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Conflict of interest
Acknowledgements The authors thank Dr. Sudarshan Bhattacharjee for his help with some initial experiments, and acknowledge grant support from the National Institutes of Health (R01-EY014370, R01-EY017313 and R01-EY022230) and the Thomas Foundation to RAK and from Research to Prevent Blindness to the Ophthalmology, Visual and Anatomical Sciences Department.
Introduction Allergic rhinitis is a global health problem and usually persists throughout life. The prevalence of allergic rhinitis confirmed in adults in Europe ranges from 17% to 28.5% . Although allergic rhinitis is not associated with severe morbidity or mortality, it broadly affects the quality of life of patients owing to the frequent symptoms such as nasal congestion, sneezing and rhinorrhea which lead to irritability, fatigue and increased costs for the medical care. Allergic airway diseases can range from the nose to lungs as the upper and lower respiratory tracts share many histologic, functional and immunological features [1,2]. Many studies have demonstrated parallel increases in the prevalence of Lovastatin and rhinitis and the new update of Allergic Rhinitis and its Impact on Asthma (ARIA) concludes that allergic rhinitis is one of the multiple risk factors for asthma development and proposes that combined strategy should be developed for treating the upper and lower airways for a better efficacy/safety ratio [3,4]. In the meantime, several reports indicate that leptin, a pleiotropic adipokine involved in immune system regulation, maintains and preserves bronchial and nasal epithelial homeostasis in epithelium affected by asthma and allergy. In contrast, there is a decreased expression of the pro-fibrogenic TGF-β activity in inflamed epithelium in comparison to non-damaged epithelium [5,6]. Particularly in nasal epithelial cells, human recombinant TGF-β1 is able to significantly decrease cell proliferation, without significantly decreasing leptin receptor expression either as mRNA or as protein . With the turbinates, previous studies performed in animals report that leptin increases the production of mucus in olfactory globular cells, thus suggesting that leptin might be a potential target for physiological modulation of mucus composition and for regulation of olfactory functions such as neuromodulation or cellular homeostasis [7,8]. Leptin signaling in the respiratory tract is known to regulate cell survival and proliferation via the NF-κB-STAT3 pathway [6,9], as well as with Notch expression that it is associated to angiogenesis, proliferation and differentiation . The Notch family consists of four receptors (Notch1-Notch4) and five ligands: Jagged (JAG1, JAG2) Delta-like (DLL1, DLL3, and DLL4). Loss of regulation of Notch signaling are critically linked to the pathogenesis of various lung diseases, included asthmatic airway remodeling . Notch signaling can interact with other signaling such as NF-κB and TGF-β . Particularly, in a process known as epithelial-mesenchymal transition (EMT), in lung cancer the crosstalk between Notch and TGF-β is imperative for induction of EMT because Notch signaling is required to maintain TGF-β-induced expression . In breast cancer, Notch can be induced and activated by leptin signaling [12,13]. Furthermore, the Notch signaling pathway is increased in nasal epithelium with differentiation abnormalities in patients suffering from nasal polyposis and it contributes to pro-inflammatory responses . Simultaneously, previous evidence indicates a significant increase of leptin receptor expression in nasal polyps as compared to normal nasal mucosa, thus suggesting that leptin may play a role in inflammation in nasal polyposis . At the moment, no data have been reported on the relationship between leptin receptor pathway and Notch signaling in human epithelium from the turbinates of subjects affected by allergic rhinitis. The present study was performed to establish the role of the leptin/leptin receptor pathway in the epithelial homeostasis in allergic rhinitis and to investigate whether deregulation of Notch-1 signaling might contribute to alterations in the leptin/leptin receptor pathway in chronic allergic rhinitis as already demonstrated in bronchial asthma.