Chronic rhinosinusitis has a significant impact on patient quality of life, creates billions of dollars of annual healthcare costs, and accounts for ∼20% of adult antibiotic prescriptions in the United States. Because of the rise of resistant microorganisms, there is a critical need to better understand how to stimulate and/or enhance innate immune responses as a therapeutic modality to treat respiratory infections. We recently identified bitter taste receptors (taste family type 2 receptors, or T2Rs) as important regulators of sinonasal immune responses and potentially important therapeutic targets. Here, we examined the immunomodulatory potential of flavones, a class of flavonoids previously demonstrated to have antibacterial and anti-inflammatory effects. Some flavones are also T2R agonists. We found that several flavones inhibit Muc5AC and inducible NOS up-regulation as well as cytokine release in primary and cultured airway cells in response to several inflammatory stimuli. This occurs at least partly through inhibition of protein kinase C and receptor tyrosine kinase activity. We also demonstrate that sinonasal ciliated epithelial cells express T2R14, which closely co-localizes (<7 nm) with the T2R38 isoform. Heterologously expressed T2R14 responds to multiple flavones. These flavones also activate T2R14-driven calcium signals in primary cells that activate nitric oxide production to increase ciliary beating and mucociliary clearance. polymorphisms encode functional (PAV:roline, lanine, andaline at positions 49, 262, and 296, respectively) or non-functional (AVI: lanine,aline, soleucine at positions 49, 262, and 296, respectively) T2R38. Our data demonstrate that T2R14 in sinonasal cilia is a potential therapeutic target for upper respiratory infections and that flavones may have clinical potential as topical therapeutics, particularly in T2R38 AVI/AVI individuals.
In the upper respiratory epithelium, bitter and sweet taste receptors present in solitary chemosensory cells influence antimicrobial innate immune defense responses. Whereas activation of the bitter taste receptor (T2R) stimulates surrounding epithelial cells to release antimicrobial peptides, activation of the sweet taste receptor (T1R) in the same cells inhibits this response. It is thought that this mechanism exists to control the magnitude of antimicrobial peptide release based upon the sugar content of airway surface liquid. We hypothesized that D-amino acids, which are produced by various bacteria and activate T1R in taste receptor cells in the mouth, may also activate T1R in the airway. Here, we show that both the T1R2 and T1R3 subunits of the sweet taste receptor (T1R2/3) are present in the same chemosensory cells of primary human sinonasal epithelial cultures. Respiratory isolates of Staphylococcus species, but not Pseudomonas aeruginosa, produced at least two D-amino acids that activate the sweet taste receptor. In addition to inhibiting P. aeruginosa biofilm formation, D-amino acids derived from Staphylococcus inhibited T2R-mediated signaling and defensin secretion in sinonasal cells by activating T1R2/3. D-amino acid–mediated activation of T1R2/3 also enhanced epithelial cell death during challenge with Staphylococcus aureus in the presence of the bitter-receptor–activating compound denatonium benzoate. These data establish a potential mechanism for interkingdom signaling in the airway mediated by bacterial D-amino acids and the mammalian sweet taste receptor in airway chemosensory cells.
Background: Protecting the upper airway from microbial infection is an important function of the immune system. Proper detection of these
Objectives (1) To determine objective criteria to predict which patients may benefit most from inferior turbinate reduction surgery. (2) To test whether the site of turbinate reduction, either along the nasal floor (bottom resection) or along the septal side (medial resection), impacts the extent to which nasal resistance is reduced. Study Design Case series. Methods Three-dimensional reconstructions of the nasal anatomy of five nasal airway obstruction patients were created based on pre-surgical computed tomography scans. Inferior turbinate reduction models were created for each patient using virtual surgery. Airflow, heat transfer, and humidity transport during inspiration were simulated using computational fluid dynamics (CFD). Results Nasal resistance curves revealed little to no difference between bottom resection and medial resection models. In two patients, little change was observed in nasal resistance after virtual inferior turbinate reduction, which was attributed to the narrowest cross-sections being restricted to the anterior nose (i.e., anterior to the inferior turbinate). The three patients whose nasal resistances decreased substantially after virtual inferior turbinate reduction had a narrower airspace in the turbinate region and higher nasal resistance pre-surgery. Nasal air conditioning capacity was more affected by medial resections. Conclusion CFD simulations predicted no significant difference in the decrease in nasal resistance between virtual inferior turbinate reductions performed by bottom vs. medial resection of the turbinate. However, bottom resections better preserved the calculated humidification efficiency. The simulations predicted that the greatest reduction in nasal resistance occurs in patients with highest pre-surgical resistance in the turbinate region.
The relationship between nasal resistance (R) and airspace minimal cross-sectional area (mCSA) remains unclear. After the introduction of acoustic rhinometry, many otolaryngologists believed that mCSA measurements would correlate with subjective perception of nasal airway obstruction (NAO), and thus could provide an objective measure of nasal patency to guide therapy. However, multiple studies reported a low correlation between mCSA and subjective nasal patency, and between mCSA and R. This apparent lack of correlation between nasal form and function has been a long-standing enigma in the field of rhinology. Here we propose that nasal resistance is described by the Bernoulli Obstruction Theory. This theory predicts two flow regimes. For mCSA > Acrit, the constriction is not too severe and there is not a tight coupling between R and mCSA. In contrast, when mCSA < Acrit, nasal resistance is dominated by the severe constriction and it is predicted to be inversely proportional to the minimal cross-sectional area (R ∝ mCSA−1). To test this hypothesis, computational fluid dynamics (CFD) simulations were run in 3-dimensional models based on computed tomography scans of 15 NAO patients pre- and post-surgery (i.e., 60 unilateral nasal cavities). Airspace cross-sectional areas were quantified perpendicular to airflow streamlines. Our computational results are consistent with the theory. Given that in most people mCSA > Acrit (estimated to be 0.37 cm2), this theory suggests that airway constrictions are rarely an exclusive contributor to nasal resistance, which may explain the weak correlation between mCSA and subjective nasal patency.
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