Latrunculin B Nitrid oxide NO and its potential endogenous

Nitrid oxide (NO) and its potential endogenous production as an endothelium-derived factor was the first gaseous molecule accepted to be a signaling mediator in the organism [4,5]. NO plays a key role in physiological regulation of the Latrunculin B and exerts physiological functions in the nervous and immune systems, such as defense mechanisms against infectious disease and tumors. The endothelial nitric oxide synthase (eNOS) is next to inducible NOS (iNOS) and neuronal NOS (nNOS) the major isoform regulating vascular functions. Several stimuli can initiate or enhance the activity of eNOS and consequently the production of NO in a calcium-dependent and -independent manner [6]. Agonists like histamine affect specific receptors on endothelial cells, leading to an increase of the intracellular concentration of calcium and thus to an activation of the calmodulin-binding domain of eNOS [[7], [8], [9]]. This promotes the NO production by electron flux from the reductase to the oxygenase domains of the enzyme [10]. Phosphorylation of eNOS activates the enzyme, because it facilitates the active production of NO [10]. This post-translational modification can have opposing effects [11]: while Ser1177 is an activation side, Thr495 is an inhibitory side of the eNOS Protein [6]. eNOS can interact with various proteins. NOSTRIN is one of the important proteins that interact with eNOS. It negatively regulates eNOS localization in the plasma membrane [10]. On the other side, once NO is produced, it regulates inter alia the nitrosylation of CASP8, which inactivates this protein and leads to the inhibition of apoptosis [12]. NO is released in the nose and paranasal sinuses and is related to different upper airway diseases like allergic rhinitis or chronic rhinosinusitis with and without nasal polyps. However, NO does not seems to play an important role in normal conditions [13,14]. In allergic rhinitis, CRS with and without nasal polyps, altered NO concentrations were found and might serve as an indicator of disease severity [15]. Actually, patients with chronic rhinosinusitis showed high levels of iNOS expression and activity. Despite low levels of nasal NO, increased exhaled NO was measured compared to controls [13,[16], [17], [18], [19], [20]]. 1,8-cineol (PubChem CID: 2758), also known as eucalyptol, is a natural monoterpene and a major compound of many plant essential oils. Extracted from Eucalyptus globulus oil, 1,8-cineol has proven clinical efficacy on the respiratory tract and therapeutic benefits in inflammatory airway diseases, such as asthma or chronic obstructive pulmonary disease (COPD). Several pre-clinical studies refer to its anti-inflammatory and anti-oxidant mode of action with strong evidence that 1,8-cineol controls inter alia inflammatory processes [21]. Little is known about the effect of 1,8-cineol in chronic rhinosinusitis. Sudhoff et al. could show that 1,8-Cineol reduces mucus-production in an ex-vivo model of rhinosinusitis [22]. However, nothing is known about the effect of 1,8-cineol in nasal polyps. The aim of this pilot study was to investigate the deeper role of eNOS in the pathogenesis of nasal polyps in vitro. We determined gene and protein expression of eNOS, as well as its phosphorylation status. Additionally, we analyzed the influence of 1,8-cineol on nasal polyp gene and protein expression of eNOS concerning its possible therapeutic effectiveness in NO synthesis or vascular permeability.
Methods
Results
Discussion CRSwNP is a multifactorial disease and considered to be a chronic inflammatory condition of the nasal and paranasal sinuses, but the etiology of nasal polyps still remains unclear [2]. NO, in general known as atmospheric pollutant, is a chemical structure being extremely reactive with a short half-life of a few seconds. Interestingly, it has been recognized to be a biological regulator in animals and humans [13,26,27] and is present in almost all mammalian organ systems and in the exhaled breath of all humans [28]. NO functions as a vasodilator, bronchodilator, neurotransmitter, and inflammatory mediator in the lung and patients with asthma have high levels of NO in their exhaled breath, with an increased enzyme expression of iNOS in epithelial cells of the lung [13,[28], [29], [30], [31]]. Following the concept of united airways disease, we would expect the same in the upper airways. Indeed, patients with chronic rhinosinusitis showed high levels of iNOS expression and activity, with increased exhaled NO, but low levels of nasal NO compared to controls [13,[16], [17], [18], [19], [20]]. Furthermore, patients with allergic rhinitis showed increased levels of nasal NO, which is due to an increased expression of iNOS in nasal epithelial cells [15].