xRead - Nasal Obstruction (September 2024) Full Articles

20426984, 2021, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/alr.22741 by Stanford University, Wiley Online Library on [01/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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disseminate innate immune products. 878 Microbes directly impact ciliary function, and can often “hijack” nor mal ciliary regulation to prevent appropriate mucus movement. 873 In CRS, patients may have dysfunctional ciliary beat ing from direct effects of the organisms or from an inap propriate inflammatory response. 879–881 Mucociliary sta sis is a common finding of CRS, which propagates the disease as the stagnant mucus can harbor infection and sustain inflammatory mediators. 841 While there does not seem to be a detectable difference between baseline CBF in CRS patients and control patients, cilia from CRS patients show an attenuated response to substances that reliably increase CBF in controls. 877 This blunted response to cil iostimulatory substances may underlie the perpetuation of pathology in CRS. Pathogens such as P. aeruginosa, H. influenzae, S. pneumoniae, and S. aureus secrete toxins that directly suppress ciliary motion. 882–885 Pyocyanin, a toxin produced by P. aeruginosa , not only causes progres sive slowing, but also makes the cilia unable to respond to mechanical simulation by other factors. 886,887 H. influenzae toxins destroy cilia entirely at high concentrations, result ing in mucus stasis from ciliary loss. 888 These toxins, when present chronically, create an environment that is very favorable for CRS development. An overactive inflammatory environment or defects in cellular transport may also be the cause of some CRS cil iary pathology. TNF- α , IL-1 β , IL-5, and IL-8 are consis tently elevated in CRS cases, 43,879,889,890 and chronic eleva tion of these factors often blunts ciliary response. 880 TNF α has been shown to prevent CBF increases in response to mechanical stimulation, 874 while cycles of inflammation can cause ciliary loss or ciliary abnormalities in a chronic setting. 873 IL-13 or IFN- γ exposure can each result in decreased cilia differentiation and function. 891 Sodiumand chloride transport play a large role in MCC as well. Sodium absorption is increased in nasal cell culture from CRS patients, resulting in greater mucus viscosity and more dif ficult clearance, as the cilia have to work harder to trans port the same load. 892 Cigarette smokers have increased rates of CRS 893,894 in part because of the reduction in chlo ride transport caused by compounds in cigarette smoke precipitating a reduction in CBF. 895,896 Acquired dysfunction of the cystic fibrosis transmem brane conductance regulator (CFTR) can also lead to inhibition of ciliary beat frequency and the mucocil iary apparatus. Numerous studies in vitro , ex vivo , and in vivo (rabbits and humans) have identified CFTR dys function and concomitant impact on ciliary function in the setting of infection (viral and bacterial), inflamma tion, hypoxia, and external perturbations such as tobacco smoke exposure. 896–907 Administration of cigarette smoke to the nares of healthy smokers causes an acute block

ade of CFTR activity, as measured by nasal potential dif ference, suggesting exposure to cigarette smoke rapidly inhibits CFTR activity in vivo , as well as reduced ASL hydration in vitro . 908 Furthermore, cigarette smoke con densate inhibits transepithelial chloride secretion through CFTR and calcium activated chloride channel transmem brane member 16A (TMEM16A) and ciliary beat frequency in upper and lower respiratory airway epithelial cells in vitro . 896,906 Hypoxia has been suggested to play a sig nificant role in acquired mucociliary dysfunction and the pathophysiology of CRS among non-cystic fibrosis individuals. 909 Obstruction of the sinus ostia can lead to reduced oxygen tension in the sinus mucosal tissue 910 and release of inflammatory mediators, thereby caus ing stasis of hyperviscous mucus. In vitro experiments of hypoxia on ion transport physiology in both murine nasal septal epithelial (MNSE) and human sinonasal epithe lial (HSNE) cultures, revealed an impaired transepithelial ion transport related to reduced CFTR function. 904 HSNE cells incubated in a hypoxic environment show a glob ally decreased transepithelial Cl − secretion and increased sodium absorption. These findings indicate that persis tent hypoxia may lead to acquired defects in sinonasal Cl − transport in a fashion likely to confer mucociliary dysfunc tion in CRS. Blount et al. established sinonasal epithe lial CFTR and TMEM16A-mediated Cl − transport and mRNA expression were robustly decreased in an oxygen depleted environment. 907 This was subsequently identi fied to reduce the airway surface layer (ASL) and CBF in hypoxic epithelium as measured by micro optical coher ence tomography. 898 Treatment of ciliary dysfunction in CRS involves the res piratory epithelium returning to normal excitability and the establishment of an appropriately regulated inflam matory environment. It appears that the cilia are capa ble of recovering their excitability and normal activity in a healthy state. In 1 study, ciliated cells that were removed from the inflammatory milieu of CRS regained their ability to be stimulated and again functioned in a normal fashion. 842 Therefore, most effort clinically should be directed in treating the underlying CRS, as opposed to treating the dysfunctional cilia separately. Topical antimi crobial therapy results in an increase in CBF back to expected levels. 911 In cases of irreversible ciliary dysfunction, structural components of the cilia may be abnormal. Increased expression of CP110, a negative regulator of ciliogenesis, has been observed in CRS patients and may contribute to the poor ciliary recovery. 852 Other studies have hypothe sized that the ciliogenesis process may be dysregulated. 805 If the cilia that are generated are in any way functionally abnormal or absent, there is increased risk of biofilm for mation and other CRS risk factors. 851,912–914 Furthermore,