Sonic Hedgehog in Nasal Mucus is a Biomarker for Smell Loss in Patients with Hyposmia

Title: Sonic hedgehog in nasal mucus is a biomarker for smell loss in patients with hyposmia Background: Many chemical moieties have been identified in nasal and olfactory mucus related to cellular activity, cell signaling and olfaction. Sonic hedgehog (Shh) has been identified as a growth factor in taste buds but not in olfactory receptor tissues. We wished to determine if Shh were present in nasal mucus and, if present, does it relate to smell function and smell loss (hyposmia). Methods and findings: Shh was evaluated in nasal mucus in 14 normal volunteers and 44 patients with smell dysfunction of several etiologies. Nasal mucus was collected over a 1-4 day period in a 50 ml plastic container, transferred to a 12 ml plastic tube, centrifuged at 18,000 rpm for 45-55 minutes, the supernatant transferred to PCR tubes and frozen at 20°C until analyzed. All samples were analyzed by use of a sensitive spectrophotometric ELISA. Shh was found in nasal mucus in all normal subjects and in hyposmia patients. Levels in hyposmia patients of several etiologies were significantly lower than in normal. Levels decreased as subjects aged. Conclusions: This is the first systematic demonstration of Shh in nasal mucus in normal subjects and in hyposmia patients. Its presence is consistent with its role as a cell signaling moiety and growth or transcription factor related to olfactory receptor function. Its measurement in lower than normal concentrations in hyposmic patients may indicate that it can serve as a biomarker for smell loss in these patients. Its measurement can help to identify patients with hyposmic on an objective basis and help to define the biochemical parameters of their smell loss. Further studies can assist in determination of the specific role for this moiety in olfaction. Introduction Investigators have identified several chemical moieties in nasal mucus [1,2], in olfactory mucus and in mucus from olfactory mucosa [3-8] and related its presence to regulation of cellular activity, cell signaling in the olfactory mucosa [3-8] or in pathology of the upper airways [9-12]. Levels of one of these moieties, olfactomedin, identified as an olfactory glycoprotein [3], was lower than normal in animals with loss of smell (hyposmia); increasing these levels was associated with what was characterized as normal olfactory function [4]. However, there are many moieties in nasal mucus in humans not identified through these and other analyses [13]. Chief among these are adenylyl cyclases [14,15] and their downstream metabolites cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) [16,17]. These latter moieties were found decreased in hyposmic patients compared to normal subjects [16,17]. Sonic hedgehog (Shh) has been characterized as a critical factor in cellular growth and development of taste receptors [18,19] with its absence associated with inhibition of growth and development of receptors of these sensory organs [20]; however, it has not been identified to play a role in olfaction per se. Based upon these [18-20] and other studies [21] we and other before us recognized that moieties in nasal mucus, including several cytokines [21] and several drugs [22], could act as regulators of cellular function and cellular signaling [21] and cytokines could be identified as so-called growth or transcription factors [23] which stimulated stem cells in the olfactory epithelium to induce stimulation, growth and perpetuation of olfactory receptors to maintain olfactory function [24]. Inhibition of secretion of these nasal mucus moieties initiated smell loss [24] whereas treatment which increased these moieties improved or even restored olfactory function to or towards normal [24]. Because of the large number of hyposmic patients in the US [24] these studies generated our interest to search for other nasal mucus moieties that might act as growth factors involved with maintaining olfactory function in humans. This search resulted in a preliminary report in which Shh was identified in nasal mucus [25]. Research Article iMedPub Journals http://www.imedpub.com/ Cellular & Molecular Medicine: Open access Vol.2 No.2:9 2016 © Copyright iMedPub | This article is available from: http://cellular-molecular-medicine.imedpub.com/ 1 In this study we report substantive studies which identify the presence of Shh in nasal mucus of normal subjects and of patients with hyposmia.