Allergic Inflammation in Aspergillus fumigatus-Induced Fungal Asthma.

Although fungi are pervasive in many environments, few cause disease in humans. Of these, Aspergillus fumigatus is particularly well suited to be a pathogen of the human lung. Its physical and biological characteristics combine to provide an organism that can cause tremendous morbidity and high mortality if left unchecked.

Hyaluronan stimulates ex vivo B lymphocyte chemotaxis and cytokine production in a murine model of fungal allergic asthma.

Allergic asthma is a chronic inflammatory disease of the airways characterized by excessive eosinophilic and lymphocytic inflammation with associated changes in the extracellular matrix (ECM) resulting in airway wall remodeling. Hyaluronan (HA) is a nonsulfated glycosaminoglycan ECM component that functions as a structural cushion in its high molecular mass (HMM) but has been implicated in metastasis and other disease processes when it is degraded to smaller fragments. However, relatively little is known about the role HA in mediating inflammatory responses in allergy and asthma.

B lymphocytes regulate airway granulocytic inflammation and cytokine production in a murine model of fungal allergic asthma.

Sensitization to fungi often leads to a severe form of asthma that is particularly difficult to manage clinically, resulting in increased morbidity and hospitalizations in these patients. Although B lymphocytes might exacerbate asthma symptoms through the production of IgE, these cells might also be important in the protective response against inhaled fungi. Through cytokine release and T-cell interactions, these lymphocytes might also influence the development and maintenance of airway wall fibrosis.

Hyaluronan deposition and co-localization with inflammatory cells and collagen in a murine model of fungal allergic asthma.

Objective: Allergic asthma is a chronic inflammatory disease of the airways characterized by excessive inflammation and remodeling of the extracellular matrix (ECM) and associated cells of the airway wall. Under inflammatory conditions, hyaluronan (HA), a major component of the ECM, undergoes dynamic changes, which may in turn affect the recruitment and activation of inflammatory cells leading to acute and chronic immunopathology of allergic asthma.

Methods: In the present study, we measured the changes in HA levels generated at sites of inflammation, and examined its effect on inflammatory responses and collagen deposition in an Aspergillus fumigatus murine inhalational model of allergic asthma.

The immune profile associated with acute allergic asthma accelerates clearance of influenza virus.

Asthma was the most common comorbidity in hospitalized patients during the 2009 influenza pandemic. For unknown reasons, hospitalized asthmatics had less severe outcomes and were less likely to die from pandemic influenza. Our data with primary human bronchial cells indicate that changes intrinsic to epithelial cells in asthma may protect against cytopathology induced by influenza virus.

The impact of Aspergillus fumigatus viability and sensitization to its allergens on the murine allergic asthma phenotype.

Aspergillus fumigatus is a ubiquitously present respiratory pathogen. The outcome of a pulmonary disease may vary significantly with fungal viability and host immune status. Our objective in this study was (1) to assess the ability of inhaled irradiation-killed or live A.

An inhalation model of allergic fungal asthma: Aspergillus fumigatus-induced inflammation and remodeling in allergic airway disease.

The ability to accurately mimic normal processes for sensitization and allergen challenge in an experimental animal model are useful in that they allow researchers to critically manipulate the complex interactions of multiple cell types. In the context of the allergic lung, multiple cell types form complex cellular networks and function to regulate a variety of temporal and spatial changes. Mouse models of allergic airway disease have proven to be highly useful for dissecting these complex interactions, particularly in addressing remodeling of the allergic airway in chronic asthma.

Eosinophils in fungus-associated allergic pulmonary disease.

Asthma is frequently caused and/or exacerbated by sensitization to fungal allergens, which are ubiquitous in many indoor and outdoor environments. Severe asthma with fungal sensitization is characterized by airway hyperresponsiveness and bronchial constriction in response to an inhaled allergen that is worsened by environmental exposure to airborne fungi and which leads to a disease course that is often very difficult to treat with standard asthma therapies. As a result of complex interactions among inflammatory cells, structural cells, and the intercellular matrix of the allergic lung, patients with sensitization to fungal allergens may experience a greater degree of airway wall remodeling and progressive, accumulated pulmonary dysfunction as part of the disease sequela.

Characterization of CD19(+)CD23(+)B2 lymphocytes in the allergic airways of BALB/c mice in response to the inhalation of Aspergillus fumigatus conidia.

Fungal sensitization in patients with asthma often indicates an unusual disease course in which traditional asthma treatments have little effect and in which morbidity is particularly severe. Airway hyperresponsiveness (AHR), inflammatory infiltrates, smooth muscle hyperplasia, and irreversible fibrotic remodeling of the bronchial architecture are features of allergic fungal asthma. The systemic production of IgE has long been associated with the immunopathogenesis of allergic asthma; however, the role of B lymphocytes and their products in the response to fungal allergens remains unclear.

μ-chain-deficient mice possess B-1 cells and produce IgG and IgE, but not IgA, following systemic sensitization and inhalational challenge in a fungal asthma model.

Allergic bronchopulmonary aspergillosis is often difficult to treat and results in morbidity associated with chronic airway changes. This study assessed the requirement for B cells and their products in the allergic pulmonary phenotype in a murine model of fungal allergic asthma that mimics allergic bronchopulmonary aspergillosis. C57BL/6 and μMT mice (assumed to lack peripheral B cells) were sensitized with Aspergillus fumigatus extract and challenged with two inhalation exposures of live conidia to induce airway disease.

Radical reversal of vasoactive intestinal peptide (VIP) receptors during early lymphopoiesis.

Successful thymocyte maturation is essential for normal, peripheral T cell function. Vasoactive intestinal peptide (VIP) is a neuropeptide which is highly expressed in the thymus that has been shown to modulate thymocyte development. VIP predominantly binds two G protein coupled receptors, termed vasoactive intestinal peptide receptor 1 (VPAC1) and VPAC2, but their expression profiles in CD4(-)/CD8(-) (double negative, DN) thymocyte subsets, termed DN1-4, have yet to be identified.

A comparison between intratracheal and inhalation delivery of Aspergillus fumigatus conidia in the development of fungal allergic asthma in C57BL/6 mice.

Allergic asthma is a debilitating disease of the airways characterized by airway hyperresponsiveness, eosinophilic inflammation, goblet cell metaplasia with associated mucus hypersecretion, and airway wall remodelling events, particularly subepithelial fibrosis and smooth muscle cell hyperplasia. Animal models that accurately mimic these hallmarks of allergic airways disease are critical for studying mechanisms associated with the cellular and structural changes that lead to disease pathogenesis. Aspergillus fumigatus, is a common aeroallergen of human asthmatics.

The absence of VPAC2 leads to aberrant antibody production in Aspergillus fumigatus sensitized and challenged mice.

Vasoactive intestinal peptide (VIP) facilitates a "pro-allergy" phenotype when signaling through its G protein-coupled receptor, VPAC(2). We have shown that VPAC(2) knock-out (KO) mice developed an allergic phenotype marked by eosinophilia and elevated serum IgE. Therefore, we hypothesized that the humoral response to allergen challenge in these mice was T(H)2 dominant similar to wild-type (WT) C57BL/6 mice.

Spatio-temporal localization of vasoactive intestinal peptide and neutral endopeptidase in allergic murine lungs.

Vasoactive intestinal peptide (VIP) is a neuropeptide with cytokine properties that is abundant in the lung. VIP null mice exhibit spontaneous airway inflammation and hyperresponsiveness emphasizing VIP's "anti-asthma" potential. Although VIP's impending protective role in the lung has been demonstrated, its localization in the naïve and allergic murine lungs has not.

An inhalation model of airway allergic response to inhalation of environmental Aspergillus fumigatus conidia in sensitized BALB/c mice.

Fungal exposure may elicit a number of pulmonary diseases in man, including allergic asthma. Fungal sensitization is linked to asthma severity, although the basis for this increased pathology remains ambiguous. To create conditions simulating environmental fungal allergen exposure in a human, nose-only inhalation delivery of Aspergillus fumigatus conidia was employed in mice previously sensitized to Aspergillus antigen extract.

Creation and characterization of an IgG1-type monoclonal antibody against intact Aspergillus fumigatus conidia.

The inability to accurately mimic and track the natural mechanisms of sensitization, challenge, and clearance in experimental models of allergic asthma restricts the ability to identify potential therapeutic targets and elucidate basic biological mechanisms of this prominent human disease. Use of a clinically relevant fungal allergen, such as Aspergillus fumigatus, allows researchers to follow an allergen's uptake and clearance from the lung. Unfortunately, there are currently limited resources to specifically visualize or sensitively quantify a small number of fungal conidia in the lung.

The therapeutic potential in targeting CCR5 and CXCR4 receptors in infectious and allergic pulmonary disease.

Targeting chemokines and chemokine receptors in various acute and chronic pulmonary diseases remains a vibrant area of basic and clinical research despite major hurdles including cross-species barriers, toxicity, and redundancy. In this review, we draw upon our basic research with a murine model in which innate and acquired immunity are linked in the development and maintenance of chronic asthma due to Aspergillus fumigatus. Using intact and genetically altered mice, studies have also been undertaken to elucidate safe and effective therapeutic strategies that interrupt the initiation and amplification of inflammatory and immune events that follow the intrapulmonary introduction of Aspergillus into A.

Therapeutic targeting of CCR1 attenuates established chronic fungal asthma in mice.

CC chemokine receptor 1 (CCR1) represents a promising target in chronic airway inflammation and remodeling due to fungus-associated allergic asthma. The present study addressed the therapeutic effect of a nonpeptide CCR1 antagonist, BX-471, in a model of chronic fungal asthma induced by Aspergillus fumigatus conidia. BX-471 treatment of isolated macrophages inhibited CCL22 and TNF-alpha and promoted IL-10 release.

Mannose-binding lectin deficiency alters the development of fungal asthma: effects on airway response, inflammation, and cytokine profile.

Aspergillus fumigatus is a major fungal pathogen that may be fatal to immunocompromised individuals and causes airway hyperreactivity and remodeling in sensitized individuals. Herein, we examined the role of mannose-binding lectin (MBL), a complement-activating plasma protein, during pulmonary innate and allergic immune responses directed against A. fumigatus spores or conidia.

Intrapulmonary targeting of RANTES/CCL5-responsive cells prevents chronic fungal asthma.

Regulated upon activation in normal T cells, expressed, and secreted (RANTES)/CCL5 is abundantly expressed during atopic asthma, suggesting that it is an important mediator of this disease. The contribution of intrapulmonary RANTES/CCL5-sensitive cells during Aspergillus fumigatus-induced airway disease in mice was assessed in this study. The intranasal delivery of a chimeric protein comprised of RANTES/CCL5 and a truncated version of Pseudomonas exotoxin A (RANTES-PE38) significantly attenuated serum IgE, peribronchial eosinophilia, and airway hyperreactivity when it was administered from day 0 to 15 after intratracheal conidia challenge in A.

Chemokines and cytokines: axis and allies in asthma and allergy.

Allergic asthma can be precipitated by many factors. For the atopic person, fungus, pollen, dust mites, cockroach antigens, and diesel exhaust are all agents that may trigger an allergic attack. Cytokines and chemokines are integral mediators of fungal asthma.

Cytokines and chemokines in allergic bronchopulmonary aspergillosis (ABPA) and experimental Aspergillus-induced allergic airway or asthmatic disease.

Allergic bronchopulmonary aspergillosis (ABPA) is a devastating clinical disease that results from an aggressive pulmonary allergic response to the antigens released by colonizing Aspergillus fumigatus (A. fumigatus) in the respiratory system. Many of the allergic features of clinical ABPA have been reproduced in murine models, thereby facilitating a detailed analysis of the inflammatory and immune events that surround the initiation and maintenance of this disease.

Airway hyperresponsiveness, but not airway remodeling, is attenuated during chronic pulmonary allergic responses to Aspergillus in CCR4-/- mice.

The role of CC chemokine receptor 4 (CCR4) during the development and maintenance of Th2-type allergic airway disease is controversial. In this study, we examined the role of CCR4 in the chronic allergic airway response to live Aspergillus fumigatus spores, or conidia, in A. fumigatus-sensitized mice.