The Role of selected Redoxins in the Manifestation and Exacerbation of Allergic Airway Inflammation

Introduction: Oxidative stress is believed to play a major role in the development of, among others, immunologic diseases. Asthma is a chronic allergic airway disease, and to date it is not clear whether the observed enhanced oxidative stress in asthmatic patients is caused by airway inflammation, or is a causative factor in the pathogenesis of this disease. Several studies have attributed the thioredoxin fold family a major impact in protection of the lung, and deregulation may bring about initiation of Th2-dominant immunity and contribute to the progression or perpetuation of existing airway inflammation. This project will investigate the role of selected redoxins with focus on thioredoxins (Trxs), glutaredoxins (Grxs) and peroxiredoxins (Prxs).

Methods: To investigate individual functions of selected redoxins, an initial screen for general distribution comparing control – and inflamed mouse lungs (OVAlbumin sensitization and challenge) was performed. For characterisation of the protein of interest, we purified a broad set of redoxins and intraperitoneal injection of 40µg/day was done on 5 consecutive days starting two days before challenge. Evaluation of the allergic phenotype in balb/c mice focussed on the analysis of airway hyperreactivity, infiltrating inflammatory cells and cytokine expression (cytokine bead array).

Results: Initial characterisation of protein distribution in the lung revealed major differences between the proteins and between healthy and diseased OVA-treated mice with respect to epithelial and endothelial cells, connective tissue and infiltrating cells like macrophages. Intraperitoneal injection of Thioredoxin1 and Glutaredoxin 2 resulted in a significant disease improvement which was reflected by a increased airway function and a reduced infiltration of eosinophiles combined with a decrease of the TH2-specific IL-5 and IL-13 cytokines in the bronchoalveolar lavage. In contrast, treatment with Peroxiredoxin 2 and Glutaredoxin 1 treated mice did not show any improvement compared to the OVA-treated allergic mice.

Conclusion: We postulate that selective modification of redoxin levels in the mouse model of allergic airway inflammation will yield further insights in the molecular effects of oxidative stress in asthma. Presented results show a significant improvement especially in the Grx2 treated group, pointing to so far unknown mechanisms and functions during the manifestation and exacerbation of allergic asthma bronchiale.