David Quarcoo

Neurogenic mechanisms in bronchial inflammatory diseases

Neurogenic inflammation encompasses the release of neuropeptides from airway nerves leading to inflammatory effects. This neurogenic inflammatory response of the airways can be initiated by exogenous irritants such as cigarette smoke or gases and is characterized by a bi‐directional linkage between airway nerves and airway inflammation. The event of neurogenic inflammation may participate in the development and progression of chronic inflammatory airway diseases such as allergic asthma or chronic obstructive pulmonary disease (COPD). The molecular mechanisms underlying neurogenic inflammation are orchestrated by a large number of neuropeptides including tachykinins such as substance P and neurokinin A, or calcitonin gene‐related peptide. Also, other biologically active peptides such as neuropeptide tyrosine, vasoactive intestinal polypeptide or endogenous opioids may modulate the inflammatory response and recently, novel tachykinins such as virokinin and hemokinins were identified. Whereas the different aspects of neurogenic inflammation have been studied in detail in laboratory animal models, only little is known about the role of airway neurogenic inflammation in human diseases. However, different functional properties of airway nerves may be used as targets for future therapeutic strategies and recent clinical data indicates that novel dual receptor antagonists may be relevant new drugs for bronchial asthma or COPD.

Stress enhances airway reactivity and airway inflammation in an animal model of allergic bronchial asthma.

Objective Despite the long-standing clinical assumption that stress and asthma morbidity are associated, convincing experimental evidence on mechanisms has been unavailable. A wide range of immunological, endocrinological, and neuronal pathways are known to mediate and modulate a systemic stress response. Interestingly, most of these mediators play a crucial role in initiating and perpetuating symptoms associated with bronchial asthma. To explore potential mechanisms linking stress to asthma exacerbation we developed an animal model that combines allergic airway inflammation and exposure to stress. Methods CBA/J mice were sensitized by intraperitoneal injection of ovalbumin (OVA) and challenged with OVA aerosol via the airways. Additionally, some mice were stressed by exposure to an ultrasonic stressor. Airway hyperreactivity (AHR) was measured in vitro by electric field stimulation (EFS) of tracheal smooth muscle elements. Bronchoalveolar lavage fluid (BAL) was obtained and cell numbers determined. Cytokine levels of IL-4, IL-5, and IFN-&ggr; in BAL were determined by ELISA. Results Our findings demonstrate that exogenously applied stress dramatically enhances airway reactivity in OVA-sensitized and challenged mice. Further, stress significantly increases allergen-induced airway inflammation identified by increased leukocyte (ie, eosinophil) numbers in bronchoalveolar lavage fluids. Conclusions We found further evidence that stress can indeed exacerbate airway hyperreactivity and airway inflammation in an animal model of allergic bronchial asthma and now introduce a novel murine model to identify stress-triggered pathways, including mediators as neurohormones, neuropeptides, and markers of inflammation.

Brain-derived neurotrophic factor (BDNF) contributes to neuronal dysfunction in a model of allergic airway inflammation

Brain‐derived neurotrophic factor (BDNF) is a candidate molecule for mediating functional neuronal changes in allergic bronchial asthma. Recently, enhanced production of BDNF during allergic airway inflammation caused by infiltrating T‐cells and macrophages as well as by resident airway epithelial cells has been described. It was the aim of this study to investigate the effect of enhanced BDNF levels on lung function and airway inflammation in a mouse model of allergic inflammation. Ovalbumin‐sensitised BALB/c mice were challenged in two consecutive allergen challenges. Prior to the challenge, the mice were treated with either anti‐BDNF antibodies or isotype‐matched control antibodies. Airway responsiveness to methacholine, capsaicin and electric field stimulation, as well as airway inflammation and chronic airway obstruction 1 week after the last allergen challenge were assessed. Anti‐BDNF blocked enhanced reactivity in response to capsaicin, but not airway smooth muscle hyper‐reactivity in vivo. Furthermore, persistent airway obstruction, as observed 1 week after the last allergen challenge, was to a large extent prevented by anti‐BDNF treatment. In vitro, BDNF and anti‐BDNF treatment had a profound effect on local neuronal hyper‐reactivity, as shown by electric field stimulation experiments. In contrast, neither BDNF nor anti‐BDNF treatment affected airway inflammation. Our data indicate that development of allergen‐induced neuronal hyper‐reactivity in mice is partially mediated by BDNF.

CD8+ T cells regulate immune responses in a murine model of allergen‐induced sensitization and airway inflammation

The role of CD8+ T cells in the development of allergic airway disease is controversial. On the one hand, CD8+ T cells are known to inhibit the development of airway hyperreactivity (AHR) in murine models of asthma. In humans, IL‐10‐producing CD8+ T cells were shown to act as regulatory cells, inhibiting both proliferation and cytokine secretion of T cells. On the other hand, CD8+ T cells can promote IL‐5‐mediated eosinophilic airway inflammation and the development of AHR in animal models. To examine this, we investigated the role of CD8+ T cells during the induction of allergen‐induced AHR and demonstrated a protective effect of CD8+ T cells. Depletion of CD8+ T cells prior to the immunization led to increased Th2 responses and increased allergic airway disease. However, after development of AHR, CD8+ T cells that infiltrated the lungs secreted high levels of IL‐4, IL‐5 and IL‐10, but little IFN‐γ, whereas CD8+ T cells in the peribronchial lymph nodes or spleen produced high levels of IFN‐γ, but little or no Th2 cytokines. These data demonstrate protective effects of CD8+T cells against the induction of immune responses and show a functional diversity of CD8+ T cells in different compartments of sensitized mice.

New quality and quantity indices in science (NewQIS): the study protocol of an international project

Benchmarking systems are important features for the implementation of efficacy in basic and applied sciences. These systems are urgently needed for many fields of science since there is an imbalance present between funding policies and research evaluation. Here, a new approach is presented with an international study project that uses visualisation techniques for benchmarking processes. The project is entitled New Quality and Quantity Indices in Science (NewQIS). The juxtaposition of classical scientometric tools and novel visualisation techniques can be used to assess quality and quantity in science. In specific, the tools can be used to assess quality and quantity of research activity for distinct areas of science, for single institutions, for countries, for single time periods, or for single scientists. Also, NewQIS may be used to compare different fields, institutions, countries, or scientists for their scientific output. Thus, decision making for funding allocation can be made more transparent. Since governmental bodies that supervise funding policies and allocation processes are often not equipped with an in depth expertise in this area, special attention is given to data visualisation techniques that allow to visualize mapping of research activity and quality.

Resiquimod, a new immune response modifier from the family of imidazoquinolinamines, inhibits allergen-induced Th2 responses, airway inflammation and airway hyper-reactivity in mice.

Background Allergen‐induced sensitization and airway disease are the results of adverse immune reactions against environmental antigens that may be prevented or inhibited by immune modifying strategies.

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

Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusion: These data indicate that the NK-1 receptor plays an important role in mediating stress effects in allergen-induced airway inflammation.

Is TRPV1 a useful target in respiratory diseases

This review focuses on the transient receptor potential vanilloid 1 (TRPV1). TRPV1 is a non-selective cation channel predominantly expressed in the cell membranes of sensory afferent fibers, which are activated multi-modally. In the mammalian respiratory system, immunohistochemical and electrophysiological studies have revealed heterogeneous localizations of TRPV1 channels in the airways and their presence in pleural afferents. TRPV1 channels in afferents are not only involved with sensory inputs, but also release several neuropeptides upon stimulation. These processes trigger pathophysiological effects (e.g. reflex bronchoconstriction, hypersecretion, cough, etc.) that cause various symptoms of airway diseases. Recent studies have identified several endogenous and exogenous substances that can activate TRPV1 in the lung. Because of its key role in initiating inflammatory processes, TRPV1 receptor antagonists have been proposed as therapeutic candidates. Therefore, a critical update of recent therapeutic results is also given in this review.

Allergic airway inflammation induces tachykinin peptides expression in vagal sensory neurons innervating mouse airways

Background Allergic airway inflammation has been shown to induce pro‐inflammatory neuropeptides such as tachykinin peptides substance P (SP) and neurokinin A (NKA) together with related peptide like calcitonin gene‐related peptide (CGRP) in nodose sensory neurons innervating guinea‐pig airways.

Glutathione peroxidase-2 protects from allergen-induced airway inflammation in mice

The aim of the present study was to identify and validate the biological significance of new genes/proteins involved in the development of allergic airway disease in a murine asthma model. Gene microarrays were used to identify genes with at least a two-fold increase in gene expression in lungs of two separate mouse strains with high and low allergic susceptibility. Validation of mRNA data was obtained by western blotting and immunohistochemistry, followed by functional analysis of one of the identified genes in mice with targeted disruption of specific gene expression. Expression of two antioxidant enzymes, glutathione peroxidase-2 (GPX2) and glutathione S-transferase omega (GSTO) 1-1 was increased in both mouse strains after induction of allergic airway disease and localised in lung epithelial cells. Mice with targeted disruption of the Gpx-2 gene showed significantly enhanced airway inflammation compared to sensitised and challenged wild-type mice. Our data indicate that genes encoding the antioxidants GPX2 and GSTO 1-1 are common inflammatory genes expressed upon induction of allergic airway inflammation, and independently of allergic susceptibility. Furthermore, we provide evidence to illustrate the importance of a single antioxidant enzyme, GPX2, in protection from allergen-induced disease.