Combined sensitization of mice to extracts of dust mite, ragweed, and Aspergillus species breaks through tolerance and establishes chronic features of asthma

Goplen, N.; Karim, Mohammad Zunayet; Qiang, Liang; Górska, M.; Rozario, Sadee; Guo, Lei; Alam, Rafeul

doi:10.1016/j.jaci.2009.02.009

Cited by 80 publications

(96 citation statements)

References 41 publications

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“…We investigated the pERK1/2 staining pattern in a mouse model of chronic asthma where we repeatedly exposed mice to three different allergens, dust mites, ragweed, and Aspergillus (DRA), 2 days a week for 8 weeks and then rested them for 3 weeks. We reported the persistence in this model of peribronchial inflammation, airway remodeling with epithelial hypertrophy, and airway hyperreactivity, which lasted longer than 3 weeks after the last allergen exposure (13). Immunofluorescence studies of the airway tissue from this model demonstrated significant pERK1/2 staining of airway epithelium and inflammatory cells (Fig.…”

Section: Establishing Erk1/2 Bistability and Sustained Activationmentioning

confidence: 56%

Establishment of Extracellular Signal-Regulated Kinase 1/2 Bistability and Sustained Activation through Sprouty 2 and Its Relevance for Epithelial Function

Liu

Tundwal

Qiang

et al. 2010

Molecular and Cellular Biology

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Our objective was to establish an experimental model of a self-sustained and bistable extracellular signalregulated kinase 1/2 (ERK1/2) signaling process. A single stimulation of cells with cytokines causes rapid ERK1/2 activation, which returns to baseline in 4 h. Repeated stimulation leads to sustained activation of ERK1/2 but not Jun N-terminal protein kinase (JNK), p38, or STAT6. The ERK1/2 activation lasts for 3 to 7 days and depends upon a positive-feedback mechanism involving Sprouty 2. Overexpression of Sprouty 2 induces, and its genetic deletion abrogates, ERK1/2 bistability. Sprouty 2 directly activates Fyn kinase, which then induces ERK1/2 activation. A genome-wide microarray analysis shows that the bistable phospho-ERK1/2 (pERK1/2) does not induce a high level of gene transcription. This is due to its nuclear exclusion and compartmentalization to Rab5 ؉ endosomes. Cells with sustained endosomal pERK1/2 manifest resistance against growth factor withdrawal-induced cell death. They are primed for heightened cytokine production. Epithelial cells from cases of human asthma and from a mouse model of chronic asthma manifest increased pERK1/2, which is associated with Rab5 ؉ endosomes. The increase in pERK1/2 was associated with a simultaneous increase in Sprouty 2 expression in these tissues. Thus, we have developed a cellular model of sustained ERK1/2 activation, which may provide a mechanistic understanding of self-sustained biological processes in chronic illnesses such as asthma.

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Section: Establishing Erk1/2 Bistability and Sustained Activationmentioning

confidence: 56%

Establishment of Extracellular Signal-Regulated Kinase 1/2 Bistability and Sustained Activation through Sprouty 2 and Its Relevance for Epithelial Function

Liu

Tundwal

Qiang

et al. 2010

Molecular and Cellular Biology

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“…We used the published triple-allergen (DRA)-induced allergic mouse asthma model with minor modifications (19) to recapitulate the pathophysiologic features of SBP-AG of human patients with asthma. Additional detail on the method for the DRA triple-allergen asthma model is provided in the online supplement and Figure E2.…”

Section: Dra Triple-allergen Asthma Modelmentioning

confidence: 99%

“…We subjected mice to sensitization and challenge with a combination of house dust mite, ragweed, and Aspergillus allergen (DRA), as previously described, with minor modifications (19).…”

Section: Increasedmentioning

confidence: 99%

Autotaxin Production of Lysophosphatidic Acid Mediates Allergic Asthmatic Inflammation

Park¹,

Lee

Berdyshev

et al. 2013

Am J Respir Crit Care Med

116

167

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Rationale: Bioactive lipid mediators, derived from membrane lipid precursors, are released into the airway and airspace where they bind high-affinity cognate receptors and may mediate asthma pathogenesis. Lysophosphatidic acid (LPA), a bioactive lipid mediator generated by the enzymatic activity of extracellular autotaxin (ATX), binds LPA receptors, resulting in an array of biological actions on cell proliferation, migration, survival, differentiation, and motility, and therefore could mediate asthma pathogenesis.Objectives: To define a role for the ATX-LPA pathway in human asthma pathogenesis and a murine model of allergic lung inflammation. Methods: We investigated the profiles of LPA molecular species and the level of ATX exoenzyme in bronchoalveolar lavage fluids of human patients with asthma subjected to subsegmental bronchoprovocation with allergen. We interrogated the role of the ATX-LPA pathway in allergic lung inflammation using a murine allergic asthma model in ATX-LPA pathway-specific genetically modified mice. Measurements and Main Results: Subsegmental bronchoprovocation with allergen in patients with mild asthma resulted in a remarkable increase in bronchoalveolar lavage fluid levels of LPA enriched in polyunsaturated 22:5 and 22:6 fatty acids in association with increased concentrations of ATX protein. Using a triple-allergen mouse asthma model, we showed that ATX-overexpressing transgenic mice had a more severe asthmatic phenotype, whereas blocking ATX activity and knockdown of the LPA 2 receptor in mice produced a marked attenuation of Th2 cytokines and allergic lung inflammation. Conclusions: The ATX-LPA pathway plays a critical role in the pathogenesis of asthma. These preclinical data indicate that targeting the ATX-LPA pathway could be an effective antiasthma treatment strategy.Keywords: asthma; lysophosphatidic acid; autotaxin; allergic airway inflammation supplied the ATX inhibitor, GWJ-23. V.A., E.K., and I.N. were involved in discussions related to animal dosage. A.J.M. and S.S.S. provided breeding pairs of ATX-Tg and ATX 1/2 mice. S.J.A. managed the inflammatory cell purification core lab for the SBP-AG protocol, designed experiments, interpreted data, coordinated regular scientific research meetings for the project, and edited the manuscript. V.N. conceptualized the study, designed mouse experiments, interpreted data, provided genetically modified mice, and wrote part of and edited the manuscript. J.W.C. obtained the SBP-AG IRB and IND approval, supervised mouse experiments and performance of the human SBP-AG protocol, designed experiments, interpreted and analyzed data, and edited the manuscript. All authors contributed to data discussion and review of the manuscript.Correspondence and requests for reprints should be addressed to John W. What This Study Adds to the FieldThe enzyme autotaxin (ATX) and two of its LPA products, LPA 22:5 and LPA 22:6, are markedly and selectively increased in the bronchoalveolar lavage fluid of human patients with asthma in response to airway allergen ch...

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“…Some other studies also achieved sensitization to co-administered antigens after only 1 or 2 challenges. They differ from our study by the fact that the antigens were given intranasally and in high amounts [20,21,26]. In the one study most comparable to ours [21], 100 µg of ragweed protein was given intranasally to OVA-primed mice, together with 20 µg of OVA, in order to induce Th2 spread to the ragweed proteins.…”

Section: Discussionmentioning

confidence: 61%

Sensitization to Inhaled Ryegrass Pollen by Collateral Priming in a Murine Model of Allergic Respiratory Disease

Cadot¹,

Meyts

Vanoirbeek

et al. 2010

Int Arch Allergy Immunol

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Background: Mouse models of asthma suffer from the necessity to prime the animals by injections before respiratory exposure. Our aim was to develop a mouse model that mimics the progression of human allergic disease upon low-dose inhaled allergen exposure. Methods: Mice were primed intraperitoneally to ovalbumin (OVA) before they were exposed repeatedly to aerosols of either OVA, ryegrass (Lolium perenne) pollen extract, or both concomitantly. The sensitization to ryegrass pollen proteins was evaluated by measurement of specific serum antibody, by the respiratory response to a challenge with ryegrass pollen extract and by lung cytokine production after challenge. Results: Inhalation of ryegrass pollen extract alone did not result in sensitization. Sensitization to inhaled ryegrass pollen proteins, however, did occur in mice that had been sensitized to OVA by intraperitoneal injections and were then exposed to inhaled ryegrass pollen extract and OVA simultaneously. T and B cell priming was ascertained by ryegrass pollen-specific IgG1 and IgE antibody production and by induction of airway inflammation and of Th2 cytokine mRNA transcripts in the lungs upon airway challenge with ryegrass pollen extract. A progressive spread of the IgE/IgG1 response to different ryegrass pollen proteins could be visualized in immunoblots by comparing antibody patterns at day 56 and 86. Conclusions: Low-dose inhalatory allergen exposure results in sensitization when airways are exposed at the same time to another allergen to which the animals are already sensitized. This model can help to unravel the mechanisms that underlie the development and progression of respiratory allergic diseases.

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Combined sensitization of mice to extracts of dust mite, ragweed, and Aspergillus species breaks through tolerance and establishes chronic features of asthma

Abstract: Background-Existing asthma models develop tolerance when chronically exposed to the same allergen.

Cited by 80 publications

References 41 publications

Establishment of Extracellular Signal-Regulated Kinase 1/2 Bistability and Sustained Activation through Sprouty 2 and Its Relevance for Epithelial Function

Establishment of Extracellular Signal-Regulated Kinase 1/2 Bistability and Sustained Activation through Sprouty 2 and Its Relevance for Epithelial Function

Autotaxin Production of Lysophosphatidic Acid Mediates Allergic Asthmatic Inflammation

Sensitization to Inhaled Ryegrass Pollen by Collateral Priming in a Murine Model of Allergic Respiratory Disease

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