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  • br Materials and methods br Results br Discussion In chronic

    2019-07-08


    Materials and methods
    Results
    Discussion In chronic nasal disorders, the role of the nasal epithelium in the coordination of inflammatory responses is now well recognized. In this report, using human in vivo and in vitro experimental approaches, we demonstrate for the first time that the leptin/leptin receptor pathway and Notch-1 expression are both hallmarks of the healthy nasal epithelium of inferior turbinates and that Notch-1 signaling regulates leptin receptor pathway, apparently controlling its expression. Particularly the following new evidence is reported: 1) leptin and leptin receptor expressions are correlated in epithelium from inferior turbinates, are reduced in patients affected by allergic rhinitis and do not co-localize with TGF-β1, 2, 3 expression; 2) ex vivo, the expression of leptin receptor seems to co-localize with the Notch-1 expression; 3) primary turbinate epithelial RVX-208 extracted from biopsies of allergic patients exhibit lower expression of leptin and Notch-1 receptors; 4) in an in vitro model of nasal epithelial cells, leptin receptor expression is induced by the Notch-1 ligand, Jagged-1. Leptin receptor and its biological ligand leptin are expressed in the nasal mucosal epithelium [[6], [7], [8],15,18]. This evidence encouraged us to further investigate this pathway. It is well demonstrated that leptin, produced mainly by the adipose tissue, but also by placenta, stomach, fibroblasts, mammary epithelium, and skeletal muscle [19], is involved in the regulation of several systems, from metabolism to immunity, leading to the condition that a genetic leptin deficiency in humans and mice impairs host defenses against respiratory tract infections [20]. Using lung tissues of humans, leptin and its receptor expression has been assessed in bronchial epithelium, in type II pneumocytes and in lipofibroblasts [[21], [22], [23]]. Leptin has a significant role in promoting normal lung maturation: in animals deficient for leptin, daily leptin administration improved respiratory complications, indicating that leptin might act as both a growth factor in the lung and as a neuro-humoral modulator of the central respiratory control mechanisms [22,24]. In the context of inflammation, the pleiotropic hormone leptin is involved in maintaining inflammatory cell survival [25,26]. In cancer, leptin induces cell proliferation and angiogenesis as well as Notch-1 [27,28]. A recent study reports that leptin knockdown could become a new approach for blocking lung cancer progression, which is likely to be mediated, at least partially, by inactivation of the Notch and JAK/STAT3 signaling pathways [29]. In lungs, leptin levels correlated with the severity of lung fibrosis and are increased in patients and mice with acute lung injury by exerting a profibrogenic effect in primary human fibroblasts by augmenting the transcriptional activity of TGF-β1 leading to the suppression of the antifibrotic activity of PPARγ [30,31]. On the other hand, on the side of the epithelium, a functional leptin signaling pathway is present in lung epithelial cells [32] and leptin can be considered a marker for a proliferative effect in epithelial cells, not only in the pathological condition of cancer [18,33,34] but also in patients with asthma and COPD [5,35]. Furthermore, a recent in vitro study in human bronchial epithelial cells demonstrated that leptin positively regulates MUC5AC production and secretion induced by IL-13 via the JAK2-STAT3 pathway [36]. Thus, leptin seems to have a therapeutic potential for treatment of mucus hypersecretion in chronic inflammatory lung diseases. In addition, it is known that leptin abolishes upper airway obstruction and a recent study demonstrated that intranasal leptin application can bypass leptin resistance, decreased the number of oxygen desaturation events during sleeping, and significantly attenuated sleep-disordered breathing, independently of body weight [37]. Therefore, intranasal administration of leptin may represent a new strategy to treat allergic rhinitis. It should be mentioned, although the role of leptin receptor pathway in lung development, respiratory immune responses and the pathogenesis of inflammatory respiratory diseases is now well established [5,6,21,38], little information has been so far available for the role of this pathway or of Notch-1 signaling in allergic rhinitis.