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    • ceramide kinase In the present study we

    2020-03-30

    In the present study, we investigated the deeper role of eNOS in the pathogenesis of nasal polyps and analyzed the influence of 1,8-cineol on nasal polyp gene and protein expression of eNOS in vitro. Different studies dealt with the localization and expression of eNOS in nasal polyps and nasal mucosa and consistent to our results, they found no significant difference of eNOS levels between nasal polyps and control groups [[32], [33], [34]]. In ceramide kinase to these studies, we additionally analyzed the phosphorylation of eNOS. For the first time, we showed that the phosphorylation of eNOS is significantly increased in nasal polyps compared to inferior turbinates. This phosphorylation activates the enzyme and facilitates the active production of NO [10]. Conversely, eNOS increases the permeability of the vascular endothelium and plays an essential role in the regulation of blood, nasal secretion and ciliary movement [32,35]. The increase of eNOS phosphorylation and the associated protein activity, could lead to increased vascular permeability associated with edema and elevated inflammation in patients with and this could potentially prevent edema formation and increased inflammation in CRSwNP. Management of CRSwNP involves a combination of medical therapy with Inhaled corticosteroids (ICSs) and surgery. Usually, glucocorticosteroids were used for both, as primary treatment and as postoperative prophylaxis against recurrence. Glucocorticosteroids have anti-inflammatory effects through protein-protein interactions, but increased nasal NO levels and longer applications increase the side effects [[36], [37], [38]]. Herbal medications could reduce these side effects. In nature, essential oils are used in humans due to their secretolytic properties, but irritation of the airway following inhalation or ingestion has limited their clinical use. 1,8-Cineol, the major constituent of eucalyptus oil, is used for the treatment of acute and chronic bronchitis, bronchial asthma, sinusitis, and respiratory infections and is well tolerated. The monoterpene 1,8 cineol is an isoprenoid with anti-inflammatory effects and related to human isoprenoids like glucocorticosteroid [21,39]. In this study we discovered a new feature of the mechanisms of 1,8-cineol in nasal polyp tissue of chronic rhinosinusitis patients. 1,8-cineol reduced the phosphorylation level of eNOS, which could have an important impact on the pathogenesis of CRSwNP. A lower eNOS activity comes along with a possible decreased vascular permeability and this potentially prevents edema formation and increased inflammation in CRSwNP.
    Conclusion In summary, we recognized for the first time that nasal polyps of patients with chronic rhinosinusitis exhibited an increased phosphorylation of eNOS in vitro. This might be important for vascular permeability and the associated edema and elevated inflammation. Additionally, we identified that 1,8-cineol has no significant influence on the protein expression of eNOS, as well as regulatory and effector proteins like NOSTRIN and CASP8. However, 1,8-cineol affects the eNOS phosphorylation significantly and thus its activation. This could have important effects on the elevated inflammation and edema formation by regulation of the vascular permeability. Nasal nitric oxide is implicated as mediator of ongoing sinus inflammation and its reduction through 1,8-cineol not only offers new perspectives for its therapeutic use in airway diseases, especially CRSwNP, but also provides a possible phytotherapeutic alternative to glucocorticosteroids. Nevertheless, this study was a pilot study with a specific selection of patients. This and the limited numbers of control patients and functional experiments allows only a conditional interpretation about the function of eNOS and 1,8-cineol in nasal polyps. For this reason, the impact of comorbidities, allergies and glucocorticoids needs to be analyzed in future studies. Furthermore, additional experiments, especially in vivo, are necessary to validate the function of eNOS and 1,8-cineol in the pathogenesis of nasal polyps, and whether its therapeutic effectiveness represents a promising strategy in the future.