect. A series of experiments on seven mongrel dogs demonstrated that the numbers of mast cells at the base of the epithelial region of small subsegmental airways exposed to 1more » ppm ozone for 5 min were significantly (p less than .01) increased 3 h following exposure compared to air exposed or nonexposed control airways. In a second series of experiments performed on eight additional mongrel dogs with inherent sensitivity to Ascaris suum antigen, antigen aerosol was administered to the sublobar segment 3 h following ozone preexposure when mast cell numbers were presumed to be increased. These experiments were performed to determine whether ozone preexposure could enhance the late-phase response to antigen by virtue of acutely increasing the number of mast cells available to bind the antigen. Four of the eight dogs tested displayed a late-phase response to antigen following air-sham preexposure. In these four dogs, simultaneous ozone preexposure of a contralateral lobe completely blocked the late-phase response to antigen. These results indicate that the consequences of a single exposure to ozone persist beyond its effects on acute antigen-induced bronchoconstriction and extend to the complex processes involved with the late response. This attenuating effect of ozone is seen under conditions where mast-cell numbers in the airways are increased above baseline levels.« less

Staphylococcal enterotoxin A-activated regulatory T cells promote allergen-specific TH2 response to intratracheal allergen inoculation.

PubMed

Zeng, Wei-Ping; McFarland, Margaret M; Zhou, Baohua; Holtfreter, Silva; Flesher, Susan; Cheung, Ambrose; Mallick, Avishek

2017-02-01

T H 2 responses are implicated in asthma pathobiology. Epidemiologic studies have found a positive association between asthma and exposure to staphylococcal enterotoxins. We used a mouse model of asthma to determine whether staphylococcal enterotoxins promote T H 2 differentiation of allergen-specific CD4 conventional T (Tcon) cells and asthma by activating allergen-nonspecific regulatory T (Treg) cells to create a T H 2-polarizing cytokine milieu. Ovalbumin (OVA)-specific, staphylococcal enterotoxin A (SEA)-nonreactive naive CD4 Tcon cells were cocultured with SEA-reactive allergen-nonspecific Treg or CD4 Tcon cells in the presence of OVA and SEA. The OVA-specific CD4 T cells were then analyzed for IL-13 and IFN-γ expression. SEA-activated Treg cells were analyzed for the expression of the T H 2-polarizing cytokine IL-4 and the T-cell activation markers CD69 and CD62L. For asthma induction, mice were intratracheally sensitized with OVA or cat dander extract (CDE) alone or together with SEA and then challenged with OVA or CDE. Mice were also subject to transient Treg cell depletion before sensitization with OVA plus SEA. Asthma features and T H 2 differentiation in these mice were analyzed. SEA-activated Treg cells induced IL-13 but suppressed IFN-γ expression in OVA-specific CD4 Tcon cells. SEA-activated Treg cells expressed IL-4, upregulated CD69, and downregulated CD62L. Sensitization with OVA plus SEA but not OVA alone induced asthma, and SEA exacerbated asthma induced by CDE. Depletion of Treg cells abolished these effects of SEA and IL-13 expression in OVA-specific T cells. SEA promoted T H 2 responses of allergen-specific T cells and asthma pathogenesis by activating Treg cells. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Aryl Hydrocarbon Receptor Protects Lungs from Cockroach Allergen-Induced Inflammation by Modulating Mesenchymal Stem Cells.

PubMed

Xu, Ting; Zhou, Yufeng; Qiu, Lipeng; Do, Danh C; Zhao, Yilin; Cui, Zhuang; Wang, Heng; Liu, Xiaopeng; Saradna, Arjun; Cao, Xu; Wan, Mei; Gao, Peisong

2015-12-15

Exposure to cockroach allergen leads to allergic sensitization and increased risk of developing asthma. Aryl hydrocarbon receptor (AhR), a receptor for many common environmental contaminants, can sense not only environmental pollutants but also microbial insults. Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the capacity to modulate immune responses. In this study, we investigated whether AhR can sense cockroach allergens and modulate allergen-induced lung inflammation through MSCs. We found that cockroach allergen-treated AhR-deficient (AhR(-/-)) mice showed exacerbation of lung inflammation when compared with wild-type (WT) mice. In contrast, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an AhR agonist, significantly suppressed allergen-induced mouse lung inflammation. MSCs were significantly reduced in cockroach allergen-challenged AhR(-/-) mice as compared with WT mice, but increased in cockroach allergen-challenged WT mice when treated with TCDD. Moreover, MSCs express AhR, and AhR signaling can be activated by cockroach allergen with increased expression of its downstream genes cyp1a1 and cyp1b1. Furthermore, we tracked the migration of i.v.-injected GFP(+) MSCs and found that cockroach allergen-challenged AhR(-/-) mice displayed less migration of MSCs to the lungs compared with WT. The AhR-mediated MSC migration was further verified by an in vitro Transwell migration assay. Epithelial conditioned medium prepared from cockroach extract-challenged epithelial cells significantly induced MSC migration, which was further enhanced by TCDD. The administration of MSCs significantly attenuated cockroach allergen-induced inflammation, which was abolished by TGF-β1-neutralizing Ab. These results suggest that AhR plays an important role in protecting lungs from allergen-induced inflammation by modulating MSC recruitment and their immune-suppressive activity. Copyright © 2015 by The American Association of Immunologists, Inc.

Repeated allergen exposure enhances excitatory nonadrenergic noncholinergic nerve-mediated bronchoconstriction in sensitized guinea-pigs.

PubMed

Kageyama, N; Ichinose, M; Igarashi, A; Miura, M; Yamauchi, H; Sasaki, Y; Ishikawa, J; Tomaki, M; Shirato, K

1996-07-01

The effect of repeated allergen inhalation challenge on the airway excitatory nonadrenergic noncholinergic (e-NANC) nerve-mediated bronchoconstrictor response was studied in ovalbumin (OA) sensitized guinea-pigs. Three weeks after sensitization, OA inhalation, 0.03% for 3 min (challenged group), or saline inhalation (control group) was repeated every day for 4 weeks. The e-NANC nerve function was examined in vitro by means of isometric tension measurement of main bronchi. After pretreatment with atropine (10(-6) M) and propranolol (10(-6) M), we performed electrical field stimulation (EFS) or exogenous neurokinin A (NKA) administration. In the challenged group, EFS-induced main bronchial contraction was significantly greater than that of the control group (p < 0.05 or p < 0.01), but exogenous NKA-mediated responses were almost the same in both groups. The e-NANC-induced main bronchial contractions after EFS were enhanced by pretreatment with the neutral endopeptidase inhibitor, phosphoramidon, to the same degree in the control and challenged groups, indicating that the peptide degradation mechanisms were not impaired even in the challenged group. Substance P immunoreactivities in the lung of the challenged group were significantly higher than those of the control group. These results suggest that chronic airway inflammation after repeated allergen challenge increases excitatory nonadrenergic noncholinergic nerve function, possibly by enhancing sensory neuropeptide production and/or release.

Airway remodeling in murine asthma correlates with a defect in PGE2 synthesis by lung fibroblasts

PubMed Central

Stumm, Camila Leindecker; Wettlaufer, Scott H.; Jancar, Sonia

2011-01-01

Asthma is a chronic lung disease characterized by local inflammation that can result in structural alterations termed airway remodeling. One component of airway remodeling involves fibroblast accumulation and activation, resulting in deposition of collagen I around small bronchi. Prostaglandin E2 (PGE2) is the main eicosanoid lipid mediator produced by lung fibroblasts, and it exerts diverse anti-fibrotic actions. Dysregulation of the PGE2 synthesis/response axis has been identified in human pulmonary fibrotic diseases and implicated in the pathogenesis of animal models of lung parenchymal fibrosis. Here we investigated the relationship between the fibroblast PGE2 axis and airway fibrosis in an animal model of chronic allergic asthma. Airway fibrosis increased progressively as the number of airway challenges with antigen increased from 3 to 7 to 12. Compared with cells from control lungs, fibroblasts grown from the lungs of asthmatic animals, regardless of challenge number, exhibited no defect in the ability of PGE2 or its analogs to inhibit cellular proliferation and collagen I expression. This correlated with intact expression of the EP2 receptor, which is pivotal for PGE2 responsiveness. However, cytokine-induced upregulation of PGE2 biosynthesis as well as expression of cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 declined with increasing numbers of antigen challenges. In addition, treatment with the COX-2-selective inhibitor nimesulide potentiated the degree of airway fibrosis following repeated allergen challenge. Because endogenous COX-2-derived PGE2 acts as a brake on airway fibrosis, the inability of fibroblasts to upregulate PGE2 generation in the inflammatory milieu presented by repeated allergen exposure could contribute to the airway remodeling and fibrosis observed in chronic asthma. PMID:21873451

Nerve growth factor-enhanced airway responsiveness involves substance P in ferret intrinsic airway neurons.

PubMed

Wu, Z-X; Dey, R D

2006-07-01

Nerve growth factor (NGF), a member of the neurotrophin family, enhances synthesis of neuropeptides in sensory and sympathetic neurons. The aim of this study was to examine the effect of NGF on airway responsiveness and determine whether these effects are mediated through synthesis and release of substance P (SP) from the intrinsic airway neurons. Ferrets were instilled intratracheally with NGF or saline. Tracheal smooth muscle contractility to methacholine and electrical field stimulation (EFS) was assessed in vitro. Contractions of isolated tracheal smooth muscle to EFS at 10 and 30 Hz were significantly increased in the NGF treatment group (10 Hz: 33.57 +/- 2.44%; 30 Hz: 40.12 +/- 2.78%) compared with the control group (10 Hz: 27.24 +/- 2.14%; 30 Hz: 33.33 +/- 2.31%). However, constrictive response to cholinergic agonist was not significantly altered between the NGF treatment group and the control group. The NGF-induced modulation of airway smooth muscle to EFS was maintained in tracheal segments cultured for 24 h, a procedure that causes a significant anatomic and functional loss of SP-containing sensory fibers while maintaining viability of intrinsic airway neurons. The number of SP-containing neurons in longitudinal trunk and superficial muscular plexus and SP nerve fiber density in tracheal smooth muscle all increased significantly in cultured trachea treated with NGF. Pretreatment with CP-99994, an antagonist of neurokinin 1 receptor, attenuated the NGF-induced increased contraction to EFS in cultured segments but had no effect in saline controls. These results show that the NGF-enhanced airway smooth muscle contractile responses to EFS are mediated by the actions of SP released from intrinsic airway neurons.

Abrogation of Airway Hyperresponsiveness but not Inflammation by Rho kinase Insufficiency

PubMed Central

Kasahara, David I.; Ninin, Fernanda M.C.; Wurmbrand, Allison P.; Liao, James K.; Shore, Stephanie A.

2015-01-01

Background Major features of allergic asthma include airway hyperresponsiveness (AHR), eosinophilic inflammation, and goblet cell metaplasia. Rho kinase (ROCK) is a serine/threonine protein kinase that regulates the actin cytoskeleton. By doing so, it can modulate airway smooth muscle cell contraction and leukocyte migration and proliferation. This study was designed to determine the contributions of the two ROCK isoforms, ROCK1 and ROCK2, to AHR, inflammation and goblet cell metaplasia in a mast-cell dependent model of allergic airways disease. Methods and Results Repeated intranasal challenges with OVA caused AHR, eosinophilic inflammation, and goblet cell hyperplasia in wildtype (WT) mice. OVA-induced AHR was partially or completely abrogated in mice haploinsufficient for ROCK2 (ROCK2+/−) or ROCK1 (ROCK1+/−), respectively. In contrast, there was no effect of ROCK insufficiency on allergic airways inflammation, although both ROCK1 and ROCK2 insufficiency attenuated mast cell degranulation. Goblet cell hyperplasia, as indicated by PAS staining, was not different in ROCK1+/− versus WT mice. However, in ROCK2+/− mice, goblet cell hyperplasia was reduced in medium but not large airways. Maximal acetylcholine-induced force generation was reduced in tracheal rings from ROCK1+/− and ROCK2+/− versus WT mice. The ROCK inhibitor, fasudil, also reduced airway responsiveness in OVA-challenged mice, without affecting inflammatory responses. Conclusion In a mast cell model of allergic airways disease, ROCK1 and ROCK2 both contribute to AHR, likely through direct effects on smooth muscle cell and effects on mast-cell degranulation. In addition, ROCK2 but not ROCK1 plays a role in allergen-induced goblet cell hyperplasia. PMID:25323425

Rhinovirus infection of allergen-sensitized and -challenged mice induces eotaxin release from functionally polarized macrophages.

PubMed

Nagarkar, Deepti R; Bowman, Emily R; Schneider, Dina; Wang, Qiong; Shim, Jee; Zhao, Ying; Linn, Marisa J; McHenry, Christina L; Gosangi, Babina; Bentley, J Kelley; Tsai, Wan C; Sajjan, Umadevi S; Lukacs, Nicholas W; Hershenson, Marc B

2010-08-15

Human rhinovirus is responsible for the majority of virus-induced asthma exacerbations. To determine the immunologic mechanisms underlying rhinovirus (RV)-induced asthma exacerbations, we combined mouse models of allergic airways disease and human rhinovirus infection. We inoculated OVA-sensitized and challenged BALB/c mice with rhinovirus serotype 1B, a minor group strain capable of infecting mouse cells. Compared with sham-infected, OVA-treated mice, virus-infected mice showed increased lung infiltration with neutrophils, eosinophils and macrophages, airway cholinergic hyperresponsiveness, and increased lung expression of cytokines including eotaxin-1/CCL11, IL-4, IL-13, and IFN-gamma. Administration of anti-eotaxin-1 attenuated rhinovirus-induced airway eosinophilia and responsiveness. Immunohistochemical analysis showed eotaxin-1 in the lung macrophages of virus-infected, OVA-treated mice, and confocal fluorescence microscopy revealed colocalization of rhinovirus, eotaxin-1, and IL-4 in CD68-positive cells. RV inoculation of lung macrophages from OVA-treated, but not PBS-treated, mice induced expression of eotaxin-1, IL-4, and IL-13 ex vivo. Macrophages from OVA-treated mice showed increased expression of arginase-1, Ym-1, Mgl-2, and IL-10, indicating a shift in macrophage activation status. Depletion of macrophages from OVA-sensitized and -challenged mice reduced eosinophilic inflammation and airways responsiveness following RV infection. We conclude that augmented airway eosinophilic inflammation and hyperresponsiveness in RV-infected mice with allergic airways disease is directed in part by eotaxin-1. Airway macrophages from mice with allergic airways disease demonstrate a change in activation state characterized in part by altered eotaxin and IL-4 production in response to RV infection. These data provide a new paradigm to explain RV-induced asthma exacerbations.

Protective effect of Bifidobacterium infantis CGMCC313-2 on ovalbumin-induced airway asthma and β-lactoglobulin-induced intestinal food allergy mouse models

PubMed Central

Liu, Meng-Yun; Yang, Zhen-Yu; Dai, Wen-Kui; Huang, Jian-Qiong; Li, Yin-Hu; Zhang, Juan; Qiu, Chuang-Zhao; Wei, Chun; Zhou, Qian; Sun, Xin; Feng, Xin; Li, Dong-Fang; Wang, He-Ping; Zheng, Yue-Jie

2017-01-01

AIM To determine whether oral administration of Bifidobacterium infantis CGMCC313-2 (B. infantis CGMCC313-2) inhibits allergen-induced airway inflammation and food allergies in a mouse model. METHODS Ovalbumin (OVA)-induced allergic asthma and β-lactoglobulin-induced food allergy mouse models were used in this study. Following oral administration of B. infantis CGMCC313-2 during or after allergen sensitization, histopathologic changes in the lung and intestine were evaluated by hematoxylin and eosin (HE) staining. In the allergic asthma mouse model, we evaluated the proportion of lung-infiltrating inflammatory cells. OVA-specific IgE and IgG1 levels in serum and cytokine levels in bronchoalveolar lavage fluid (BALF) were also assessed. In the food allergy mouse model, the levels of total IgE and cytokines in serum were measured. RESULTS Oral administration of B. infantis CGMCC313-2 during or after allergen sensitization suppressed allergic inflammation in lung and intestinal tissues, while the proportion of infiltrating inflammatory cells was significantly decreased in the BALF of allergic asthma mice. Moreover, B. infantis CGMCC313-2 decreased the serum levels of total IgE in food allergy mice, and reductions in IgE and IgG1 were also observed in OVA-induced allergic asthma mice. The expression of interleukin-4 (IL-4) and IL-13 in both serum and BALF was suppressed following the administration of B. infantis CGMCC313-2, while an effect on serum IL-10 levels was not observed. CONCLUSION B. infantis CGMCC313-2 inhibits the secretion of allergen-induced IgE, IL-4 and IL-13, and attenuates allergic inflammation. PMID:28405142

Allergen-induced Th1 and Th2 cytokine secretion in relation to specific allergen sensitization and atopic symptoms in children.

PubMed

Jenmalm, M C; Van Snick, J; Cormont, F; Salman, B

2001-10-01

Allergic diseases are believed to be due to T helper (Th)2-like immunity to allergens in affected tissues, and immune responses to allergens are characterized by a cross-regulation between Th1 and Th2 cells. Atopic individuals may develop IgE antibodies to only one or more allergens. However, the mechanisms behind sensitization to a specific allergen, e.g. why an individual develops IgE to cat but not birch, are not known. Our aim was to study birch- and cat-induced Th1 and Th2 cytokine secretion in children who were sensitized to birch but not to cat, and vice versa. The subjects in the study were 60 12-year-old children. Seventeen of the children were sensitized (skin prick test and circulating IgE positive) to birch but not cat, 13 were sensitized to cat but not birch, 11 were sensitized both to birch and cat, and 19 children were skin prick test and circulating IgE negative. Forty-six children had a history of atopic symptoms, and 42 of them had current symptoms. Peripheral blood mononuclear cells were separated from venous blood and stimulated with cat or birch allergen. The levels of IL-4, IL-5, IL-9, IL-10, IL-13 and IFN-gamma in the cell supernatants were analysed by ELISA. Sensitized children produced more of the Th2 cytokines IL-4, IL-5, IL-9 and IL-13 than non-sensitized atopic and non-atopic children in response to stimulation with the allergen they were sensitized to. High levels of the Th2 cytokines IL-4 and IL-5 and low levels of the anti-inflammatory cytokine IL-10 were associated with atopic symptoms, and high cat-induced IL-9 levels with asthma. The Th2 cytokines IL-4, IL-5, IL-9 and IL-13 were all commonly detected in sensitized children after stimulation with the specific, in contrast to an unrelated, allergen. Atopic symptoms were associated with increased levels of IL-4 and IL-5 and tended to be associated with low levels of IL-10, and asthma with high cat-induced IL-9 levels.

Protease-activated receptor 2 activation of myeloid dendritic cells regulates allergic airway inflammation

PubMed Central

2011-01-01

Background A common characteristic of allergens is that they contain proteases that can activate protease-activated receptor (PAR-2); however the mechanism by which PAR-2 regulates allergic airway inflammation is unclear. Methods Mice (wild type and PAR-2-deficient) were sensitized using German cockroach (GC) feces (frass), the isolated protease from GC frass, or through adoptive transfer of GC frass-treated bone marrow-derived dendritic cells (BMDC) and measurements of airway inflammation (cellular infiltration, cytokine expression, and mucin production), serum IgE levels and airway hyperresponsiveness (AHR) were assessed. BMDC were cultured, treated with GC frass and assessed for cytokine production. PAR-2 expression on pulmonary mDCs was determined by flow cytometry. Results Exposure to GC frass induced AHR and airway inflammation in wild type mice; however PAR-2-deficient mice had significantly attenuated responses. To directly investigate the role of the protease, we isolated the protease from GC frass and administered the endotoxin-free protease into the airways of mice in the presence of OVA. GC frass proteases were sufficient to promote the development of AHR, serum IgE, and Th2 cytokine production. PAR-2 expression on mDC was upregulated following GC frass exposure, but the presence of a functional PAR-2 did not alter antigen uptake. To determine if PAR-2 activation led to differential cytokine production, we cultured BMDC in the presence of GM-CSF and treated these cells ex vivo with GC frass. PAR-2-deficient BMDC released significantly less IL-6, IL-23 and TNFα compared to BMDC from wild type mice, suggesting PAR-2 activation was important in Th2/Th17 skewing cytokine production. To determine the role for PAR-2 on mDCs on the initiation of allergic airway inflammation, BMDCs from wild type and PAR-2-deficient mice were treated in the presence or absence of GC frass and then adoptively transferred into the airway of wild type mice. Importantly, GC frass

Discovery of a potent nanoparticle P-selectin antagonist with anti-inflammatory effects in allergic airway disease

PubMed Central

John, Alison E.; Lukacs, Nicholas W.; Berlin, Aaron A.; Palecanda, Aiyappa; Bargatze, Robert F.; Stoolman, Lloyd M.; Nagy, Jon O.

2010-01-01

The severity of allergic asthma is dependent, in part, on the intensity of peribronchial inflammation. P-selectin is known to play a role in the development of allergen-induced peribronchial inflammation and airway hyperreactivity. Selective inhibitors of P-selectin-mediated leukocyte endothelial-cell interactions may therefore attenuate the inflammatory processes associated with allergic airway disease. Novel P-selectin inhibitors were created using a polyvalent polymer nanoparticle capable of displaying multiple synthetic, low molecular weight ligands. By assembling a particle that presents an array of groups, which as monomers interact with only low affinity, we created a construct that binds extremely efficiently to P-selectin. The ligands acted as mimetics of the key binding elements responsible for the high-avidity adhesion of P-selectin to the physiologic ligand, PSGL-1. The inhibitors were initially evaluated using an in vitro shear assay system in which interactions between circulating cells and P-selectin-coated capillary tubes were measured. The nanoparticles were shown to preferentially bind to selectins expressed on activated endothelial cells. We subsequently demonstrated that nanoparticles displaying P-selectin blocking arrays were functionally active in vivo, significantly reducing allergen-induced airway hyperreactivity and peribronchial eosinophilic inflammation in a murine model of asthma. PMID:14563683

Effect of a 5-lipoxygenase inhibitor and leukotriene antagonist (PF 5901) on antigen-induced airway responses in neonatally immunized rabbits.

PubMed Central

Herd, C. M.; Donigi-Gale, D.; Shoupe, T. S.; Burroughs, D. A.; Yeadon, M.; Page, C. P.

1994-01-01

1. The effect of a single intratracheal dose (10 mg) of PF 5901 (2-[3(1-hydroxyhexyl) phenoxymethyl] quinoline hydrochloride, a specific inhibitor of the 5-lipoxygenase pathway of arachidonic acid metabolism and a leukotriene D4 antagonist) on airway changes induced in response to Alternaria tenuis aerosol challenge was assessed in adult rabbits neonatally immunized. Leukotriene generation was determined in vivo by measuring leukotriene B4 (LTB4) levels in bronchoalveolar lavage (BAL) fluid and ex vivo by measuring calcium ionophore-stimulated production of LTB4 in whole blood. 2. While PF 5901 (10 mg) had no significant effect on the acute bronchoconstriction induced by antigen, this dose was sufficient to inhibit significantly the increase in airway responsiveness to inhaled histamine 24 h following antigen challenge (P < 0.05). 3. Total leucocyte infiltration into the airways induced by antigen, as assessed by bronchoalveolar lavage, was significantly inhibited by pretreatment with PF 5901 (10 mg). However, the pulmonary infiltration of neutrophils and eosinophils induced by antigen was unaltered by prior treatment with PF 5901 (10 mg). 4. PF 5901 (10 mg) had no effect on ex vivo LTB4 synthesis in whole blood. However, the antigen-induced increase in LTB4 levels in BAL 24 h following challenge was significantly inhibited (P < 0.05). 5. We suggest from the results of the present study that the antigen-induced airway hyperresponsiveness to inhaled histamine in immunized rabbits is mediated, at least in part, by products of the 5-lipoxygenase metabolic pathway, and is not dependent on the extent of eosinophil or neutrophil influx into the airway lumen. PMID:8032653

The effect of antioxidants on ozone-induced airway hyperresponsiveness in dogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matsui, S.; Jones, G.L.; Woolley, M.J.

1991-12-01

The role of oxygen radicals in causing ozone-induced airway hyperresponsiveness in dogs was examined by pretreating dogs with allopurinol and/or deferoxamine mesylate (desferal), which are inhibitors of oxygen radical generation, before ozone inhalation. Acetylcholine airway responsiveness was measured before and after either air or ozone inhalation (3 ppm for 20 min) on 5 experimental days separated by at least 2 wk. On each day, the dogs were pretreated intravenously with allopurinol (50 mg/kg) followed by inhaled desferal (1,000 mg inhalation) or with allopurinol followed by the diluent for desferal or with the diluent for allopurinol and desferal or with bothmore » diluents. The effect of ozone on acetylcholine airway responsiveness was expressed as the differences in the log-transformed preozone-postozone acetylcholine provocative concentrations. When dogs received both diluents or either treatment alone, ozone inhalation caused airway hyperresponsiveness. The mean log differences for the preozone-postozone acetylcholine provocative concentration were 0.804 (SEM, 0.17) for both diluents, 0.524 (SEM, 0.16) for allopurinol alone, and 0.407 (SEM, 0.22) for desferal alone. However, the combination of allopurinol and desferal significantly inhibited the development of ozone-induced airway hyperresponsiveness, the log difference being 0.195 (SEM, 0.11) (p less than 0.05), without inhibiting ozone-induced neutrophil influx into the airways. The results suggest that the production of oxygen radicals is important in the pathogenesis of ozone-induced airway hyperresponsiveness.« less

Effect of a chemical chaperone, tauroursodeoxycholic acid, on HDM-induced allergic airway disease

PubMed Central

Siddesha, Jalahalli M.; Nakada, Emily M.; Mihavics, Bethany R.; Hoffman, Sidra M.; Rattu, Gurkiranjit K.; Chamberlain, Nicolas; Cahoon, Jonathon M.; Lahue, Karolyn G.; Daphtary, Nirav; Aliyeva, Minara; Chapman, David G.; Desai, Dhimant H.; Poynter, Matthew E.

2016-01-01

Endoplasmic reticulum (ER) stress-induced unfolded protein response plays a critical role in inflammatory diseases, including allergic airway disease. However, the benefits of inhibiting ER stress in the treatment of allergic airway disease are not well known. Herein, we tested the therapeutic potential of a chemical chaperone, tauroursodeoxycholic acid (TUDCA), in combating allergic asthma, using a mouse model of house dust mite (HDM)-induced allergic airway disease. TUDCA was administered during the HDM-challenge phase (preventive regimen), after the HDM-challenge phase (therapeutic regimen), or therapeutically during a subsequent HDM rechallenge (rechallenge regimen). In the preventive regimen, TUDCA significantly decreased HDM-induced inflammation, markers of ER stress, airway hyperresponsiveness (AHR), and fibrosis. Similarly, in the therapeutic regimen, TUDCA administration efficiently decreased HDM-induced airway inflammation, mucus metaplasia, ER stress markers, and AHR, but not airway remodeling. Interestingly, TUDCA administered therapeutically in the HDM rechallenge regimen markedly attenuated HDM-induced airway inflammation, mucus metaplasia, ER stress markers, methacholine-induced AHR, and airway fibrotic remodeling. These results indicate that the inhibition of ER stress in the lungs through the administration of chemical chaperones could be a valuable strategy in the treatment of allergic airway diseases. PMID:27154200

Repeated episodes of ozone inhalation amplifies the effects of allergen sensitization and inhalation on airway immune and structural development in Rhesus monkeys.

PubMed

Schelegle, Edward S; Miller, Lisa A; Gershwin, Laurel J; Fanucchi, Michelle V; Van Winkle, Laura S; Gerriets, Joan E; Walby, William F; Mitchell, Valerie; Tarkington, Brian K; Wong, Viviana J; Baker, Gregory L; Pantle, Lorraine M; Joad, Jesse P; Pinkerton, Kent E; Wu, Reen; Evans, Michael J; Hyde, Dallas M; Plopper, Charles G

2003-08-15

Twenty-four infant rhesus monkeys (30 days old) were exposed to 11 episodes of filtered air (FA), house dust mite allergen aerosol (HDMA), ozone (O3), or HDMA + O3 (5 days each followed by 9 days of FA). Ozone was delivered for 8 h/day at 0.5 ppm. Twelve of the monkeys were sensitized to house dust mite allergen (Dermatophagoides farinae) at ages 14 and 28 days by subcutaneous inoculation (SQ) of HDMA in alum and intraperitoneal injection of heat-killed Bordetella pertussis cells. Sensitized monkeys were exposed to HDMA aerosol for 2 h/day on days 3-5 of either FA (n = 6) or O3 (n = 6) exposure. Nonsensitized monkeys were exposed to either FA (n = 6) or O3 (n = 6). During the exposure regimen, parameters of allergy (i.e., serum IgE, histamine, and eosinophilia), airways resistance, reactivity, and structural remodeling were evaluated. Eleven repeated 5-day cycles of inhaling 0.5 ppm ozone over a 6-month period had only mild effects on the airways of nonsensitized infant rhesus monkeys. Similarly, the repeated inhalation of HDMA by HDMA-sensitized infant monkeys resulted in only mild airway effects, with the exception of a marked increase in proximal airway and terminal bronchiole content of eosinophils. In contrast, the combined cyclic inhalation of ozone and HDMA by HDMA sensitized infants monkeys resulted in a marked increase in serum IgE, serum histamine, and airways eosinophilia. Furthermore, combined cyclic inhalation of ozone and HDMA resulted in even greater alterations in airway structure and content that were associated with a significant elevation in baseline airways resistance and reactivity. These results suggest that ozone can amplify the allergic and structural remodeling effects of HDMA sensitization and inhalation.

Local small airway epithelial injury induces global smooth muscle contraction and airway constriction.

PubMed

Zhou, Jian; Alvarez-Elizondo, Martha B; Botvinick, Elliot; George, Steven C

2012-02-01

Small airway epithelial cells form a continuous sheet lining the conducting airways, which serves many functions including a physical barrier to protect the underlying tissue. In asthma, injury to epithelial cells can occur during bronchoconstriction, which may exacerbate airway hyperreactivity. To investigate the role of epithelial cell rupture in airway constriction, laser ablation was used to precisely rupture individual airway epithelial cells of small airways (<300-μm diameter) in rat lung slices (∼250-μm thick). Laser ablation of single epithelial cells using a femtosecond laser reproducibly induced airway contraction to ∼70% of the original cross-sectional area within several seconds, and the contraction lasted for up to 40 s. The airway constriction could be mimicked by mechanical rupture of a single epithelial cell using a sharp glass micropipette but not with a blunt glass pipette. These results suggest that soluble mediators released from the wounded epithelial cell induce global airway contraction. To confirm this hypothesis, the lysate of primary human small airway epithelial cells stimulated a similar airway contraction. Laser ablation of single epithelial cells triggered a single instantaneous Ca(2+) wave in the epithelium, and multiple Ca(2+) waves in smooth muscle cells, which were delayed by several seconds. Removal of extracellular Ca(2+) or decreasing intracellular Ca(2+) both blocked laser-induced airway contraction. We conclude that local epithelial cell rupture induces rapid and global airway constriction through release of soluble mediators and subsequent Ca(2+)-dependent smooth muscle shortening.

Immune responses to novel allergens and modulation of inflammation by vitamin K3 analogue: a ROS dependent mechanism.

PubMed

Kohli, Vineet; Sharma, Deepak; Sandur, Santosh Kumar; Suryavanshi, Shweta; Sainis, Krishna B

2011-02-01

The possibility of newer allergens being responsible for atopy needs to be explored at regional level due to environmental variables. Current studies were undertaken to identify common environmental allergens causing atopy in a defined population of India and to correlate the presence of various risk factors with the clinical presentation of allergy. Newer allergens like human dander and rice grain dust were identified and reported as the most common cause of atopy in this region. Atopy, elevated serum total IgE and familial tendency, was observed in 88%, 69% and 58% of allergic patients respectively. Further, allergen-specific immune responses like lymphocyte proliferation and cytokine secretion were studied in vitro using peripheral blood mononuclear cells (PBMC) isolated from both allergic and non-allergic individuals. Although, some allergens induced significant lymphocyte proliferation in vitro, allergen-induced cytokine secretion except that of TNF-α was not seen. Significantly higher ratio of secreted IL-4/IFN-γ cytokines was observed in PBMC isolated from allergic subjects in response to PHA. Plumbagin (vitamin K3 analogue) completely inhibited PHA-induced cytokine production in PBMC, in both allergic and non-allergic individuals. Plumbagin modulated the levels of intracellular reactive oxygen species and glutathione and suppressed PHA induced activation of NF-κB in human PBMC. The results thus show in human PMBC, for the first time, the anti-allergic and anti-inflammatory effects of plumbagin and underscore its therapeutic potential. Copyright © 2010 Elsevier B.V. All rights reserved.

PM2.5-induced airway inflammation and hyperresponsiveness in NC/Nga mice.

PubMed

Ogino, Keiki; Nagaoka, Kenjiro; Okuda, Tomoaki; Oka, Akira; Kubo, Masayuki; Eguchi, Eri; Fujikura, Yoshihisa

2017-03-01

The allergic inflammatory effects of particulate matter (PM) 2.5, collected with the cyclone system in Yokohama city in Japan, were investigated in NC/Nga mice, which are hypersensitive to mite allergens. PM2.5 with alum was injected intraperitoneally for sensitization. Five days later, 200 μg of PM2.5 in 25 μL of saline was administered to mice intranasally five times for further sensitization. On the 11th day, PM2.5 was administered as a challenge. On the 12th day, mice were examined for airway hyperresponsiveness (AHR), the bronchoalveolar lavage fluid (BALF) cell count, mRNA expression of Th 1 , Th 2 cytokines, and metallothioneins in lung tissue, and histopathology. PM2.5 increased AHR, total cell numbers including eosinophils in BALF, and mRNA levels of IL-5, IL-22, eotaxin, eotaxin 2, and metallothionein 3. In PM2.5-induced lungs, inflammation was observed around the bronchus. These results demonstrate that PM2.5 alone, collected with the cyclone system in Yokohama city in Japan, induces asthma-like airway inflammation. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1047-1054, 2017. © 2016 Wiley Periodicals, Inc.

TIMING OF DIESEL PARTICLE INSTILLATION AND MAGNITUDE OF DOSE INFLUENCE THE SEVERITY OF ALLERGIC AIRWAYS RESPONSES IN MICE

EPA Science Inventory

Exposure to diesel exhaust particulates (DEP) arising from the combustion of diesel fuel exacerbates asthma. Several studies have shown that particulate and allergen co-exposure leads to an exacerbation of the hallmark features of allergic airways disease relative to allergen exp...

Allergen-specific IgG and IgA in serum and bronchoalveolar lavage fluid in a model of experimental feline asthma.

PubMed

Norris, C R; Byerly, J R; Decile, K C; Berghaus, R D; Walby, W F; Schelegle, E S; Hyde, D M; Gershwin, L J

2003-12-15

Allergic asthma, a Th2 cell driven response to inhaled allergens, has classically been thought of as predominantly mediated by IgE antibodies. To investigate the role of other immunoglobulin classes (e.g., IgG and IgA) in the immunopathogenesis of allergic asthma, levels of these allergen-specific immunoglobulins were measured in serum and mucosal fluids. Bermuda grass allergen (BGA)-specific IgG and IgA ELISAs in serum and bronchoalveolar lavage fluid (BALF) were developed and optimized in an experimental model of BGA-induced feline asthma. Levels of BGA-specific IgG and IgA significantly increased over time in serum and BALF after allergen sensitization. Additionally, these elevated levels of BGA-specific IgG and IgA were seen in conjunction with the development of an asthmatic phenotype indicated by positive intradermal skin tests, enhanced airways hyperreactivity, and increased eosinophil percentages in the BALF.

Local small airway epithelial injury induces global smooth muscle contraction and airway constriction

PubMed Central

Zhou, Jian; Alvarez-Elizondo, Martha B.; Botvinick, Elliot

2012-01-01

Small airway epithelial cells form a continuous sheet lining the conducting airways, which serves many functions including a physical barrier to protect the underlying tissue. In asthma, injury to epithelial cells can occur during bronchoconstriction, which may exacerbate airway hyperreactivity. To investigate the role of epithelial cell rupture in airway constriction, laser ablation was used to precisely rupture individual airway epithelial cells of small airways (<300-μm diameter) in rat lung slices (∼250-μm thick). Laser ablation of single epithelial cells using a femtosecond laser reproducibly induced airway contraction to ∼70% of the original cross-sectional area within several seconds, and the contraction lasted for up to 40 s. The airway constriction could be mimicked by mechanical rupture of a single epithelial cell using a sharp glass micropipette but not with a blunt glass pipette. These results suggest that soluble mediators released from the wounded epithelial cell induce global airway contraction. To confirm this hypothesis, the lysate of primary human small airway epithelial cells stimulated a similar airway contraction. Laser ablation of single epithelial cells triggered a single instantaneous Ca2+ wave in the epithelium, and multiple Ca2+ waves in smooth muscle cells, which were delayed by several seconds. Removal of extracellular Ca2+ or decreasing intracellular Ca2+ both blocked laser-induced airway contraction. We conclude that local epithelial cell rupture induces rapid and global airway constriction through release of soluble mediators and subsequent Ca2+-dependent smooth muscle shortening. PMID:22114176

Neurogenic airway microvascular leakage induced by toluene inhalation in rats.

PubMed

Sakamoto, Tatsuo; Kamijima, Michihiro; Miyake, Mio

2012-06-15

Toluene is a representative airborne occupational and domestic pollutant that causes eye and respiratory tract irritation. We investigated whether a single inhalation of toluene elicits microvascular leakage in the rat airway. We also evaluated the effects of CP-99,994, a tachykinin NK(1) receptor antagonist, and ketotifen, a histamine H1 receptor antagonist with mast cell-stabilizing properties, on the airway response. The content of Evans blue dye that extravasated into the tissues was measured as an index of plasma leakage. Toluene (18-450 ppm, 10 min) concentration-dependently induced dye leakage into the trachea and main bronchi of anesthetized and mechanically ventilated rats. Toluene at concentrations of ≥ 50 and ≥ 30 ppm caused significant responses in the trachea and main bronchi, respectively, which both peaked after exposure to 135 ppm toluene for 10 min. This response was abolished by CP-99,994 (5 mg/kg i.v.), but not by ketotifen (1mg/kg i.v.). Nebulized phosphoramidon (1 mM, 1 min), a neutral endopeptidase 24.11 inhibitor, significantly enhanced the response induced by toluene (135 ppm, 10 min) compared with nebulized 0.9% saline (1 min). These results show that toluene can rapidly increase airway plasma leakage that is predominantly mediated by tachykinins endogenously released from airway sensory nerves. However, mast cell activation might not be important in this airway response. Copyright © 2012 Elsevier B.V. All rights reserved.

Chimeric Antigen Receptor-Redirected Regulatory T Cells Suppress Experimental Allergic Airway Inflammation, a Model of Asthma.

PubMed

Skuljec, Jelena; Chmielewski, Markus; Happle, Christine; Habener, Anika; Busse, Mandy; Abken, Hinrich; Hansen, Gesine

2017-01-01

Cellular therapy with chimeric antigen receptor (CAR)-redirected cytotoxic T cells has shown impressive efficacy in the treatment of hematologic malignancies. We explored a regulatory T cell (Treg)-based therapy in the treatment of allergic airway inflammation, a model for asthma, which is characterized by an airway hyper-reactivity (AHR) and a chronic, T helper-2 (Th2) cell-dominated immune response to allergen. To restore the immune balance in the lung, we redirected Tregs by a CAR toward lung epithelia in mice upon experimentally induced allergic asthma, closely mimicking the clinical situation. Adoptively transferred CAR Tregs accumulated in the lung and in tracheobronchial lymph nodes, reduced AHR and diminished eosinophilic airway inflammation, indicated by lower cell numbers in the bronchoalveolar lavage fluid and decreased cell infiltrates in the lung. CAR Treg cells furthermore prevented excessive pulmonary mucus production as well as increase in allergen-specific IgE and Th2 cytokine levels in exposed animals. CAR Tregs were more efficient in controlling asthma than non-modified Tregs, indicating the pivotal role of specific Treg cell activation in the affected organ. Data demonstrate that lung targeting CAR Treg cells ameliorate key features of experimental airway inflammation, paving the way for cell therapy of severe allergic asthma.

Chemical modification of birch allergen extract leads to a reduction in allergenicity as well as immunogenicity.

PubMed

Würtzen, Peter Adler; Lund, Lise; Lund, Gitte; Holm, Jens; Millner, Anders; Henmar, Helene

2007-01-01

In Europe, specific immunotherapy is currently conducted with vaccines containing allergen preparations based on intact extracts. In addition to this, chemically modified allergen extracts (allergoids) are used for specific allergy treatment. Reduced allergenicity and thereby reduced risk of side effects in combination with retained ability to activate T cells and induce protective allergen-specific antibody responses has been claimed for allergoids. In the current study, we compared intact allergen extracts and allergoids with respect to allergenicity and immunogenicity. The immunological response to birch allergen extract, alum-adsorbed extract, birch allergoid and alum-adsorbed allergoid was investigated in vitro in human basophil histamine release assay and by stimulation of human allergen-specific T cell lines. In vivo, Bet v 1-specific IgG titers in mice were determined after repetitive immunizations. In all patients tested (n = 8), allergoid stimulations led to reduced histamine release compared to the intact allergen extract. However, the allergoid preparations were not recognized by Bet v 1-specific T cell lines (n = 7), which responded strongly to the intact allergen extract. Mouse immunizations showed a clearly reduced IgG induction by allergoids and a strongly potentiating effect of the alum adjuvant. Optimal IgG titers were obtained after 3 immunizations with intact allergen extracts, while 5 immunizations were needed to obtain maximal response to the allergoid. The reduced histamine release observed for allergoid preparations may be at the expense of immunological efficacy because the chemical modifications lead to a clear reduction in T cell activation and the ability to induce allergen-specific IgG antibody responses. Copyright 2007 S. Karger AG, Basel.

Eosinophils contribute to the resolution of lung-allergic responses following repeated allergen challenge.

PubMed

Takeda, Katsuyuki; Shiraishi, Yoshiki; Ashino, Shigeru; Han, Junyan; Jia, Yi; Wang, Meiqin; Lee, Nancy A; Lee, James J; Gelfand, Erwin W

2015-02-01

Eosinophils accumulate at the site of allergic inflammation and are critical effector cells in allergic diseases. Recent studies have also suggested a role for eosinophils in the resolution of inflammation. To determine the role of eosinophils in the resolution phase of the response to repeated allergen challenge. Eosinophil-deficient (PHIL) and wild-type (WT) littermates were sensitized and challenged to ovalbumin (OVA) 7 or 11 times. Airway inflammation, airway hyperresponsiveness (AHR) to inhaled methacholine, bronchoalveolar lavage (BAL) cytokine levels, and lung histology were monitored. Intracellular cytokine levels in BAL leukocytes were analyzed by flow cytometry. Groups of OVA-sensitized PHIL mice received bone marrow from WT or IL-10(-/-) donors 30 days before the OVA challenge. PHIL and WT mice developed similar levels of AHR and numbers of leukocytes and cytokine levels in BAL fluid after OVA sensitization and 7 airway challenges; no eosinophils were detected in the PHIL mice. Unlike WT mice, sensitized PHIL mice maintained AHR, lung inflammation, and increased levels of IL-4, IL-5, and IL-13 in BAL fluid after 11 challenges whereas IL-10 and TGF-β levels were decreased. Restoration of eosinophil numbers after injection of bone marrow from WT but not IL-10-deficient mice restored levels of IL-10 and TGF-β in BAL fluid as well as suppressed AHR and inflammation. Intracellular staining of BAL leukocytes revealed the capacity of eosinophils to produce IL-10. After repeated allergen challenge, eosinophils appeared not essential for the development of AHR and lung inflammation but contributed to the resolution of AHR and inflammation by producing IL-10. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Aggravation of airway inflammation and hyper-responsiveness following nasal challenge with Dermatophagoides pteronyssinus in perennial allergic rhinitis without symptoms of asthma.

PubMed

Wang, W; Xian, M; Xie, Y; Zheng, J; Li, J

2016-03-01

House dust mites are the most prevalent allergen causing sensitizations in patients with rhinitis and asthma in China. We aimed to investigate the changes in both upper and lower airway inflammation and responsiveness following Dermatophagoides pteronyssinus (Der-p) nasal provocation test (NPT) in rhinitis patients. Study subjects included 15 nonasthmatic Der-p-sensitized rhinitis (AR) patients with airway hyper-responsiveness (AHR) (AR+AHR+), 15 AR patients without AHR (AR+AHR-), 15 healthy controls (HCs) with Der-p sensitization (HC+DP+), and 15 HC without Der-p sensitization (HC+DP-). All subjects underwent Der-p NPT. Visual analogue scale (VAS) scores of nasal symptoms, nasal lavage and nasal airway resistance (NAR) measurement, sputum induction, and forced expiratory volume in 1 second (FEV1 ) were performed. Airway responsiveness to histamine bronchoprovocation (PD20 -FEV1 ) and exhaled nitric oxide (FeNO) was determined. NAR increased significantly in all subjects with the greatest effect seen in AR+AHR+ individuals. VAS increased in all subjects at 30 min and returned to baseline at 6 h, with significantly higher levels in AR+AHR+ and AR+AHR- subjects (P < 0.05). Eosinophils in nasal lavage fluid and sputum increased significantly after NPT in AR+AHR+ and AR+AHR- subjects (P < 0.001). FEV1 % and PD20 -FEV1 decreased and FeNO increased significantly after NPT only in AR+AHR+ subjects (P < 0.05). Nasal lavage eosinophil count was positively correlated with sputum eosinophil count and the level of FeNO and negatively correlated with FEV1 and PD20 . House dust mite nasal provocation test induces and aggravates both upper and lower airway inflammation and hyper-responsiveness in patients with persistent allergic rhinitis without asthmatic symptoms. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effect of airway acidosis and alkalosis on airway vascular smooth muscle responsiveness to albuterol.

PubMed

Cancado, Jose E; Mendes, Eliana S; Arana, Johana; Horvath, Gabor; Monzon, Maria E; Salathe, Matthias; Wanner, Adam

2015-04-02

In vitro and animal experiments have shown that the transport and signaling of β2-adrenergic agonists are pH-sensitive. Inhaled albuterol, a hydrophilic β2-adrenergic agonist, is widely used for the treatment of obstructive airway diseases. Acute exacerbations of obstructive airway diseases can be associated with changes in ventilation leading to either respiratory acidosis or alkalosis thereby affecting albuterol responsiveness in the airway. The purpose of this study was to determine if airway pH has an effect on albuterol-induced vasodilation in the airway. Ten healthy volunteers performed the following respiratory maneuvers: quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation (to dissociate the effect of pH from the effect of ventilation). During these breathing maneuvers, exhaled breath condensate (EBC) pH and airway blood flow response to inhaled albuterol (ΔQ̇aw) were assessed. Mean ± SE EBC pH (units) and ΔQ̇aw (μl.min(-1).mL(-1)) were 6.4 ± 0.1 and 16.8 ± 1.9 during quiet breathing, 6.3 ± 0.1 and 14.5 ± 2.4 during eucapnic hyperventilation, 6.6 ± 0.2 and -0.2 ± 1.8 during hypocapnic hyperventilation (p = 0.02 and <0.01 vs. quiet breathing), and 5.9 ± 0.1 and 2.0 ± 1.5 during hypercapnic hyperventilation (p = 0.02 and <0.02 vs quiet breathing). Albuterol responsiveness in the airway as assessed by ΔQ̇aw is pH sensitive. The breathing maneuver associated with decreased and increased EBC pH both resulted in a decreased responsiveness independent of the level of ventilation. These findings suggest an attenuated response to hydrophilic β2-adrenergic agonists during airway disease exacerbations associated with changes in pH. Registered at clinicaltrials.gov: NCT01216748 .

Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma

PubMed Central

Yarova, Polina L.; Stewart, Alecia L.; Sathish, Venkatachalem; Britt, Rodney D; Thompson, Michael A.; Lowe, Alexander P. P.; Freeman, Michelle; Aravamudan, Bharathi; Kita, Hirohito; Brennan, Sarah C.; Schepelmann, Martin; Davies, Thomas; Yung, Sun; Cholisoh, Zakky; Kidd, Emma J.; Ford, William R.; Broadley, Kenneth J.; Rietdorf, Katja; Chang, Wenhan; Khayat, Mohd E. Bin; Ward, Donald T.; Corrigan, Christopher J.; Ward, Jeremy P. T.; Kemp, Paul J.; Pabelick, Christina M.; Prakash, Y. S.; Riccardi, Daniela

2016-01-01

Airway hyperresponsiveness and inflammation are fundamental hallmarks of allergic asthma that are accompanied by increases in certain polycations, such as eosinophil cationic protein. Levels of these cations in body fluids correlate with asthma severity. We show that polycations and elevated extracellular calcium activate the human recombinant and native calcium-sensing receptor (CaSR), leading to intracellular calcium mobilization, cyclic adenosine monophosphate breakdown, and p38 mitogen-activated protein kinase phosphorylation in airway smooth muscle (ASM) cells. These effects can be prevented by CaSR antagonists, termed calcilytics. Moreover, asthmatic patients and allergen-sensitized mice expressed more CaSR in ASMs than did their healthy counterparts. Indeed, polycations induced hyper-reactivity in mouse bronchi, and this effect was prevented by calcilytics and absent in mice with CaSR ablation from ASM. Calcilytics also reduced airway hyperresponsiveness and inflammation in allergen-sensitized mice in vivo. These data show that a functional CaSR is up-regulated in asthmatic ASM and targeted by locally produced polycations to induce hyperresponsiveness and inflammation. Thus, calcilytics may represent effective asthma therapeutics. PMID:25904744

IL-18 Does not Increase Allergic Airway Disease in Mice When Produced by BCG

PubMed Central

Amniai, L.; Biet, F.; Marquillies, P.; Locht, C.; Pestel, J.; Tonnel, A.-B.; Duez, C.

2007-01-01

Whilst BCG inhibits allergic airway responses in murine models, IL-18 has adversary effects depending on its environment. We therefore constructed a BCG strain producing murine IL-18 (BCG-IL-18) and evaluated its efficiency to prevent an asthma-like reaction in mice. BALB/cByJ mice were sensitized (day (D) 1 and D10) by intraperitoneal injection of ovalbumin (OVA)-alum and primary (D20–22) and secondary (D62, 63) challenged with OVA aerosols. BCG or BCG-IL-18 were intraperitonealy administered 1 hour before each immunization (D1 and D10). BCG-IL-18 and BCG were shown to similarly inhibit the development of AHR, mucus production, eosinophil influx, and local Th2 cytokine production in BAL, both after the primary and secondary challenge. These data show that IL-18 did not increase allergic airway responses in the context of the mycobacterial infection, and suggest that BCG-IL-18 and BCG are able to prevent the development of local Th2 responses and therefore inhibit allergen-induced airway responses even after restimulation. PMID:18299704

Clonorchis sinensis-derived total protein attenuates airway inflammation in murine asthma model by inducing regulatory T cells and modulating dendritic cell functions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jeong, Young-Il; Kim, Seung Hyun; Ju, Jung Won

Highlights: {yields} Treatment with Clonorchis sinensis-derived total protein attenuates OVA-induced airway inflammation and AHR to methacholine. {yields} Induction of CD4{sup +}CD25{sup +}Foxp3{sup +} T cells and IL-10 along with suppression of splenocyte proliferation by C. sinensis-derived total protein. {yields} C. sinensis-derived total protein interferes with the expression of co-stimulatory molecules in DCs. -- Abstract: Asthma is characterized by Th2-mediated inflammation, resulting in airway hyperresponsiveness (AHR) through airway remodeling. Recent epidemiological and experimental reports have suggested an inverse relationship between the development of allergy and helminth infections. Infection by Clonorchis sinensis, a liver fluke that resides in the bile duct ofmore » humans, is endemic predominantly in Asia including Korea and China. Using a murine model for asthma, we investigated the effects of C. sinensis-derived total protein (Cs-TP) on allergen-induced airway inflammation and the mechanism underlying the protective effects of Cs-TP administration on asthma. Treatment with Cs-TP attenuated OVA-induced airway inflammation and methacholine-induced AHR, as well as eosinophilia development, lymphocyte infiltration into the lung, and goblet cell metaplasia. This protective effect of Cs-TP is associated with markedly reduced OVA-specific IgE and Th1/Th2 cytokine production. Moreover, Cs-TP increased the number of CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T (Treg) cells as well as their suppressive activity. In fact, proliferation of OVA-restimulated splenocytes was suppressed significantly. Cs-TP also inhibited the expression of such co-stimulatory molecules as CD80, CD86, and CD40 in LPS- or OVA-stimulated dendritic cells (DCs), suggesting that Cs-TP could interfere with the capacity of airway DCs to prime naive T cells. These data demonstrate the capacity of C. sinensis to ameliorate allergic asthma and broaden our understanding of the

L-2-Oxothiazolidine-4-Carboxylic Acid or α-Lipoic Acid Attenuates Airway Remodeling: Involvement of Nuclear Factor-κB (NF-κB), Nuclear Factor Erythroid 2p45-Related Factor-2 (Nrf2), and Hypoxia-Inducible Factor (HIF)

PubMed Central

Park, Seoung Ju; Lee, Kyung Sun; Lee, Su Jeong; Kim, So Ri; Park, Seung Yong; Jeon, Myoung Shin; Lee, Heung Bum; Lee, Yong Chul

2012-01-01

Reactive oxygen species (ROS) play a crucial role in the pathogenesis of acute and chronic respiratory diseases. Antioxidants have been found to ameliorate airway inflammation and hyperresponsiveness in animal models employing short-term exposure to allergen. However, little data are available on the effect of antioxidants on airway remodeling and signaling pathways in chronic asthma. In the present study, we used a long-term exposure murine model of allergic airway disease to evaluate the effects of an antioxidant, L-2-oxothiazolidine-4-carboxylic acid (OTC) or α-lipoic acid (LA) on airway remodeling, focusing on the ROS-related hypoxia-inducible signaling. Long-term challenge of ovalbumin (OVA) increased ROS production, airway inflammation, and airway hyperresponsiveness, and developed features of airway remodeling such as excessive mucus secretion, subepithelial fibrosis, and thickening of the peribronchial smooth muscle layer. Administration of OTC or LA reduced these features of asthma, including airway remodeling, which was accompanied by suppression of transforming growth factor-β1, vascular endothelial growth factor, and T-helper 2 cytokines. In addition, OVA-induced activation of nuclear factor-κB (NF-κB), nuclear factor erythroid 2p45-related factor-2 (Nrf2), hypoxia-inducible factor (HIF)-1α, and HIF-2α was reduced by OTC or LA. Our results also showed that OTC or LA down-regulated phosphoinositide 3-kinase activity and decreased phosphorylation of p38 mitogen-activated protein kinase but not extracellular signal-regulated kinase 1/2 or c-Jun N-terminal kinase. These findings demonstrate that OTC and LA can inhibit activation of NF-κB, Nrf2, and HIF, leading to attenuate allergen-induced airway remodeling. PMID:22942681

Facilitation of Allergic Sensitization and Allergic Airway Inflammation by Pollen-Induced Innate Neutrophil Recruitment.

PubMed

Hosoki, Koa; Aguilera-Aguirre, Leopoldo; Brasier, Allan R; Kurosky, Alexander; Boldogh, Istvan; Sur, Sanjiv

2016-01-01

Neutrophil recruitment is a hallmark of rapid innate immune responses. Exposure of airways of naive mice to pollens rapidly induces neutrophil recruitment. The innate mechanisms that regulate pollen-induced neutrophil recruitment and the contribution of this neutrophilic response to subsequent induction of allergic sensitization and inflammation need to be elucidated. Here we show that ragweed pollen extract (RWPE) challenge in naive mice induces C-X-C motif ligand (CXCL) chemokine synthesis, which stimulates chemokine (C-X-C motif) receptor 2 (CXCR2)-dependent recruitment of neutrophils into the airways. Deletion of Toll-like receptor 4 (TLR4) abolishes CXCL chemokine secretion and neutrophil recruitment induced by a single RWPE challenge and inhibits induction of allergic sensitization and airway inflammation after repeated exposures to RWPE. Forced induction of CXCL chemokine secretion and neutrophil recruitment in mice lacking TLR4 also reconstitutes the ability of multiple challenges of RWPE to induce allergic airway inflammation. Blocking RWPE-induced neutrophil recruitment in wild-type mice by administration of a CXCR2 inhibitor inhibits the ability of repeated exposures to RWPE to stimulate allergic sensitization and airway inflammation. Administration of neutrophils derived from naive donor mice into the airways of Tlr4 knockout recipient mice after each repeated RWPE challenge reconstitutes allergic sensitization and inflammation in these mice. Together these observations indicate that pollen-induced recruitment of neutrophils is TLR4 and CXCR2 dependent and that recruitment of neutrophils is a critical rate-limiting event that stimulates induction of allergic sensitization and airway inflammation. Inhibiting pollen-induced recruitment of neutrophils, such as by administration of CXCR2 antagonists, may be a novel strategy to prevent initiation of pollen-induced allergic airway inflammation.

Chloride channel blockers promote relaxation of TEA-induced contraction in airway smooth muscle

PubMed Central

Yim, Peter D.; Gallos, George; Perez-zoghbi, Jose F.; Trice, Jacquelyn; Zhang, Yi; Siviski, Matthew; Sonett, Joshua; Emala, Charles W.

2014-01-01

Enhanced airway smooth muscle (ASM) contraction is an important component in the pathophysiology of asthma. We have shown that ligand gated chloride channels modulate ASM contractile tone during the maintenance phase of an induced contraction, however the role of chloride flux in depolarization-induced contraction remains incompletely understood. To better understand the role of chloride flux under these conditions, muscle force (human ASM, guinea pig ASM), peripheral small airway luminal area (rat ASM) and airway smooth muscle plasma membrane electrical potentials (human cultured ASM) were measured. We found ex vivo guinea pig airway rings, human ASM strips and small peripheral airways in rat lungs slices relaxed in response to niflumic acid following depolarization-induced contraction induced by K+ channel blockade with tetraethylammonium chloride (TEA). In isolated human airway smooth muscle cells TEA induce depolarization as measured by a fluorescent indicator or whole cell patch clamp and this depolarization was reversed by niflumic acid. These findings demonstrate that ASM depolarization induced contraction is dependent on chloride channel activity. Targeting of chloride channels may be a novel approach to relax hypercontractile airway smooth muscle in bronchoconstrictive disorders. PMID:24662476

Chloride channel blockers promote relaxation of TEA-induced contraction in airway smooth muscle.

PubMed

Yim, Peter D; Gallos, George; Perez-Zoghbi, Jose F; Trice, Jacquelyn; Zhang, Yi; Siviski, Matthew; Sonett, Joshua; Emala, Charles W

2013-01-01

Enhanced airway smooth muscle (ASM) contraction is an important component in the pathophysiology of asthma. We have shown that ligand gated chloride channels modulate ASM contractile tone during the maintenance phase of an induced contraction, however the role of chloride flux in depolarization-induced contraction remains incompletely understood. To better understand the role of chloride flux under these conditions, muscle force (human ASM, guinea pig ASM), peripheral small airway luminal area (rat ASM) and airway smooth muscle plasma membrane electrical potentials (human cultured ASM) were measured. We found ex vivo guinea pig airway rings, human ASM strips and small peripheral airways in rat lungs slices relaxed in response to niflumic acid following depolarization-induced contraction induced by K(+) channel blockade with tetraethylammonium chloride (TEA). In isolated human airway smooth muscle cells TEA induce depolarization as measured by a fluorescent indicator or whole cell patch clamp and this depolarization was reversed by niflumic acid. These findings demonstrate that ASM depolarization induced contraction is dependent on chloride channel activity. Targeting of chloride channels may be a novel approach to relax hypercontractile airway smooth muscle in bronchoconstrictive disorders.

Sensory neuropeptides modulate cigarette smoke-induced decrease in neutral endopeptidase activity in guinea pig airways.

PubMed

Kuo, H P; Lu, L C

1995-01-01

Cigarette smoke (CS) inhalation stimulates C-fibers to release sensory neuropeptides which mediate airway reflex responses to prevent irritants from entering the lower airways. When CS is inhaled via the upper airways, these airway defense responses may modulate the effect of CS on airway NEP activity and related airway hyperresponsiveness. To examine this possibility, we exposed guinea pigs to 1:10 diluted mid-tar cigarette smoke 100 puffs per day for 7 days and recorded pulmonary resistance of cumulative doses of neurokinin A (NKA, 10(-12)-10(-8) mol/kg, i.v.) or methacholine (Mch, 1-50 micrograms/kg, i.v.). NEP activity in the tracheobronchi was measured using fluorometric assay. Exposure of CS alone failed to alter the dose-response to NKA or Mch compared with air control. NEP activity in the airways after CS exposure was slightly but significantly lower than that of air control. Capsaicin pretreatment 1 week before CS exposure significantly shifted the dose-response curves of NKA, but not Mch, to the left and decreased NEP activity in the airways to a greater extent compared with CS exposure alone group. Capsaicin pretreatment alone failed to alter the responsiveness to NKA or NEP activity. CS also induced a significant increase in neutrophil counts in airways. Capsaicin pretreatment enhanced the effect of CS on neutrophil recruitment. We conclude that sensory neuropeptides may have a protective role in modulation of airways NEP activity downregulation induced by CS, probably by preventing CS from entering the lower airways or the chronic release of sensory neuropeptides induced by CS providing increased amount of substrata for NEP upregulation, and therefore modify the direct effect of CS on NEP activity and related airway hyperresponsiveness.

Novel Small Airway Bronchodilator Responses to Rosiglitazone in Mouse Lung Slices

PubMed Central

Bai, Yan; Donovan, Chantal; Esposito, James G.; Tan, Xiahui; Sanderson, Michael J.

2014-01-01

There is a need to identify novel agents that elicit small airway relaxation when β2-adrenoceptor agonists become ineffective in difficult-to-treat asthma. Because chronic treatment with the synthetic peroxisome proliferator activated receptor (PPAR)γ agonist rosiglitazone (RGZ) inhibits airway hyperresponsiveness in mouse models of allergic airways disease, we tested the hypothesis that RGZ causes acute airway relaxation by measuring changes in small airway size in mouse lung slices. Whereas the β-adrenoceptor agonists albuterol (ALB) and isoproterenol induced partial airway relaxation, RGZ reversed submaximal and maximal contraction to methacholine (MCh) and was similarly effective after precontraction with serotonin or endothelin-1. Concentration-dependent relaxation to RGZ was not altered by the β-adrenoceptor antagonist propranolol and was enhanced by ALB. RGZ-induced relaxation was mimicked by other synthetic PPARγ agonists but not by the putative endogenous agonist 15-deoxy-PGJ2 and was not prevented by the PPARγ antagonist GW9662. To induce airway relaxation, RGZ inhibited the amplitude and frequency of MCh-induced Ca2+ oscillations of airway smooth muscle cells (ASMCs). In addition, RGZ reduced MCh-induced Ca2+ sensitivity of the ASMCs. Collectively, these findings demonstrate that acute bronchodilator responses induced by RGZ are PPARγ independent, additive with ALB, and occur by the inhibition of ASMC Ca2+ signaling and Ca2+ sensitivity. Because RGZ continues to elicit relaxation when β-adrenoceptor agonists have a limited effect, RGZ or related compounds may have potential as bronchodilators for the treatment of difficult asthma. PMID:24188042

Role of OSGIN1 in mediating smoking-induced autophagy in the human airway epithelium.

PubMed

Wang, Guoqing; Zhou, Haixia; Strulovici-Barel, Yael; Al-Hijji, Mohammed; Ou, Xuemei; Salit, Jacqueline; Walters, Matthew S; Staudt, Michelle R; Kaner, Robert J; Crystal, Ronald G

2017-07-03

Enhanced macroautophagy/autophagy is recognized as a component of the pathogenesis of smoking-induced airway disease. Based on the knowledge that enhanced autophagy is linked to oxidative stress and the DNA damage response, both of which are linked to smoking, we used microarray analysis of the airway epithelium to identify smoking upregulated genes known to respond to oxidative stress and the DNA damage response. This analysis identified OSGIN1 (oxidative stress induced growth inhibitor 1) as significantly upregulated by smoking, in both the large and small airway epithelium, an observation confirmed by an independent small airway microarray cohort, TaqMan PCR of large and small airway samples and RNA-Seq of small airway samples. High and low OSGIN1 expressors have different autophagy gene expression patterns in vivo. Genome-wide correlation of RNAseq analysis of airway basal/progenitor cells showed a direct correlation of OSGIN1 mRNA levels to multiple classic autophagy genes. In vitro cigarette smoke extract exposure of primary airway basal/progenitor cells was accompanied by a dose-dependent upregulation of OSGIN1 and autophagy induction. Lentivirus-mediated expression of OSGIN1 in human primary basal/progenitor cells induced puncta-like staining of MAP1LC3B and upregulation of MAP1LC3B mRNA and protein and SQSTM1 mRNA expression level in a dose and time-dependent manner. OSGIN1-induction of autophagosome, amphisome and autolysosome formation was confirmed by colocalization of MAP1LC3B with SQSTM1 or CD63 (endosome marker) and LAMP1 (lysosome marker). Both OSGIN1 overexpression and knockdown enhanced the smoking-evoked autophagic response. Together, these observations support the concept that smoking-induced upregulation of OSGIN1 is one link between smoking-induced stress and enhanced-autophagy in the human airway epithelium.

Newly divided eosinophils limit ozone-induced airway hyperreactivity in nonsensitized guinea pigs

PubMed Central

Jacoby, David B.

2017-01-01

Ozone causes vagally mediated airway hyperreactivity and recruits inflammatory cells, including eosinophils, to lungs, where they mediate ozone-induced hyperreactivity 1 day after exposure but are paradoxically protective 3 days later. We aimed to test the role of newly divided eosinophils in ozone-induced airway hyperreactivity in sensitized and nonsensitized guinea pigs. Nonsensitized and sensitized guinea pigs were treated with 5-bromo-2-deoxyuridine (BrdU) to label newly divided cells and were exposed to air or ozone for 4 h. Later (1 or 3 days later), vagally induced bronchoconstriction was measured, and inflammatory cells were harvested from bone marrow, blood, and bronchoalveolar lavage. Ozone induced eosinophil hematopoiesis. One day after ozone, mature eosinophils dominate the inflammatory response and potentiate vagally induced bronchoconstriction. However, by 3 days, newly divided eosinophils have reached the lungs, where they inhibit ozone-induced airway hyperreactivity because depleting them with antibody to IL-5 or a TNF-α antagonist worsened vagally induced bronchoconstriction. In sensitized guinea pigs, both ozone-induced eosinophil hematopoiesis and subsequent recruitment of newly divided eosinophils to lungs 3 days later failed to occur. Thus mature eosinophils dominated the ozone-induced inflammatory response in sensitized guinea pigs. Depleting these mature eosinophils prevented ozone-induced airway hyperreactivity in sensitized animals. Ozone induces eosinophil hematopoiesis and recruitment to lungs, where 3 days later, newly divided eosinophils attenuate vagally mediated hyperreactivity. Ozone-induced hematopoiesis of beneficial eosinophils is blocked by a TNF-α antagonist or by prior sensitization. In these animals, mature eosinophils are associated with hyperreactivity. Thus interventions targeting eosinophils, although beneficial in atopic individuals, may delay resolution of airway hyperreactivity in nonatopic individuals. PMID:28258108

Newly divided eosinophils limit ozone-induced airway hyperreactivity in nonsensitized guinea pigs.

PubMed

Wicher, Sarah A; Jacoby, David B; Fryer, Allison D

2017-06-01

Ozone causes vagally mediated airway hyperreactivity and recruits inflammatory cells, including eosinophils, to lungs, where they mediate ozone-induced hyperreactivity 1 day after exposure but are paradoxically protective 3 days later. We aimed to test the role of newly divided eosinophils in ozone-induced airway hyperreactivity in sensitized and nonsensitized guinea pigs. Nonsensitized and sensitized guinea pigs were treated with 5-bromo-2-deoxyuridine (BrdU) to label newly divided cells and were exposed to air or ozone for 4 h. Later (1 or 3 days later), vagally induced bronchoconstriction was measured, and inflammatory cells were harvested from bone marrow, blood, and bronchoalveolar lavage. Ozone induced eosinophil hematopoiesis. One day after ozone, mature eosinophils dominate the inflammatory response and potentiate vagally induced bronchoconstriction. However, by 3 days, newly divided eosinophils have reached the lungs, where they inhibit ozone-induced airway hyperreactivity because depleting them with antibody to IL-5 or a TNF-α antagonist worsened vagally induced bronchoconstriction. In sensitized guinea pigs, both ozone-induced eosinophil hematopoiesis and subsequent recruitment of newly divided eosinophils to lungs 3 days later failed to occur. Thus mature eosinophils dominated the ozone-induced inflammatory response in sensitized guinea pigs. Depleting these mature eosinophils prevented ozone-induced airway hyperreactivity in sensitized animals. Ozone induces eosinophil hematopoiesis and recruitment to lungs, where 3 days later, newly divided eosinophils attenuate vagally mediated hyperreactivity. Ozone-induced hematopoiesis of beneficial eosinophils is blocked by a TNF-α antagonist or by prior sensitization. In these animals, mature eosinophils are associated with hyperreactivity. Thus interventions targeting eosinophils, although beneficial in atopic individuals, may delay resolution of airway hyperreactivity in nonatopic individuals. Copyright �

Enhanced sensitization and elicitation responses caused by mixtures of common fragrance allergens.

PubMed

Bonefeld, Charlotte Menné; Nielsen, Morten Milek; Rubin, Ingrid Maria Cecilia; Vennegaard, Marie Torp; Dabelsteen, Sally; Gimenéz-Arnau, Elena; Lepoittevin, Jean-Pierre; Geisler, Carsten; Johansen, Jeanne Duus

2011-12-01

Perfumes are complex mixtures composed of many fragrance ingredients, many of which are known to be only weak allergens when tested individually. It is therefore surprising that fragrance contact allergy is one of the most common forms of contact allergy. To investigate whether mixing different fragrance allergens leads to increased sensitization potency, and to examine the difference in the challenge response to one chemical in mice sensitized either with the mixture of allergens or with only the relevant allergen. CBA mice were sensitized with three different concentrations of three fragrance allergens alone or as a mixture. The sensitization and elicitation responses were measured by ear thickness plus infiltration of B and T cells and T cell proliferation in the draining lymph nodes. We found a dose-dependent sensitization response for each of the allergens. An increased response was seen when the allergens were mixed. A stronger challenge response to cinnamal was seen in mice sensitized with the allergen mixture than in mice sensitized with cinnamal alone. Our findings suggest that mixtures of allergens increase the primary response that potentiates the generation of memory T cells in response to the specific allergen. Thus, allergen mixtures enhance both induction and elicitation of contact allergy. © 2011 John Wiley & Sons A/S.

Cockroach Allergen Exposure and Risk of Asthma

PubMed Central

Do, Danh C.; Zhao, Yilin; Gao, Peisong

2015-01-01

Cockroach sensitization is an important risk factor for the development of asthma. However, its underlying immune mechanisms and the genetic etiology for differences in allergic responses remain unclear. Cockroach allergens identification and their expression as biologically active recombinant proteins has provided a basis for studying the mechanisms regarding cockroach allergens induced allergic sensitization and asthma. Glycans in allergens may play a crucial role in the immunogenicity of allergic diseases. Protease-activated receptor (PAR)-2, Toll-like receptor (TLR), and C-type lectin receptors have been suggested to be important for the penetration of cockroach allergens through epithelial cells to mediate allergen uptake, dendritic cell maturation, antigen presenting cell (APC) function in T cell polarization, and cytokine production. Environmental pollutants, which often co-exist with the allergen, could synergistically elicit allergic inflammation, and aryl hydrocarbon receptor (AhR) activation and signaling may serve as a link between these two elements. Genetic factors may also play an important role in conferring the susceptibility to cockroach sensitization. Several genes have been associated with cockroach sensitization and asthma-related phenotypes. In this review, we will discuss the epidemiological evidence for cockroach allergen-induced asthma, cockroach allergens, the mechanisms regarding cockroach allergens induced innate immune responses, and the genetic basis for cockroach sensitization. PMID:26706467

Aerosolized polymerized type I collagen reduces airway inflammation and remodelling in a guinea pig model of allergic asthma.

PubMed

Moreno-Alvarez, Paola; Sánchez-Guerrero, Edgar; Martínez-Cordero, Erasmo; Hernández-Pando, Rogelio; Campos, María G; Cetina, Lucely; Bazán-Perkins, Blanca

2010-04-01

Collagen-polyvinylpyrrolidone (Collagen-PVP) has been demonstrated to elicit immunomodulatory properties in different chronic inflammatory diseases. Nevertheless, its effects on asthma are still unknown. We have evaluated whether collagen-PVP could modulate airway inflammation and remodelling in a guinea pig model of allergic asthma. Sensitized guinea pigs were challenged with the allergen (ovalbumin) six times (at 10-day intervals). From the third challenge on, animals were treated every 5 days with saline aerosols containing 0.16, 0.33, or 0.66 mg/ml of collagen-PVP (n = 5, respectively). Some guinea pigs, sensitized and challenged with saline as well as treated with 0 or 0.66 mg/ml collagen-PVP, were included in the study as control (n = 7) and sham groups (n = 5), respectively. From the first challenge on, ovalbumin induced a transient airway obstruction, measured by barometric plethysmography, which was not modified by collagen-PVP treatments. After the last allergen challenge, guinea pigs were anesthetized to obtain bronchoalveolar lavage (BAL) and the left lung caudal lobe. As expected, BAL cell count from allergen-challenged guinea pigs showed abundant neutrophils and eosinophils, as well as numerous tumor necrosis factor (TNF)-alpha-expressing granulocytes and macrophages in airway wall (determined by immunohistochemical assay). Neutrophilia and TNF-alpha-expressing leukocytes, from collagen-PVP treated animals, diminished from 0.16 mg/ml, and eosinophilia from 0.66 mg/ml of collagen-PVP doses. Histological changes induced by allergen challenges include thickening of connective tissue below airway epithelium and vascular wall widening of airway adjacent vessels; these changes were reduced by collagen-PVP treatment. Collagen-PVP seems to have anti-inflammatory and antifibrotic properties in this guinea pig asthma model.

Effect of choline chloride in allergen-induced mouse model of airway inflammation.

PubMed

Mehta, A K; Gaur, S N; Arora, N; Singh, B P

2007-10-01

The incidence of asthma has increased the world over, and current therapies for the disease suffer from potential side-effects. This has created an opportunity to develop novel therapeutic approaches. Here, the anti-inflammatory activity of choline was investigated in a mouse model of allergic airway inflammation. Choline (1 mg.kg(-1)) was administered via oral gavage or intranasally before and after ovalbumin (OVA) challenge in sensitised mice. Airway hyperresponsiveness (AHR) to methacholine was measured in the mice by whole-body plethysmography. Type-2 T-helper cell cytokine and leukotriene levels were estimated in bronchoalveolar lavage fluid (BALF) and spleen culture supernatant by ELISA. Eosinophil peroxidase activity was also determined in the BALF supernatant. Choline treatment in sensitised mice before OVA challenge via oral/intranasal routes significantly inhibited eosinophilic airway inflammation and eosinophil peroxidase activity. It also reduced immunoglobulin E and G1 production and inhibited the release of type-2 T-helper cell cytokines and leukotrienes. However, the development of AHR was prevented effectively by intranasal choline treatment. Most importantly, choline treatment after OVA challenge by both routes could reverse established asthmatic conditions in mice by inhibiting AHR, eosinophilic airway inflammation and other inflammatory parameters. This study provides a new therapeutic approach for controlling as well as preventing asthma exacerbations.

Mechanisms determining cholinergic neural responses in airways of young and mature rabbits.

PubMed

Larsen, Gary L; Loader, Joan; Nguyen, Dee Dee; Fratelli, Cori; Dakhama, Azzeddine; Colasurdo, Giuseppe N

2004-08-01

Neural pathways help control airway caliber and responsiveness. Yet little is known of how neural control changes as a function of development. In rabbits, we found electrical field stimulation (EFS) of airway nerves led to more marked contractile responses in 2- vs. 13-week-old animals. This enhanced response to EFS may be due to prejunctional, junctional, and/or postjunctional neural mechanisms. We assessed these mechanisms in airways of 2- and 13-week-old rabbits. The contractile responses to methacholine did not differ in the groups, suggesting postjunctional neural events are not primarily responsible for differing responses to EFS. To address junctional events, acetylcholinesterase (AChE) was measured (spectrophotometry). AChE was elevated in 2-week-olds. However, this should lead to less and not greater responses. Prejunctionally, EFS-induced acetylcholine (ACh) release was assessed by HPLC. Airways of 2-week-old rabbits released significantly more ACh than airways from mature rabbits. Choline acetyltransferase, a marker of cholinergic nerves, was not different between groups, suggesting that more ACh release in young rabbits was not due to increased nerve density. ACh release in the presence of polyarginine increased significantly in both groups, supporting the presence of functional muscarinic autoreceptors (M2) at both ages. Because substance P (SP) increases release of ACh, SP was measured by ELISA. This neuropeptide was significantly elevated in airways of younger rabbits. Nerve growth factor (NGF) increased SP and was also significantly increased in airways from younger rabbits. This work suggests that increases in EFS-induced responsiveness in young rabbits are likely due to prejunctional events with enhanced release of ACh. Increases in NGF and SP early in life may contribute to this increased responsiveness. Copyright 2004 Wiley-Liss, Inc.

Facilitation of Allergic Sensitization and Allergic Airway Inflammation by Pollen-Induced Innate Neutrophil Recruitment

PubMed Central

Hosoki, Koa; Aguilera-Aguirre, Leopoldo; Brasier, Allan R.; Kurosky, Alexander; Boldogh, Istvan

2016-01-01

Neutrophil recruitment is a hallmark of rapid innate immune responses. Exposure of airways of naive mice to pollens rapidly induces neutrophil recruitment. The innate mechanisms that regulate pollen-induced neutrophil recruitment and the contribution of this neutrophilic response to subsequent induction of allergic sensitization and inflammation need to be elucidated. Here we show that ragweed pollen extract (RWPE) challenge in naive mice induces C-X-C motif ligand (CXCL) chemokine synthesis, which stimulates chemokine (C-X-C motif) receptor 2 (CXCR2)-dependent recruitment of neutrophils into the airways. Deletion of Toll-like receptor 4 (TLR4) abolishes CXCL chemokine secretion and neutrophil recruitment induced by a single RWPE challenge and inhibits induction of allergic sensitization and airway inflammation after repeated exposures to RWPE. Forced induction of CXCL chemokine secretion and neutrophil recruitment in mice lacking TLR4 also reconstitutes the ability of multiple challenges of RWPE to induce allergic airway inflammation. Blocking RWPE-induced neutrophil recruitment in wild-type mice by administration of a CXCR2 inhibitor inhibits the ability of repeated exposures to RWPE to stimulate allergic sensitization and airway inflammation. Administration of neutrophils derived from naive donor mice into the airways of Tlr4 knockout recipient mice after each repeated RWPE challenge reconstitutes allergic sensitization and inflammation in these mice. Together these observations indicate that pollen-induced recruitment of neutrophils is TLR4 and CXCR2 dependent and that recruitment of neutrophils is a critical rate-limiting event that stimulates induction of allergic sensitization and airway inflammation. Inhibiting pollen-induced recruitment of neutrophils, such as by administration of CXCR2 antagonists, may be a novel strategy to prevent initiation of pollen-induced allergic airway inflammation. PMID:26086549

Acetyl salicylic acid inhibits Th17 airway inflammation via blockade of IL-6 and IL-17 positive feedback

PubMed Central

Moon, Hyung-Geun; Kang, Chil Sung; Choi, Jun-Pyo; Choi, Dong Sic; Choi, Hyun Il; Choi, Yong Wook; Jeon, Seong Gyu; Yoo, Joo-Yeon; Jang, Myoung Ho; Gho, Yong Song; Kim, Yoon-Keun

2013-01-01

T-helper (Th)17 cell responses are important for the development of neutrophilic inflammatory disease. Recently, we found that acetyl salicylic acid (ASA) inhibited Th17 airway inflammation in an asthma mouse model induced by sensitization with lipopolysaccharide (LPS)-containing allergens. To investigate the mechanism(s) of the inhibitory effect of ASA on the development of Th17 airway inflammation, a neutrophilic asthma mouse model was generated by intranasal sensitization with LPS plus ovalbumin (OVA) and then challenged with OVA alone. Immunologic parameters and airway inflammation were evaluated 6 and 48 h after the last OVA challenge. ASA inhibited the production of interleukin (IL)-17 from lung T cells as well as in vitro Th17 polarization induced by IL-6. Additionally, ASA, but not salicylic acid, suppressed Th17 airway inflammation, which was associated with decreased expression of acetyl-STAT3 (downstream signaling of IL-6) in the lung. Moreover, the production of IL-6 from inflammatory cells, induced by IL-17, was abolished by treatment with ASA, whereas that induced by LPS was not. Altogether, ASA, likely via its acetyl moiety, inhibits Th17 airway inflammation by blockade of IL-6 and IL-17 positive feedback. PMID:23306703

Endogenous gamma-aminobutyric acid modulates tonic guinea pig airway tone and propofol-induced airway smooth muscle relaxation.

PubMed

Gallos, George; Gleason, Neil R; Virag, Laszlo; Zhang, Yi; Mizuta, Kentaro; Whittington, Robert A; Emala, Charles W

2009-04-01

Emerging evidence indicates that an endogenous autocrine/paracrine system involving gamma-aminobutyric acid (GABA) is present in airways. GABAA channels, GABAB receptors, and the enzyme that synthesizes GABA have been identified in airway epithelium and smooth muscle. However, the endogenous ligand itself, GABA, has not been measured in airway tissues. The authors sought to demonstrate that GABA is released in response to contractile agonists and tonically contributes a prorelaxant component to contracted airway smooth muscle. The amount and cellular localization of GABA in upper guinea pig airways under resting and contracted tone was determined by high pressure liquid chromatography and immunohistochemistry, respectively. The contribution that endogenous GABA imparts on the maintenance of airway smooth muscle acetylcholine-induced contraction was assessed in intact guinea pig airway tracheal rings using selective GABAA antagonism (gabazine) under resting or acetylcholine-contracted conditions. The ability of an allosteric agent (propofol) to relax a substance P-induced relaxation in an endogenous GABA-dependent manner was assessed. GABA levels increased and localized to airway smooth muscle after contractile stimuli in guinea pig upper airways. Acetylcholine-contracted guinea pig tracheal rings exhibited an increase in contracted force upon addition of the GABAA antagonist gabazine that was subsequently reversed by the addition of the GABAA agonist muscimol. Propofol dose-dependently relaxed a substance P contraction that was blocked by gabazine. These studies demonstrate that GABA is endogenously present and increases after contractile stimuli in guinea pig upper airways and that endogenous GABA contributes a tonic prorelaxant component in the maintenance of airway smooth muscle tone.

Endogenous γ-aminobutyric Acid Modulates Tonic Guinea Pig Airway Tone and Propofol-induced Airway Smooth Muscle Relaxation

PubMed Central

Gallos, George; Gleason, Neil R.; Virag, Laszlo; Zhang, Yi; Mizuta, Kentauro; Whittington, Robert A.; Emala, Charles W.

2009-01-01

Background Emerging evidence indicates that an endogenous autocrine/paracrine system involving γ-aminobutyric acid (GABA) is present in airways. GABAA channels, GABAB receptors and the enzyme that synthesizes GABA have been identified in airway epithelium and smooth muscle. However, the endogenous ligand itself, GABA, has not been measured in airway tissues. We sought to demonstrate that GABA is released in response to contractile agonists and tonically contributes a pro-relaxant component to contracted airway smooth muscle. Methods The amount and cellular localization of GABA in upper guinea pig airways under resting and contracted tone was determined by high pressure liquid chromatography and immunohistochemistry, respectively. The contribution that endogenous GABA imparts on the maintenance of airway smooth muscle acetylcholine-induced contraction was assessed in intact guinea pig airway tracheal rings using selective GABAA antagonism (gabazine) under resting or acetylcholine-contracted conditions. The ability of an allosteric agent (propofol) to relax a substance P-induced relaxation in an endogenous GABA-dependent manner was assessed. Results GABA levels increased and localized to airway smooth muscle following contractile stimuli in guinea pig upper airways. Acetylcholine-contracted guinea pig tracheal rings exhibited an increase in contracted force upon addition of the GABAA antagonist gabazine which was subsequently reversed by the addition of the GABAA agonist muscimol. Propofol dose-dependently relaxed a substance P contraction that was blocked by gabazine. Conclusion These studies demonstrate that GABA is endogenously present and increases following contractile stimuli in guinea pig upper airways and that endogenous GABA contributes a tonic pro-relaxant component in the maintenance of airway smooth muscle tone. PMID:19322939

Asthma, Airway Symptoms and Rhinitis in Office Workers in Malaysia: Associations with House Dust Mite (HDM) Allergy, Cat Allergy and Levels of House Dust Mite Allergens in Office Dust.

PubMed

Lim, Fang Lee; Hashim, Zailina; Than, Leslie Thian Lung; Md Said, Salmiah; Hisham Hashim, Jamal; Norbäck, Dan

2015-01-01

A prevalence study was conducted among office workers in Malaysia (N= 695). The aim of this study was to examine associations between asthma, airway symptoms, rhinitis and house dust mites (HDM) and cat allergy and HDM levels in office dust. Medical data was collected by a questionnaire. Skin prick tests were performed for HDM allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae) and cat allergen Felis domesticus. Indoor temperature and relative air humidity (RH) were measured in the offices and vacuumed dust samples were analyzed for HDM allergens. The prevalence of D. pteronyssinus, D. farinae and cat allergy were 50.3%, 49.0% and 25.5% respectively. Totally 9.6% had doctor-diagnosed asthma, 15.5% had current wheeze and 53.0% had current rhinitis. The Der p 1 (from D. pteronyssinus) and Der f 1 (from D. farinae) allergens levels in dust were 556 ng/g and 658 ng/g respectively. Statistical analysis was conducted by multilevel logistic regression, adjusting for age, gender, current smoking, HDM or cat allergy, home dampness and recent indoor painting at home. Office workers with HDM allergy had more wheeze (p= 0.035), any airway symptoms (p= 0.032), doctor-diagnosed asthma (p= 0.005), current asthma (p= 0.007), current rhinitis (p= 0.021) and rhinoconjuctivitis (p< 0.001). Cat allergy was associated with wheeze (p= 0.021), wheeze when not having a cold (p= 0.033), any airway symptoms (p= 0.034), doctor-diagnosed asthma (p= 0.010), current asthma (p= 0.020) and nasal allergy medication (p= 0.042). Der f 1 level in dust was associated with daytime breathlessness (p= 0.033) especially among those with HDM allergy. Der f 1 levels were correlated with indoor temperature (p< 0.001) and inversely correlated with RH (p< 0.001). In conclusion, HDM and cat allergies were common and independently associated with asthma, airway symptoms and rhinitis. Der f 1 allergen can be a risk factor for daytime breathlessness.

Asthma, Airway Symptoms and Rhinitis in Office Workers in Malaysia: Associations with House Dust Mite (HDM) Allergy, Cat Allergy and Levels of House Dust Mite Allergens in Office Dust

PubMed Central

Lim, Fang Lee; Hashim, Zailina; Than, Leslie Thian Lung; Md Said, Salmiah; Hisham Hashim, Jamal; Norbäck, Dan

2015-01-01

A prevalence study was conducted among office workers in Malaysia (N= 695). The aim of this study was to examine associations between asthma, airway symptoms, rhinitis and house dust mites (HDM) and cat allergy and HDM levels in office dust. Medical data was collected by a questionnaire. Skin prick tests were performed for HDM allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae) and cat allergen Felis domesticus. Indoor temperature and relative air humidity (RH) were measured in the offices and vacuumed dust samples were analyzed for HDM allergens. The prevalence of D. pteronyssinus, D. farinae and cat allergy were 50.3%, 49.0% and 25.5% respectively. Totally 9.6% had doctor-diagnosed asthma, 15.5% had current wheeze and 53.0% had current rhinitis. The Der p 1 (from D. pteronyssinus) and Der f 1 (from D. farinae) allergens levels in dust were 556 ng/g and 658 ng/g respectively. Statistical analysis was conducted by multilevel logistic regression, adjusting for age, gender, current smoking, HDM or cat allergy, home dampness and recent indoor painting at home. Office workers with HDM allergy had more wheeze (p= 0.035), any airway symptoms (p= 0.032), doctor-diagnosed asthma (p= 0.005), current asthma (p= 0.007), current rhinitis (p= 0.021) and rhinoconjuctivitis (p< 0.001). Cat allergy was associated with wheeze (p= 0.021), wheeze when not having a cold (p= 0.033), any airway symptoms (p= 0.034), doctor-diagnosed asthma (p= 0.010), current asthma (p= 0.020) and nasal allergy medication (p= 0.042). Der f 1 level in dust was associated with daytime breathlessness (p= 0.033) especially among those with HDM allergy. Der f 1 levels were correlated with indoor temperature (p< 0.001) and inversely correlated with RH (p< 0.001). In conclusion, HDM and cat allergies were common and independently associated with asthma, airway symptoms and rhinitis. Der f 1 allergen can be a risk factor for daytime breathlessness. PMID:25923543

EGR-1 and DUSP-1 are important negative regulators of pro-allergic responses in airway epithelium.

PubMed

Golebski, Korneliusz; van Egmond, Danielle; de Groot, Esther J; Roschmann, Kristina I L; Fokkens, Wytske J; van Drunen, Cornelis M

2015-05-01

Primary nasal epithelium of house dust mite allergic individuals is in a permanently activated inflammatory transcriptional state. To investigate whether a deregulated expression of EGR-1 and/or DUSP-1, two potential negative regulators of pro-inflammatory responses, could contribute to the activation of the inflammatory state. We silenced the expression of EGR-1 or DUSP-1 in the airway epithelial cell line NCI-H292. The cell lines were stimulated in a 24-h time course with the house dust mite allergen or poly(I:C). RNA expression profiles of cytokines were established using q-PCR and protein levels were determined in supernatants with ELISA. The shRNA-mediated gene silencing reduced expression levels of EGR-1 by 92% (p<0.0001) and of DUSP-1 by 76% (p<0.0001). Both mutant cells lines showed an increased and prolonged response to the HDM allergen. The mRNA induction of IL-6 was 4.6 fold (p=0.02) and 2.4 fold higher (p=0.01) in the EGR-1 and DUSP-1 knock-down, respectively when compared to the induced levels in the control cell line. For IL-8, the induction levels were 4.6 fold (p=0.01) and 13.0 (p=0.001) fold higher. The outcome was largely similar, yet not identical at the secreted protein levels. Furthermore, steroids were able to suppress the poly(I:C) induced cytokine levels by 70-95%. Deregulation of EGR-1 and/or DUSP-1 in nasal epithelium could be responsible for the prolonged activated transcriptional state observed in vivo in allergic disease. This could have clinical consequences as cytokine levels after the steroid treatment in EGR-1 or DUSP-1 knock-down remained higher than in the control cell line. Copyright © 2015 Elsevier Ltd. All rights reserved.

IL-33 promotes the migration and proliferation of circulating fibrocytes from patients with allergen-exacerbated asthma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bianchetti, Lorenza, E-mail: lbianchetti@avail-research.com; Laboratory of Cytopathology and Cytogenetics, Italian ABR Operative Unit, Milan; Marini, Maurizio A., E-mail: mam.marini@yahoo.com

2012-09-14

Highlights: Black-Right-Pointing-Pointer IL-33 is considered a new therapeutic target for reducing inflammation in asthma. Black-Right-Pointing-Pointer This study shows that IL-33 is a potent chemoattractant for fibrocytes in asthma. Black-Right-Pointing-Pointer IL-33 also promotes fibrocyte proliferation without reducing collagen production. Black-Right-Pointing-Pointer The study uncovers a novel non-inflammatory, profibrotic function of IL-33. -- Abstract: The release of IL-33 increases in the bronchial mucosa of asthmatic patients in relation to disease severity and several studies have demonstrated that IL-33 may enhance airway inflammation in asthma. This study tested the hypothesis that IL-33 may also contribute to the development of irreversible structural changes in asthmamore » by favoring the airway recruitment and profibrotic function of circulating fibrocytes during episodes of allergen-induced asthma exacerbation. The circulating fibrocytes from patients with allergen-exacerbated asthma (PwAA) showed increased expression of the specific IL-33 receptor component ST2L in comparison with the cells from non-asthmatic individuals (NAI). Recombinant IL-33 induced the migration of circulating fibrocytes from PwAA at clinically relevant concentrations and stimulated their proliferation in a concentration-dependent manner between 0.1 and 10 ng/ml, without affecting the constitutive release of type I collagen. The recombinant protein did not induce similar responses in circulating fibrocytes from NAI. This study uncovers an important mechanism through which fibrocytes may accumulate in the airways of allergic asthmatics when their disease is not adequately controlled by current treatment and provides novel information on the function of IL-33 in asthma.« less

Glove-derived foreign proteins induce allergen-specific IgE in a mouse model.

PubMed

Busch, Marion; Schröder, Claudia; Baron, Jens-Malte; Ott, Hagen; Bruckner, Thomas; Diepgen, Thomas L; Mahler, Vera

2008-04-01

Currently, most medical gloves are produced with a low content of natural rubber latex (NRL) protein. However, they may be substituted by proteins of foreign origin to maintain specific properties of the material. The aim of this study was to investigate the allergenicity and immunogenicity of unexpected proteins (i.e., soy and casein) compared with NRL proteins in a murine model in BALB/c mice. All respective allergen sources (extracts from three brands of NRL gloves, soy, and casein) were able to induce significant allergen-specific IgE and IgG(1) responses. On average, the highest IgE induction occurred after immunization with NRL, followed by soy and casein. Certain individuals from each treatment group exhibited levels of specific IgE as high as due to NRL. To analyze further specific IgE responses on a single allergen level, we established a microarray based on recombinant allergens for allergen-specific murine IgE detection. Besides specific IgE against rHev b 3, -6, -7, -8, and -11, specific IgE against kappa-casein could be detected in mice immunized with NRL glove extract, indicating a sensitization potential of the contained foreign protein. The substitution of genuine latex proteins by proteins of foreign origin may lead to a shift and de novo increase in sensitization to the finished products.

Mast Cells Can Amplify Airway Reactivity and Features of Chronic Inflammation in an Asthma Model in Mice

PubMed Central

Williams, Cara M.M.; Galli, Stephen J.

2000-01-01

The importance of mast cells in the development of the allergen-induced airway hyperreactivity and inflammation associated with asthma remains controversial. We found that genetically mast cell–deficient WBB6F1-W/Wv mice that were sensitized to ovalbumin (OVA) without adjuvant, then challenged repetitively with antigen intranasally, exhibited much weaker responses in terms of bronchial hyperreactivity to aerosolized methacholine, lung tissue eosinophil infiltration, and numbers of proliferating cells within the airway epithelium than did identically treated WBB6F1-+/+ normal mice. However, W/Wv mice that had undergone selective reconstitution of tissue mast cells with in vitro–derived mast cells of congenic +/+ mouse origin exhibited airway responses that were very similar to those of the +/+ mice. By contrast, W/Wv mice that were sensitized with OVA emulsified in alum and challenged with aerosolized OVA exhibited levels of airway hyperreactivity and lung tissue eosinophil infiltration that were similar to those of the corresponding +/+ mice. Nevertheless, these W/Wv mice exhibited significantly fewer proliferating cells within the airway epithelium than did identically treated +/+ mice. These results show that, depending on the “asthma model” investigated, mast cells can either have a critical role in, or not be essential for, multiple features of allergic airway responses in mice. PMID:10934234

Aeroallergens Induce Reactive Oxygen Species Production and DNA Damage and Dampen Antioxidant Responses in Bronchial Epithelial Cells.

PubMed

Chan, Tze Khee; Tan, W S Daniel; Peh, Hong Yong; Wong, W S Fred

2017-07-01

Exposure to environmental allergens is a major risk factor for asthma development. Allergens possess proteolytic activity that is capable of disrupting the airway epithelium. Although there is increasing evidence pointing to asthma as an epithelial disease, the underlying mechanism that drives asthma has not been fully elucidated. In this study, we investigated the direct DNA damage potential of aeroallergens on human bronchial epithelial cells and elucidated the mechanisms mediating the damage. Human bronchial epithelial cells, BEAS-2B, directly exposed to house dust mites (HDM) resulted in enhanced DNA damage, as measured by the CometChip and the staining of DNA double-strand break marker, γH2AX. HDM stimulated cellular reactive oxygen species production, increased mitochondrial oxidative stress, and promoted nitrosative stress. Notably, expression of nuclear factor erythroid 2-related factor 2-dependent antioxidant genes was reduced immediately after HDM exposure, suggesting that HDM altered antioxidant responses. HDM exposure also reduced cell proliferation and induced cell death. Importantly, HDM-induced DNA damage can be prevented by the antioxidants glutathione and catalase, suggesting that HDM-induced reactive oxygen and nitrogen species can be neutralized by antioxidants. Mechanistic studies revealed that HDM-induced cellular injury is NADPH oxidase (NOX)-dependent, and apocynin, a NOX inhibitor, protected cells from double-strand breaks induced by HDM. Our results show that direct exposure of bronchial epithelial cells to HDM leads to the production of reactive oxygen and nitrogen species that damage DNA and induce cytotoxicity. Antioxidants and NOX inhibitors can prevent HDM-induced DNA damage, revealing a novel role for antioxidants and NOX inhibitors in mitigating allergic airway disease. Copyright © 2017 by The American Association of Immunologists, Inc.

Repeated Nitrogen Dioxide Exposures and Eosinophilic Airway Inflammation in Asthmatics: A Randomized Crossover Study

PubMed Central

Guillossou, Gaëlle; Neukirch, Catherine; Dehoux, Monique; Koscielny, Serge; Bonay, Marcel; Cabanes, Pierre-André; Samet, Jonathan M.; Mure, Patrick; Ropert, Luc; Tokarek, Sandra; Lambrozo, Jacques; Aubier, Michel

2014-01-01

Background: Nitrogen dioxide (NO2), a ubiquitous atmospheric pollutant, may enhance the asthmatic response to allergens through eosinophilic activation in the airways. However, the effect of NO2 on inflammation without allergen exposure is poorly studied. Objectives: We investigated whether repeated peaks of NO2, at various realistic concentrations, induce changes in airway inflammation in asthmatics. Methods: Nineteen nonsmokers with asthma were exposed at rest in a double-blind, crossover study, in randomized order, to 200 ppb NO2, 600 ppb NO2, or clean air once for 30 min on day 1 and twice for 30 min on day 2. The three series of exposures were separated by 2 weeks. The inflammatory response in sputum was measured 6 hr (day 1), 32 hr (day 2), and 48 hr (day 3) after the first exposure, and compared with baseline values measured twice 10–30 days before the first exposure. Results: Compared with baseline measurements, the percentage of eosinophils in sputum increased by 57% after exposure to 600 ppb NO2 (p = 0.003) but did not change significantly after exposure to 200 ppb. The slope of the association between the percentage of eosinophils and NO2 exposure level was significant (p = 0.04). Eosinophil cationic protein in sputum was highly correlated with eosinophil count and increased significantly after exposure to 600 ppb NO2 (p = 0.001). Lung function, which was assessed daily, was not affected by NO2 exposure. Conclusions: We observed that repeated peak exposures of NO2 performed without allergen exposure were associated with airway eosinophilic inflammation in asthmatics in a dose-related manner. Citation: Ezratty V, Guillossou G, Neukirch C, Dehoux M, Koscielny S, Bonay M, Cabanes PA, Samet JM, Mure P, Ropert L, Tokarek S, Lambrozo J, Aubier M. 2014. Repeated nitrogen dioxide exposures and eosinophilic airway inflammation in asthmatics: a randomized crossover study. Environ Health Perspect 122:850–855; http://dx.doi.org/10.1289/ehp.1307240 PMID

Postnatal remodeling of the neural components of the epithelial-mesenchymal trophic unit in the proximal airways of infant rhesus monkeys exposed to ozone and allergen.

PubMed

Larson, Shawnessy D; Schelegle, Edward S; Walby, William F; Gershwin, Laural J; Fanuccihi, Michelle V; Evans, Michael J; Joad, Jesse P; Tarkington, Brian K; Hyde, Dallas M; Plopper, Charles G

2004-02-01

Nerves and neuroendocrine cells located within the airway epithelium are ideally situated to sample a changing airway environment, to transmit that information to the central nervous system, and to promote trophic interactions between epithelial and mesenchymal cellular and acellular components. We tested the hypothesis that the environmental stresses of ozone (O(3)) and house dust mite allergen (HDMA) in atopic infant rhesus monkeys alter the distribution of airway nerves. Midlevel bronchi and bronchioles from 6-month-old infant monkeys that inhaled filtered air (FA), house dust mite allergen HDMA, O(3), or HDMA + O(3) for 11 episodes (5 days each, 0.5 ppm O(3), 8 h/day followed by 9 days recovery) were examined using immunohistochemistry for the presence of Protein gene product 9.5 (PGP 9.5), a nonspecific neural indicator, and calcitonin gene-related peptide (CGRP). Along the axial path between the sixth and the seventh intrapulmonary airway generations, there were small significant (P < 0.05) decrements in the density of epithelial nerves in monkeys exposed to HDMA or O(3), while in monkeys exposed to HDMA + O(3) there was a greater significant (P < 0.05) reduction in epithelial innervation. In animals exposed to O(3) or HDMA + O(3) there was a significant increase in the number of PGP 9.5 positive/CGRP negative cells that were anchored to the basal lamina and emitted projections in primarily the lateral plain and often intertwined with projections and cell bodies of other similar cells. We conclude that repeated cycles of acute injury and repair associated with the episodic pattern of ozone and allergen exposure alter the normal development of neural innervation of the epithelial compartment and the appearance of a new population of undefined PGP 9.5 positive cells within the epithelium.

RGS4 Overexpression in Lung Attenuates Airway Hyperresponsiveness in Mice.

PubMed

Madigan, Laura A; Wong, Gordon S; Gordon, Elizabeth M; Chen, Wei-Sheng; Balenga, Nariman; Koziol-White, Cynthia J; Panettieri, Reynold A; Levine, Stewart J; Druey, Kirk M

2018-01-01

A cardinal feature of asthma is airway hyperresponsiveness (AHR) to spasmogens, many of which activate G protein-coupled receptors (GPCRs) on airway smooth muscle (ASM) cells. Asthma subtypes associated with allergy are characterized by eosinophilic inflammation in the lung due to the type 2 immune response to allergens and proinflammatory mediators that promote AHR. The degree to which intrinsic abnormalities of ASM contribute to this phenotype remains unknown. The regulators of G protein signaling (RGS) proteins are a large group of intracellular proteins that inhibit GPCR signaling pathways. RGS2- and RGS5-deficient mice develop AHR spontaneously. Although RGS4 is upregulated in ASM from patients with severe asthma, the effects of increased RGS4 expression on AHR in vivo are unknown. Here, we examined the impact of forced RGS4 overexpression in lung on AHR using transgenic (Tg) mice. Tg RGS4 was expressed in bronchial epithelium and ASM in vivo, and protein expression in lung was increased at least 4-fold in Tg mice compared with wild-type (WT) mice. Lung slices from Tg mice contracted less in response to the m3 muscarinic receptor agonist methacholine compared with the WT, although airway resistance in live, unchallenged mice of both strains was similar. Tg mice were partially protected against AHR induced by fungal allergen challenge due to weakened contraction signaling in ASM and reduced type 2 cytokine (IL-5 and IL-13) levels in Tg mice compared with the WT. These results provide support for the hypothesis that increasing RGS4 expression and/or function could be a viable therapeutic strategy for asthma.

Enhanced glucocorticoid-induced leucine zipper in dendritic cells induces allergen-specific regulatory CD4(+) T-cells in respiratory allergies.

PubMed

Karaki, S; Garcia, G; Tcherakian, C; Capel, F; Tran, T; Pallardy, M; Humbert, M; Emilie, D; Godot, V

2014-05-01

Respiratory allergies rely on a defect of IL-10-secreting regulatory CD4(+) T-cells (IL-10-Tregs ) leading to excessive Th2-biased immune responses to allergens. According to clinical data, the restoration of allergen-specific IL-10-Tregs is required to control respiratory allergies and cure patients. The discovery of mechanisms involved in the generation of IL-10-Tregs will thus help to provide effective treatments. We previously demonstrated that dendritic cells (DCs) expressing high levels of the glucocorticoid-induced leucine zipper protein (GILZ) generate antigen-specific IL-10-Tregs . We suspect a defective expression of GILZ in the DCs of respiratory allergic patients and speculate that increasing its expression might restore immune tolerance against allergens through the induction of IL-10-Tregs . We assessed GILZ expression in blood DCs of patients and healthy nonallergic donors by qPCR. We compared the ability of patients' DCs to induce allergen-specific IL-10-Tregs before and after an in vivo up-regulation of GILZ expression by steroid administration, steroids being inducers of GILZ. We report lower levels of GILZ in DCs of respiratory allergic patients that return to normal levels after steroid administration. We show that patients' DCs with increased levels of GILZ generate allergen-specific IL-10-Tregs again. We further confirm unequivocally that GILZ is required in patients' DCs to activate these IL-10-Tregs . This proof of concept study shows that the re-establishment of GILZ expression in patients' DCs to normal levels restores their capacity to activate allergen-specific IL-10-Tregs . We thus highlight the up-regulation of GILZ in DCs as a new interventional approach to restore the immune tolerance to allergens. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cerium dioxide nanoparticles exacerbate house dust mite induced type II airway inflammation.

PubMed

Meldrum, Kirsty; Robertson, Sarah B; Römer, Isabella; Marczylo, Tim; Dean, Lareb S N; Rogers, Andrew; Gant, Timothy W; Smith, Rachel; Tetley, Terry D; Leonard, Martin O

2018-05-23

Nanomaterial inhalation represents a potential hazard for respiratory conditions such as asthma. Cerium dioxide nanoparticles (CeO 2 NPs) have the ability to modify disease outcome but have not been investigated for their effect on models of asthma and inflammatory lung disease. The aim of this study was to examine the impact of CeO 2 NPs in a house dust mite (HDM) induced murine model of asthma. Repeated intranasal instillation of CeO 2 NPs in the presence of HDM caused the induction of a type II inflammatory response, characterised by increased bronchoalveolar lavage eosinophils, mast cells, total plasma IgE and goblet cell metaplasia. This was accompanied by increases in IL-4, CCL11 and MCPT1 gene expression together with increases in the mucin and inflammatory regulators CLCA1 and SLC26A4. CLCA1 and SLC26A4 were also induced by CeO 2 NPs + HDM co-exposure in air liquid interface cultures of human primary bronchial epithelial cells. HDM induced airway hyperresponsiveness and airway remodelling in mice were not altered with CeO 2 NPs co-exposure. Repeated HMD instillations followed by a single exposure to CeO 2 NPs failed to produce changes in type II inflammatory endpoints but did result in alterations in the neutrophil marker CD177. Treatment of mice with CeO 2 NPs in the absence of HDM did not have any significant effects. RNA-SEQ was used to explore early effects 24 h after single treatment exposures. Changes in SAA3 expression paralleled increased neutrophil BAL levels, while no changes in eosinophil or lymphocyte levels were observed. HDM resulted in a strong induction of type I interferon and IRF3 dependent gene expression, which was inhibited with CeO 2 NPs co-exposure. Changes in the expression of genes including CCL20, CXCL10, NLRC5, IRF7 and CLEC10A suggest regulation of dendritic cells, macrophage functionality and IRF3 modulation as key early events in how CeO 2 NPs may guide pulmonary responses to HDM towards type II inflammation. CeO 2 NPs

K+-induced alterations in airway muscle responsiveness to electrical field stimulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murlas, C.; Ehring, G.; Suszkiw, J.

1986-07-01

We investigated possible pre- and postsynaptic effects of K+-induced depolarization on ferret tracheal smooth muscle (TSM) responsiveness to cholinergic stimulation. To assess electromechanical activity, cell membrane potential (Em) and tension (Tm) were simultaneously recorded in buffer containing 6, 12, 18, or 24 mM K+ before and after electrical field stimulation (EFS) or exogenous acetylcholine (ACh). In 6 mM K+, Em was -58.1 +/- 1.0 mV (mean +/- SE). In 12 mM K+, Em was depolarized to -52.3 +/- 0.9 mV, basal Tm did not change, and both excitatory junctional potentials and contractile responses to EFS at short stimulus duration weremore » larger than in 6 mM K+. No such potentiation occurred at a higher K+, although resting Em and Tm increased progressively above 12 mM K+. The sensitivity of ferret TSM to exogenous ACh appeared unaffected by K+. To determine whether the hyperresponsiveness in 12 mM K+ was due, in part, to augmented ACh release from intramural airway nerves, experiments were done using TSM preparations incubated with (3H)choline to measure (3H)ACh release at rest and during EFS. Although resting (3H)ACh release increased progressively in higher K+, release evoked by EFS was maximal in 12 mM K+ and declined in higher concentrations. We conclude that small elevations in the extracellular K+ concentration augment responsiveness of the airways, by increasing the release of ACh both at rest and during EFS from intramural cholinergic nerve terminals. Larger increases in K+ appear to be inhibitory, possibly due to voltage-dependent effects that occur both pre- and postsynaptically.« less

Toxoplasma gondii infection induces suppression in a mouse model of allergic airway inflammation.

PubMed

Fenoy, Ignacio M; Chiurazzi, Romina; Sánchez, Vanesa R; Argenziano, Mariana A; Soto, Ariadna; Picchio, Mariano S; Martin, Valentina; Goldman, Alejandra

2012-01-01

Allergic asthma is an inflammatory disorder characterized by infiltration of the airway wall with inflammatory cells driven mostly by activation of Th2-lymphocytes, eosinophils and mast cells. There is a link between increased allergy and a reduction of some infections in Western countries. Epidemiological data also show that respiratory allergy is less frequent in people exposed to orofecal and foodborne microbes such as Toxoplasma gondii. We previously showed that both acute and chronic parasite T. gondii infection substantially blocked development of airway inflammation in adult BALB/c mice. Based on the high levels of IFN-γ along with the reduction of Th2 phenotype, we hypothesized that the protective effect might be related to the strong Th1 immune response elicited against the parasite. However, other mechanisms could also be implicated. The possibility that regulatory T cells inhibit allergic diseases has received growing support from both animal and human studies. Here we investigated the cellular mechanisms involved in T. gondii induced protection against allergy. Our results show for the first time that thoracic lymph node cells from mice sensitized during chronic T. gondii infection have suppressor activity. Suppression was detected both in vitro, on allergen specific T cell proliferation and in vivo, on allergic lung inflammation after adoptive transference from infected/sensitized mice to previously sensitized animals. This ability was found to be contact-independent and correlated with high levels of TGF-β and CD4(+)FoxP3(+) cells.

S100A8 protein attenuates airway hyperresponsiveness by suppressing the contraction of airway smooth muscle.

PubMed

Xu, Yu-Dong; Wang, Yu; Yin, Lei-Miao; Park, Gyoung-Hee; Ulloa, Luis; Yang, Yong-Qing

2017-02-26

Airway hyperresponsiveness (AHR) is a major clinical problem in allergic asthma mainly caused by the hypercontractility of airway smooth muscles (ASM). S100A8 is an important member of the S100 calcium-binding protein family with a potential to regulate cell contractility. Here, we analyze the potential of S100A8 to regulate allergen-induced AHR and ASM contraction. Treatment with recombinant S100A8 (rS100A8) diminished airway hyperresponsiveness in OVA-sensitized rats. ASM contraction assays showed that rS100A8 reduced hypercontractility in both isolated tracheal rings and primary ASM cells treated by acetylcholine. rS100A8 markedly rescued the phosphorylation level of myosin light chain induced by acetylcholine in ASM cells. These results show that rS100A8 plays a protective role in regulating AHR in asthma by inhibiting ASM contraction. These results support S100A8 as a novel therapeutic target to control ASM contraction in asthma. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Compartmental and temporal dynamics of chronic inflammation and airway remodelling in a chronic asthma mouse model.

PubMed

Alrifai, Mohammed; Marsh, Leigh M; Dicke, Tanja; Kılıç, Ayse; Conrad, Melanie L; Renz, Harald; Garn, Holger

2014-01-01

Allergic asthma is associated with chronic airway inflammation and progressive airway remodelling. However, the dynamics of the development of these features and their spontaneous and pharmacological reversibility are still poorly understood. We have therefore investigated the dynamics of airway remodelling and repair in an experimental asthma model and studied how pharmacological intervention affects these processes. Using BALB/c mice, the kinetics of chronic asthma progression and resolution were characterised in absence and presence of inhaled corticosteroid (ICS) treatment. Airway inflammation and remodelling was assessed by the analysis of bronchoalveolar and peribronichal inflammatory cell infiltrate, goblet cell hyperplasia, collagen deposition and smooth muscle thickening. Chronic allergen exposure resulted in early (goblet cell hyperplasia) and late remodelling (collagen deposition and smooth muscle thickening). After four weeks of allergen cessation eosinophilic inflammation, goblet cell hyperplasia and collagen deposition were resolved, full resolution of lymphocyte inflammation and smooth muscle thickening was only observed after eight weeks. ICS therapy when started before the full establishment of chronic asthma reduced the development of lung inflammation, decreased goblet cell hyperplasia and collagen deposition, but did not affect smooth muscle thickening. These effects of ICS on airway remodelling were maintained for a further four weeks even when therapy was discontinued. Utilising a chronic model of experimental asthma we have shown that repeated allergen exposure induces reversible airway remodelling and inflammation in mice. Therapeutic intervention with ICS was partially effective in inhibiting the transition from acute to chronic asthma by reducing airway inflammation and remodelling but was ineffective in preventing smooth muscle hypertrophy.

Inhibition of pan neurotrophin receptor p75 attenuates diesel particulate-induced enhancement of allergic airway responses in C57/B16J mice.

PubMed

Farraj, Aimen K; Haykal-Coates, Najwa; Ledbetter, Allen D; Evansky, Paul A; Gavett, Stephen H

2006-06-01

Recent investigations have linked neurotrophins, including nerve growth factor (NGF), neurotrophin-3 (NT-3), and brain-derived neurotrophic factor (BDNF), to allergic airways diseases. Antibody blockade of NGF attenuates airway resistance in allergic mice. Diesel exhaust particle (DEP) exposure has been linked to asthma exacerbation in many cities with vehicular traffic congestion. We tested the hypothesis that DEP-induced enhancement of the hallmark features of allergic airway disease in a murine model is dependent on the function of the pan neurotrophin receptor p75. Ovalbumin (OVA)-sensitized C57B1/6J mice were intranasally instilled with an antibody against the p75 receptor or saline alone 1 h before OVA challenge. The mice were then exposed nose-only to the PM2.5 fraction of SRM2975 DEP or air alone for 5 h beginning 1 h after OVA challenge. Two days later, air-exposed OVA-allergic mice developed a small but insignificant increase in methacholine-induced airflow obstruction relative to air-exposed, vehicle-sensitized mice. DEP-exposed OVA-allergic mice had a significantly greater degree of airway obstruction than all other groups. Instillation of anti-p75 significantly attenuated the DEP-induced increase in airway obstruction in OVA-allergic mice to levels similar to non-sensitized mice. The DEP-induced exacerbation of allergic airway responses may, in part, be mediated by neurotrophins.

Diesel exhaust particulate induces airway hyperresponsiveness in a murine model: essential role of GM-CSF.

PubMed

Ohta, K; Yamashita, N; Tajima, M; Miyasaka, T; Nakano, J; Nakajima, M; Ishii, A; Horiuchi, T; Mano, K; Miyamoto, T

1999-11-01

Inhaled pollutants were recently shown to be responsible for an increased incidence of airway allergic diseases, including asthma. A common feature of all forms of asthma is airway hyperresponsiveness. Our purpose was to elucidate the effects of diesel exhaust particulate (DEP), one of the most prevalent inhaled pollutants, on airway responsiveness. A/J and C57Bl/6 mice were used; the former are genetically predisposed to be hyperresponsive to acetylcholine, whereas the latter are not. DEP was administered intranasally for 2 weeks, after which pulmonary function was analyzed by whole-body plethysmography. Intranasal administration of DEP increased airway responsiveness to acetylcholine in both A/J and C57Bl/6 mice and induced displacement of ciliated epithelial cells by mucus-secreting Clara cells. The effect was mediated by M(3) muscarinic receptors. Acetylcholine-evoked bronchial constriction was reversed by administration of terbutaline, a beta(2)-adrenergic antagonist, which is also characteristic of human asthma. Intranasal administration of antibody raised against GM-CSF abolished DEP-evoked increases in airway responsiveness and Clara cell hyperplasia. The antibody raised against IL-4 also inhibited DEP-evoked increases in airway responsiveness. However, it was to a lesser extent compared with antibody against GM-CSF. In addition, DEP stimulated GM-CSF messenger RNA expression in the lung. DEP induces airway hyperresponsiveness by stimulating GM-CSF synthesis.

Nanoparticle-allergen interactions mediate human allergic responses: protein corona characterization and cellular responses.

PubMed

Radauer-Preiml, Isabella; Andosch, Ancuela; Hawranek, Thomas; Luetz-Meindl, Ursula; Wiederstein, Markus; Horejs-Hoeck, Jutta; Himly, Martin; Boyles, Matthew; Duschl, Albert

2016-01-16

Engineered nanomaterials (ENMs) interact with different biomolecules as soon as they are in contact, resulting in the formation of a biomolecule 'corona'. Hence, the 'corona' defines the biological identity of the ENMs and could affect the response of the immune system to ENM exposure. With up to 40 % of the world population suffering from type I allergy, a possible modulation of allergen effects by binding to ENMs is highly relevant with respect to work place and consumer safety. Therefore, the aim of this present study was to gain an insight into the interactions of gold nanoparticles with different seasonally and perennially occurring outdoor and indoor allergens. Gold nanoparticles (AuNPs) were conjugated with the major allergens of birch pollen (Bet v 1), timothy grass pollen (Phl p 5) and house dust mite (Der p 1). The AuNP-allergen conjugates were characterized by means of TEM negative staining, dynamic light scattering (DLS), z-potential measurements and hyperspectral imaging. Furthermore, 3D models were constructed, based on the characterization data, to visualize the interaction between the allergens and the AuNPs surface. Differences in the activation of human basophil cells derived from birch/grass pollen- and house dust mite-allergic patients in response to free allergen and AuNP-allergen conjugates were determined using the basophil activation assay (BAT). Potential allergen corona replacement during BAT was controlled for using Western blotting. The protease activity of AuNP-Der p 1 conjugates compared to free Der p 1 was assessed, by an enzymatic activity assay and a cellular assay pertaining to lung type II alveolar epithelial cell tight junction integrity. The formation of a stable corona was found for all three allergens used. Our data suggest, that depending on the allergen, different effects are observed after binding to ENMs, including enhanced allergic responses against Der p 1 and also, for some patients, against Bet v 1. Moreover elevated

Role of Rho kinase isoforms in murine allergic airway responses.

PubMed

Zhu, M; Liu, P-Y; Kasahara, D I; Williams, A S; Verbout, N G; Halayko, A J; Fedulov, A; Shoji, T; Williams, E S; Noma, K; Shore, S A; Liao, J K

2011-10-01

Inhibition of Rho-associated coiled-coil forming kinases (ROCKs) reduces allergic airway responses in mice. The purpose of this study was to determine the roles of the two ROCK isoforms, ROCK1 and ROCK2, in these responses. Wildtype (WT) mice and heterozygous ROCK1 and ROCK2 knockout mice (ROCK1(+/-) and ROCK2(+/-), respectively) were sensitised and challenged with ovalbumin. ROCK expression and activation were assessed by western blotting. Airway responsiveness was measured by forced oscillation. Bronchoalveolar lavage was performed and the lungs were fixed for histological assessment. Compared with WT mice, ROCK1 and ROCK2 expression were 50% lower in lungs of ROCK1(+/-) and ROCK2(+/-) mice, respectively, without changes in the other isoform. In WT lungs, ROCK activation increased after ovalbumin challenge and was sustained for several hours. This activation was reduced in ROCK1(+/-) and ROCK2(+/-) lungs. Airway responsiveness was comparable in WT, ROCK1(+/-), and ROCK2(+/-) mice challenged with PBS. Ovalbumin challenge caused airway hyperresponsiveness in WT, but not ROCK1(+/-) or ROCK2(+/-) mice. Lavage eosinophils and goblet cell hyperplasia were significantly reduced in ovalbumin-challenged ROCK1(+/-) and ROCK2(+/-) versus WT mice. Ovalbumin-induced changes in lavage interleukin-13, interleukin-5 and lymphocytes were also reduced in ROCK1(+/-) mice. In conclusion, both ROCK1 and ROCK2 are important in regulating allergic airway responses.

Lymphocyte blastogenic responses to inciting food allergens in dogs with food hypersensitivity.

PubMed

Ishida, Rinei; Masuda, Kenichi; Kurata, Keigo; Ohno, Koichi; Tsujimoto, Hajime

2004-01-01

Lymphocyte blastogenic responses against food allergens in dogs with food hypersensitivity were evaluated in this study. Eleven dogs with food hypersensitivity, based on food elimination and oral food provocation tests and allergic responses to food allergens, were examined by various tests such as intradermal testing, antigen-specific IgE testing, and lymphocyte blastogenic responses. The number and kinds of food allergens identified as positive by these tests were compared with the offending food allergens that were found in an oral food provocation test. In 9 (82%) of the 11 dogs with food hypersensitivity, there was close agreement for positive allergens between the results of lymphocyte blastogenic responses and oral food provocation test; however, there was little agreement for intradermal and IgE testing of the positive allergens with those of the oral food provocation test (11% and 31%, respectively). In the 9 dogs, the stimulation indices of lymphocyte blastogenic responses increased to 2.0-10.1 upon food provocation but decreased significantly to 0.7-1.4 upon feeding the elimination diet until clinical signs disappeared. These results indicate that lymphocyte blastogenic responses may fluctuate because of exposure to offending food allergens in dogs with food hypersensitivity. Lymphocytes reactive to food allergens may play an important role in the pathogenesis of food hypersensitivity in dogs.

Epithelium-generated neuropeptide Y induces smooth muscle contraction to promote airway hyperresponsiveness.

PubMed

Li, Shanru; Koziol-White, Cynthia; Jude, Joseph; Jiang, Meiqi; Zhao, Hengjiang; Cao, Gaoyuan; Yoo, Edwin; Jester, William; Morley, Michael P; Zhou, Su; Wang, Yi; Lu, Min Min; Panettieri, Reynold A; Morrisey, Edward E

2016-05-02

Asthma is one of the most common chronic diseases globally and can be divided into presenting with or without an immune response. Current therapies have little effect on nonimmune disease, and the mechanisms that drive this type of asthma are poorly understood. Here, we have shown that loss of the transcription factors forkhead box P1 (Foxp1) and Foxp4, which are critical for lung epithelial development, in the adult airway epithelium evokes a non-Th2 asthma phenotype that is characterized by airway hyperresponsiveness (AHR) without eosinophilic inflammation. Transcriptome analysis revealed that loss of Foxp1 and Foxp4 expression induces ectopic expression of neuropeptide Y (Npy), which has been reported to be present in the airways of asthma patients, but whose importance in disease pathogenesis remains unclear. Treatment of human lung airway explants with recombinant NPY increased airway contractility. Conversely, loss of Npy in Foxp1- and Foxp4-mutant airway epithelium rescued the AHR phenotype. We determined that NPY promotes AHR through the induction of Rho kinase activity and phosphorylation of myosin light chain, which induces airway smooth muscle contraction. Together, these studies highlight the importance of paracrine signals from the airway epithelium to the underlying smooth muscle to induce AHR and suggest that therapies targeting epithelial induction of this phenotype may prove useful in treatment of noneosinophilic asthma.

Early life exposure to bisphenol A investigated in mouse models of airway allergy, food allergy and oral tolerance.

PubMed

Nygaard, Unni Cecilie; Vinje, Nina Eriksen; Samuelsen, Mari; Andreassen, Monica; Groeng, Else-Carin; Bølling, Anette Kocbach; Becher, Rune; Lovik, Martinus; Bodin, Johanna

2015-09-01

The impact of early life exposure to bisphenol A (BPA) through drinking water was investigated in mouse models of respiratory allergy, food allergy and oral tolerance. Balb/c mice were exposed to BPA (0, 10 or 100 μg/ml), and the offspring were intranasally exposed to the allergen ovalbumin (OVA). C3H/HeJ offspring were sensitized with the food allergen lupin by intragastric gavage, after exposure to BPA (0, 1, 10 or 100 μg/ml). In separate offspring, oral tolerance was induced by gavage of 5 mg lupin one week before entering the protocol for the food allergy induction. In the airway allergy model, BPA (100 μg/ml) caused increased eosinophil numbers in bronchoalveolar lavage fluid (BALF) and a trend of increased OVA-specific IgE levels. In the food allergy and tolerance models, BPA did not alter the clinical anaphylaxis or antibody responses, but induced alterations in splenocyte cytokines and decreased mouse mast cell protease (MMCP)-1 serum levels. In conclusion, early life exposure to BPA through drinking water modestly augmented allergic responses in a mouse model of airway allergy only at high doses, and not in mouse models for food allergy and tolerance. Thus, our data do not support that BPA promotes allergy development at exposure levels relevant for humans. Copyright © 2015 Elsevier Ltd. All rights reserved.

Intervention effect and dose-dependent response of tanreqing injection on airway inflammation in lipopolysaccharide-induced rats.

PubMed

Dong, Shoujin; Zhong, Yunqing; Yang, Kun; Xiong, Xiaoling; Mao, Bing

2013-08-01

To assess the effect of Tanreqing injection on airway inflammation in rats. A rat model of airway inflammation was generated with lipopolysaccharide (LPS). Tanreqing injection was given by intratracheal instillation, and bronchoalveolar lavage fluid (BALF) from the right lung was collected. BALF total cell and neutrophil counts were then determined. In addition, BALF levels of inflammatory cytokines interleukin-13, cytokine-induced neutrophil chemoat-tractant-1, and tumor necrosis factor-alpha were measured using enzyme linked immunosorbent assay. The middle lobe of the right lung was stained with hematoxylin-eosin and histological changes examined. LPS increased airway inflammation, decreased BALF inflammatory cell count, inflammatory cytokine levels, and suppressed leukocyte influx of the lung. The LPS-induced airway inflammation peaked at 24 h, decreased beginning at 48 h, and had decreased markedly by 96 h. Tanreqing injection contains anti-inflammatory properties, and inhibits airway inflammation in a dose-dependent manner.

Neurokinin-1 receptor mediates stress-exacerbated allergic airway inflammation and airway hyperresponsiveness in mice.

PubMed

Joachim, Ricarda A; Sagach, Viktoriya; Quarcoo, David; Dinh, Q Thai; Arck, Petra C; Klapp, Burghard F

2004-01-01

A wealth of clinical observation has suggested that stress and asthma morbidity are associated. We have previously established a mouse model of stress-exacerbated allergic airway inflammation, which reflects major clinical findings. The aim of the current study was to investigate the role of the neurokinin- (NK-)1 receptor in the mediation of stress effects in allergic airway inflammation. BALB/c mice were systemically sensitized with ovalbumin (OVA) on assay days 1, 14, and 21 and repeatedly challenged with OVA aerosol on days 26 and 27. Sound stress was applied to the animals for 24 hours, starting with the first airway challenge. Additionally, one group of stressed and one group of nonstressed mice received the highly specific NK-1 receptor antagonist RP 67580. Bronchoalveolar lavage fluid was obtained, and cell numbers and differentiation were determined. Airway hyperreactivity was measured in vitro by electrical field stimulation of tracheal smooth-muscle elements. Application of stress in sensitized and challenged animals resulted in a significant increase in leukocyte number in the bronchoalveolar lavage fluid. Furthermore, stressed animals showed enhanced airway reactivity. The increase of inflammatory cells and airway reactivity was blocked by treatment of animals with the NK-1 receptor antagonist. These data indicate that the NK-1 receptor plays an important role in mediating stress effects in allergen-induced airway inflammation.

Inhibition of poly(ADP-ribose) polymerase prevents allergen-induced asthma-like reaction in sensitized Guinea pigs.

PubMed

Suzuki, Ylenia; Masini, Emanuela; Mazzocca, Cosimo; Cuzzocrea, Salvatore; Ciampa, Anna; Suzuki, Hisanori; Bani, Daniele

2004-12-01

Poly(ADP-ribose) polymerase (PARP) plays an important role in tissue injury in conditions associated with oxidative stress and inflammation. Because asthma is a chronic inflammatory disorder of the airways, we designed the present experimental study to evaluate the effects of PARP inhibition on allergen-induced asthma-like reaction in ovalbumin-sensitized guinea pigs. Cough and dyspnea in response to ovalbumin aerosol were absent in naive guinea pigs, whereas they became severe in the sensitized animals. In the latter ones, ovalbumin aerosol also induced a rapid increase in PARP activity, bronchiolar constriction, pulmonary air space inflation, mast cell degranulation, poly(ADP-ribose) and nitrotyrosine immunostaining, myeloperoxidase activity, and malondialdehyde in lung tissue, as well as a rise in the amounts of nitrites and tumor necrosis factor-alpha in bronchoalveolar lavage fluid. Pretreatment with the PARP inhibitors 3-aminobenzamide (10 mg/kg b.wt.) or 5-aminoisoquinolinone (0.5 mg/kg b.wt.) given i.p. 3 h before ovalbumin challenge significantly reduced the severity of cough and the occurrence of dyspnea and delayed the onset of respiratory abnormalities. Both PARP inhibitors were also able to prevent the above morphological and biochemical changes of lung tissue or bronchoalveolar lavage fluid induced by ovalbumin challenge. Conversely, p-aminobenzoic acid, the inactive analog of 3-aminobenzamide, had no effects.

Environmental Causes of Asthma.

PubMed

Cockcroft, Donald W

2018-02-01

Environmental factors which cause asthma are those that induce airway inflammation with eosinophils (more common) or neutrophils along with airway hyperresponsiveness (AHR). The most common of these (indeed the most common cause of asthma) are IgE-mediated inhalant allergen exposures. Allergen-induced AHR and inflammation are both associated with the allergen-induced late asthmatic response (LAR). Although allergens were previously recognized only as causes of symptoms and bronchoconstriction in asthmatics, we now appreciate them as causes of the fundamental pathophysiologic features of asthma. Low-molecular-weight chemical sensitizers, causes of occupational asthma, also cause asthma in a manner analogous to allergen. Acute irritant-induced asthma (reactive airways dysfunction syndrome) following a very heavy irritant exposure and chronic irritant-induced asthma following repeated high exposures can also induce persistent or permanent changes (inflammation and AHR) consistent with asthma. Textile dust exposure produces a different form of airway disease (byssinosis) which is less frequently observed currently. Environmental exposure to tobacco smoke facilitates the development of asthma in children. Personal smoking and environmental air pollution have an inconsistent and likely generally small effect in causing asthma. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The minor house dust mite allergen Der p 13 is a fatty acid-binding protein and an activator of a TLR2-mediated innate immune response.

PubMed

Satitsuksanoa, P; Kennedy, M; Gilis, D; Le Mignon, M; Suratannon, N; Soh, W T; Wongpiyabovorn, J; Chatchatee, P; Vangveravong, M; Rerkpattanapipat, T; Sangasapaviliya, A; Piboonpocanun, S; Nony, E; Ruxrungtham, K; Jacquet, A

2016-10-01

The house dust mite (HDM) allergen Der p 13 could be a lipid-binding protein able to activate key innate signaling pathways in the initiation of the allergic response. We investigated the IgE reactivity of recombinant Der p 13 (rDer p 13), its lipid-binding activities, and its capacity to stimulate airway epithelium cells. Purified rDer p 13 was characterized by mass spectrometry, circular dichroism, fluorescence-based lipid-binding assays, and in silico structural prediction. IgE-binding activity and allergenic potential of Der p 13 were examined by ELISA, basophil degranulation assays, and in vitro airway epithelial cell activation assays. Protein modeling and biophysical analysis indicated that Der p 13 adopts a β-barrel structure with a predominately apolar pocket representing a potential binding site for hydrophobic ligands. Fluorescent lipid-binding assays confirmed that the protein is highly selective for ligands and that it binds a fatty acid with a dissociation constant typical of lipid transporter proteins. The low IgE-binding frequency (7%, n = 224) in Thai HDM-allergic patients as well as the limited propensity to activate basophil degranulation classifies Der p 13 as a minor HDM allergen. Nevertheless, the protein with its presumptively associated lipid(s) triggered the production of IL-8 and GM-CSF in respiratory epithelial cells through a TLR2-, MyD88-, NF-kB-, and MAPK-dependent signaling pathway. Although a minor allergen, Der p 13 may, through its lipid-binding capacity, play a role in the initiation of the HDM-allergic response through TLR2 activation. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Timothy grass pollen extract-induced gene expression and signalling pathways in airway epithelial cells.

PubMed

Röschmann, K I L; Luiten, S; Jonker, M J; Breit, T M; Fokkens, W J; Petersen, A; van Drunen, C M

2011-06-01

Grass pollen allergy is one of the most common allergies worldwide and airborne allergens are the major cause of allergic rhinitis. Airway epithelial cells (AECs) are the first to encounter and respond to aeroallergens and are therefore interesting targets for the development of new therapeutics. Our understanding of the epithelial contribution to immune responses is limited as most studies focus on only a few individual genes or proteins. To describe in detail the Timothy grass pollen extract (GPE)-induced gene expression in AECs. NCI-H292 cells were exposed to GPE for 24 h, and isolated RNA and cell culture supernatants were used for microarray analysis and multiplex ELISA, respectively. Eleven thousand and seven hundred fifty-eight transcripts were affected after exposure to GPE, with 141 genes up-regulated and 121 genes down-regulated by more than threefold. The gene ontology group cell communication was among the most prominent categories. Network analysis revealed that a substantial part of regulated genes are related to the cytokines IL-6, IL-8, IL-1A, and the transcription factor FOS. After analysing significantly regulated signalling pathways, we found, among others, epidermal growth factor receptor 1, IL-1, Notch-, and Wnt-related signalling members. Unexpectedly, we found Jagged to be down-regulated and an increased release of IL-12, in line with a more Th1-biased response induced by GPE. Our data show that the stimulation of AECs with GPE results in the induction of a broad response on RNA and protein level by which they are able to affect the initiation and regulation of local immune responses. Detailed understanding of GPE-induced genes and signalling pathways will allow us to better define the pathogenesis of the allergic response and to identify new targets for treatment. © 2011 Blackwell Publishing Ltd.

Dietary sodium intake and the risk of airway hyperreactivity in a random adult population.

PubMed Central

Britton, J.; Pavord, I.; Richards, K.; Knox, A.; Wisniewski, A.; Weiss, S.; Tattersfield, A.

1994-01-01

BACKGROUND--High dietary sodium intake has been identified as a potential cause of asthma and airway hyperreactivity. This study was designed to test the hypothesis that dietary sodium intake is an independent determinant of the risk of hyperreactivity in the general population, and to assess the role of atopy in the association between these factors. METHODS--Airway reactivity to methacholine, atopy, 24 hour urinary sodium excretion, and self-reported smoking and symptom history were measured in a random sample of 1702 adults aged 18-70 from an administrative district of Nottingham. Hyperreactivity was defined as a PD20FEV1 of 12.25 mumol or less, and atopy was defined quantitatively as the mean allergen skin weal response to Dermatophagoides pteronyssinus, cat fur, and grass pollen, and categorically as the occurrence of any allergen response 1 mm or greater than the saline control. Multiple logistic regression analysis was used to estimate the independent relative odds of hyperreactivity, atopy, or symptoms in relation to sodium excretion in all 1702 subjects, and multiple linear regression to assess the independent relation between sodium excretion and mean allergen skin weal diameter, and the PD20 value amongst hyperreactive subjects. RESULTS--There was no relation between the relative odds of hyperreactivity to methacholine and 24 hour urinary sodium excretion, either before or after adjustment for age, smoking, allergen skin weal diameter, and sex, and similarly no relation if the analysis was restricted to men or women only. The relative odds of having at least one allergen skin test response 1 mm greater than the saline control were increased in relation to sodium excretion after adjustment for age, sex, and smoking by a ratio of 2.08 (95% CI 1.04 to 4.15) per log10 unit increase in sodium excretion, but there was no evidence of an association between sodium excretion and the occurrence of self-reported wheeze, hay fever, eczema, or asthma. There was no

Phleum pratense pollen starch granules induce humoral and cell-mediated immune responses in a rat model of allergy.

PubMed

Motta, A; Peltre, G; Dormans, J A M A; Withagen, C E T; Lacroix, G; Bois, F; Steerenberg, P A

2004-02-01

Timothy grass (Phleum pratense) pollen allergens are an important cause of allergic symptoms. However, pollen grains are too large to penetrate the deeper airways. Grass pollen is known to release allergen-bearing starch granules (SG) upon contact with water. These granules can create an inhalable allergenic aerosol capable of triggering an early asthmatic response and are implicated in thunderstorm-associated asthma. We studied the humoral (IgE) and bronchial lymph node cells reactivities to SG from timothy grass pollen in pollen-sensitized rats. Brown-Norway rats were sensitized (day 0) and challenged (day 21) intratracheally with intact pollen and kept immunized by pollen intranasal instillation by 4 weeks intervals during 3 months. Blood and bronchial lymph nodes were collected 7 days after the last intranasal challenge. SG were purified from fresh timothy grass pollen using 5 microm mesh filters. To determine the humoral response (IgE) to SG, we developed an original ELISA inhibition test, based on competition between pollen allergens and purified SG. The cell-mediated response to SG in the bronchial lymph node cells was determined by measuring the uptake of [3H]thymidine in a proliferation assay. An antibody response to SG was induced, and purified SG were able to inhibit the IgE ELISA absorbance by 45%. Pollen extract and intact pollen gave inhibitions of 55% and 52%, respectively. A cell-mediated response was also found, as pollen extract, intact pollen and SG triggered proliferation of bronchial lymph node cells. It was confirmed that timothy grass pollen contains allergen-loaded SG, which are released upon contact with water. These granules were shown to be recognized by pollen-sensitized rats sera and to trigger lymph node cell proliferation in these rats. These data provide new arguments supporting the implication of grass pollen SG in allergic asthma.

Eicosanoids modulate hyperpnea-induced late phase airway obstruction and hyperreactivity in dogs.

PubMed

Davis, Michael S; McCulloch, Sharron; Myers, Teresa; Freed, Arthur N

2002-01-01

A canine model of exercise-induced asthma was used to test the hypothesis that the development of a late phase response to hyperventilation depends on the acute production of pro-inflammatory mediators. Peripheral airway resistance, reactivity to hypocapnia and aerosol histamine, and bronchoalveolar lavage fluid (BALF) cell and eicosanoid content were measured in dogs approximately 5 h after dry air challenge (DAC). DAC resulted in late phase obstruction, hyperreactivity to histamine, and neutrophilic inflammation. Both cyclooxygenase and lipoxygenase inhibitors administered in separate experiments attenuated the late phase airway obstruction and hyperreactivity to histamine. Neither drug affected the late phase inflammation nor the concentrations of eicosanoids in the BALF obtained 5 h after DAC. This study confirms that hyperventilation of peripheral airways with unconditioned air causes late phase neutrophilia, airway obstruction, and hyperreactivity. The late phase changes in airway mechanics are related to the hyperventilation-induced release of both prostaglandins and leukotrienes, and appear to be independent of the late phase infiltration of inflammatory cells.

Cannabinoid receptor 2 augments eosinophil responsiveness and aggravates allergen-induced pulmonary inflammation in mice.

PubMed

Frei, R B; Luschnig, P; Parzmair, G P; Peinhaupt, M; Schranz, S; Fauland, A; Wheelock, C E; Heinemann, A; Sturm, E M

2016-07-01

Accumulation of activated eosinophils in tissue is a hallmark of allergic inflammation. The endocannabinoid 2-arachidonoylglycerol (2-AG) has been proposed to elicit eosinophil migration in a CB2 receptor/Gi/o -dependent manner. However, it has been claimed recently that this process may also involve other mechanisms such as cytokine priming and the metabolism of 2-AG into eicosanoids. Here, we explored the direct contribution of specific CB2 receptor activation to human and mouse eosinophil effector function in vitro and in vivo. In vitro studies including CB2 expression, adhesion and migratory responsiveness, respiratory burst, degranulation, and calcium mobilization were conducted in human peripheral blood eosinophils and mouse bone marrow-derived eosinophils. Allergic airway inflammation was assessed in mouse models of acute OVA-induced asthma and directed eosinophil migration. CB2 expression was significantly higher in eosinophils from symptomatic allergic donors. The selective CB2 receptor agonist JWH-133 induced a moderate migratory response in eosinophils. However, short-term exposure to JWH-133 potently enhanced chemoattractant-induced eosinophil shape change, chemotaxis, CD11b surface expression, and adhesion as well as production of reactive oxygen species. Receptor specificity of the observed effects was confirmed in eosinophils from CB2 knockout mice and by using the selective CB2 antagonist SR144528. Of note, systemic application of JWH-133 clearly primed eosinophil-directed migration in vivo and aggravated both AHR and eosinophil influx into the airways in a CB2 -specific manner. This effect was completely absent in eosinophil-deficient ∆dblGATA mice. Our data indicate that CB2 may directly contribute to the pathogenesis of eosinophil-driven diseases. Moreover, we provide new insights into the molecular mechanisms underlying the CB2 -mediated priming of eosinophils. Hence, antagonism of CB2 receptors may represent a novel pharmacological approach

Effects of multi-walled carbon nanotubes on a murine allergic airway inflammation model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Inoue, Ken-ichiro; Koike, Eiko; Yanagisawa, Rie

The development of nanotechnology has increased the risk of exposure to types of particles other than combustion-derived particles in the environment, namely, industrial nanomaterials. On the other hand, patients with bronchial asthma are sensitive to inhaled substances including particulate matters. This study examined the effects of pulmonary exposure to a type of nano-sized carbon nanotube (multi-walled nanotubes: MWCNT) on allergic airway inflammation in vivo and their cellular mechanisms in vitro. In vivo, ICR mice were divided into 4 experimental groups. Vehicle, MWCNT (50 {mu}g/animal), ovalbumin (OVA), and OVA + MWCNT were repeatedly administered intratracheally. Bronchoalveolar lavage (BAL) cellularity, lung histology,more » levels of cytokines related to allergic inflammation in lung homogenates/BAL fluids (BALFs), and serum immunoglobulin levels were studied. Also, we evaluated the impact of MWCNT (0.1-1 {mu}g/ml) on the phenotype and function of bone marrow-derived dendritic cells (DC) in vitro. MWCNT aggravated allergen-induced airway inflammation characterized by the infiltration of eosinophils, neutrophils, and mononuclear cells in the lung, and an increase in the number of goblet cells in the bronchial epithelium. MWCNT with allergen amplified lung protein levels of Th cytokines and chemokines compared with allergen alone. MWCNT exhibited adjuvant activity for allergen-specific IgG{sub 1} and IgE. MWCNT significantly increased allergen (OVA)-specific syngeneic T-cell proliferation, particularly at a lower concentration in vitro. Taken together, MWCNT can exacerbate murine allergic airway inflammation, at least partly, via the promotion of a Th-dominant milieu. In addition, the exacerbation may be partly through the inappropriate activation of antigen-presenting cells including DC.« less

Cough induced by mechanical stimulation of the upper airway in humans.

PubMed

Lee, Patrick; Eccles, Ronald

2004-08-01

Cough has previously been induced in animals by means of mechanical stimulation of the upper airway but this method has not previously been applied to humans. The aims of this study were to determine if cough could be induced in humans on mechanical stimulation of the upper airway and to see if this mechanically induced cough was reproducible. We also wished to investigate if there was any difference in cough sensitivity between healthy subjects and those with acute upper respiratory tract infection (URTI). In the first investigation, 2 groups were studied: 15 healthy subjects and 30 subjects with URTI with a mean age of 20 years. Cough was induced by vibration of the airway at the level of the trachea using a modified men's shaver. In the second investigation to determine the reproducibility of this mechanically induced cough, two groups from a different population were studied: 15 healthy subjects and 29 subjects with URTI with a mean age of 20.3 years. Cough was induced by airway vibration before and after a 90-min rest period. In the first investigation it was demonstrated that cough can be induced within 2 s of vibration; subjects with URTI are more sensitive to cough induction and cough approximately five times more than healthy subjects; cough increases with repeated stimulation and reaches a maximum after three periods of vibration; the cough response may be mediated by rapidly adapting airway sensory receptors. In the second investigation there was no significant difference in mean cough counts before and after a 90-min rest period in both groups, which demonstrates that the mechanically induced cough is reproducible. This is the first study to elicit cough in humans by mechanical stimulation of the upper airway. This new method of inducing cough in subjects with URTI may be useful for studying both the mechanism of cough and the effects of antitussive medicines.

Targeting Phosphoinositide 3-Kinase γ in Airway Smooth Muscle Cells to Suppress Interleukin-13-Induced Mouse Airway Hyperresponsiveness

PubMed Central

Jiang, Haihong; Xie, Yan; Abel, Peter W.; Toews, Myron L.; Townley, Robert G.; Casale, Thomas B.

2012-01-01

We recently reported that phosphoinositide 3-kinase γ (PI3Kγ) directly regulates airway smooth muscle (ASM) contraction by modulating Ca2+ oscillations. Because ASM contraction plays a critical role in airway hyperresponsiveness (AHR) of asthma, the aim of the present study was to determine whether targeting PI3Kγ in ASM cells could suppress AHR in vitro and in vivo. Intranasal administration into mice of interleukin-13 (IL-13; 10 μg per mouse), a key pathophysiologic cytokine in asthma, induced AHR after 48 h, as assessed by invasive tracheostomy. Intranasal administration of a broad-spectrum PI3K inhibitor or a PI3Kγ-specific inhibitor 1 h before AHR assessment attenuated IL-13 effects. Airway responsiveness to bronchoconstrictor agonists was also examined in precision-cut mouse lung slices pretreated without or with IL-13 for 24 h. Acetylcholine and serotonin dose-response curves indicated that IL-13-treated lung slices had a 40 to 50% larger maximal airway constriction compared with controls. Furthermore, acetylcholine induced a larger initial Ca2+ transient and increased Ca2+ oscillations in IL-13-treated primary mouse ASM cells compared with control cells, correlating with increased cell contraction. As expected, PI3Kγ inhibitor treatment attenuated IL-13-augmented airway contractility of lung slices and ASM cell contraction. In both control and IL-13-treated ASM cells, small interfering RNA-mediated knockdown of PI3Kγ by 70% only reduced the initial Ca2+ transient by 20 to 30% but markedly attenuated Ca2+ oscillations and contractility of ASM cells by 50 to 60%. This report is the first to demonstrate that PI3Kγ in ASM cells is important for IL-13-induced AHR and that acute treatment with a PI3Kγ inhibitor can ameliorate AHR in a murine model of asthma. PMID:22543031

Toluene diisocyanate increases airway responsiveness to substance P and decreases airway neutral endopeptidase.

PubMed

Sheppard, D; Thompson, J E; Scypinski, L; Dusser, D; Nadel, J A; Borson, D B

1988-04-01

Substance P and related tachykinins contribute to the airway hyperresponsiveness caused by toluene diisocyanate (TDI) in guinea pigs. Neutral endopeptidase (NEP) is an important modulator of substance P-induced responses. To test the hypothesis that exposure to TDI would increase responsiveness to substance P by inhibiting activity of this enzyme, we determined the dose of substance P required to increase pulmonary resistance by 200% above baseline (PD200) before and after administration of the pharmacologic inhibitor phosphoramidon in guinea pigs studied 1 h after a 1-h exposure to air or 3 ppm TDI. TDI exposure increased responsiveness to substance P significantly. However, phosphoramidon caused a significantly greater leftward shift of the substance P dose-response curve in air-exposed animals than it did in TDI-exposed animals, so that after phosphoramidon, mean values of PD200 in animals exposed to air or TDI did not differ. Tracheal NEP activity was significantly less after exposure to TDI than after exposure to air, whereas activity in the esophagus was the same in both groups. These results suggest that TDI exposure increases the bronchoconstrictor responsiveness of guinea pigs to substance P, in large part through inhibition of airway NEP.

Toluene diisocyanate increases airway responsiveness to substance P and decreases airway neutral endopeptidase.

PubMed Central

Sheppard, D; Thompson, J E; Scypinski, L; Dusser, D; Nadel, J A; Borson, D B

1988-01-01

Substance P and related tachykinins contribute to the airway hyperresponsiveness caused by toluene diisocyanate (TDI) in guinea pigs. Neutral endopeptidase (NEP) is an important modulator of substance P-induced responses. To test the hypothesis that exposure to TDI would increase responsiveness to substance P by inhibiting activity of this enzyme, we determined the dose of substance P required to increase pulmonary resistance by 200% above baseline (PD200) before and after administration of the pharmacologic inhibitor phosphoramidon in guinea pigs studied 1 h after a 1-h exposure to air or 3 ppm TDI. TDI exposure increased responsiveness to substance P significantly. However, phosphoramidon caused a significantly greater leftward shift of the substance P dose-response curve in air-exposed animals than it did in TDI-exposed animals, so that after phosphoramidon, mean values of PD200 in animals exposed to air or TDI did not differ. Tracheal NEP activity was significantly less after exposure to TDI than after exposure to air, whereas activity in the esophagus was the same in both groups. These results suggest that TDI exposure increases the bronchoconstrictor responsiveness of guinea pigs to substance P, in large part through inhibition of airway NEP. PMID:2450892

A mechanism for the induction of type 2 immune responses by a protease allergen in the genital tract.

PubMed

Oh, Ji Eun; Oh, Dong Sun; Jung, Hi Eun; Lee, Heung Kyu

2017-02-14

The genital mucosa is a barrier that is constantly exposed to a variety of pathogens, allergens, and external stimuli. Although both allergen exposure and parasite infections frequently occur in the genital area, the mechanism by which immune responses-particularly type 2 immunity-are induced has rarely been studied in the genital mucosa. Here, we demonstrate the induction of T helper type 2 (Th2) immunity in the genital mucosa in response to a model allergen, the protease papain. Intravaginal papain immunization induced type 2 immunity in a manner that was dependent on protease activity and the estrous phase of the mice. In addition, IL-33 was released from the vaginal epithelia after intravaginal papain immunization, leading to the activation of type 2 innate lymphoid cells (ILC2s). Moreover, the IL-33-MyD88 (myeloid differentiation primary response gene 88) signaling pathway was critical for the induction of type 2 immunity. We also found that Th2 differentiation in response to intravaginal papain treatment requires a specific dendritic cell (DC) subset that is controlled by interferon regulatory factor 4 (IRF4). These findings suggest that type 2 immunity is induced by a unique mechanism in the genital tract, which is an important, but often overlooked, barrier surface.

Characterization of airway and vascular responses in murine lungs

PubMed Central

Held, Heinz-Dieter; Martin, Christian; Uhlig, Stefan

1999-01-01

We characterized the responses of murine airways and pulmonary vessels to a variety of endogenous mediators in the isolated perfused and ventilated mouse lung (IPL) and compared them with those in precision-cut lung slices. Airways: The EC50 (μM) for contractions of airways in IPL/slices was methacholine (Mch), 6.1/1.5>serotonin, 0.7/2.0>U46619 (TP-receptor agonist), 0.1/0.06>endothelin-1, 0.1/0.05. In the IPL, maximum increase in airway resistance (RL) was 0.6, 0.4, 0.8 and 11 cmH2O s ml−1, respectively. Adenosine (⩽1 mM), bombesin (⩽100 μM), histamine (⩽10 mM), LTC4 (⩽1 μM), PAF (0.25 μM) and substance P (⩽100 μM) had only weak effects (<5% of Mch) on RL. Vessels: The EC50 (μM) for vasoconstriction in the IPL was LTC4, 0.06>U46619, 0.05airway response to Mch 5 fold and the maximum PAF-induced vasoconstriction 4 fold. Conclusion: Murine precision-cut lung slices maintain important characteristics of the whole organ. The maximum reagibility of murine airways to endogenous mediators is serotoninairway and vessel hyperreactivity induced by U46619 raises the possibility that thromboxane contributes directly to airway hyperresponsiveness in various experimental and clinical settings. PMID:10205008

Glucocorticoids inhibit sulfur mustard-induced airway muscle hyperresponsiveness to substance P.

PubMed

Calvet, J H; D'Ortho, M P; Jarreau, P H; Levame, M; Harf, A; Macquin-Mavier, I

1994-11-01

To explore the mechanisms of airway hyperreactivity to aerosolized substance P observed in guinea pigs 14 days after intratracheal injection of sulfur mustard (SM), we studied the effects of epithelium removal and inhibition of neutral endopeptidase (NEP) activity on airway muscle responsiveness. Tracheal rings from SM-intoxicated guinea pigs expressed a greater contractile response to substance P than rings from nonintoxicated guinea pigs. After epithelium removal or incubation with the NEP inhibitor phosphoramidon, the contractile responses of tracheal rings to substance P did not differ in guinea pigs injected with SM or ethanol (SM solvent). Treatment of the guinea pigs with betamethasone for 7 days before measurement abolished the airway muscle hyperresponsiveness observed in untreated SM-intoxicated guinea pigs and partially restored tracheal epithelium NEP activity. In addition, the tracheal epithelium height and cell density of SM-intoxicated guinea pigs treated with betamethasone were significantly greater than in those without betamethasone. These results demonstrate that SM intoxication induces airway muscle hyperresponsiveness to substance P by reducing tracheal epithelial NEP activity and that glucocorticoids might inhibit this hyperresponsiveness by increasing this activity.

IL-17 and TNF-α Are Key Mediators of Moraxella catarrhalis Triggered Exacerbation of Allergic Airway Inflammation

PubMed Central

Alnahas, Safa; Hagner, Stefanie; Raifer, Hartmann; Kilic, Ayse; Gasteiger, Georg; Mutters, Reinier; Hellhund, Anne; Prinz, Immo; Pinkenburg, Olaf; Visekruna, Alexander; Garn, Holger; Steinhoff, Ulrich

2017-01-01

Alterations of the airway microbiome are often associated with pulmonary diseases. For example, detection of the bacterial pathogen Moraxella catarrhalis in the upper airways is linked with an increased risk to develop or exacerbate asthma. However, the mechanisms by which M. catarrhalis augments allergic airway inflammation (AAI) remain unclear. We here characterized the cellular and soluble mediators of M. catarrhalis triggered excacerbation of AAI in wt and IL-17 deficient as well as in animals treated with TNF-α and IL-6 neutralizing antibodies. We compared the type of inflammatory response in M. catarrhalis infected, house dust mite (HDM)-allergic and animals infected with M. catarrhalis at different time points of HDM sensitization. We found that airway infection of mice with M. catarrhalis triggers a strong inflammatory response with massive neutrophilic infiltrates, high amounts of IL-6 and TNF-α and moderate levels of CD4+ T-cell-derived IFN-γ and IL-17. If bacterial infection occurred during HDM allergen sensitization, the allergic airway response was exacerbated, particularly by the expansion of Th17 cells and increased TNF-α levels. Neutralization of IL-17 or TNF-α but not IL-6 resulted in accelerated clearance of M. catarrhalis and effectively prevented infection-induced exacerbation of AAI. Taken together, our data demonstrate an essential role for TNF-α and IL-17 in infection-triggered exacerbation of AAI. PMID:29184554

Adenovirus-mediated Foxp3 expression in lung epithelial cells reduces airway inflammation in ovalbumin and cockroach-induced asthma model

PubMed Central

Park, Soojin; Chung, Hwan-Suck; Shin, Dasom; Jung, Kyung-Hwa; Lee, Hyunil; Moon, Junghee; Bae, Hyunsu

2016-01-01

Foxp3 is a master regulator of CD4+CD25+ regulatory T-cell (Treg) function and is also a suppressor of SKP2 and HER2/ErbB2. There are an increasing number of reports describing the functions of Foxp3 in cell types other than Tregs. In this context, we evaluated the functions of Foxp3 in ovalbumin- and cockroach-induced asthma models. Foxp3-EGFP-expressing adenovirus or EGFP control adenovirus was administered intratracheally (i.t.), followed by challenge with ovalbumin (OVA) or cockroach extract to induce asthma. Th2 cytokine and immune cell profiles of bronchoalveolar lavage fluid (BALF), as well as serum IgE levels, were analyzed. Histological analyses were also conducted to demonstrate the effects of Foxp3 expression on airway remodeling, goblet cell hyperplasia and inflammatory responses in the lung. Adenoviral Foxp3 was expressed only in lung epithelial cells, and not in CD4+ or CD8+ cells. BALF from Foxp3 gene-delivered mice showed significantly reduced numbers of total immune cells, eosinophils, neutrophils, macrophages and lymphocytes in response to cockroach allergen or OVA. In addition, Foxp3 expression in the lung reduced the levels of Th2 cytokines and IgE in BALF and serum, respectively. Moreover, histopathological analysis also showed that Foxp3 expression substantially inhibited eosinophil infiltration into the airways, goblet cell hyperplasia and smooth muscle cell hypertrophy. Furthermore, when Tregs were depleted by diphtheria toxin in Foxp3DTR mice, the anti-asthmatic functions of Foxp3 were not altered in OVA-challenged asthma models. In this study, our results suggest that Foxp3 expression in lung epithelial cells, and not in Tregs, inhibited OVA- and cockroach extract-induced asthma. PMID:27633092

Comparison of allergenicity and immunogenicity of an intact allergen vaccine and commercially available allergoid products for birch pollen immunotherapy.

PubMed

Lund, L; Henmar, H; Würtzen, P A; Lund, G; Hjortskov, N; Larsen, J N

2007-04-01

Specific immunotherapy with intact allergen vaccine is a well-documented treatment for allergic diseases. Different vaccine formulations are currently commercially available, the active ingredient either being intact allergens or chemically modified allergoids. The rationale behind allergoids is to decrease allergenicity while maintaining immunogenicity. However, data from the German health authorities based on reporting of adverse events over a 10-year period did not indicate increased safety of allergoids over intact allergens. The objective of this study was to investigate the effect of chemical modification on allergenicity and immunogenicity comparing four commercial allergoid products for birch pollen immunotherapy with an intact allergen vaccine. Solid-phase IgE inhibition and histamine release assays were selected as model systems for allergenicity, and a combination of human T cell proliferation and IgG titres following mouse immunizations were used to address the immunogenicity of the intact allergen vaccine and the four allergoids. In all assays, the products were normalized with respect to the manufacturer's recommended maintenance dose. IgE inhibition experiments showed a change in epitope composition comparing intact allergen vaccine with allergoid. One allergoid product induced enhanced histamine release compared to the intact allergens, while the other three allergoids showed reduced release. Standard T cell stimulation assays using lines from allergic patients showed a reduced response for all allergoids compared with the intact allergen vaccine regardless of the cell type used for antigen presentation. All allergoids showed reduced capacity to induce allergen-specific IgG responses in mice. While some allergoids were associated with reduced allergenicity, a clear reduction in immunogenicity was observed for all allergoid products compared with the intact allergen vaccine, and the commercial allergoids tested therefore do not fulfil the allergoid

Nitrogen Dioxide Exposure and Airway Responsiveness in ...

EPA Pesticide Factsheets

Controlled human exposure studies evaluating the effect of inhaled NO2 on the inherent responsiveness of the airways to challenge by bronchoconstricting agents have had mixed results. In general, existing meta-analyses show statistically significant effects of NO2 on the airway responsiveness of individuals with asthma. However, no meta-analysis has provided a comprehensive assessment of clinical relevance of changes in airway responsiveness, the potential for methodological biases in the original papers, and the distribution of responses. This paper provides analyses showing that a statistically significant fraction, 70% of individuals with asthma exposed to NO2 at rest, experience increases in airway responsiveness following 30-minute exposures to NO2 in the range of 200 to 300 ppb and following 60-minute exposures to 100 ppb. The distribution of changes in airway responsiveness is log-normally distributed with a median change of 0.75 (provocative dose following NO2 divided by provocative dose following filtered air exposure) and geometric standard deviation of 1.88. About a quarter of the exposed individuals experience a clinically relevant reduction in their provocative dose due to NO2 relative to air exposure. The fraction experiencing an increase in responsiveness was statistically significant and robust to exclusion of individual studies. Results showed minimal change in airway responsiveness for individuals exposed to NO2 during exercise. A variety of fa

DIESEL PARTICLE INSTILLATION ENHANCES INFLAMMATORY AND NEUROTROPHIN RESPONSES IN THE LUNGS OF ALLERGIC BALB/C MICE

EPA Science Inventory

Neurotrophins, including nerve growth factor (NGF) partially mediate many features of allergic airways disease including airways resistance and inflammation. Antibody blockade of NGF attenuates airways resistance associated with the allergen-specific airways responses in mice. ...

Differential cellular responses in healthy mice and in mice with established airway inflammation when exposed to hematite nanoparticles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gustafsson, Åsa, E-mail: asa.gustafsson@foi.se; Dept of Public Health and Clinical Medicine, Umeå University; Bergström, Ulrika

The aim of this study was to investigate the inflammatory and immunological responses in airways and lung-draining lymph nodes (LDLNs), following lung exposure to iron oxide (hematite) nanoparticles (NPs). The responses to the hematite NPs were evaluated in both healthy non-sensitized mice, and in sensitized mice with an established allergic airway disease. The mice were exposed intratracheally to either hematite NPs or to vehicle (PBS) and the cellular responses were evaluated on days 1, 2, and 7, post-exposure. Exposure to hematite NPs increased the numbers of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on days 1 andmore » 2 post-exposure; at these time points the number of lymphocytes was also elevated in the LDLNs. In contrast, exposing sensitized mice to hematite NPs induced a rapid and unspecific cellular reduction in the alveolar space on day 1 post-exposure; a similar decrease of lymphocytes was also observed in the LDLN. The results indicate that cells in the airways and in the LDLN of individuals with established airway inflammation undergo cell death when exposed to hematite NPs. A possible explanation for this toxic response is the extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways. This study demonstrates how sensitized and non-sensitized mice respond differently to hematite NP exposure, and it highlights the importance of including individuals with respiratory disorders when evaluating health effects of inhaled nanomaterials. - Highlights: • Hematite NPs induce differential responses in airways of healthy and allergic mice. • Hematite induced an airway inflammation in healthy mice. • Hematite induced cellular reduction in the alveolus and lymph nodes of allergic mice. • Cell death is possible due to extensive pro-oxidative environment in allergic mice. • It is important to include sensitive individuals when valuing health effects of NPs.« less

The who, where, and when of IgE in allergic airway disease.

PubMed

Dullaers, Melissa; De Bruyne, Ruth; Ramadani, Faruk; Gould, Hannah J; Gevaert, Philippe; Lambrecht, Bart N

2012-03-01

Allergic asthma and allergic rhinitis/conjunctivitis are characterized by a T(H)2-dominated immune response associated with increased serum IgE levels in response to inhaled allergens. Because IgE is a key player in the induction and maintenance of allergic inflammation, it represents a prime target for therapeutic intervention. However, our understanding of IgE biology remains fragmentary. This article puts together our current knowledge on IgE in allergic airway diseases with a special focus on the identity of IgE-secreting cells ("who"), their location ("where"), and the circumstances in which they are induced ("when"). We further consider the therapeutic implications of the insights gained. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Adam8 Limits the Development of Allergic Airway Inflammation in Mice

PubMed Central

Knolle, Martin D.; Nakajima, Takahiro; Hergrueter, Anja; Gupta, Kushagra; Polverino, Francesca; Craig, Vanessa J.; Fyfe, Susanne E.; Zahid, Muhammad; Permaul, Perdita; Cernadas, Manuela; Montano, Gilbert; Tesfaigzi, Yohannes; Sholl, Lynette; Kobzik, Lester; Israel, Elliot; Owen, Caroline A.

2013-01-01

To determine whether a disintegrin and a metalloproteinase-8 (Adam8) regulates allergic airway inflammation (AAI) and airway hyper-responsiveness (AHR), we compared AAI and AHR in wild type (WT) versus Adam8−/− mice in different genetic backgrounds sensitized and challenged with ovalbumin (OVA) or house dust mite protein extract (HDM). OVA- and HDM-treated Adam8−/− mice had higher lung leukocyte counts, more airway mucus metaplasia, greater lung levels of some TH2 cytokines, and higher methacholine-induced increases in central airway resistance than allergen-treated WT mice. Studies of OVA-treated Adam8 bone marrow chimeric mice confirmed that leukocyte-derived Adam8 predominantly mediated Adam8’s anti-inflammatory activities in murine airways. Airway eosinophils and macrophages both expressed Adam8 in WT mice with AAI. Adam8 limited AAI and AHR in mice by reducing leukocyte survival because: 1) Adam8−/− mice with AAI had fewer apoptotic eosinophils and macrophages in their airways than WT mice with AAI; and 2) Adam8−/− macrophages and eosinophils had reduced rates of apoptosis compared with WT leukocytes when the intrinsic (but not the extrinsic) apoptosis pathway was triggered in the cells in vitro. ADAM8 was robustly expressed by airway granulocytes in lung sections from human asthma patients but, surprisingly, airway macrophages had less ADAM8 staining than airway eosinophils. Thus, ADAM8 has anti-inflammatory activities during AAI in mice by activating the intrinsic apoptosis pathway in myeloid leukocytes. Strategies that increase ADAM8 levels in myeloid leukocytes may have therapeutic efficacy in asthma. PMID:23670189

Effects of sodium metabisulphite on guinea pig contractile airway smooth muscle responses in vitro.

PubMed

Sun, J; Sakamoto, T; Chung, K F

1995-08-01

Sodium metabisulphite (MBS) is known to induce bronchoconstriction in asthmatic patients. The effects of MBS on guinea pig airway smooth muscle and on neurally mediated contraction in vitro have been examined. Tracheal and bronchial airway segments were placed in oxygenated buffer solution and electrical field stimulation was performed in the presence of indomethacin (10(-5) M) and propranolol (10(-6) M) for the measurement of isometric tension. Atropine (10(-6) M) was added to bronchial tissues. Concentrations of MBS up to 10(-3) M had no direct effect on airway smooth muscle contraction and did not alter either tracheal smooth muscle contraction induced by electrical field stimulation at all frequencies or acetylcholine-induced tracheal smooth muscle contraction. There was a similar response in the absence of epithelium, except for potentiation of the response induced by electrical field stimulation at 0.5 Hz (24 (10)% increase). However, MBS (10(-5), 10(-6) and 10(-7) M) augmented neurally-mediated non-adrenergic non-cholinergic contractile responses in the bronchi (13.3 (3.2)%, 23.8 (9.6)%, and 6.4 (1.6)%, respectively). MBS had no effect on the contractile response induced by substance P, but at higher concentrations (10(-3) M and 10(-4) M) it caused a time-dependent attenuation of responses induced by either electrical field stimulation or exogenously applied acetylcholine or substance P. MBS had no direct contractile responses but enhanced bronchoconstriction induced by activation of non-cholinergic neural pathways in the bronchus, probably through increased release of neuropeptides. At high concentrations MBS inhibited contractile responses initiated by receptor or neural stimulation.

Effects of sodium metabisulphite on guinea pig contractile airway smooth muscle responses in vitro.

PubMed Central

Sun, J.; Sakamoto, T.; Chung, K. F.

1995-01-01

BACKGROUND--Sodium metabisulphite (MBS) is known to induce bronchoconstriction in asthmatic patients. The effects of MBS on guinea pig airway smooth muscle and on neurally mediated contraction in vitro have been examined. METHODS--Tracheal and bronchial airway segments were placed in oxygenated buffer solution and electrical field stimulation was performed in the presence of indomethacin (10(-5) M) and propranolol (10(-6) M) for the measurement of isometric tension. Atropine (10(-6) M) was added to bronchial tissues. RESULTS--Concentrations of MBS up to 10(-3) M had no direct effect on airway smooth muscle contraction and did not alter either tracheal smooth muscle contraction induced by electrical field stimulation at all frequencies or acetylcholine-induced tracheal smooth muscle contraction. There was a similar response in the absence of epithelium, except for potentiation of the response induced by electrical field stimulation at 0.5 Hz (24 (10)% increase). However, MBS (10(-5), 10(-6) and 10(-7) M) augmented neurally-mediated non-adrenergic non-cholinergic contractile responses in the bronchi (13.3 (3.2)%, 23.8 (9.6)%, and 6.4 (1.6)%, respectively). MBS had no effect on the contractile response induced by substance P, but at higher concentrations (10(-3) M and 10(-4) M) it caused a time-dependent attenuation of responses induced by either electrical field stimulation or exogenously applied acetylcholine or substance P. CONCLUSIONS--MBS had no direct contractile responses but enhanced bronchoconstriction induced by activation of non-cholinergic neural pathways in the bronchus, probably through increased release of neuropeptides. At high concentrations MBS inhibited contractile responses initiated by receptor or neural stimulation. Images PMID:7570440

Effects of drug treatment on inflammation and hyperreactivity of airways and on immune variables in cats with experimentally induced asthma.

PubMed

Reinero, Carol R; Decile, Kendra C; Byerly, Jenni R; Berghaus, Roy D; Walby, William E; Berghaus, Londa J; Hyde, Dallas M; Schelegle, Edward S; Gershwin, Laurel J

2005-07-01

To compare the effects of an orally administered corticosteroid (prednisone), an inhaled corticosteroid (flunisolide), a leukotriene-receptor antagonist (zafirlukast), an antiserotonergic drug (cyproheptadine), and a control substance on the asthmatic phenotype in cats with experimentally induced asthma. 6 cats with asthma experimentally induced by the use of Bermuda grass allergen (BGA). A randomized, crossover design was used to assess changes in the percentage of eosinophils in bronchoalveolar lavage fluid (BALF); airway hyperresponsiveness; blood lymphocyte phenotype determined by use of flow cytometry; and serum and BALF content of BGA-specific IgE, IgG, and IgA determined by use of ELISAs. Mean +/- SE eosinophil percentages in BALF when cats were administered prednisone (5.0 +/- 2.3%) and flunisolide (2.5 +/- 1.7%) were significantly lower than for the control treatment (33.7 +/- 11.1%). We did not detect significant differences in airway hyperresponsiveness or lymphocyte surface markers among treatments. Content of BGA-specific IgE in serum was significantly lower when cats were treated with prednisone (25.5 +/- 5.4%), compared with values for the control treatment (63.6 +/- 12.9%); no other significant differences were observed in content of BGA-specific immunoglobulins among treatments. Orally administered and inhaled corticosteroids decreased eosinophilic inflammation in airways of cats with experimentally induced asthma. Only oral administration of prednisone decreased the content of BGA-specific IgE in serum; no other significant local or systemic immunologic effects were detected among treatments. Inhaled corticosteroids can be considered as an alternate method for decreasing airway inflammation in cats with asthma.

K/sup +/-induced alterations in airway muscle responsiveness to electrical field stimulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murlas, C.; Ehring, G.; Suszkiw, J.

1986-07-01

The authors investigated possible pre- and postsynaptic effects of K/sup +/-induced depolarization on ferret tracheal smooth muscle (TSM) responsiveness to cholinergic stimulation. To assess electromechanical activity, cell membrane potential (E/sub m/) and tension (T/sub m/) were simultaneously recorded in buffer containing 6, 12, 18, or 24 mM K/sup +/ before and after electrical field stimulation (EFS) or exogenous acetylcholine (ACh). In 6 mM K/sup +/ E/sub m/ was -58.1 +/- 1.0 m V (mean +/- SE). In 12 mM K/sup +/, E/sub m/ was depolarized to -52.3 +/- 0.9 mV, basal T/sub m/ did not change, and both excitatory junctionalmore » potentials and contractile responses to EFS at short stimulus duration were larger than in 6 mM K/sup +/. No such potentiation occurred at a higher K/sup +/, although resting E/sub m/ and T/sub m/ increased progressively above 12 mM K/sup +/. The sensitivity of ferret TSM to exogenous ACh appeared unaffected by K/sup +/. To determine whether the hyperresponsiveness in 12 mM K/sup +/ was due, in part, to augmented ACh release from intramural airway nerves, experiments were done using TSM preparations incubated with (/sup 3/H)choline to measure (/sup 3/H)ACh release at rest and during EFS. Although resting (/sup 3/H)ACh release increased progressively in higher K/sup +/, release evoked by EFS was maximal in 12 mM K/sup +/ and declined in higher concentrations. They conclude that small elevations in the extracellular K/sup +/ concentration augment responsiveness of the airways, by increasing the release of ACh both at rest and during EFS from intramural cholinergic nerve terminals. Larger increases in K/sup +/ appear to be inhibitory, possibly due to voltage-dependent effects that occur both pre- and postsynaptically.« less

Construction of a Der p2-transgenic plant for the alleviation of airway inflammation

PubMed Central

Lee, CC; Ho, H; Lee, KT; Jeng, ST; Chiang, BL

2011-01-01

In clinical therapy, the amount of antigen administered to achieve oral tolerance for allergic diseases is large, and the cost is a major consideration. In this study, we used tobacco plants to develop a large-scale protein production system for allergen-specific immunotherapy, and we investigated the mechanisms of oral tolerance induced by a transgenic plant-derived antigen. We used plants (tobacco leaves) transgenic for the Dermatophagoides pteronyssinus 2 (Der p2) antigen to produce Der p2. Mice received total protein extract from Der p2 orally once per day over 6 days (days 0–2 and days 6–8). Mice were also sensitized and challenged with yeast-derived recombinant Der p2 (rDer p2), after which the mice were examined for airway hyper-responsiveness and airway inflammation. After sensitization and challenge with rDer p2, mice that were fed with total protein extracted from transgenic plants showed decreases in serum Der p2-specific IgE and IgG1 titers, decreased IL-5 and eotaxin levels in bronchial alveolar lavage fluid, and eosinophil infiltration in the airway. In addition, hyper-responsiveness was also decreased in mice that were fed with total protein extracted from transgenic plants, and CD4+CD25+Foxp3+ regulatory T cells were significantly increased in mediastinal and mesenteric lymph nodes. Furthermore, splenocytes isolated from transgenic plant protein-fed mice exhibited decreased proliferation and increased IL-10 secretion after stimulation with rDer p2. The data here suggest that allergen-expressing transgenic plants could be used for therapeutic purposes for allergic diseases. PMID:21602845

FABP4 induces asthmatic airway epithelial barrier dysfunction via ROS-activated FoxM1.

PubMed

Wu, Gaohui; Yang, Liteng; Xu, Yi; Jiang, Xiaohong; Jiang, Xiaomin; Huang, Lisha; Mao, Ling; Cai, Shaoxi

2018-01-01

Functional abnormal airway epithelial cells, along with activated inflammatory cells, resulting in chronic airway inflammation, are considered as the characteristic of asthma. Fatty Acid Binding Protein 4 (FABP4) takes part in glucose and lipid homeostasis, and also have an important role in allergic airway inflammation. However, whether FABP4 influence barrier function of airway epithelial cells is unknown. In vivo, a HDM-induced murine model of asthma was obtained to assessed airway inflammation and protein expression of E-cadherin and Forkhead Box M1 (FoxM1). In vitro, 16-HBE was cultured and was treated with hrFABP4, siFABP4, FABPF4 inhibitor BMS, or FoxM1 inhibitor RCM-1. IL-4, IL-5, and IL-13 level was determined by ELISA. Transepithelial electrical resistance (TER), paracellular permeability and E-cadherin-special immunofluorescence were measured to value airway epithelial barrier function. Intracellular ROS production was determined by DCF-DA fluorescence. FABP4 inhibitor BMS alleviate airway inflammation and destruction of E-cad in allergic mouse. Treatment with HDM or hrFABP4 aggravated inflammatory response, damaged airway epithelial barrier, which could be inhibited by siFABP4 and BMS. Treatment with HDM or hrFABP4 also enhanced levels of FoxM1, and Inhibited FoxM1 suppressed HDM- and hrFABP4-induced inflammation and airway epithelial barrier dysfunction. In addition, H 2 O 2 promoted FoxM1 expression, HDM and hrFABP4 induced-FoxM1 could be inhibited by NAC, leading to decreased inflammation and improved airway epithelial barrier. Upregulated ROS induced by FABP4 was of significance in activating FoxM1 leading to airway inflammation and epithelial barrier dysfunction. Copyright © 2017 Elsevier Inc. All rights reserved.

Infection-induced airway fibrosis in two rat strains with differential susceptibility.

PubMed Central

McIntosh, J C; Simecka, J W; Ross, S E; Davis, J K; Miller, E J; Cassell, G H

1992-01-01

Chronic infections play a significant role in the morbidity and mortality of patients with chronic airflow limitation. By stimulating airway inflammation, persistent infection has the potential to cause airway fibrosis. However, in patient this condition is most typically found in lungs damaged by other factors, such as smoking, abnormal secretions, or barotrauma. We report the characterization of Mycoplasma pulmonis infection-induced lung fibrosis in two immunocompetent rat strains with no preexisting lung disease. The fibrosis was predominantly in the airways, as demonstrated by the findings for infected animals of increased airway inflammation, airway fibrosis, and airway wall thickness, which correlated with the collagen content of the lungs. Also, the physiological alterations were the opposite of those found in interstitial fibrosis, with a positive correlation between lung compliance and collagen content. The airway fibrosis was noted earlier and to a greater extent in Lewis rats than in Fisher rats, and this result apparently was related to regulation of the inflammatory response. Airway wall thickness, airway inflammation, and airway fibrosis are commonly reported in tissue specimens from patients with chronic airway diseases and have been shown to correlate with airflow limitation in patients with chronic obstructive pulmonary disease. Thus, this model may be useful in furthering our understanding of the role of chronic infection and airway inflammation in airflow obstruction. Images PMID:1612760

Dimethylthiourea protects against chlorine induced changes in airway function in a murine model of irritant induced asthma.

PubMed

McGovern, Toby K; Powell, William S; Day, Brian J; White, Carl W; Govindaraju, Karuthapillai; Karmouty-Quintana, Harry; Lavoie, Normand; Tan, Ju Jing; Martin, James G

2010-10-06

Exposure to chlorine (Cl2) causes airway injury, characterized by oxidative damage, an influx of inflammatory cells and airway hyperresponsiveness. We hypothesized that Cl2-induced airway injury may be attenuated by antioxidant treatment, even after the initial injury. Balb/C mice were exposed to Cl2 gas (100 ppm) for 5 mins, an exposure that was established to alter airway function with minimal histological disruption of the epithelium. Twenty-four hours after exposure to Cl2, airway responsiveness to aerosolized methacholine (MCh) was measured. Bronchoalveolar lavage (BAL) was performed to determine inflammatory cell profiles, total protein, and glutathione levels. Dimethylthiourea (DMTU;100 mg/kg) was administered one hour before or one hour following Cl2 exposure. Mice exposed to Cl2 had airway hyperresponsiveness to MCh compared to control animals pre-treated and post-treated with DMTU. Total cell counts in BAL fluid were elevated by Cl2 exposure and were not affected by DMTU treatment. However, DMTU-treated mice had lower protein levels in the BAL than the Cl2-only treated animals. 4-Hydroxynonenal analysis showed that DMTU given pre- or post-Cl2 prevented lipid peroxidation in the lung. Following Cl2 exposure glutathione (GSH) was elevated immediately following exposure both in BAL cells and in fluid and this change was prevented by DMTU. GSSG was depleted in Cl2 exposed mice at later time points. However, the GSH/GSSG ratio remained high in chlorine exposed mice, an effect attenuated by DMTU. Our data show that the anti-oxidant DMTU is effective in attenuating Cl2 induced increase in airway responsiveness, inflammation and biomarkers of oxidative stress.

Attenuation of tachykinin-induced airflow obstruction and microvascular leakage in immature airways.

PubMed Central

Tokuyama, K.; Yokoyama, T.; Morikawa, A.; Mochizuki, H.; Kuroume, T.; Barnes, P. J.

1993-01-01

1. To study the effect of maturation on substance P (SP)- and neurokinin A (NKA)-induced airflow obstruction and airway microvascular leakage (MVL), we have measured changes in both lung resistance (RL) and extravasation of Evans blue dye in anaesthetized immature (aged 14 +/- 1 days) and adult guinea-pigs (aged 80 +/- 3 days). 2. RL and its recovery after hyperinflation at 5 min were measured for 6 min after i.v. SP (0.2, 1 and 30 nmol kg-1), NKA (1 and 10 nmol kg-1) or vehicle (0.9% NaCl). After measurement of RL, MVL in trachea, main bronchi and intrapulmonary airways was also examined. 3. The order of potency in inducing airflow obstruction did not change with age (NKA > SP) but immature animals required a larger dose of SP or NKA than adults to cause a significant increase in RL. 4. The order of potency in inducing airway microvascular leakage was SP > NKA in both immature and adult animals. The amount of extravasated dye after SP was significantly less in immature airways, especially in central airways. 5. Phosphoramidon (2.5 mg kg-1), a neutral endopeptidase (NEP) inhibitor, significantly increased RL after 0.2 nmol kg-1 SP only in adult airways. Phosphoramidon enhanced the dye extravasation after 0.2 nmol kg-1 SP in both immature and adult airways with a significantly greater amount of dye in adult animals, suggesting that mechanisms other than changes in NEP activity may be responsible for this age-related difference.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7679033

Inhibition of allergen-induced basophil activation by ASM-024, a nicotinic receptor ligand.

PubMed

Watson, Brittany M; Oliveria, John Paul; Nusca, Graeme M; Smith, Steven G; Beaudin, Sue; Dua, Benny; Watson, Rick M; Assayag, Evelynne Israël; Cormier, Yvon F; Sehmi, Roma; Gauvreau, Gail M

2014-01-01

Nicotinic acetylcholine receptors (nAChRs) were identified on eosinophils and shown to regulate inflammatory responses, but nAChR expression on basophils has not been explored yet. We investigated surface receptor expression of nAChR α4, α7 and α1/α3/α5 subunits on basophils. Furthermore, we examined the effects of ASM-024, a synthetic nicotinic ligand, on in vitro anti-IgE and in vivo allergen-induced basophil activation. Basophils were enriched from the peripheral blood of allergic donors and the expression of nAChR subunits and muscarinic receptors was determined. Purified basophils were stimulated with anti-IgE in the presence of ASM-024 with or without muscarinic or nicotinic antagonists for the measurement of CD203c expression and histamine release. The effect of 9 days of treatment with 50 and 200 mg ASM-024 on basophil CD203c expression was examined in the blood of mild allergic asthmatics before and after allergen inhalation challenge. nAChR α4, α7 and α1/α3/α5 receptor subunit expression was detected on basophils. Stimulation of basophils with anti-IgE increased CD203c expression and histamine release, which was inhibited by ASM-024 (10(-5) to 10(-)(3) M, p < 0.05). The effect of ASM-024 was reversed in the presence of muscarinic and nicotinic antagonists. In subjects with mild asthma, ASM-024 inhalation significantly inhibited basophil CD203c expression measured 24 h after allergen challenge (p = 0.03). This study shows that ASM-024 inhibits IgE- and allergen-induced basophil activation through both nicotinic and muscarinic receptors, and suggests that ASM-024 may be an efficacious agent for modulating allergic asthma responses. © 2015 S. Karger AG, Basel.

Eosinophil Activities Modulate the Immune/Inflammatory Character of Allergic Respiratory Responses in Mice

PubMed Central

Jacobsen, Elizabeth A.; LeSuer, William E.; Willetts, Lian; Zellner, Katie R.; Mazzolini, Kirea; Antonios, Nathalie; Beck, Brandon; Protheroe, Cheryl; Ochkur, Sergei I.; Colbert, Dana; Lacy, Paige; Moqbel, Redwan; Appleton, Judith; Lee, Nancy A.; Lee, James J.

2014-01-01

Background The importance and specific role(s) of eosinophils in modulating the immune/inflammatory phenotype of allergic pulmonary disease remain to be defined. Established animals models assessing the role(s) of eosinophils as contributors and/or causative agents of disease have relied on congenitally deficient mice where the developmental consequences of eosinophil depletion are unknown. Methods We developed a novel conditional eosinophil-deficient strain of mice (iPHIL) through a gene knock-in strategy inserting the human diphtheria toxin (DT) receptor (DTR) into the endogenous eosinophil peroxidase genomic locus. Results Expression of DTR rendered resistant mouse eosinophil progenitors sensitive to DT without affecting any other cell types. The presence of eosinophils was shown to be unnecessary during the sensitization phase of either ovalbumin (OVA) or house dust mite (HDM) acute asthma models. However, eosinophil ablation during airway challenge led to a predominantly neutrophilic phenotype (>15% neutrophils) accompanied by allergen-induced histopathologies and airway hyperresponsiveness in response to methacholine indistinguishable from eosinophilic wild type mice. Moreover, the iPHIL neutrophilic airway phenotype was shown to be a steroid-resistant allergic respiratory variant that was reversible upon restoration of peripheral eosinophils. Conclusions Eosinophil contributions to allergic immune/inflammatory responses appear to be limited to the airway challenge and not the sensitization phase of allergen provocation models. The reversible steroid-resistant character of the iPHIL neutrophilic airway variant suggests underappreciated mechanisms by which eosinophils shape the character of allergic respiratory responses. PMID:24266710

Trichuris suis ova therapy for allergic rhinitis does not affect allergen-specific cytokine responses despite a parasite-specific cytokine response.

PubMed

Bourke, C D; Mutapi, F; Nausch, N; Photiou, D M F; Poulsen, L K; Kristensen, B; Arnved, J; Rønborg, S; Roepstorff, A; Thamsborg, S; Kapel, C; Melbye, M; Bager, P

2012-11-01

Parasitic helminths have been shown to reduce inflammation in most experimental models of allergic disease, and this effect is mediated via cytokine responses. However, in humans, the effects of controlled helminth infection on cytokine responses during allergy have not been studied. The aim was to investigate whether infection with the nematode parasite Trichuris suis alters systemic cytokine levels, cellular cytokine responses to parasite antigens and pollen allergens and/or the cytokine profile of allergic individuals. In a randomized double-blinded placebo-controlled clinical trial (UMIN trial registry, Registration no. R000001298, Trial ID UMIN000001070, URL: http://www.umin.ac.jp/map/english), adults with grass pollen-induced allergic rhinitis received three weekly doses of 2500 Trichuris suis ova (n = 45) or placebo (n = 44) over 6 months. IFN-γ, TNF-α, IL-4, IL-5, IL-10 and IL-13 were quantified via cytometric bead array in plasma. Cytokines, including active TGF-β, were also quantified in supernatants from peripheral blood mononuclear cells cultured with parasite antigens or pollen allergens before, during and after the grass pollen season for a sub-cohort of randomized participants (T. suis ova-treated, n = 12, Placebo-treated, n = 10). Helminth infection induced a Th2-polarized cytokine response comprising elevated plasma IL-5 and parasite-specific IL-4, IL-5 and IL-13, and a global shift in the profile of systemic cytokine responses. Infection also elicited high levels of the regulatory cytokine IL-10 in response to T. suis antigens. Despite increased production of T. suis-specific cytokines in T. suis ova-treated participants, allergen-specific cytokine responses during the grass pollen season and the global profile of PBMC cytokine responses were not affected by T. suis ova treatment. This study suggests that cytokines induced by Trichuris suis ova treatment do not alter allergic reactivity to pollen during the peak of allergic rhinitis

Measurements of intracellular calcium signals in polarized primary cultures of normal and cystic fibrosis human airway epithelia.

PubMed

Ribeiro, Carla M P

2011-01-01

The airways are continuously challenged by a variety of stimuli including bacteria, viruses, allergens, and inflammatory factors that act as agonists for G protein-coupled receptors (GPCR). Intracellular calcium (Ca(2+) (i)) mobilization in airway epithelia in response to extracellular stimuli regulates key airway innate defense functions, e.g., Ca(2+)-activated Cl(-) secretion, ciliary beating, mucin secretion, and inflammatory responses. Because Ca(2+) (i) mobilization in response to luminal stimuli is larger in CF vs. normal human airway epithelia, alterations in Ca(2+) (i) signals have been associated with the pathogenesis of CF airway disease. Hence, assessment of Ca(2+) (i) signaling has become an important area of CF research. This chapter will focus on measurements of cytoplasmic and mitochondrial Ca(2+) signals resulting from GPCR activation in polarized primary cultures of normal and CF human bronchial epithelia (HBE).

Inhibition of neutral endopeptidase increases airway responsiveness to ACh in nonsensitized normal rats.

PubMed

Chiba, Y; Misawa, M

1995-02-01

The effects of sensory neuropeptides on the airway responsiveness to acetylcholine (ACh) were investigated in normal nonsensitized rats. The airway responsiveness to inhaled ACh was significantly increased after treatment with neurokinin A (NKA; 0.001%) or substance P (SP; 0.01%) aerosol in the presence of the neutral endopeptidase (NEP) inhibitor. NKA had a more potent effect than SP. Interestingly, the intravenous treatment with NEP inhibitor alone also induced airway hyperresponsiveness (AHR) to inhaled ACh. This AHR was significantly attenuated by pretreatment with a nonselective NK-receptor antagonist, [D-Pro2,D-Trp7,9]SP, systemic capsaicin, or bilateral cervical vagotomy, indicating that decreased NEP activity results in accumulation of endogenous sensory neuropeptide(s) and enhancement of vagal reflex to cause AHR. The airway responsiveness to ACh of isolated left main bronchus was also increased after treatment with 10(-6) M NKA, but not SP, together with 10(-6) M phosphoramidon. This in vitro AHR to ACh induced by phosphoramidon plus NKA was significantly attenuated by pretreatment with 10(-6) M tetrodotoxin. These findings suggest that overaccumulated sensory neuropeptides, especially NKA, may enhance the probability of transmitter release, probably via NK2 receptors, and that the enhanced transmitter release might be involved in AHR in rats.

The Effects of Airway Microbiome on Corticosteroid Responsiveness in Asthma

PubMed Central

Goleva, Elena; Jackson, Leisa P.; Harris, J. Kirk; Robertson, Charles E.; Sutherland, E. Rand; Hall, Clifton F.; Good, James T.; Gelfand, Erwin W.; Martin, Richard J.

2013-01-01

Rationale: The role of airway microbiome in corticosteroid response in asthma is unknown. Objectives: To examine airway microbiome composition in patients with corticosteroid-resistant (CR) asthma and compare it with patients with corticosteroid-sensitive (CS) asthma and normal control subjects and explore whether bacteria in the airways of subjects with asthma may direct alterations in cellular responses to corticosteroids. Methods: 16S rRNA gene sequencing was performed on bronchoalveolar lavage (BAL) samples of 39 subjects with asthma and 12 healthy control subjects. In subjects with asthma, corticosteroid responsiveness was characterized, BAL macrophages were stimulated with pathogenic versus commensal microorganisms, and analyzed by real-time polymerase chain reaction for the expression of corticosteroid-regulated genes and cellular p38 mitogen-activated protein kinase (MAPK) activation. Measurements and Main Results: Of the 39 subjects with asthma, 29 were CR and 10 were CS. BAL microbiome from subjects with CR and CS asthma did not differ in richness, evenness, diversity, and community composition at the phylum level, but did differ at the genus level, with distinct genus expansions in 14 subjects with CR asthma. Preincubation of asthmatic airway macrophages with Haemophilus parainfluenzae, a uniquely expanded potential pathogen found only in CR asthma airways, resulted in p38 MAPK activation, increased IL-8 (P < 0.01), mitogen-activated kinase phosphatase 1 mRNA (P < 0.01) expression, and inhibition of corticosteroid responses (P < 0.05). This was not observed after exposure to commensal bacterium Prevotella melaninogenica. Inhibition of transforming growth factor-β–associated kinase-1 (TAK1), upstream activator of MAPK, but not p38 MAPK restored cellular sensitivity to corticosteroids. Conclusions: A subset of subjects with CR asthma demonstrates airway expansion of specific gram-negative bacteria, which trigger TAK1/MAPK activation and induce

Allergen-Induced Dermatitis Causes Alterations in Cutaneous Retinoid-Mediated Signaling in Mice

PubMed Central

Gericke, Janine; Ittensohn, Jan; Mihály, Johanna; Dubrac, Sandrine; Rühl, Ralph

2013-01-01

Nuclear receptor-mediated signaling via RARs and PPARδ is involved in the regulation of skin homeostasis. Moreover, activation of both RAR and PPARδ was shown to alter skin inflammation. Endogenous all-trans retinoic acid (ATRA) can activate both receptors depending on specific transport proteins: Fabp5 initiates PPARδ signaling whereas Crabp2 promotes RAR signaling. Repetitive topical applications of ovalbumin (OVA) in combination with intraperitoneal injections of OVA or only intraperitoneal OVA applications were used to induce allergic dermatitis. In our mouse model, expression of IL-4, and Hbegf increased whereas expression of involucrin, Abca12 and Spink5 decreased in inflamed skin, demonstrating altered immune response and epidermal barrier homeostasis. Comprehensive gene expression analysis showed alterations of the cutaneous retinoid metabolism and retinoid-mediated signaling in allergic skin immune response. Notably, ATRA synthesis was increased as indicated by the elevated expression of retinaldehyde dehydrogenases and increased levels of ATRA. Consequently, the expression pattern of genes downstream to RAR was altered. Furthermore, the increased ratio of Fabp5 vs. Crabp2 may indicate an up-regulation of the PPARδ pathway in allergen-induced dermatitis in addition to the altered RAR signaling. Thus, our findings suggest that ATRA levels, RAR-mediated signaling and signaling involved in PPARδ pathways are mainly increased in allergen-induced dermatitis and may contribute to the development and/or maintenance of allergic skin diseases. PMID:23977003

Allergen-induced dermatitis causes alterations in cutaneous retinoid-mediated signaling in mice.

PubMed

Gericke, Janine; Ittensohn, Jan; Mihály, Johanna; Dubrac, Sandrine; Rühl, Ralph

2013-01-01

Nuclear receptor-mediated signaling via RARs and PPARδ is involved in the regulation of skin homeostasis. Moreover, activation of both RAR and PPARδ was shown to alter skin inflammation. Endogenous all-trans retinoic acid (ATRA) can activate both receptors depending on specific transport proteins: Fabp5 initiates PPARδ signaling whereas Crabp2 promotes RAR signaling. Repetitive topical applications of ovalbumin (OVA) in combination with intraperitoneal injections of OVA or only intraperitoneal OVA applications were used to induce allergic dermatitis. In our mouse model, expression of IL-4, and Hbegf increased whereas expression of involucrin, Abca12 and Spink5 decreased in inflamed skin, demonstrating altered immune response and epidermal barrier homeostasis. Comprehensive gene expression analysis showed alterations of the cutaneous retinoid metabolism and retinoid-mediated signaling in allergic skin immune response. Notably, ATRA synthesis was increased as indicated by the elevated expression of retinaldehyde dehydrogenases and increased levels of ATRA. Consequently, the expression pattern of genes downstream to RAR was altered. Furthermore, the increased ratio of Fabp5 vs. Crabp2 may indicate an up-regulation of the PPARδ pathway in allergen-induced dermatitis in addition to the altered RAR signaling. Thus, our findings suggest that ATRA levels, RAR-mediated signaling and signaling involved in PPARδ pathways are mainly increased in allergen-induced dermatitis and may contribute to the development and/or maintenance of allergic skin diseases.

Fatty Acid Binding Protein 4 Regulates VEGF-Induced Airway Angiogenesis and Inflammation in a Transgenic Mouse Model

PubMed Central

Ghelfi, Elisa; Yu, Chen-Wei; Elmasri, Harun; Terwelp, Matthew; Lee, Chun G.; Bhandari, Vineet; Comhair, Suzy A.; Erzurum, Serpil C.; Hotamisligil, Gökhan S.; Elias, Jack A.; Cataltepe, Sule

2014-01-01

Neovascularization of the airways occurs in several inflammatory lung diseases, including asthma. Vascular endothelial growth factor (VEGF) plays an important role in vascular remodeling in the asthmatic airways. Fatty acid binding protein 4 (FABP4 or aP2) is an intracellular lipid chaperone that is induced by VEGF in endothelial cells. FABP4 exhibits a proangiogenic function in vitro, but whether it plays a role in modulation of angiogenesis in vivo is not known. We hypothesized that FABP4 promotes VEGF-induced airway angiogenesis and investigated this hypothesis with the use of a transgenic mouse model with inducible overexpression of VEGF165 under a CC10 promoter [VEGF-TG (transgenic) mice]. We found a significant increase in FABP4 mRNA levels and density of FABP4-expressing vascular endothelial cells in mouse airways with VEGF overexpression. FABP4−/− mouse airways showed a significant decrease in neovessel formation and endothelial cell proliferation in response to VEGF overexpression. These alterations in airway vasculature were accompanied by attenuated expression of proinflammatory mediators. Furthermore, VEGF-TG/FABP4−/− mice showed markedly decreased expression of endothelial nitric oxide synthase, a well-known mediator of VEGF-induced responses, compared with VEGF-TG mice. Finally, the density of FABP4-immunoreactive vessels in endobronchial biopsy specimens was significantly higher in patients with asthma than in control subjects. Taken together, these data unravel FABP4 as a potential target of pathologic airway remodeling in asthma. PMID:23391391

Airway epithelial cell response to human metapneumovirus infection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bao, X.; Liu, T.; Spetch, L.

2007-11-10

Human metapneumovirus (hMPV) is a major cause of lower respiratory tract infections (LRTIs) in infants, elderly and immunocompromised patients. In this study, we show that hMPV can infect in a similar manner epithelial cells representative of different tracts of the airways. hMPV-induced expression of chemokines IL-8 and RANTES in primary small alveolar epithelial cells (SAE) and in a human alveolar type II-like epithelial cell line (A549) was similar, suggesting that A549 cells can be used as a model to study lower airway epithelial cell responses to hMPV infection. A549 secreted a variety of CXC and CC chemokines, cytokines and typemore » I interferons, following hMPV infection. hMPV was also a strong inducer of transcription factors belonging to nuclear factor (NF)-{kappa}B, interferon regulatory factors (IRFs) and signal transducers and activators of transcription (STATs) families, which are known to orchestrate the expression of inflammatory and immunomodulatory mediators.« less

Vaccination against IL-33 Inhibits Airway Hyperresponsiveness and Inflammation in a House Dust Mite Model of Asthma

PubMed Central

Lei, Ying; Adner, Mikael; Hellman, Lars; Nilsson, Gunnar

2015-01-01

In several clinical and experimental studies IL-33 and its receptor have been found to play important roles in the development of asthma and allergic airway inflammation. We evaluated the effects of vaccination against IL-33 in a mouse model of airway inflammation induced by house dust mite (HDM) allergen. Balb/c mice received the IL-33 vaccine subcutaneously, followed by intranasal administration of HDM for up to six weeks. Vaccination against IL-33 induced high titers of specific anti-IL-33 IgG antibodies that inhibited HDM-induced airway hyperresponsiveness (AHR) in the conducting airways and tissue damping. The vaccination also attenuated the HDM-induced elevation in the numbers of eosinophils in bronchoalveolar lavage fluid (BALF) and suppressed the accumulation of inflammatory cells in the airways. Furthermore, the levels of IL-17A, IL-25, IL-33 and TSLP in lung tissue homogenates were reduced by vaccination against IL-33. These observations demonstrate that vaccination against IL-33 inhibits HDM-induced development of AHR, airway inflammation and production of inflammatory cytokines. The results also indicate an important role of IL-33 in the regulation of AHR of the distal lung compartments. Thus, administration of such a vaccine is potentially an effective therapeutic tool for treating allergic asthma. PMID:26214807

Difficult airway response team: a novel quality improvement program for managing hospital-wide airway emergencies.

PubMed

Mark, Lynette J; Herzer, Kurt R; Cover, Renee; Pandian, Vinciya; Bhatti, Nasir I; Berkow, Lauren C; Haut, Elliott R; Hillel, Alexander T; Miller, Christina R; Feller-Kopman, David J; Schiavi, Adam J; Xie, Yanjun J; Lim, Christine; Holzmueller, Christine; Ahmad, Mueen; Thomas, Pradeep; Flint, Paul W; Mirski, Marek A

2015-07-01

Difficult airway cases can quickly become emergencies, increasing the risk of life-threatening complications or death. Emergency airway management outside the operating room is particularly challenging. We developed a quality improvement program-the Difficult Airway Response Team (DART)-to improve emergency airway management outside the operating room. DART was implemented by a team of anesthesiologists, otolaryngologists, trauma surgeons, emergency medicine physicians, and risk managers in 2005 at The Johns Hopkins Hospital in Baltimore, Maryland. The DART program had 3 core components: operations, safety, and education. The operations component focused on developing a multidisciplinary difficult airway response team, standardizing the emergency response process, and deploying difficult airway equipment carts throughout the hospital. The safety component focused on real-time monitoring of DART activations and learning from past DART events to continuously improve system-level performance. This objective entailed monitoring the paging system, reporting difficult airway events and DART activations to a Web-based registry, and using in situ simulations to identify and mitigate defects in the emergency airway management process. The educational component included development of a multispecialty difficult airway curriculum encompassing case-based lectures, simulation, and team building/communication to ensure consistency of care. Educational materials were also developed for non-DART staff and patients to inform them about the needs of patients with difficult airways and ensure continuity of care with other providers after discharge. Between July 2008 and June 2013, DART managed 360 adult difficult airway events comprising 8% of all code activations. Predisposing patient factors included body mass index >40, history of head and neck tumor, prior difficult intubation, cervical spine injury, airway edema, airway bleeding, and previous or current tracheostomy. Twenty

Difficult Airway Response Team: A Novel Quality Improvement Program for Managing Hospital-Wide Airway Emergencies

PubMed Central

Mark, Lynette J.; Herzer, Kurt R.; Cover, Renee; Pandian, Vinciya; Bhatti, Nasir I.; Berkow, Lauren C.; Haut, Elliott R.; Hillel, Alexander T.; Miller, Christina R.; Feller-Kopman, David J.; Schiavi, Adam J.; Xie, Yanjun J.; Lim, Christine; Holzmueller, Christine; Ahmad, Mueen; Thomas, Pradeep; Flint, Paul W.; Mirski, Marek A.

2015-01-01

Background Difficult airway cases can quickly become emergencies, increasing the risk of life-threatening complications or death. Emergency airway management outside the operating room is particularly challenging. Methods We developed a quality improvement program—the Difficult Airway Response Team (DART)—to improve emergency airway management outside the operating room. DART was implemented by a team of anesthesiologists, otolaryngologists, trauma surgeons, emergency medicine physicians, and risk managers in 2005 at The Johns Hopkins Hospital in Baltimore, Maryland. The DART program had three core components: operations, safety, and education. The operations component focused on developing a multidisciplinary difficult airway response team, standardizing the emergency response process, and deploying difficult airway equipment carts throughout the hospital. The safety component focused on real-time monitoring of DART activations and learning from past DART events to continuously improve system-level performance. This objective entailed monitoring the paging system, reporting difficult airway events and DART activations to a web-based registry, and using in situ simulations to identify and mitigate defects in the emergency airway management process. The educational component included development of a multispecialty difficult airway curriculum encompassing case-based lectures, simulation, and team building/communication to ensure consistency of care. Educational materials were also developed for non-DART staff and patients to inform them about the needs of patients with difficult airways and ensure continuity of care with other providers after discharge. Results Between July 2008 and June 2013, DART managed 360 adult difficult airway events comprising 8% of all code activations. Predisposing patient factors included body mass index > 40, history of head and neck tumor, prior difficult intubation, cervical spine injury, airway edema, airway bleeding, and previous

Maximal degree of airway narrowing induced by methacholine and adenosine monophosphate: relationship with the decrease in forced vital capacity.

PubMed

Prieto, Luis; Lopez, Victoria; Perez-Frances, Carmen; Marin, Julio

2010-12-01

Changes in forced vital capacity (FVC) may represent an indirect method for the detection of plateau in response to inhaled bronchoconstrictor agents. To determine the relationship between the level of plateau obtained with either methacholine or adenosine monophosphate (AMP) and the decrease in FVC induced by each bronchoconstrictor agent. Airway responsiveness to high concentrations of methacholine and AMP was determined in patients with intermittent asthma (n = 41) or allergic rhinitis (n = 26). Furthermore, allergen-induced changes in the response to each bronchoconstrictor agent were investigated in 18 pollen-sensitive patients. Concentration-response curves were characterized by the slope of the FVC values recorded at each step of the challenge against the corresponding forced expiratory volume in 1 second (FEV1) values and, if possible, by the level of plateau. The slope FVC vs FEV1 was similar in patients with plateau and in those without plateau. In patients with pollen allergy, the mean (95% confidence interval) for the level of plateau detected with methacholine increased from 16.8% (11.8%-22.0%) before the pollen season to 21.7% (14.8%-28.6%, P = .008) during the pollen season, whereas pollen-induced changes in the slope FVC vs FEV1 were not significant. Similar results were obtained with AMP. In patients with allergic rhinitis or intermittent asthma, methacholine or AMP-induced changes in FVC are not significantly related to the presence or level of plateau. Furthermore, these 2 constituents of the concentration-response curve can be modified independently by a proinflammatory stimulus. These results suggest that the bronchoconstrictor-induced change in FVC cannot be used as a surrogate estimation of the level of plateau. Copyright © 2010 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Airway responsiveness and airway remodeling after chronic exposure to procaterol and fenoterol in guinea pigs in vivo.

PubMed

Nishimura, Hideko; Tokuyama, Kenichi; Arakawa, Hirokazu; Ohki, Yasushi; Sato, Akira; Kato, Masahiko; Mochizuki, Hiroyuki; Morikawa, Akihiro

2002-12-01

Chronic exposure to fenoterol (FEN), a beta(2)-adrenergic receptor (beta(2)-AR) agonist, was shown to induce both airway hyperresponsiveness and airway remodeling in experimental animals. We wanted to know the effects of chronic exposure to procaterol (PRO), a beta(2)-AR agonist, on airway function and structure, because this agent is widely used as a bronchodilator in Japan. For comparison, the effects of FEN were also examined. Aerosolized PRO (0.1 or 1 mg/ml), FEN (1 mg/ml) or vehicle (0.9% NaCl) was given to guinea pigs 3 times a day for 6 weeks. Sublaryngeal deposition of these agents was calculated using radioisotopes. At 72 h after the last inhalation of PRO, FEN or vehicle, the dose-response relationship between lung resistance (R(L)) and intravenously administered acetylcholine (ACh) was measured. After measuring R(L), histological changes in noncartilaginous airway dimensions were evaluated. The amount of sublaryngeal deposition of 0.1 mg/ml PRO in the present study was speculated to be 100 times larger than that of therapeutic dose. ACh concentrations causing 2-fold, 10-fold and maximal increases in R(L) were not different in 4 groups tested. In the smaller membranous airways (<0.4 mm in diameter), but not the larger ones, thickening of adventitial areas was significantly greater in animals treated with beta(2)-AR agonists than in control animals (23 and 25, and 96% higher in animals treated with 0.1 and 1 mg/ml PRO or 1 mg/ml FEN, respectively). The degree of the increase was significantly less in PRO-treated animals than in FEN-treated animals (p < 0.01). Our results did not provide any evidence that regular inhalation of PRO at the therapeutic dose might induce bronchial hyperresponsiveness. In addition, huge amounts of PRO only caused a mild thickening of the adventitial areas, suggesting that PRO may be a weak inducer of airway remodeling compared with FEN. Copyright 2002 S. Karger AG, Basel

Development of asthmatic inflammation in mice following early-life exposure to ambient environmental particulates and chronic allergen challenge

PubMed Central

Herbert, Cristan; Siegle, Jessica S.; Shadie, Alexander M.; Nikolaysen, Stina; Garthwaite, Linda; Hansbro, Nicole G.; Foster, Paul S.; Kumar, Rakesh K.

2013-01-01

SUMMARY Childhood exposure to environmental particulates increases the risk of development of asthma. The underlying mechanisms might include oxidant injury to airway epithelial cells (AEC). We investigated the ability of ambient environmental particulates to contribute to sensitization via the airways, and thus to the pathogenesis of childhood asthma. To do so, we devised a novel model in which weanling BALB/c mice were exposed to both ambient particulate pollutants and ovalbumin for sensitization via the respiratory tract, followed by chronic inhalational challenge with a low mass concentration of the antigen. We also examined whether these particulates caused oxidant injury and activation of AEC in vitro. Furthermore, we assessed the potential benefit of minimizing oxidative stress to AEC through the period of sensitization and challenge by dietary intervention. We found that characteristic features of asthmatic inflammation developed only in animals that received particulates at the same time as respiratory sensitization, and were then chronically challenged with allergen. However, these animals did not develop airway hyper-responsiveness. Ambient particulates induced epithelial injury in vitro, with evidence of oxidative stress and production of both pro-inflammatory cytokines and Th2-promoting cytokines such as IL-33. Treatment of AEC with an antioxidant in vitro inhibited the pro-inflammatory cytokine response to these particulates. Ambient particulates also induced pro-inflammatory cytokine expression following administration to weanling mice. However, early-life dietary supplementation with antioxidants did not prevent the development of an asthmatic inflammatory response in animals that were exposed to particulates, sensitized and challenged. We conclude that injury to airway epithelium by ambient environmental particulates in early life is capable of promoting the development of an asthmatic inflammatory response in sensitized and antigen-challenged mice

Polyclonal and allergen-induced cytokine responses in adults with asthma: resolution of asthma is associated with normalization of IFN-gamma responses.

PubMed

Smart, Joanne M; Horak, Elisabeth; Kemp, Andrew S; Robertson, Colin F; Tang, Mimi L K

2002-09-01

. This suggests that reduced HDM-induced IFN-gamma production might be an important factor contributing to ongoing severe asthma and that normalization of allergen-induced T(H)1 responses might be important for disease resolution. The finding that all subjects with a history of asthma displayed increased HDM-induced T(H)2 (IL-5 and IL-13) cytokine responses, irrespective of the presence or absence of asthma, suggests that increased T(H)2 responses reflect the presence of the atopic state per se rather than being specifically linked to asthma.

Caveolin-1: Functional Insights into Its Role in Muscarine- and Serotonin-Induced Smooth Muscle Constriction in Murine Airways

PubMed Central

Keshavarz, Maryam; Schwarz, Heike; Hartmann, Petra; Wiegand, Silke; Skill, Melanie; Althaus, Mike; Kummer, Wolfgang; Krasteva-Christ, Gabriela

2017-01-01

An increased bronchoconstrictor response is a hallmark in the progression of obstructive airway diseases. Acetylcholine and 5-hydroxytryptamine (5-HT, serotonin) are the major bronchoconstrictors. There is evidence that both cholinergic and serotonergic signaling in airway smooth muscle (ASM) involve caveolae. We hypothesized that caveolin-1 (cav-1), a structural protein of caveolae, plays an important regulatory role in ASM contraction. We analyzed airway contraction in different tracheal segments and extra- and intrapulmonary bronchi in cav-1 deficient (cav-1−/−) and wild-type mice using organ bath recordings and videomorphometry of methyl-beta-cyclodextrin (MCD) treated and non-treated precision-cut lung slices (PCLS). The presence of caveolae was investigated by electron microscopy. Receptor subtypes driving 5-HT-responses were studied by RT-PCR and videomorphometry after pharmacological inhibition with ketanserin. Cav-1 was present in tracheal epithelium and ASM. Muscarine induced a dose dependent contraction in all airway segments. A significantly higher Emax was observed in the caudal trachea. Although, caveolae abundancy was largely reduced in cav-1−/− mice, muscarine-induced airway contraction was maintained, albeit at diminished potency in the middle trachea, in the caudal trachea and in the bronchus without changes in the maximum efficacy. MCD-treatment of PLCS from cav-1−/− mice reduced cholinergic constriction by about 50%, indicating that cholesterol-rich plasma domains account for a substantial portion of the muscarine-induced bronchoconstriction. Notably, cav-1-deficiency fully abrogated 5-HT-induced contraction of extrapulmonary airways. In contrast, 5-HT-induced bronchoconstriction was fully maintained in cav-1-deficient intrapulmonary bronchi, but desensitization upon repetitive stimulation was enhanced. RT-PCR analysis revealed 5-HT1B, 5-HT2A, 5-HT6, and 5-HT7 receptors as the most prevalent subtypes in the airways. The 5-HT-induced

Diesel Exhaust Particle-Induced Airway Responses are Augmented in Obese Rats

PubMed Central

Moon, Kuk-Young; Park, Moo-Kyun; Leikauf, George D.; Park, Choon-Sik; Jang, An-Soo

2015-01-01

Air pollutants and obesity are important factors that contribute to asthma. The aim of this study was to assess the airway responsiveness and inflammation in Otsuka-Long Evans Tokushima Fatty (OLETF) obese rats and Long Evans Tokushima-Otsuka (LETO) nonobese rats exposed to diesel exhaust particles (DEPs). Otsuka Long Evans Tokushima fatty rats and LETO rats were exposed intranasally to DEP and then challenged with aerosolized DEP on days 6 to 8. Body plethysmography, bronchoalveolar lavage (BAL), and histology were performed. Enhanced pause (Penh) was measured as an indicator of airway resistance on day 9 and samples were collected on day 10. After exposure to DEP, the OLETF group exhibited a greater increase in Penh compared to that in the LETO group. Moreover, the BAL fluid in mice showed an increase in the total and differential cell counts in the DEP-exposed OLETF group compared to that in the DEP-exposed LETO group. Histological assessment of lung tissue from each group revealed that the DEP-exposed OLETF group tended to have increased inflammatory cell infiltrations in the prebronchial area. Increased peroxisome proliferator-activated receptor γ, coactivator 1β messenger RNA was observed in the lungs of obese rats compared to that in nonobese rats following DEP exposure. These data indicate that the DEP-exposed OLETF group had increased airway responses and inflammation compared to the DEP-exposed LETO group, indicating that diesel particulates and obesity may be co-contributors to asthma. PMID:24536021

Specific IgE and IgG measured by the MeDALL allergen-chip depend on allergen and route of exposure: The EGEA study.

PubMed

Siroux, Valérie; Lupinek, Christian; Resch, Yvonne; Curin, Mirela; Just, Jocelyne; Keil, Thomas; Kiss, Renata; Lødrup Carlsen, Karin; Melén, Erik; Nadif, Rachel; Pin, Isabelle; Skrindo, Ingebjørg; Vrtala, Susanne; Wickman, Magnus; Anto, Josep Maria; Valenta, Rudolf; Bousquet, Jean

2017-02-01

The nature of allergens and route and dose of exposure may affect the natural development of IgE and IgG responses. We sought to investigate the natural IgE and IgG responses toward a large panel of respiratory and food allergens in subjects exposed to different respiratory allergen loads. A cross-sectional analysis was conducted in 340 adults of the EGEA (Epidemiological study of the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy) (170 with and 170 without asthma) cohort. IgE and IgG responses to 47 inhalant and food allergen components were analyzed in sera using allergen microarray and compared between 5 French regions according to the route of allergen exposure (inhaled vs food allergens). Overall 48.8% of the population had allergen-specific IgE levels of 0.3 ISAC standardized units (ISU) or more to at least 1 of the 47 allergens with no significant differences across the regions. For ubiquitous respiratory allergens (ie, grass, olive/ash pollen, house dust mites), specific IgE did not show marked differences between regions and specific IgG (≥0.5 ISU) was present in most subjects everywhere. For regionally occurring pollen allergens (ragweed, birch, cypress), IgE sensitization was significantly associated with regional pollen exposure. For airborne allergens cross-reacting with food allergens, frequent IgG recognition was observed even in regions with low allergen prevalence (Bet v 1) or for allergens less frequently recognized by IgE (profilins). The variability in allergen-specific IgE and IgG frequencies depends on exposure, route of exposure, and overall immunogenicity of the allergen. Allergen contact by the oral route might preferentially induce IgG responses. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Neonatal aerosol exposure to Bermuda grass allergen prevents subsequent induction of experimental allergic feline asthma: evidence for establishing early immunologic tolerance.

PubMed

Heller, M C; Lee-Fowler, T M; Liu, H; Cohn, L A; Reinero, C R

2014-07-15

Allergic asthma is increasing in industrialized countries, especially in children. Rodent and human studies suggest an opportunity to "prevent" asthma in the perinatal period. The aims of this study were to create a more "natural" model of feline asthma by exposing offspring of asthmatic queens to Bermuda grass allergen (BGA) by inhalation only, and to investigate maternal-fetal-infant interactions in the development of asthma. Kittens from asthmatic queens were divided into four groups: maternal exposure to aerosolized BGA during the third trimester, neonatal exposure to aerosolized BGA in the first three months of life, both maternal and neonatal exposure, or saline control. Kittens failing to achieve an asthmatic phenotype based on bronchoalveolar lavage fluid (BALF) analysis by 6 months underwent traditional sensitization: adjuvanted allergen injection, intranasal allergen, and aerosol challenges. BALF was collected at 3, 4 and 6 months, and after sensitization at 8 months, and analyzed for eosinophil counts and BGA-specific IgG and IgA. Intradermal testing (IDT) was performed at 6 and 7 months. At six months none of the kittens had airway eosinophilia, BGA-specific IgG or IgA, and were non-responsive to IDT. After sensitization, kittens receiving neonatal aerosolization failed to develop airway eosinophilia as seen in the controls. Kittens exposed to BGA aerosols, either in-utero or neonatally, continued to lack IDT response. Chronic exposure to BGA aerosols failed to induce asthma in kittens, and instead tolerized the kittens to BGA. This is the first evidence that neonatal intervention could potentially "prevent" allergic asthma in cats. Copyright © 2014 Elsevier B.V. All rights reserved.

Interaction of ozone exposure with airway hyperresponsiveness and inflammation induced by trimellitic anhydride in sensitized guinea pigs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Jian; Chung, K.Fan

1997-09-01

The effect of prior ozone (O{sub 3}) exposure on airway hyperresponsiveness and inflammation induced by trimellitic anhydride (TMA) has been investigated in TMA-sensitized guinea pigs. Airway responsiveness was measured as the concentration of acetylcholine needed to increase baseline lung resistance (RL) by 300% (PC300). Ozone (3 ppm, for 3 h) caused an increase in-log PC300 at 1 h after exposure, with return of -log PC300 to control levels at 8 h. Ozone also increased baseline RL at 8 h. TMA challenge increase -log PC300 in TMA-sensitized guinea pigs at 8 h after challenge from 3.85 {+-} 0.09 to 4.11 {+-}more » 0.09. Ozone exposure prior to TMA challenge prevented the induction of airway hyperresponsiveness with a mean -log PC300 of 3.51 {+-} 0.20, which was not different from that of control TMA-Sensitized group. Baseline RL was significantly higher in ozone-pretreated animals after TMA challenge when compared to those of either control or challenged with TMA alone. Ozone had no effect on TMA challenge-induced BAL eosinophilia and neutrophilia. We conclude that a single exposure to ozone inhibits the increase in airway responsiveness, but increases the bronchoconstrictor response induced by TMA in TMA-Sensitized guinea pigs; however, the inflammatory airway response to TMA is unchanged by preexposure to ozone. 29 refs., 2 figs., 1 tab.« less

Long-term nicotine exposure dampens LPS-induced nerve-mediated airway hyperreactivity in murine airways.

PubMed

Xu, Yuan; Cardell, Lars-Olaf

2017-09-01

Nicotine is a major component of cigarette smoke. It causes addiction and is used clinically to aid smoke cessation. The aim of the present study is to investigate the effect of nicotine on lipopolysaccharide (LPS)-induced airway hyperreactivity (AHR) and to explore the potential involvement of neuronal mechanisms behind nicotine's effects in murine models in vivo and in vitro. BALB/c mice were exposed to nicotine in vivo via subcutaneous Alzet osmotic minipumps containing nicotine tartate salt solution (24 mg·kg -1 ·day -1 ) for 28 days. LPS (0.1 mg/ml, 20 µl) was administered intranasally for 3 consecutive days during the end of this period. Lung functions were measured with flexiVent. For the in vitro experiments, mice tracheae were organcultured with either nicotine (10 μM) or vehicle (DMSO, 0.1%) for 4 days. Contractile responses of the tracheal segments were measured in myographs following electric field stimulation (EFS; increasing frequencies of 0.2 to 12.8 Hz) before and after incubation with 10 µg/ml LPS for 1 h. Results showed that LPS induced AHR to methacholine in vivo and increased contractile responses to EFS in vitro. Interestingly, long-term nicotine exposure markedly dampened this LPS-induced AHR both in vitro and in vivo. Tetrodotoxin (TTX) inhibited LPS-induced AHR but did not further inhibit nicotine-suppressed AHR in vivo. In conclusion, long-term nicotine exposure dampened LPS-induced AHR. The effect of nicotine was mimicked by TTX, suggesting the involvement of neuronal mechanisms. This information might be used for evaluating the long-term effects of nicotine and further exploring of how tobacco products interact with bacterial airway infections. Copyright © 2017 the American Physiological Society.

Role of tachykinins in ozone-induced airway hyperresponsiveness to cigarette smoke in guinea pigs.

PubMed

Wu, Z X; Morton, R F; Lee, L Y

1997-09-01

Acute exposure to ozone (O3) induces airway hyperresponsiveness to various inhaled bronchoactive substances. Inhalation of cigarette smoke, a common inhaled irritant in humans, is known to evoke a transient bronchoconstrictive effect. To examine whether O3 increases airway responsiveness to cigarette smoke, effects of smoke inhalation challenge on total pulmonary resistance (RL) and dynamic lung compliance (Cdyn) were compared before and after exposure to O3 (1.5 ppm, 1 h) in anesthetized guinea pigs. Before O3 exposure, inhalation of two breaths of cigarette smoke (7 ml) at a low concentration (33%) induced a mild and reproducible bronchoconstriction that slowly developed and reached its peak (DeltaRL = 67 +/- 19%, DeltaCdyn = -29 +/- 6%) after a delay of >1 min. After exposure to O3 the same cigarette smoke inhalation challenge evoked an intense bronchoconstriction that occurred more rapidly, reaching its peak (DeltaRL = 620 +/- 224%, DeltaCdyn = -35 +/- 7%) within 20 s, and was sustained for >2 min. By contrast, sham exposure to room air did not alter the bronchomotor response to cigarette smoke challenge. Pretreatment with CP-99994 and SR-48968, the selective antagonists of neurokinin type 1 and 2 receptors, respectively, completely blocked the enhanced responses of RL and Cdyn to cigarette smoke challenge induced by O3. These results show that O3 exposure induces airway hyperresponsiveness to inhaled cigarette smoke and that the enhanced responses result primarily from the bronchoconstrictive effect of endogenous tachykinins.

Serum concentrations of allergen-specific IgE in horses with equine recurrent airway obstruction and healthy controls assessed by ELISA.

PubMed

Niedzwiedz, Artur; Jaworski, Zbigniew; Kubiak, Krzysztof

2015-09-01

Equine recurrent airway obstruction (RAO), also known as heaves, is one of the most common respiratory problems in older horses. When RAO-affected horses stay pastured or in a dust-free environment for a prolonged time, clinical signs as well as airway inflammation wane. A number of environmental, immunologic, infectious, and genetic factors play an important role in the pathogenesis of RAO, and the immunologic basis of this disease is still poorly understood. The aim of this study was to investigate the concentrations of allergen-specific IgE in the serum of horses suffering from RAO and healthy controls. The study included a group of 14 adult Polish Konik horses, kept in a standardized environment, and divided into 2 groups: 7 horses which did not have any respiratory problems comprised the control group and 7 horses with a history of RAO constituted the study group. A clinical and laboratory evaluation, endoscopic examination, and bronchoalveolar lavage (BAL) were performed in all horses. Sera of all horses were tested against allergens from 9 molds and 3 mites using the Heska Allercept assay. In the serologic tests, a statistically significant difference between both groups was found for specific IgE against mites, wherein Tyrophagus putrescentia correlated most clearly with RAO. There was no difference between groups for IgE specific against molds. On the basis of our observations and results, we conclude that RAO is associated with increased serum concentrations of specific serum IgE against mites, in particular T putrescentia. © 2015 American Society for Veterinary Clinical Pathology.

Airway-Specific Inducible Transgene Expression Using Aerosolized Doxycycline

PubMed Central

Tata, Purushothama Rao; Pardo-Saganta, Ana; Prabhu, Mythili; Vinarsky, Vladimir; Law, Brandon M.; Fontaine, Benjamin A.; Tager, Andrew M.

2013-01-01

Tissue-specific transgene expression using tetracycline (tet)-regulated promoter/operator elements has been used to revolutionize our understanding of cellular and molecular processes. However, because most tet-regulated mouse strains use promoters of genes expressed in multiple tissues, to achieve exclusive expression in an organ of interest is often impossible. Indeed, in the extreme case, unwanted transgene expression in other organ systems causes lethality and precludes the study of the transgene in the actual organ of interest. Here, we describe a novel approach to activating tet-inducible transgene expression solely in the airway by administering aerosolized doxycycline. By optimizing the dose and duration of aerosolized doxycycline exposure in mice possessing a ubiquitously expressed Rosa26 promoter–driven reverse tet-controlled transcriptional activator (rtTA) element, we induce transgene expression exclusively in the airways. We detect no changes in the cellular composition or proliferative behavior of airway cells. We used this newly developed method to achieve airway basal stem cell–specific transgene expression using a cytokeratin 5 (also known as keratin 5)–driven rtTA driver line to induce Notch pathway activation. We observed a more robust mucous metaplasia phenotype than in mice receiving doxycycline systemically. In addition, unwanted phenotypes outside of the lung that were evident when doxycycline was received systemically were now absent. Thus, our approach allows for rapid and efficient airway-specific transgene expression. After the careful strain by strain titration of the dose and timing of doxycycline inhalation, a suite of preexisting transgenic mice can now be used to study airway biology specifically in cases where transient transgene expression is sufficient to induce a phenotype. PMID:23848320

Prophylactic and therapeutic vaccination with carrier-bound Bet v 1 peptides lacking allergen-specific T cell epitopes reduces Bet v 1-specific T cell responses via blocking antibodies in a murine model for birch pollen allergy.

PubMed

Linhart, B; Narayanan, M; Focke-Tejkl, M; Wrba, F; Vrtala, S; Valenta, R

2014-02-01

Vaccines consisting of allergen-derived peptides lacking IgE reactivity and allergen-specific T cell epitopes bound to allergen-unrelated carrier molecules have been suggested as candidates for allergen-specific immunotherapy. To study whether prophylactic and therapeutic vaccination with carrier-bound peptides from the major birch pollen allergen Bet v 1 lacking allergen-specific T cell epitopes has influence on Bet v 1-specific T cell responses. Three Bet v 1-derived peptides, devoid of Bet v 1-specific T cell epitopes, were coupled to KLH and adsorbed to aluminium hydroxide to obtain a Bet v 1-specific allergy vaccine. Groups of BALB/c mice were immunized with the peptide vaccine before or after sensitization to Bet v 1. Bet v 1- and peptide-specific antibody responses were analysed by ELISA. T cell and cytokine responses to Bet v 1, KLH, and the peptides were studied in proliferation assays. The effects of peptide-specific and allergen-specific antibodies on T cell responses and allergic lung inflammation were studied using specific antibodies. Prophylactic and therapeutic vaccination with carrier-bound Bet v 1 peptides induced a Bet v 1-specific IgG antibody response without priming/boosting of Bet v 1-specific T cells. Prophylactic and therapeutic vaccination of mice with the peptide vaccine induced Bet v 1-specific antibodies which suppressed Bet v 1-specific T cell responses and allergic lung inflammation. Vaccination with carrier-bound allergen-derived peptides lacking allergen-specific T cell epitopes induces allergen-specific IgG antibodies which suppress allergen-specific T cell responses and allergic lung inflammation. © 2013 John Wiley & Sons Ltd.

Airway epithelial phosphoinositide 3-kinase-δ contributes to the modulation of fungi-induced innate immune response.

PubMed

Jeong, Jae Seok; Lee, Kyung Bae; Kim, So Ri; Kim, Dong Im; Park, Hae Jin; Lee, Hern-Ku; Kim, Hyung Jin; Cho, Seong Ho; Kolliputi, Narasaiah; Kim, Soon Ha; Lee, Yong Chul

2018-04-05

Respiratory fungal exposure is known to be associated with severe allergic lung inflammation. Airway epithelium is an essential controller of allergic inflammation. An innate immune recognition receptor, nucleotide-binding domain, leucine-rich-containing family, pyrin-domain-containing-3 (NLRP3) inflammasome, and phosphoinositide 3 kinase (PI3K)-δ in airway epithelium are involved in various inflammatory processes. We investigated the role of NLRP3 inflammasome in fungi-induced allergic lung inflammation and examined the regulatory mechanism of NLRP3 inflammasome, focusing on PI3K-δ in airway epithelium. We used two in vivo models induced by exposure to Aspergillus fumigatus ( Af ) and Alternaria alternata ( Aa ), as well as an Af -exposed in vitro system. We also checked NLRP3 expression in lung tissues from patients with allergic bronchopulmonary aspergillosis (ABPA). Assembly/activation of NLRP3 inflammasome was increased in the lung of Af -exposed mice. Elevation of NLRP3 inflammasome assembly/activation was observed in Af -stimulated murine and human epithelial cells. Similarly, pulmonary expression of NLRP3 in patients with ABPA was increased. Importantly, neutralisation of NLRP3 inflammasome derived IL-1β alleviated pathophysiological features of Af -induced allergic inflammation. Furthermore, PI3K-δ blockade improved Af -induced allergic inflammation through modulation of NLRP3 inflammasome, especially in epithelial cells. This modulatory role of PI3K-δ was mediated through the regulation of mitochondrial reactive oxygen species (mtROS) generation. NLRP3 inflammasome was also implicated in Aa -induced eosinophilic allergic inflammation, which was improved by PI3K-δ blockade. These findings demonstrate that fungi-induced assembly/activation of NLRP3 inflammasome in airway epithelium may be modulated by PI3K-δ, which is mediated partly through the regulation of mtROS generation. Inhibition of PI3K-δ may have potential for treating fungi-induced severe

Interleukin(IL)-1 Regulates Ozone-enhanced Tracheal Smooth Muscle Responsiveness by Increasing Substance P (SP) Production in Intrinsic Airway Neurons of Ferret

PubMed Central

Wu, Z.-X.; Barker, J. S.; Batchelor, T. P.; Dey, R.D.

2008-01-01

Exposure to ozone induces airway hyperresponsiveness (AHR) mediated partly by SP released from nerve terminals of intrinsic airway neurons. Our recent studies showed that IL-1, an important multifunctional proinflammatory cytokine, increases synthesis and release of SP from intrinsic airway neurons. The purpose of this study is to investigate the possible involvement of endogenous IL-1 in modulating neural responses associated with ozone-enhanced airway responsiveness. Ferrets were exposed to 2 ppm ozone or filtered air for 3 hrs. IL-1 in the bronchoalveolar lavage (BAL) fluid was significantly increased in ozone-exposed animals and responses of tracheal smooth muscle to methacholine (MCh) and electrical field stimulation (EFS) were elevated significantly. Both the SP nerve fiber density in tracheal smooth muscle and the number of SP-containing neurons in airway ganglia were significantly increased following ozone exposure. Pretreatment with IL-1 receptor antagonist (IL-1 Ra) significantly diminished ozone-enhanced airway responses to EFS as well as ozone-increased SP in the airway. To selectively investigate intrinsic airway neurons, segments of ferret trachea were maintained in culture conditions for 24 hrs to eliminate extrinsic contributions from sensory nerves. The segments were then exposed to 2 ppm ozone in vitro for 3 hrs. The changes of ozone-induced airway responses to MCh and EFS, and the SP levels in airway neurons paralleled those observed with in vivo ozone exposure. The ozone-enhanced airway responses and neuronal SP levels were inhibited by pretreatment with IL-1 Ra. These findings show that IL-1 is released during ozone exposure enhances airway responsiveness by modulating SP expression in airway neurons. PMID:18718561

An experimental model of allergic asthma in cats sensitized to house dust mite or bermuda grass allergen.

PubMed

Norris Reinero, Carol R; Decile, Kendra C; Berghaus, Roy D; Williams, Kurt J; Leutenegger, Christian M; Walby, William F; Schelegle, Edward S; Hyde, Dallas M; Gershwin, Laurel J

2004-10-01

Animal models are used to mimic human asthma, however, not all models replicate the major characteristics of the human disease. Spontaneous development of asthma with hallmark features similar to humans has been documented to occur with relative frequency in only one animal species, the cat. We hypothesized that we could develop an experimental model of feline asthma using clinically relevant aeroallergens identified from cases of naturally developing feline asthma, and characterize immunologic, physiologic, and pathologic changes over 1 year. House dust mite (HDMA) and Bermuda grass (BGA) allergen were selected by screening 10 privately owned pet cats with spontaneous asthma using a serum allergen-specific IgE ELISA. Parenteral sensitization and aerosol challenges were used to replicate the naturally developing disease in research cats. The asthmatic phenotype was characterized using intradermal skin testing, serum allergen-specific IgE ELISA, serum and bronchoalveolar lavage fluid (BALF) IgG and IgA ELISAs, airway hyperresponsiveness testing, BALF cytology, cytokine profiles using TaqMan PCR, and histopathologic evaluation. Sensitization with HDMA or BGA in cats led to allergen-specific IgE production, allergen-specific serum and BALF IgG and IgA production, airway hyperreactivity, airway eosinophilia, an acute T helper 2 cytokine profile in peripheral blood mononuclear cells and BALF cells, and histologic evidence of airway remodeling. Using clinically relevant aeroallergens to sensitize and challenge the cat provides an additional animal model to study the immunopathophysiologic mechanisms of allergic asthma. Chronic exposure to allergen in the cat leads to a variety of immunologic, physiologic, and pathologic changes that mimic the features seen in human asthma.

Toxoplasma gondii infection blocks the development of allergic airway inflammation in BALB/c mice.

PubMed

Fenoy, I; Giovannoni, M; Batalla, E; Martin, V; Frank, F M; Piazzon, I; Goldman, A

2009-02-01

There is a link between increased allergy and a reduction of some infections in western countries. Epidemiological data also show that respiratory allergy is less frequent in people exposed to orofaecal and foodborne microbes such as Toxoplasma gondii. Infection with T. gondii induces a strong cell-mediated immunity with a highly polarized T helper type 1 (Th1) response in early stages of infection. Using a well-known murine model of allergic lung inflammation, we sought to investigate whether T. gondii infection could modulate the susceptibility to develop respiratory allergies. Both acute and chronic infection with T. gondii before allergic sensitization resulted in a diminished allergic inflammation, as shown by a decrease in bronchoalveolar lavage (BAL) eosinophilia, mononuclear and eosinophil cell infiltration around airways and vessels and goblet cell hyperplasia. Low allergen-specific immunoglobulin (Ig)E and IgG1 and high levels of allergen-specific IgG2a serum antibodies were detected. A decreased interleukin (IL)-4 and IL-5 production by lymph node cells was observed, while no antigen-specific interferon-gamma increase was detected. Higher levels of the regulatory cytokine IL-10 were found in BAL from infected mice. These results show that both acute and chronic parasite infection substantially blocked development of airway inflammation in adult BALB/c mice. Our results support the hypothesis that T. gondii infection contributes to protection against allergy in humans.

Investigations of immunogenic, allergenic and adjuvant properties of Cry1Ab protein after intragastric exposure in a food allergy model in mice.

PubMed

Andreassen, Monica; Bøhn, Thomas; Wikmark, Odd-Gunnar; Bodin, Johanna; Traavik, Terje; Løvik, Martinus; Nygaard, Unni Cecilie

2016-05-04

In genetically modified (GM) crops there is a risk that the inserted genes may introduce new allergens and/or adjuvants into the food and feed chain. The MON810 maize, expressing the insecticidal Cry1Ab toxin, is grown in many countries worldwide. In animal models, intranasal and intraperitoneal immunisations with the purified Cry1Ab proteins have induced immune responses, and feeding trials with Cry1Ab-containing feed have revealed some altered immune responses. Previous investigations have primarily measured antibody responses to the protein, while investigations of clinical food allergy symptoms, or allergy promotion (adjuvant effect) associated with the Cry1Ab protein are largely missing. We aimed to investigate immunogenic, allergenic and adjuvant properties of purified Cry1Ab toxin (trypCry1Ab, i.e., trypsin activated Cry1Ab) in a mouse model of food allergy. Female C3H/HeJ mice were immunized by intragastric gavage of 10 μg purified, trypsin activated Cry1Ab toxin (trypCry1Ab) alone or together with the food allergen lupin. Cholera toxin was added as a positive control for adjuvant effect to break oral tolerance. Clinical symptoms (anaphylaxis) as well as humoral and cellular responses were assessed. In contrast to results from previous airway investigations, we observed no indication of immunogenic properties of trypCry1Ab protein after repeated intragastric exposures to one dose, with or without CT as adjuvant. Moreover, the results indicated that trypCry1Ab given by the intragastric route was not able to promote allergic responses or anaphylactic reactions against the co-administered allergen lupin at the given dose. The study suggests no immunogenic, allergenic or adjuvant capacity of the given dose of trypCry1Ab protein after intragastric exposure of prime aged mice.

Endocrine disruptors found in food contaminants enhance allergic sensitization through an oxidative stress that promotes the development of allergic airway inflammation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kato, Takuma, E-mail: katotaku@doc.medic.mie-u.ac.jp; Tada-Oikawa, Saeko; Wang, Linan

In the past few decades, there has been a significant increase in incidence of allergic diseases. The hygiene hypothesis may provide some clues to explain this rising trend, but it may also be attributable to other environmental factors that exert a proallergic adjuvant effects. However, there is limited information on the risks of developing allergic asthma and related diseases through the ingestion of environmental chemicals found in food contaminants. In the present study, we have shown that oral administration of tributyltin, used as a model environmental chemical, induced oxidative-stress status in the bronchial lymph node, mesenteric lymph node and spleen,more » but not in the lung, where the initial step of allergic asthma pathogenesis takes place. Mice exposed to tributyltin exhibited heightened Th2 immunity to the allergen with more severe airway inflammation. Tributyltin also induced Treg cells apoptosis preferentially over non-Treg cells. All these effects of tributyltin exposure were canceled by the administration of glutathione monoethyl ester. Meanwhile, tributyltin did not affect airway inflammation of mice transferred with allergen-specific Th2 cells. Collectively, these results suggest that tributyltin exerts its pathological effect during the sensitization phase through oxidative stress that enhances the development of allergic diseases. The current study dissects the pathogenic role of oxidative stress induced by oral exposure to an environmental chemical during the sensitization phase of allergic airway inflammation and would be important for developing therapeutics for prevention of allergic diseases. - Highlights: • Oral exposure to TBT exacerbates airway inflammation. • TBT induces oxidative stress in secondary lymphoid organs, but not in the lung. • TBT preferentially induces regulatory T cell apoptosis over non-Treg cells. • TBT does not enhance pre-existing airway inflammation in sensitized mice. • Chemicals in food

Fungal Allergen β-Glucans Trigger p38 Mitogen-Activated Protein Kinase–Mediated IL-6 Translation in Lung Epithelial Cells

PubMed Central

Neveu, Wendy A.; Bernardo, Edgar; Allard, Jenna L.; Nagaleekar, Viswas; Wargo, Matthew J.; Davis, Roger J.; Iwakura, Yoichiro; Whittaker, Laurie A.

2011-01-01

In addition to immune cells, airway epithelial cells can contribute to and shape the immune response in the lung by secreting specific cytokines. IL-6 is a key factor in determining the effector fate of CD4+ T cells. Here we show that under basal conditions, the IL-6 gene is already highly expressed in lung epithelial cells, but not in immune cells resident in the lung. However, upon exposure of the lungs to fungal allergens, the direct contact of β-glucans present in the fungus cell wall with lung epithelial cells is sufficient to trigger the rapid synthesis and secretion of IL-6 protein. This posttranscriptional regulation of IL-6 in response to fungal extracts is mediated by the p38 mitogen-activated protein kinase pathway. The inhalation of β-glucans with a nonallergenic antigen is sufficient to provide an adjuvant effect that leads to mucous hyperplasia in the airways. Thus, β-glucans may constitute a common determinant of the fungal and plant-derived allergens responsible for some of the pathological features in allergic asthma. PMID:21642586

Perillyl alcohol suppresses antigen-induced immune responses in the lung

DOE Office of Scientific and Technical Information (OSTI.GOV)

Imamura, Mitsuru; Sasaki, Oh; Okunishi, Katsuhide

Highlights: •Perillyl alcohol (POH) is an isoprenoid which inhibits the mevalonate pathway. •We examined whether POH suppresses immune responses with a mouse model of asthma. •POH treatment during sensitization suppressed Ag-induced priming of CD4{sup +} T cells. •POH suppressed airway eosinophila and cytokine production in thoracic lymph nodes. -- Abstract: Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes,more » its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4{sup +} T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects.« less

Cigarette smoke induces bronchoconstrictor hyperresponsiveness to substance P and inactivates airway neutral endopeptidase in the guinea pig. Possible role of free radicals.

PubMed

Dusser, D J; Djokic, T D; Borson, D B; Nadel, J A

1989-09-01

We examined the effects of acute exposure to cigarette smoke on the airway responses to substance P in anesthetized guinea pigs and on the activity of airway neutral endopeptidase (NEP). After exposure to air or to cigarette smoke we measured the change in total pulmonary resistance (RL) induced by increasing concentrations of aerosolized substance P in the absence or presence of the NEP inhibitor phosphoramidon. In the absence of phosphramidon the bronchoconstrictor responses to substance P were greater in cigarette smoke-exposed guinea pigs than in air-exposed animals. Phosphoramidon did not further potentiate the responses to substance P in smoke-exposed guinea pigs, whereas it did so in air-exposed animals. In the presence of phosphoramidon, bronchoconstrictor responses to substance P in animals exposed to air or to cigarette smoke were not different. Aerosols of SOD delivered before cigarette smoke exposures dramatically reduced smoke-induced hyperresponsiveness to substance P, whereas heat-inactivated SOD had no effect on smoke-induced hyper-responsiveness to substance P. Cigarette smoke solution inhibited NEP activity from tracheal homogenate in a concentration-dependent fashion, an inhibitory effect that was mostly due to the gas phase of the smoke, but not to nicotine. The mild chemical oxidant N-chlorosuccinimide mimicked the concentration-dependent inhibitory effect of smoke solution on airway NEP activity. We conclude that cigarette smoke causes enhanced airway responsiveness to substance P in vivo by inactivating airway NEP. We suggest that cigarette smoke-induced inhibition of airway NEP is due to effects of free radicals.

Cigarette smoke induces bronchoconstrictor hyperresponsiveness to substance P and inactivates airway neutral endopeptidase in the guinea pig. Possible role of free radicals.

PubMed Central

Dusser, D J; Djokic, T D; Borson, D B; Nadel, J A

1989-01-01

We examined the effects of acute exposure to cigarette smoke on the airway responses to substance P in anesthetized guinea pigs and on the activity of airway neutral endopeptidase (NEP). After exposure to air or to cigarette smoke we measured the change in total pulmonary resistance (RL) induced by increasing concentrations of aerosolized substance P in the absence or presence of the NEP inhibitor phosphoramidon. In the absence of phosphramidon the bronchoconstrictor responses to substance P were greater in cigarette smoke-exposed guinea pigs than in air-exposed animals. Phosphoramidon did not further potentiate the responses to substance P in smoke-exposed guinea pigs, whereas it did so in air-exposed animals. In the presence of phosphoramidon, bronchoconstrictor responses to substance P in animals exposed to air or to cigarette smoke were not different. Aerosols of SOD delivered before cigarette smoke exposures dramatically reduced smoke-induced hyperresponsiveness to substance P, whereas heat-inactivated SOD had no effect on smoke-induced hyper-responsiveness to substance P. Cigarette smoke solution inhibited NEP activity from tracheal homogenate in a concentration-dependent fashion, an inhibitory effect that was mostly due to the gas phase of the smoke, but not to nicotine. The mild chemical oxidant N-chlorosuccinimide mimicked the concentration-dependent inhibitory effect of smoke solution on airway NEP activity. We conclude that cigarette smoke causes enhanced airway responsiveness to substance P in vivo by inactivating airway NEP. We suggest that cigarette smoke-induced inhibition of airway NEP is due to effects of free radicals. PMID:2474576

Induction of tachykinin gene and peptide expression in guinea pig nodose primary afferent neurons by allergic airway inflammation.

PubMed Central

Fischer, A; McGregor, G P; Saria, A; Philippin, B; Kummer, W

1996-01-01

Substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP) have potent proinflammatory effects in the airways. They are released from sensory nerve endings originating in jugular and dorsal root ganglia. However, the major sensory supply to the airways originates from the nodose ganglion. In this study, we evaluated changes in neuropeptide biosynthesis in the sensory airway innervation of ovalbumin-sensitized and -challenged guinea pigs at the mRNA and peptide level. In the airways, a three- to fourfold increase of SP, NKA, and CGRP, was seen 24 h following allergen challenge. Whereas no evidence of local tachykinin biosynthesis was found 12 h after challenge, increased levels of preprotachykinin (PPT)-A mRNA (encoding SP and NKA) were found in nodose ganglia. Quantitative in situ hybridization indicated that this increase could be accounted for by de novo induction of PPT-A mRNA in nodose ganglion neurons. Quantitative immunohistochemistry showed that 24 h after challenge, the number of tachykinin-immunoreactive nodose ganglion neurons had increased by 25%. Their projection to the airways was shown. Changes in other sensory ganglia innervating the airways were not evident. These findings suggest that an induction of sensory neuropeptides in nodose ganglion neurons is crucially involved in the increase of airway hyperreactivity in the late response to allergen challenge. PMID:8941645

Inducible nitric oxide synthase evoked nitric oxide counteracts capsaicin-induced airway smooth muscle contraction, but exacerbates plasma extravasation.

PubMed

Li, Ping-Chia; Shaw, Chen-Fu; Kuo, Tin-Fan; Chien, Chiang-Ting

2005-04-18

The contribution of nitric oxide (NO) to capsaicin-evoked airway responses was investigated in rats. The measurement of plasma NO level, airway dynamics, airway smooth muscle electromyogram, and plasma extravasation by India ink and Evans blue leakage technique was adapted. Capsaicin-evoked hypotension, bronchoconstriction, trachea plasma extravasation as well as increases in plasma NO level in a dose-dependent manner. L-732138 (NK1 receptor antagonist) or SR-48968 (NK2 receptor antagonist) pretreatment reduced capsaicin-enhanced hypotension, bronchoconstriction, plasma extravasation, and plasma NO level. N(G)-nitro-L-Arginine methyl ester (L-NAME, 10 mg/kg, i.v.), a non-selective NO synthase (NOS) inhibitor, or aminoguanidine (10 mg/kg, i.v.), a selective inducible NOS (iNOS) inhibitor, reduced capsaicin-induced increases in plasma NO level and protected against capsaicin-induced plasma extravasation, whereas L-arginine (150 mg/kg, i.v.), a NO precursor, enhanced capsaicin-evoked plasma NO level and plasma extravasation. L-Arginine pretreatment ameliorated capsaicin-induced bronchoconstriction, whereas L-NAME and aminoguanidine exaggerated capsaicin-induced bronchoconstriction. In summary, NK1 and NK2 receptors and iNOS play a role in NO formation and on capsaicin-induced bronchoconstriction and plasma extravasation. NO generated by iNOS counteracts tachykinin-mediated bronchoconstriction, but exacerbates tachykinin-mediated plasma extravasation.

SERCA2 Regulates Non-CF and CF Airway Epithelial Cell Response to Ozone

PubMed Central

Ahmad, Shama; Nichols, David P.; Strand, Matthew; Rancourt, Raymond C.; Randell, Scott H.; White, Carl W.; Ahmad, Aftab

2011-01-01

Calcium mobilization can regulate a wide range of essential functions of respiratory epithelium, including ion transport, ciliary beat frequency, and secretion of mucus, all of which are modified in cystic fibrosis (CF). SERCA2, an important controller of calcium signaling, is deficient in CF epithelium. We conducted this study to determine whether SERCA2 deficiency can modulate airway epithelial responses to environmental oxidants such as ozone. This could contribute to the pathogenesis of pulmonary exacerbations, which are important and frequent clinical events in CF. To address this, we used air-liquid interface (ALI) cultures of non-CF and CF cell lines, as well as differentiated cultures of cells derived from non-CF and CF patients. We found that ozone exposure caused enhanced membrane damage, mitochondrial dysfunction and apoptotic cell death in CF airway epithelial cell lines relative to non-CF. Ozone exposure caused increased proinflammatory cytokine production in CF airway epithelial cell lines. Elevated proinflammatory cytokine production also was observed in shRNA-mediated SERCA2 knockdown cells. Overexpression of SERCA2 reversed ozone-induced proinflammatory cytokine production. Ozone-induced proinflammatory cytokine production was NF-κB- dependent. In a stable NF-κB reporter cell line, SERCA2 inhibition and knockdown both upregulated cytomix-induced NF-κB activity, indicating importance of SERCA2 in modulating NF-κB activity. In this system, increased NF-κB activity was also accompanied by increased IL-8 production. Ozone also induced NF-κB activity and IL-8 release, an effect that was greater in SERCA2-silenced NF-κB-reporter cells. SERCA2 overexpression reversed cytomix-induced increased IL-8 release and total nuclear p65 in CFTR-deficient (16HBE-AS) cells. These studies suggest that SERCA2 is an important regulator of the proinflammatory response of airway epithelial cells and could be a potential therapeutic target. PMID:22096575

Responses of human birch pollen allergen-reactive T cells to chemically modified allergens (allergoids).

PubMed

Dormann, D; Ebner, C; Jarman, E R; Montermann, E; Kraft, D; Reske-Kunz, A B

1998-11-01

Allergoids are widely used in specific immunotherapy for the treatment of IgE-mediated allergic diseases. The aim of this study was to analyse whether a modification of birch pollen allergens with formaldehyde affects the availability of T-cell epitopes. Efficient modification of the allergens was verified by determining IgE and IgG binding activity using ELISA inhibition tests. T-cell responses to birch pollen allergoids were analysed in polyclonal systems, using peripheral blood mononuclear cells (PBMC) of five birch pollen-allergic individuals, as well as birch pollen extract-reactive T-cell lines (TCL), established from the peripheral blood of 14 birch pollen-allergic donors. To determine whether the modification of natural (n)Bet v 1 with formaldehyde or maleic anhydride results in epitope-specific changes in T-cell reactivities, 22 Bet v 1-specific T-cell clones (TCC), established from nine additional birch pollen-allergic individuals, were tested for their reactivity with these products. The majority of PBMC and TCL showed a reduced response to the birch pollen extract allergoid. Bet v 1-specific TCC could be divided into allergoid-reactive and -non-reactive TCC. No simple correlation between possible modification sites of formaldehyde in the respective T-cell epitopes and the stimulatory potential of the allergoid was observed. Mechanisms of suppression or of anergy induction were excluded as an explanation for the non-reactivity of representative TCC. All TCC could be stimulated by maleylated and unmodified nBet v 1 to a similar extent. These results demonstrate differences in the availability of T-cell epitopes between allergoids and unmodified allergens, which are most likely due to structural changes within the allergen molecule.

Allergen exposure modifies the relation of sensitization to FENO levels in children at risk for allergy and asthma

PubMed Central

Sordillo, Joanne E; Webb, Tara; Kwan, Doris; Kamel, Jimmy; Hoffman, Elaine; Milton, Donald K; Gold, Diane R

2011-01-01

Background Studies on airway inflammation, measured as fraction exhaled nitric oxide (FENO), have focused on its relation to control of asthma, but the contribution of allergen exposure to elevation of FENO is unknown. Objective We evaluated (1) whether FENO was elevated in children with allergic sensitization or asthma; (2) whether specific allergen exposure increased FENO levels in sensitized, but not in unsensitized children; and (3) whether sedentary behavior increased FENO, independent of allergen exposures. Methods At age 12, in a birth cohort of children with parental history of allergy or asthma, we measured bed dust allergen (dust mite, cat, cockroach) by ELISA; specific allergic sensitization primarily by specific IgE ; and respiratory disease (current asthma, rhinitis, and wheeze) and hours of TV viewing/video game playing by questionnaire. Children performed spirometry maneuvers before and after bronchodilator responses, and had FENO measured using electrochemical detection methods (NIOX MINO). Results FENO was elevated in children with current asthma (32.2 ppb), wheeze (27.0 ppb), or rhinitis (23.2ppb) as compared to individuals without these respective symptoms/diagnoses (16.4 ppb to 16.6 ppb, p< 0.005 for all comparisons). Allergic sensitization to indoor allergens (cat, dog, dust mite) predicted higher levels of FENO, and explained one third of the variability of FENO. FENO levels were highest in children both sensitized and exposed to dust mite. Greater than 10 hours of weekday TV viewing was associated with a 0.64 log increase in FENO, after controlling indoor allergen exposure, BMI and allergic sensitization. Conclusion Allergen exposures and sedentary behavior (TV viewing/ video game playing), may increase airway inflammation, measured as FENO. PMID:21463890

Airway smooth muscle responsiveness from dogs with airway hyperresponsiveness after O/sub 3/ inhalation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jones, G.L.; O'Byrne, P.M.; Pashley, M.

1988-07-01

Airway hyperresponsiveness occurs after inhalation of O3 in dogs. The purpose of this study was to examine the responsiveness of trachealis smooth muscle in vitro to electrical field stimulation, exogenous acetylcholine, and potassium chloride from dogs with airway hyperresponsiveness after inhaled O3 in vivo and to compare this with the responsiveness of trachealis muscle from control dogs. In addition, excitatory junction potentials were measured with the use of single and double sucrose gap techniques in both groups of dogs to determine whether inhaled O3 affects the release of acetylcholine from parasympathetic nerves in trachealis muscle. Airway hyperresponsiveness developed in allmore » dogs after inhaled O3 (3 ppm for 30 min). The acetylcholine provocative concentration decreased from 4.11 mg/ml before O3 inhalation to 0.66 mg/ml after O3 (P less than 0.0001). The acetylcholine provocative concentration increased slightly after control inhalation of dry room air. Airway smooth muscle showed increased responses to both electrical field stimulation and exogenous acetylcholine but not to potassium chloride in preparations from dogs with airway hyperresponsiveness in vivo. The increased response to electrical field stimulation was not associated with a change in excitatory junctional potentials. These results suggest that a postjunctional alteration in trachealis muscle function occurs after inhaled O3 in dogs, which may account for airway hyperresponsiveness after O3 in vivo.« less

Food-cooking processes modulate allergenic properties of hen's egg white proteins.

PubMed

Liu, Xiaoyu; Feng, Bai-Sui; Kong, Xiaoli; Xu, Hong; Li, Xiumin; Yang, Ping-Chang; Liu, Zhigang

2013-01-01

Reducing the allergenicity of food allergens can suppress the clinical symptoms of food allergy. The objective of the present study was to investigate the effects of processing on the allergenic properties of hen's egg white proteins. Eggs were processed by traditional Chinese cooking, including steaming, water boiling, frying, spicing and tea boiling. The contents of processed egg protein were assessed by sodium dodecyl sulfate polyacrylamide gel electrophoresis; the allergenicity was evaluated by Western blotting, enzyme-linked immunosorbent assay and enzyme allergosorbent test inhibition. Circular dichroism spectrum analysis of four major egg allergens from various egg products was performed as well. A mouse model of food allergy was developed to test the allergenicity of processed egg protein in vivo. Protein degradation was significant following tea boiling and spiced-tea boiling. The total allergenic potential of water-boiled egg and fried egg was relatively higher than that of steamed egg, spiced egg and tea-boiled egg. Challenge with proteins from raw egg, water-boiled egg and fried egg induced skewed T-helper 2 pattern responses (Th2 responses) in the intestine of mice sensitized to egg proteins; however, when the mice sensitized to egg proteins were challenged with proteins from steamed egg, spiced egg and tea-boiled egg, respectively, only weak Th2 responses were induced in their intestine. Processing by steaming, spicing, or tea boiling can weaken the allergenicity of egg proteins. Copyright © 2012 S. Karger AG, Basel.

Differential effects of airway anesthesia on ozone-induced pulmonary responses in human subjects.

PubMed

Schelegle, E S; Eldridge, M W; Cross, C E; Walby, W F; Adams, W C

2001-04-01

We examined the effect of tetracaine aerosol inhalation, a local anesthetic, on lung volume decrements, rapid shallow breathing, and subjective symptoms of breathing discomfort induced by the acute inhalation of 0.30 ppm ozone for 65 min in 22 ozone-sensitive healthy human subjects. After 50 min of ozone inhalation FEV(1) was reduced 24%, breathing frequency was increased 40%, tidal volume was decreased 31%, and total subjective symptom score was increased (71.2, compared with 3.8 for filtered air exposure). Inhalation of tetracaine aerosol resulted in marked reductions in ozone-induced subjective symptoms of throat tickle and/or irritation (92.1%), cough (78.5%), shortness of breath (72.5%), and pain on deep inspiration (69.4%). In contrast, inhalation of tetracaine aerosol (mass median aerodynamic diameter of 3.52 microm with a geometric standard deviation of 1.92) resulted in only minor and inconsistent rectification of FEV(1) decrements (5.0%) and breathing frequency (-3.8%) that was not significantly different from that produced by saline aerosol alone (FEV(1), 5.1% and breathing frequency, -2.7%). Our data are consistent with afferent endings located within the large conducting airways of the tracheobronchial tree being primarily responsible for ozone-induced subjective symptoms and provides strong evidence that ozone-induced inhibition of maximal inspiratory effort is not dependent on conscious sensations of inspiratory discomfort.

TH17-induced neutrophils enhance the pulmonary allergic response following BALB/c exposure to house dust mite allergen and fine particulate matter from California and China.

PubMed

Zhang, Jingjing; Fulgar, Ciara C; Mar, Tiffany; Young, Dominique E; Zhang, Qi; Bein, Keith J; Cui, Liangliang; Castañeda, Alejandro; Vogel, Christoph F A; Sun, Xiaolin; Li, Wei; Smiley-Jewell, Suzette; Zhang, Zunzhen; Pinkerton, Kent E

2018-05-28

Asthma is a global and increasingly prevalent disease. According to the World Health Organization, approximately 235 million people suffer from asthma. Studies suggest that fine particulate matter (PM2.5) can induce innate immune responses, promote allergic sensitization, and exacerbate asthmatic symptoms and airway hyper-responsiveness. Recently, severe asthma and allergic sensitization have been associated with T-helper cell type 17 (TH17) activation. Few studies have investigated the links between PM2.5 exposure, allergic sensitization, asthma, and TH17 activation. This study aimed to determine whether 1) low-dose extracts of PM2.5 from California (PMCA) or China (PMCH) enhance allergic sensitization in mice following exposure to house dust mite (HDM) allergen; 2) eosinophilic or neutrophilic inflammatory responses result from PM and HDM exposure; and 3) TH17-associated cytokines are increased in the lung following exposure to PM and/or HDM.Ten-week old male BALB/c mice (n = 6-10/group) were intranasally instilled with phosphate-buffered saline (PBS), PM+PBS, HDM, or PM+HDM, on Days 1, 3, and 5 (sensitization experiments), and PBS or HDM on Days 12-14 (challenge experiments). Pulmonary function, bronchoalveolar lavage cell differentials, plasma immunoglobulin (Ig) protein levels, and lung tissue pathology, cyto-/chemo-kine proteins, and gene expression were assessed on Day 15.Results indicated low-dose PM2.5 extracts can enhance allergic sensitization and TH17-associated responses. While PMCA+HDM significantly decreased pulmonary function, and significantly increased neutrophils, Igs, and TH17-related protein and gene levels compared to HDM, there were no significant differences between HDM and PMCH+HDM treatments. This may result from greater copper and oxidized organic content in PMCA versus PMCH.

Soybean flour asthma: detection of allergens by immunoblotting

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bush, R.K.; Schroeckenstein, D.; Meier-Davis, S.

1988-08-01

A 43-year-old woman developed asthma 6 years after beginning work in a food-processing plant in which soybean flour was used as a protein extender. Symptoms of sneezing, coughing, and wheezing would begin within minutes of exposure to soybean flour and resolve 2 hours after exposure ceased. Skin tests were positive to a soy extract prepared from the flour. Airway hyperreactivity was confirmed by a positive bronchial challenge to methacholine. Bronchial challenge with soybean flour produced an immediate increase in specific airway resistance from 5.0 to 22.7 L. cm of H2O/L/sec. There was no response to challenge with lactose. The patient'smore » allergic response to soy-flour extract was further characterized by several immunologic methods. IgE binding to soy-flour protein by direct RAST was 5.98 times that of a normal control serum. The soy-flour extract was separated by dodecyl sulfate-polyacrylamide gel electrophoresis. Twenty-four protein bands were detected in the crude soy-flour extract. After immunoblotting and subsequent autoradiography, nine proteins with molecular weights ranging from 54,500 to 14,875 were found. Cross-reactivity studies with other legumes demonstrated apparent immunologic identity between a component in green pea extract and a soybean protein with a molecular weight of 17,000. The clinical significance of this cross-reactivity is not known. We conclude that in this case of occupational asthma to soybean flour, multiple allergens were involved. Immunoblotting may be useful in identifying the allergens involved in occupational asthma.« less

Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dhawale, Vaibhav Shrirang; Amara, Venkateswara Rao

Angiotensin-I converting enzyme (ACE) is positively correlated to asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and is highly expressed in lungs. ACE2, the counteracting enzyme of ACE, was proven to be protective in pulmonary, cardiovascular diseases. In the present study we checked the effect of ACE2 activation in animal model of asthma. Asthma was induced in male wistar rats by sensitization and challenge with ovalbumin and then treated with ACE2 activator, diminazene aceturate (DIZE) for 2 weeks. 48 h after last allergen challenge, animals were anesthetized, blood, BALF, femoral bone marrow lavage were collected for leucocytemore » count; trachea for measuring airway responsiveness to carbachol; lungs and heart were isolated for histological studies and western blotting. In our animal model, the characteristic features of asthma such as altered airway responsiveness to carbachol, eosinophilia and neutrophilia were observed. Western blotting revealed the increased pulmonary expression of ACE1, IL-1β, IL-4, NF-κB, BCL2, p-AKT, p-p38 and decreased expression of ACE2 and IκB. DIZE treatment prevented these alterations. Intraalveolar interstitial thickening, inflammatory cell infiltration, interstitial fibrosis, oxidative stress and right ventricular hypertrophy in asthma control animals were also reversed by DIZE treatment. Activation of ACE2 by DIZE conferred protection against asthma as evident from biochemical, functional, histological and molecular parameters. To the best of our knowledge, we report for the first time that activation of ACE2 by DIZE prevents asthma progression by altering AKT, p38, NF-κB and other inflammatory markers. - Highlights: • Diminazene aceturate (DIZE), an ACE2 activator prevents ovalbumin-induced asthma. • DIZE acted by upregulating ACE2, downregulating ACE1, MAPKs, markers of inflammation, apoptosis. • DIZE reduced airway inflammation, fibrosis, right ventricular

Endocrine regulation of airway contractility is overlooked.

PubMed

Bossé, Ynuk

2014-08-01

Asthma is a prevalent respiratory disorder triggered by a variety of inhaled environmental factors, such as allergens, viruses, and pollutants. Asthma is characterized by an elevated activation of the smooth muscle surrounding the airways, as well as a propensity of the airways to narrow excessively in response to a spasmogen (i.e. contractile agonist), a feature called airway hyperresponsiveness. The level of airway smooth muscle (ASM) activation is putatively controlled by mediators released in its vicinity. In asthma, many mediators that affect ASM contractility originate from inflammatory cells that are mobilized into the airways, such as eosinophils. However, mounting evidence indicates that mediators released by remote organs can also influence the level of activation of ASM, as well as its level of responsiveness to spasmogens and relaxant agonists. These remote mediators are transported through circulating blood to act either directly on ASM or indirectly via the nervous system by tuning the level of cholinergic activation of ASM. Indeed, mediators generated from diverse organs, including the adrenals, pancreas, adipose tissue, gonads, heart, intestines, and stomach, affect the contractility of ASM. Together, these results suggest that, apart from a paracrine mode of regulation, ASM is subjected to an endocrine mode of regulation. The results also imply that defects in organs other than the lungs can contribute to asthma symptoms and severity. In this review, I suggest that the endocrine mode of regulation of ASM contractility is overlooked. © 2014 Society for Endocrinology.

Vinegar decreases allergenic response in lentil and egg food allergy.

PubMed

Armentia, A; Dueñas-Laita, A; Pineda, F; Herrero, M; Martín, B

2010-01-01

Food allergy results from an atypical response of the mucosal immune system to orally consumed allergens. Antacid medication inhibits the digestion of dietary proteins and causes food allergy. A decrease of the gastric pH might enhance the function of digestion and reduce the risk of food allergy. To test a possible decrease in the allergenicity of powerful food allergens (egg, chicken, lentils) with the addition of vinegar during the cooking process. We included seven patients who suffered from anaphylaxis due to egg, chicken and lentils. We added vinegar to egg, chicken and lentil processed extracts used for skin prick tests (SPT) and compared the wheal areas obtained with the same extracts sources and the same way but without vinegar addition. Immunodetection was performed with the different processed extracts and patients' sera. Only one patient consented food challenge with vinegar-marinated-chicken. Wheal areas were significantly minor with the food extract with vinegar. Immunodetection showed a decrease of the response with vinegar processed extracts. Vinegar addition during the cooking process may decrease lentil and chicken allergenicity. Copyright 2009 SEICAP. Published by Elsevier Espana. All rights reserved.

Responses of lung parenchyma and airways to tachykinin peptides in piglets.

PubMed

Dreshaj, I A; Martin, R J; Miller, M J; Haxhiu, M A

1994-07-01

The tachykinin peptides substance P (SP) and neurokinin A (NKA) have been shown to induce tracheal smooth muscle contraction in piglets, and the enzyme neutral endopeptidase has been shown to modulate this effect. In these studies, we compared the SP and NKA responsiveness of piglet airways and lung parenchymal tissues in anesthetized paralyzed open-chest piglets 2-3 wk old, partitioning total lung resistance (RL) into airway resistance (Raw) and tissue resistance (Rti). During tidal breathing, pressure was measured at the trachea and in two alveolar regions by means of alveolar capsules. Intravenous administration of SP caused concentration-dependent increases in Rti and Raw and a decrease in dynamic lung compliance. Under baseline conditions, Rti contributed 74.6 +/- 1.9% (SE) of RL, and at any level of constriction, Rti accounted for > 50% of RL. The responses of Rti and Raw to NKA were negligible and were always significantly weaker than those to SP. These results indicate that both central airways and tissue contractile elements respond vigorously to SP, but not to NKA, in maturing piglets.

Genetic control of indirect airway responsiveness in the rat.

PubMed

Pauwels, R A; Germonpré, P R; Kips, J C; Joos, G F

1995-11-01

Many of the airway responses to endogenous and exogenous stimuli are caused by indirect mechanisms such as the activation of neurons and/or inflammatory cells. In the present study we compare the bronchoconstrictor and the plasma protein extravasation response to adenosine and tachykinins in two highly inbred rat strains, F344 and BDE. BDE-rats have a bronchoconstrictor response to adenosine at lower doses. Challenge with the A3-adenosine receptor agonist APNEA demonstrates that the difference in airway responsiveness to adenosine between BDE- and F344-rats is probably related to a higher number of A3-receptors on the airway mast cells of BDE-rats. In contrast, F344-rats have a higher airway responsiveness to tachykinins than BDE-rats. Tachykinins cause bronchoconstriction in F344-rats mainly by an indirect mechanism, involving stimulation of NK1-receptors and mast cell activation. In BDE-rats they cause bronchoconstriction by a direct effect on airway smooth muscle via activation of NK2-receptors. Finally we also observed a difference between F344- and BDE-rats with regard to the mechanisms involved in the plasma protein extravasation in the airways caused by substance P or capsaicin. In F344-rats but not in BDE-rats mast cell activation and the release of 5-hydroxytryptamine is partly responsible for this plasma protein extravasation.

Corticosteroid treatment inhibits airway hyperresponsiveness and lung injury in a murine model of chemical-induced airway inflammation.

PubMed

Wigenstam, Elisabeth; Jonasson, Sofia; Koch, Bo; Bucht, Anders

2012-11-15

Exposure to toxic alkylating mustard agents causes both acute and long-term effects to the lungs as indicated by increased number of inflammatory cells in airways, lung edema and lung tissue fibrosis. We have previously demonstrated that treatment with the corticosteroid dexamethasone 1 h after lung exposure to the nitrogen mustard analog melphalan protects mice from acute and sub-acute inflammatory responses, as well as from lung tissue fibrosis. In order to address the importance of early anti-inflammatory treatment, we investigated the therapeutic effect of dexamethasone administered 1, 2 or 6 h following exposure to melphalan. C57BL/6 mice were exposed to melphalan and treated with dexamethasone 1, 2 or 6 h after exposure. Twenty hours or 14 days post exposure mice were subjected to analysis of respiratory mechanics where the effects of incremental doses of methacholine on central and peripheral lung components were measured. We also determined the amount of inflammatory cells in the bronchoalveolar lavage fluid and measured the amount of collagen content in the lungs. Melphalan exposure increased airway hyperresponsiveness in both central and peripheral airways and induced an airway inflammation dominated by infiltration of macrophages and neutrophils. Dexamethasone given 1 h after exposure to melphalan provided better protection against airway inflammation than administration 2 or 6 h after exposure. Collagen deposition 14 days after exposure was decreased due to dexamethasone treatment. Early treatment with dexamethasone is important in order to reduce the airway hyperresponsiveness and inflammation caused by toxic alkylating mustards such as melphalan. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Recent developments in the role of reactive oxygen species in allergic asthma

PubMed Central

Qu, Jingjing; Li, Yuanyuan; Zhong, Wen

2017-01-01

Allergic asthma has a global prevalence, morbidity, and mortality. Many environmental factors, such as pollutants and allergens, are highly relevant to allergic asthma. The most important pathological symptom of allergic asthma is airway inflammation. Accordingly, the unique role of reactive oxygen species (ROS) had been identified as a main reason for this respiratory inflammation. Many studies have shown that inhalation of different allergens can promote ROS generation. Recent studies have demonstrated that several pro-inflammatory mediators are responsible for the development of allergic asthma. Among these mediators, endogenous or exogenous ROS are responsible for the airway inflammation of allergic asthma. Furthermore, several inflammatory cells induce ROS and allergic asthma development. Airway inflammation, airway hyper-responsiveness, tissue injury, and remodeling can be induced by excessive ROS production in animal models. Based on investigations of allergic asthma and ROS formation mechanisms, we have identified several novel anti-inflammatory therapeutic treatments. This review describes the recent data linking ROS to the pathogenesis of allergic asthma. PMID:28203435

Arsenic Alters ATP-Dependent Ca2+ Signaling in Human Airway Epithelial Cell Wound Response

PubMed Central

Sherwood, Cara L.; Lantz, R. Clark; Burgess, Jefferey L.; Boitano, Scott

2011-01-01

Arsenic is a natural metalloid toxicant that is associated with occupational inhalation injury and contaminates drinking water worldwide. Both inhalation of arsenic and consumption of arsenic-tainted water are correlated with malignant and nonmalignant lung diseases. Despite strong links between arsenic and respiratory illness, underlying cell responses to arsenic remain unclear. We hypothesized that arsenic may elicit some of its detrimental effects on the airway through limitation of innate immune function and, specifically, through alteration of paracrine ATP (purinergic) Ca2+ signaling in the airway epithelium. We examined the effects of acute (24 h) exposure with environmentally relevant levels of arsenic (i.e., < 4μM as Na-arsenite) on wound-induced Ca2+ signaling pathways in human bronchial epithelial cell line (16HBE14o-). We found that arsenic reduces purinergic Ca2+ signaling in a dose-dependent manner and results in a reshaping of the Ca2+ signaling response to localized wounds. We next examined arsenic effects on two purinergic receptor types: the metabotropic P2Y and ionotropic P2X receptors. Arsenic inhibited both P2Y- and P2X-mediated Ca2+ signaling responses to ATP. Both inhaled and ingested arsenic can rapidly reach the airway epithelium where purinergic signaling is essential in innate immune functions (e.g., ciliary beat, salt and water transport, bactericide production, and wound repair). Arsenic-induced compromise of such airway defense mechanisms may be an underlying contributor to chronic lung disease. PMID:21357385

Asthmatic bronchial epithelium activated by the proteolytic allergen Der p 1 increases selective dendritic cell recruitment.

PubMed

Pichavant, Muriel; Charbonnier, Anne-Sophie; Taront, Solenne; Brichet, Anne; Wallaert, Benoît; Pestel, Joel; Tonnel, André-Bernard; Gosset, Philippe

2005-04-01

Airway dendritic cells (DCs) are crucial for allergen-induced sensitization and inflammation in allergic asthma. After allergen challenge, an increased number of DCs is observed in airway epithelium from patients with allergy. Because Der p 1, a cysteine protease allergen from Dermatophagoides pteronyssinus , induces chemokine production by bronchial epithelial cells (BECs), the purpose of this investigation was to evaluate the capacity of BEC exposed to Der p 1 to recruit DCs. Chemotactic activity of BEAS-2B, a bronchial epithelial cell line, and BECs from nonatopic controls and patients with allergic asthma was evaluated on the migration of precursors, immature and mature monocyte-derived DCs (MDDCs), and CD34 + -derived Langerhans cells (LCs). C-C chemokine ligand (CCL)-2, CCL5, and C-X-C chemokine ligand 10 production by BEAS-2B and BEC was increased after Der p 1 exposure, whereas the proenzyme proDer p 1 devoid of enzymatic activity had no effect. Der p 1 stimulation of BEAS-2B and BEC from both groups increased significantly the recruitment of MDDC precursors, depending on CCL2, CCL5, and C-X-C chemokine ligand 10 production. In a reconstituted polarized epithelium, apical application of Der p 1 enhanced MDDC precursor migration into the epithelial layer. Moreover, Der p 1 stimulation of BEC from patients with asthma but not from controls increased the migration of LC precursors, mainly dependent on CCL20 secretion. No migration of immature and mature DCs was observed. These data confirmed that BECs participate in the homeostasis of the DC network present within the bronchial epithelium through the secretion of chemokines. In allergic asthma, upregulation of CCL20 production induced LC recruitment, the role of which remains to be determined.

Endotoxin-induced nitric oxide production rescues airway growth and maturation in atrophic fetal rat lung explants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rae, C.; Cherry, J.I.; Land, F.M.

Inflammation induces premature maturation of the fetal lung but the signals causing this effect remain unclear. We determined if nitric oxide (NO) synthesis, evoked by Escherichia coli lipopolysaccharide (LPS, 2 {mu}g ml{sup -1}), participated in this process. Fetal rat lung airway surface complexity rose 2.5-fold over 96 h in response to LPS and was associated with increased iNOS protein expression and activity. iNOS inhibition by N6-(1-iminoethyl)-L-lysine-2HCl (L-NIL) abolished this and induced airway atrophy similar to untreated explants. Surfactant protein-C (SP-C) expression was also induced by LPS and abolished by L-NIL. As TGF{beta} suppresses iNOS activity, we determined if feedback regulationmore » modulated NO-dependent maturation. LPS induced TGF{beta}1 release and SMAD4 nuclear translocation 96 h after treatment. Treatment of explants with a blocking antibody against TGF{beta}1 sustained NO production and airway morphogenesis whereas recombinant TGF{beta}1 antagonized these effects. Feedback regulation of NO synthesis by TGF{beta} may, thus, modulate airway branching and maturation of the fetal lung.« less

Toxoplasma gondii infection blocks the development of allergic airway inflammation in BALB/c mice

PubMed Central

Fenoy, I; Giovannoni, M; Batalla, E; Martin, V; Frank, F M; Piazzon, I; Goldman, A

2009-01-01

There is a link between increased allergy and a reduction of some infections in western countries. Epidemiological data also show that respiratory allergy is less frequent in people exposed to orofaecal and foodborne microbes such as Toxoplasma gondii. Infection with T. gondii induces a strong cell-mediated immunity with a highly polarized T helper type 1 (Th1) response in early stages of infection. Using a well-known murine model of allergic lung inflammation, we sought to investigate whether T. gondii infection could modulate the susceptibility to develop respiratory allergies. Both acute and chronic infection with T. gondii before allergic sensitization resulted in a diminished allergic inflammation, as shown by a decrease in bronchoalveolar lavage (BAL) eosinophilia, mononuclear and eosinophil cell infiltration around airways and vessels and goblet cell hyperplasia. Low allergen-specific immunoglobulin (Ig)E and IgG1 and high levels of allergen-specific IgG2a serum antibodies were detected. A decreased interleukin (IL)-4 and IL-5 production by lymph node cells was observed, while no antigen-specific interferon-γ increase was detected. Higher levels of the regulatory cytokine IL-10 were found in BAL from infected mice. These results show that both acute and chronic parasite infection substantially blocked development of airway inflammation in adult BALB/c mice. Our results support the hypothesis that T. gondii infection contributes to protection against allergy in humans. PMID:19032550

Airway Surface Dehydration Aggravates Cigarette Smoke-Induced Hallmarks of COPD in Mice.

PubMed

Seys, Leen J M; Verhamme, Fien M; Dupont, Lisa L; Desauter, Elke; Duerr, Julia; Seyhan Agircan, Ayca; Conickx, Griet; Joos, Guy F; Brusselle, Guy G; Mall, Marcus A; Bracke, Ken R

2015-01-01

Airway surface dehydration, caused by an imbalance between secretion and absorption of ions and fluid across the epithelium and/or increased epithelial mucin secretion, impairs mucociliary clearance. Recent evidence suggests that this mechanism may be implicated in chronic obstructive pulmonary disease (COPD). However, the role of airway surface dehydration in the pathogenesis of cigarette smoke (CS)-induced COPD remains unknown. We aimed to investigate in vivo the effect of airway surface dehydration on several CS-induced hallmarks of COPD in mice with airway-specific overexpression of the β-subunit of the epithelial Na⁺ channel (βENaC). βENaC-Tg mice and wild-type (WT) littermates were exposed to air or CS for 4 or 8 weeks. Pathological hallmarks of COPD, including goblet cell metaplasia, mucin expression, pulmonary inflammation, lymphoid follicles, emphysema and airway wall remodelling were determined and lung function was measured. Airway surface dehydration in βENaC-Tg mice aggravated CS-induced airway inflammation, mucin expression and destruction of alveolar walls and accelerated the formation of pulmonary lymphoid follicles. Moreover, lung function measurements demonstrated an increased compliance and total lung capacity and a lower resistance and hysteresis in βENaC-Tg mice, compared to WT mice. CS exposure further altered lung function measurements. We conclude that airway surface dehydration is a risk factor that aggravates CS-induced hallmarks of COPD.

SPDEF regulates goblet cell hyperplasia in the airway epithelium

PubMed Central

Park, Kwon-Sik; Korfhagen, Thomas R.; Bruno, Michael D.; Kitzmiller, Joseph A.; Wan, Huajing; Wert, Susan E.; Khurana Hershey, Gurjit K.; Chen, Gang; Whitsett, Jeffrey A.

2007-01-01

Goblet cell hyperplasia and mucous hypersecretion contribute to the pathogenesis of chronic pulmonary diseases including cystic fibrosis, asthma, and chronic obstructive pulmonary disease. In the present work, mouse SAM pointed domain-containing ETS transcription factor (SPDEF) mRNA and protein were detected in subsets of epithelial cells lining the trachea, bronchi, and tracheal glands. SPDEF interacted with the C-terminal domain of thyroid transcription factor 1, activating transcription of genes expressed selectively in airway epithelial cells, including Sftpa, Scgb1a1, Foxj1, and Sox17. Expression of Spdef in the respiratory epithelium of adult transgenic mice caused goblet cell hyperplasia, inducing both acidic and neutral mucins in vivo, and stainined for both acidic and neutral mucins in vivo. SPDEF expression was increased at sites of goblet cell hyperplasia caused by IL-13 and dust mite allergen in a process that was dependent upon STAT-6. SPDEF was induced following intratracheal allergen exposure and after Th2 cytokine stimulation and was sufficient to cause goblet cell differentiation of Clara cells in vivo. PMID:17347682

Effect of the glucocorticosteroid budesonide and a novel phosphodiesterase type 4 inhibitor CDP840 on antigen-induced airway responses in neonatally immunised rabbits.

PubMed Central

Gozzard, N.; el-Hashim, A.; Herd, C. M.; Blake, S. M.; Holbrook, M.; Hughes, B.; Higgs, G. A.; Page, C. P.

1996-01-01

1. The effects of the inhaled corticosteroid budesonide and a novel PDE 4 inhibitor CDP840 given systematically, were evaluated in a model of antigen-induced airway inflammation in the rabbit. 2. Adult litter-matched NZW rabbits (2.4-3.5 kg) immunised within 24 h of birth with Alternaria tenuis antigen were pretreated with budesonide (total dose 100 micrograms, inhaled over 2 days) or CDP840 (total dose 7 mg kg-1, i.p. over 3 days), before antigen challenge. For each drug-treated group a parallel group of rabbits was pretreated with the appropriate vehicle. In all groups airway responsiveness to inhaled histamine was assessed and bronchoalveolar lavage (BAL) performed 24 h before and after antigen challenge. 3. Basal lung function in terms of total lung resistance (RL; cmH2O l 1s-1) and dynamic compliance (Cdyn; ml cmH2O-1) were unaltered by pretreatment with budesonide or CDP840 compared to their respective vehicles 24 h before or after antigen challenge. 4. The RL component of the acute bronchoconstriction induced by inhaled Alternaria tenuis aerosol was unaffected by pretreatment with budesonide. However, budesonide prevented the fall in Cdyn due to antigen. Treatment with CDP840 significantly reduced antigen-induced acute bronchoconstriction in terms of both RL and Cdyn. 5. Airway hyperresponsiveness (AHR) to inhaled histamine was indicated by reduced RL PC50 (2.4-4.5 fold) and Cdyn PC35 (2.1-3.9 fold) values 24 h after antigen challenge. Treatment with either budesonide or CDP840 abolished the antigen-induced increase in responsiveness to inhaled histamine. 6. Total cells recovered per ml of BAL fluid increased 24 h after antigen challenge. Antigen-induced pulmonary eosinophilia was reduced (93%) in budesonide and (85%) in CDP840 treated rabbits. Antigen-induced increases in neutrophil numbers were reduced (76%) with budesonide but not CDP840 pretreatment. 7. Inhalation of Alternaria tenuis aerosol elicited an acute bronchoconstriction, followed 24 hours later

Treatment with grass allergen peptides improves symptoms of grass pollen-induced allergic rhinoconjunctivitis.

PubMed

Ellis, Anne K; Frankish, Charles W; O'Hehir, Robyn E; Armstrong, Kristen; Steacy, Lisa; Larché, Mark; Hafner, Roderick P

2017-08-01

Synthetic peptide immunoregulatory epitopes are a new class of immunotherapy to treat allergic rhinoconjunctivitis (ARC). Grass allergen peptides, comprising 7 synthetic T-cell epitopes derived from Cyn d 1, Lol p 5, Dac g 5, Hol l 5, and Phl p 5, is investigated for treatment of grass pollen-induced ARC. We sought to evaluate the efficacy, safety, and tolerability of intradermally administered grass allergen peptides. A multicenter, randomized, double-blind, placebo-controlled study evaluated 3 regimens of grass allergen peptides versus placebo in patients with grass pollen-induced allergy (18-65 years). After a 4-day baseline challenge to rye grass in the environmental exposure unit (EEU), subjects were randomized to receive grass allergen peptides at 6 nmol at 2-week intervals for a total of 8 doses (8x6Q2W), grass allergen peptides at 12 nmol at 4-week intervals for a total of 4 doses (4x12Q4W), or grass allergen peptides at 12 nmol at 2-week intervals for a total of 8 doses (8x12Q2W) or placebo and treated before the grass pollen season. The primary efficacy end point was change from baseline in total rhinoconjunctivitis symptom score across days 2 to 4 of a 4-day posttreatment challenge (PTC) in the EEU after the grass pollen season. Secondary efficacy end points and safety were also assessed. Two hundred eighty-two subjects were randomized. Significantly greater improvement (reduction of total rhinoconjunctivitis symptom score from baseline to PTC) occurred across days 2 to 4 with grass allergen peptide 8x6Q2W versus placebo (-5.4 vs -3.8, respectively; P = .0346). Greater improvement at PTC also occurred for grass allergen peptide 8x6Q2W versus placebo (P = .0403) in patients with more symptomatic ARC. No safety signals were detected. Grass allergen peptide 8x6Q2W significantly improved ARC symptoms after rye grass allergen challenge in an EEU with an acceptable safety profile. Copyright © 2017 American Academy of Allergy, Asthma & Immunology

The Role of COX-2 in the Inflammatory and Fibrotic Response in the Lung Following Exposure to Multi-Walled Carbon Nanotubes

NASA Astrophysics Data System (ADS)

Sayers, Brian C.

Exposure to multiwalled carbon nanotubes (MWCNT) has been demonstrated to exacerbate airway inflammation and fibrosis in allergen-challenged mouse model. These data have led to concern that individuals with asthma could represent a susceptible population to adverse health effects following exposure to MWCNT, and possibly other engineered nanoparticles. Asthma pathogenesis is caused by the interaction of a complex genetic predisposition and environmental exposures. Because chronic airway inflammation is common to all asthma phenotypes, it is logical to investigate genes that are involved in inflammatory pathways in order to understand the genetic basis of asthma. The metabolism of arachidonic acid by cyclooxygenase (COX) enzymes is the rate-determining step in the synthesis of prostanoids, which are biologically active lipids that are important modulators of inflammation. Based on the role of COX enzymes in inflammatory pathways, we sought to investigate how COX enzymes are involved in the inflammatory response following MWCNT exposure in asthmatic airways. We report that MWCNT significantly exacerbated allergen-induced airway inflammation and mucus cell metaplasia in COX-2 deficient mice compared to wild type mice. In addition, MWCNTs significantly enhanced allergen-induced cytokines involved in Th2 (IL-13, IL-5), Th1 (CXCL10), and Th17 (IL-17A) inflammatory responses in COX-2 deficient mice but not in WT mice. We conclude that exacerbation of allergen-induced airway inflammation and mucus cell metaplasia by MWCNTs is enhanced by deficiency in COX-2 and associated with activation of a mixed Th1/Th2/Th17 immune response. Based on our observation that COX-2 deficient mice developed a mixed Th immune response following MWCNT exposure, we sought to evaluate how cytokines associated with different Th immune responses alter COX expression following MWCNT exposure. For this study, a mouse macrophage cell line (RAW264.7) was used because MWCNT were largely sequestered

Pollen derived low molecular compounds enhance the human allergen specific immune response in vivo.

PubMed

Gilles-Stein, S; Beck, I; Chaker, A; Bas, M; McIntyre, M; Cifuentes, L; Petersen, A; Gutermuth, J; Schmidt-Weber, C; Behrendt, H; Traidl-Hoffmann, C

2016-10-01

Besides allergens, pollen release bioactive, low molecular weight compounds that modulate and stimulate allergic reactions. Clinical relevance of these substances has not been investigated to date. To elucidate the effect of a non-allergenic, low molecular weight factors from aqueous birch pollen extracts (Bet-APE < 3 kDa) on the human allergic immune response in vivo. Birch and grass pollen allergic individuals underwent skin prick testing with allergen alone, allergen plus Bet-APE < 3 kDa, or allergen plus pre-identified candidate substances from low molecular pollen fraction. Nasal allergen challenges were performed in non-atopic and pollen allergic individuals using a 3 day repeated threshold challenge battery. Subjects were either exposed to allergen alone or to allergen plus Bet-APE< 3 kDa. Local cytokine levels, nasal secretion weights, nasal congestion and symptom scores were determined. Skin prick test reactions to pollen elicited larger weals when allergens were tested together with the low molecular weight compounds from pollen. Similar results were obtained with candidate pollen-associated lipid mediators. In nasal lining fluids of allergic patients challenged with allergen plus Bet-APE < 3 kDa, IL-8 and IgE was significantly increased as compared to allergen-only challenged patients. These patients also produced increased amounts of total nasal secretion and reported more severe rhinorrhea than the allergen-only challenged group. Low molecular compounds from pollen enhance the allergen specific immune response in the skin and nose. They are therefore of potential clinical relevance in allergic patients. © 2016 John Wiley & Sons Ltd.

Airway Fibrinogenolysis and the Initiation of Allergic Inflammation

PubMed Central

Millien, Valentine Ongeri; Lu, Wen; Mak, Garbo; Yuan, Xiaoyi; Knight, J. Morgan; Porter, Paul; Kheradmand, Farrah

2014-01-01

The past 15 years of allergic disease research have produced extraordinary improvements in our understanding of the pathogenesis of airway allergic diseases such as asthma. Whereas it was previously viewed as largely an immunoglobulin E-mediated process, the gradual recognition that T cells, especially Type 2 T helper (Th2) cells and Th17 cells, play a major role in asthma and related afflictions has inspired clinical trials targeting cytokine-based inflammatory pathways that show great promise. What has yet to be clarified about the pathogenesis of allergic inflammatory disorders, however, are the fundamental initiating factors, both exogenous and endogenous, that drive and sustain B- and T-cell responses that underlie the expression of chronic disease. Here we review how proteinases derived from diverse sources drive allergic responses. A central discovery supporting the proteinase hypothesis of allergic disease pathophysiology is the role played by airway fibrinogen, which in part appears to serve as a sensor of unregulated proteinase activity and which, when cleaved, both participates in a novel allergic signaling pathway through Toll-like receptor 4 and forms fibrin clots that contribute to airway obstruction. Unresolved at present is the ultimate source of airway allergenic proteinases. From among many potential candidates, perhaps the most intriguing is the possibility such enzymes derive from airway fungi. Together, these new findings expand both our knowledge of allergic disease pathophysiology and options for therapeutic intervention. PMID:25525732

Current overview of allergens of plant pathogenesis related protein families.

PubMed

Sinha, Mau; Singh, Rashmi Prabha; Kushwaha, Gajraj Singh; Iqbal, Naseer; Singh, Avinash; Kaushik, Sanket; Kaur, Punit; Sharma, Sujata; Singh, Tej P

2014-01-01

Pathogenesis related (PR) proteins are one of the major sources of plant derived allergens. These proteins are induced by the plants as a defense response system in stress conditions like microbial and insect infections, wounding, exposure to harsh chemicals, and atmospheric conditions. However, some plant tissues that are more exposed to environmental conditions like UV irradiation and insect or fungal attacks express these proteins constitutively. These proteins are mostly resistant to proteases and most of them show considerable stability at low pH. Many of these plant pathogenesis related proteins are found to act as food allergens, latex allergens, and pollen allergens. Proteins having similar amino acid sequences among the members of PR proteins may be responsible for cross-reactivity among allergens from diverse plants. This review analyzes the different pathogenesis related protein families that have been reported as allergens. Proteins of these families have been characterized in regard to their biological functions, amino acid sequence, and cross-reactivity. The three-dimensional structures of some of these allergens have also been evaluated to elucidate the antigenic determinants of these molecules and to explain the cross-reactivity among the various allergens.

Role of EP2 and EP4 receptors in airway microvascular leak induced by prostaglandin E2.

PubMed

Jones, Victoria C; Birrell, Mark A; Maher, Sarah A; Griffiths, Mark; Grace, Megan; O'Donnell, Valerie B; Clark, Stephen R; Belvisi, Maria G

2016-03-01

Airway microvascular leak (MVL) involves the extravasation of proteins from post-capillary venules into surrounding tissue. MVL is a cardinal sign of inflammation and an important feature of airway inflammatory diseases such as asthma. PGE2, a product of COX-mediated metabolism of arachidonic acid, binds to four receptors, termed EP1–4. PGE2 has a wide variety of effects within the airway, including modulation of inflammation, sensory nerve activation and airway tone. However, the effect of PGE2 on airway MVL and the receptor/s that mediate this have not been described. Evans Blue dye was used as a marker of airway MVL, and selective EP receptor agonists and antagonists were used alongside EP receptor-deficient mice to define the receptor subtype involved. PGE2 induced significant airway MVL in mice and guinea pigs. A significant reduction in PGE2-induced MVL was demonstrated in Ptger2−/− and Ptger4−/− mice and in wild-type mice pretreated simultaneously with EP2 (PF-04418948) and EP4 (ER-819762) receptor antagonists. In a model of allergic asthma, an increase in airway levels of PGE2 was associated with a rise in MVL; this change was absent in Ptger2−/− and Ptger4−/− mice. PGE2 is a key mediator produced by the lung and has widespread effects according to the EP receptor activated. Airway MVL represents a response to injury and under ‘disease’ conditions is a prominent feature of airway inflammation. The data presented highlight a key role for EP2 and EP4 receptors in MVL induced by PGE2.

A liver-X-receptor ligand, T0901317, attenuates IgE production and airway remodeling in chronic asthma model of mice.

PubMed

Shi, Ying; Xu, Xiantao; Tan, Yan; Mao, Shan; Fang, Surong; Gu, Wei

2014-01-01

The liver-X-receptors have shown anti-inflammatory ability in several animal models of respiratory disease. Our purpose is to investigate the effect of LXR ligand in allergen-induced airway remodeling in mice. Ovalbumin-sensitized mice were chronically challenged with aerosolized ovalbumin for 8 weeks. Some mice were administered a LXR agonist, T0901317 (12.5, 25, 50 mg/kg bodyweight) before challenge. Then mice were evaluated for airway inflammation, airway hyperresponsiveness and airway remodeling. T0901317 failed to attenuate the inflammatory cells and Th2 cytokines in bronchoalveolar lavage fluid. But the application of T0901317 reduced the thickness of airway smooth muscle and the collagen deposition. Meanwhile, T0901317 treatment evidently abolished the high level of OVA-specific IgE, TGF-β1 and MMP-9 in lung. So LXRs may attenuate the progressing of airway remodeling, providing a potential treatment of asthma.

SNOR and wheeze: the asthma enzyme?

PubMed

Henderson, Edward M; Gaston, Benjamin

2005-11-01

Conventionally, asthma is defined as involving both airway inflammation and airway smooth muscle hyper-responsiveness. However, Que and coworkers have recently uncoupled these concepts, showing that mice lacking an S-nitrosothiol reductase have allergen-induced airway inflammation but do not have airway hyper-responsiveness. These data are consistent with recent clinical evidence that: (i) S-nitrosothiol signaling is abnormal in human asthma, (ii) nitric oxide in exhaled air might be only a biomarker for the metabolism of more physiologically relevant nitrogen oxides and (iii) the biochemical response to airway inflammation is central to asthma pathophysiology.

Preventive Intra Oral Treatment of Sea Cucumber Ameliorate OVA-Induced Allergic Airway Inflammation.

PubMed

Lee, Da-In; Park, Mi-Kyung; Kang, Shin Ae; Choi, Jun-Ho; Kang, Seok-Jung; Lee, Jeong-Yeol; Yu, Hak Sun

2016-01-01

Sea cucumber extracts have potent biological effects, including anti-viral, anti-cancer, antibacterial, anti-oxidant, and anti-inflammation effects. To understand their anti-asthma effects, we induced allergic airway inflammation in mice after 7 oral administrations of the extract. The hyper-responsiveness value in mice with ovalbumin (OVA)-alum-induced asthma after oral injection of sea cucumber extracts was significantly lower than that in the OVA-alum-induced asthma group. In addition, the number of eosinophils in the lungs of asthma-induced mice pre-treated with sea cucumber extract was significantly decreased compared to that of PBS pre-treated mice. Additionally, CD4[Formula: see text]CD25[Formula: see text]Foxp3[Formula: see text]T (regulatory T; Treg) cells significantly increased in mesenteric lymph nodes after 7 administrations of the extract. These results suggest that sea cucumber extract can ameliorate allergic airway inflammation via Treg cell activation and recruitment to the lung.

Type 2 Innate Lymphoid Cells: Friends or Foes—Role in Airway Allergic Inflammation and Asthma

PubMed Central

Pishdadian, Abbas; Varasteh, Abdol-Reza; Sankian, Mojtaba

2012-01-01

Innate-like lymphocytes (ILLs) and innate lymphoid cells (ILCs) are two newly characterized families of lymphocytes with limited and no rearranged antigen receptors, respectively. These soldiers provide a first line of defense against foreign insults by triggering a prompt innate immune response and bridging the gap of innate and adaptive immunity. Type 2 innate lymphoid cells (ILCs2) are newly identified members of the ILC family that play a key role in type 2 immune responses by prompt production of type 2 cytokines (especially IL-5 and IL-13) in response to antigen-induced IL-25/33 and by recruiting type 2 “immune franchise.” Regarding the two different roles of type 2 cytokines, helminth expulsion and type 2-related diseases, here we review the latest advances in ILC2 biology and examine the pivotal role of resident ILCs2 in allergen-specific airway inflammation and asthma. PMID:23209480

Type 2 innate lymphoid cells: friends or foes-role in airway allergic inflammation and asthma.

PubMed

Pishdadian, Abbas; Varasteh, Abdol-Reza; Sankian, Mojtaba

2012-01-01

Innate-like lymphocytes (ILLs) and innate lymphoid cells (ILCs) are two newly characterized families of lymphocytes with limited and no rearranged antigen receptors, respectively. These soldiers provide a first line of defense against foreign insults by triggering a prompt innate immune response and bridging the gap of innate and adaptive immunity. Type 2 innate lymphoid cells (ILCs2) are newly identified members of the ILC family that play a key role in type 2 immune responses by prompt production of type 2 cytokines (especially IL-5 and IL-13) in response to antigen-induced IL-25/33 and by recruiting type 2 "immune franchise." Regarding the two different roles of type 2 cytokines, helminth expulsion and type 2-related diseases, here we review the latest advances in ILC2 biology and examine the pivotal role of resident ILCs2 in allergen-specific airway inflammation and asthma.

A role for Waldeyer's ring in immunological response to allergens.

PubMed

Masieri, Simonetta; Trabattoni, Daria; Incorvaia, Cristoforo; De Luca, Maria Cristina; Dell'Albani, Ilaria; Leo, Gualtiero; Frati, Franco

2014-02-01

Adenoids, tubal tonsil, palatine tonsil, and lingual tonsil are immunological organs included in the Waldeyer's ring, the basic function of which is the antibody production to common environmental antigens. Adenoidal hypertrophy (AH) is a major medical issue in children, and adenoidectomy is still the most used treatment worldwide. The response of adenoids to allergens is a good model to evaluate their immunological function. This report assessed the immunological changes in adenoid tissues from children with allergic rhinitis (AR) undergoing sublingual immunotherapy (SLIT). Adenoid samples from 16 children (seven males, nine females, mean age 7.12 years) with AH and clinical indication to adenoidectomy were collected. Of them, five children were not allergic and 11 had house dust mite and grass pollen-induced AR. Among allergic children, in four AR was treated by antihistamines while in seven AR was treated by high-dose SLIT during 4-6 months. The evaluation addressed the T helper 1 (Th1), Th2, and Th3 cells by performing a PCR array on mRNA extracted from adenoid samples. In non-allergic children, a typical Th1 pattern was found. SLIT induced a strong down-regulation of genes involved in Th2 and Th1 activation and function. In particular, in SLIT-treated allergic children IL-4, CCR2, CCR3, and PTGDR2 (Th2 related genes) and CD28, IL-2, and INHA (Th1 related genes) expression was reduced, compared with children treated with antihistamines. These preliminary findings warrant investigation in trials including larger numbers of patients, but indicate that hypertrophic adenoids of allergic children have the typical response to the specific allergen administered by SLIT. This should suggest that one should reconsider the immunological role of adenoids.

Bronchial biopsy evidence for leukocyte infiltration and upregulation of leukocyte-endothelial cell adhesion molecules 6 hours after local allergen challenge of sensitized asthmatic airways.

PubMed Central

Montefort, S; Gratziou, C; Goulding, D; Polosa, R; Haskard, D O; Howarth, P H; Holgate, S T; Carroll, M P

1994-01-01

We have examined the mucosal changes occurring in bronchial biopsies from six atopic asthmatics 5-6 h after local endobronchial allergen challenge and compared them with biopsies from saline-challenged segments from the same subjects at the same time point. All the subjects developed localized bronchoconstriction in the allergen-challenged segment and had a decrease in forced expiratory volume in 1 s (FEV1) (P < 0.01) and a decrease in their methacholine provocative concentration of agonist required to reduce FEV1 from baseline by 20% (P < 0.05) 24 h postchallenge. At 6 h we observed an increase in neutrophils (P = 0.03), eosinophils (P = 0.025), mast cells (P = 0.03), and CD3+ lymphocytes (P = 0.025), but not in CD4+ or CD8+ lymphocyte counts. We also detected an increase in endothelial intercellular adhesion molecule type 1 (P < 0.05) and E-selectin (P < 0.005), but not vascular cell adhesion molecule type 1 expression with a correlative increase in submucosal and epithelial LFA+ leucocytes (P < 0.01). Thus, in sensitized asthmatics, local endobronchial allergen instillation leads to an increased inflammatory cell infiltrate of the airway mucosa that involves upregulation of specific adhesion molecules expressed on the microvasculature. Images PMID:7512980

BLOCKADE OF TRKA OR P75 NEUROTROPHIN RECEPTORS ATTENUATES DIESEL PARTICULATE-INDUCED ENHANCEMENT OF ALLERGIC AIRWAYS RESPONSES IN BALB/C MICE

EPA Science Inventory

Neurotrophins, including nerve growth factor (NGF) partially mediate many features of allergic airways disease including airway resistance. Exposure to diesel exhaust particles (DEP) associated with the combustion of diesel fuel exacerbates allergic airways responses. We tested t...

Hyperoside attenuates OVA-induced allergic airway inflammation by activating Nrf2.

PubMed

Ye, Peng; Yang, Xi-Liang; Chen, Xing; Shi, Cai

2017-03-01

Allergic airways disease (AAD) is one of the most common medical illnesses that is associated with an increased allergic airway inflammation. Hyperoside, an active compound isolated from Rhododendron brachycarpum G. Don, has been reported to have anti-inflammatory effect. The aim of this study was to analyze the protective effect of hyperoside on OVA-induced allergic airway inflammation in mice. In the present study, the mouse asthma model was induced by given OVA and hyperoside was administrated 1h before OVA challenge. The levels of IL-4, IL-5, IL-13, and IgE were detected by ELISA. H&E staining was used to assess lung histopathological changes. The expression of NF-κB p65, IκB, HO-1, and Nf-E2 related factor 2 (Nrf2) were measured by western blot analysis. The results showed that hyperoside significantly reduced the inflammatory cells infiltration and the levels of IL-4, IL-5, IL-13, and IgE. Hyperoside significantly inhibited OVA-induced oxidative stress as demonstrated by decreased MDA, and increased GSH and SOD levels. Treatment of hyperoside also inhibited OVA-induced airway hyperresponsiveness (AHR). Furthermore, the results showed that treatment of hyperoside significantly inhibited LPS-induced NF-κB activation. In addition, hyperoside was found to activate Nrf2/HO-1 signaling pathway. In conclusion, these results suggest that hyperoside ameliorates OVA-induced allergic airway inflammation by activating Nrf2 signaling pathway. Copyright © 2017 Elsevier B.V. All rights reserved.