Orphan receptor GPR37L1 contributes to the sexual dimorphism of central cardiovascular control.

BACKGROUND: Over 100 mammalian G protein-coupled receptors are yet to be matched with endogenous ligands; these so-called orphans are prospective drug targets for the treatment of disease. GPR37L1 is one such orphan, abundant in the brain and detectable as mRNA in the heart and kidney. GPR37L1 ablation was reported to cause hypertension and left ventricular hypertrophy, and thus, we sought to further define the role of GPR37L1 in blood pressure homeostasis. METHODS: We investigated the cardiovascular effects of GPR37L1 using wild-type (GPR37L1wt/wt) and null (GPR37L1KO/KO) mice established on a C57BL/6J background, both under baseline conditions and during AngII infusion. We profiled GPR37L1 tissue expression, examining the endogenous receptor by immunoblotting and a ß-galactosidase reporter mouse by immunohistochemistry. RESULTS: GPR37L1 protein was abundant in the brain but not detectable in the heart and kidney. We measured blood pressure in GPR37L1wt/wt and GPR37L1KO/KO mice and found that deletion of GPR37L1 causes a female-specific increase in systolic, diastolic, and mean arterial pressures. When challenged with short-term AngII infusion, only male GPR37L1KO/KO mice developed exacerbated left ventricular hypertrophy and evidence of heart failure, while the female GPR37L1KO/KO mice were protected from cardiac fibrosis. CONCLUSIONS: Despite its absence in the heart and kidney, GPR37L1 regulates baseline blood pressure in female mice and is crucial for cardiovascular compensatory responses in males. The expression of GPR37L1 in the brain, yet absence from peripheral cardiovascular tissues, suggests this orphan receptor is a hitherto unknown contributor to central cardiovascular control.

Metalloprotease cleavage of the N terminus of the orphan G protein-coupled receptor GPR37L1 reduces its constitutive activity.

Little is known about the pharmacology or physiology of GPR37L1, a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor that is abundant in the cerebellum. Mice deficient in this receptor exhibit precocious cerebellar development and hypertension. We showed that GPR37L1 coupled to the G protein Gα(s) when heterologously expressed in cultured cells in the absence of any added ligand, whereas a mutant receptor that lacked the amino terminus was inactive. Conversely, inhibition of ADAMs (a disintegrin and metalloproteases) enhanced receptor activity, indicating that the presence of the amino terminus is necessary for GPR37L1 signaling. Metalloprotease-dependent processing of GPR37L1 was evident in rodent cerebellum, where we detected predominantly the cleaved, inactive form. However, comparison of the accumulation of cAMP (adenosine 3',5'-monophosphate) in response to phosphodiesterase inhibition in cerebellar slice preparations from wild-type and GPR37L1-null mice showed that some constitutive signaling remained in the wild-type mice. In reporter assays of Gα(s) or Gα(i) signaling, the synthetic, prosaposin-derived peptide prosaptide (TX14A) did not increase GPR37L1 activity. Our data indicate that GPR37L1 may be a constitutively active receptor, or perhaps its ligand is present under the conditions that we used for analysis, and that the activity of this receptor is instead controlled by signals that regulate metalloprotease activity in the tissue.

The Olfactory Strip and Its Preservation in Endoscopic Pituitary Surgery Maintains Smell and Sinonasal Function.

Background The return of olfaction and of sinonasal function are important end points after pituitary surgery. Opinions differ on the impact of surgery because techniques vary greatly. A modified preservation of the so-called olfactory strip is described that utilizes a small nasoseptal flap and wide exposure. Methods A cohort of patients undergoing pituitary surgery and endoscopic sinonasal tumor surgery were assessed. Patient-reported outcomes (Sino-Nasal Outcome Test [SNOT22] and Nasal Symptom Score [NSS]) were recorded. A global score of sinonasal function and the impact on smell and taste were obtained. Objective smell discrimination testing was performed in the pituitary group with the Smell Identification Test. Outcomes were assessed at baseline and at 6 months. Results Ninety-eight patients, n = 40 pituitary (50.95 ± 15.31 years; 47.5% female) and n = 58 tumor (52.35 ± 18.51 years; 52.5% female) were assessed. For pituitary patients, NSSs were not significantly different pre- and postsurgery (2.75 ± 3.40 versus 3.05 ± 3.03; p = 0.53). SNOT22 scores improved postsurgery (1.02 ± 0.80 versus 0.83 ± 0.70; p = 0.046). Objective smell discrimination scores between baseline and 6 months were similar (31.63 ± 3.49 versus 31.35 ± 4.61; p = 0.68). No difference in change of olfaction was seen compared with controls (Kendall tau-b p = 0.46). Conclusions Preservation of the olfactory strip can provide a low morbidity approach without adversely affecting olfaction and maintaining reconstruction options.

Sinonasal morbidity following tumour resection with and without nasoseptal flap reconstruction.

BACKGROUND: Sinonasal function can be affected by multiple treatment modalities but surgical techniques, such as the nasoseptal flap or Draf 3 procedure, have been implicated in poor post-treatment function. Prior studies have rarely used comparable populations and this study aims to assess the impact of surgical technique, mainly the nasoseptal flap, on sinonasal function in a group of comparable patients. METHODS: A prospective cohort of patients undergoing endoscopic surgery for sinonasal and skull base tumours was studied. Patients were analysed according to whether a nasoseptal flap was used. Other treatment factors included; use of the Draf 3, radiotherapy, removal of olfactory apparatus and dural resection. The Sinonasal Outcome Test 22 (SNOT22), a nasal symptom score (NSS), global function score and nasal obstruction scores were recorded pre and post treatment. RESULTS: One hundred and eighteen patients were assessed. Forty-two patients had a nasoseptal flap. Perioperative radiotherapy was higher in the nasoseptal group, as was dural resection and the need to remove the olfactory apparatus. Despite this, there was no significant difference in SNOT22 scores and NSS. Radiotherapy was detrimental to sinonasal function with SNOT22 and NSS. CONCLUSION: The use of a nasospetal flap in surgery does not affect patient quality of life and sinonasal function after endoscopic tumour resection. Pathology is a better predictor of morbidity, with loss of function from radiotherapy or resection of functional areas such as the olfactory apparatus having a greater impact.

Remodeling changes of the upper airway with chronic rhinosinusitis.

BACKGROUND: Although remodeling changes of the lower airway are well described, similar changes in the upper airway are less well known. Remodeling changes of the upper airway in chronic rhinosinusitis (CRS) relevant to different phenotypes and endotypes and their clinical characteristics are investigated. METHODS: A cross-sectional study of adult patients with CRS was performed. Mucosal samples were taken during endoscopic sinus surgery (ESS). Histopathological analysis included eosinophil count, eosinophil activation (eosinophilic mucin), and remodeling changes. Mucosal damage was defined as ulceration, edema, and hypertrophic changes. Patient-reported outcomes (PROMs) were assessed using a Nasal Symptom Score (NSS) and Sino-Nasal Outcome Test (SNOT-22). Patients were subgrouped by presence of polyps (CRSwNP/CRSsNP) or tissue eosinophilia (>10/high power field). Subgroup analysis was performed when both eosinophilic chronic rhinosinusitis (eCRS) and eosinophil activation (eCRSwEA) were coexistent. Analysis between subgroups, pathology, and PROMs was also performed. RESULTS: A total of 259 patients (age 48.5 ± 15.6 years, 45% female) were recruited; 53% CRSwNP, 51% eCRS. Remodeling changes were present in 85%, higher in both CRSwNP (90%, p = 0.006) and eCRS (91%, p = 0.004). Mucosal damage changes were common in eCRS (ulceration 18%, p = 0.003; edema 98%, p < 0.001; hypertrophic changes 25%, p = 0.007). NSS was worse in CRSwNP compared to CRSsNP (2.84 ± 1.1 vs 2.29 ± 1.1, p < 0.001) and eCRSwEA (2.95 ± 0.16 vs 2.51 ± 0.11, p = 0.04). "Loss of sense of smell or taste" was worse in patients with evidence of mucosal damage (p = 0.006). CONCLUSION: Remodeling features are present in CRS. Tissue eosinophilia and evidence of eosinophil activation is closely associated with remodeling features of CRS, associated mucosal damage and clinical symptoms.

Airflow and patient-perceived improvement following rhinoplastic correction of external nasal valve dysfunction.

IMPORTANCE: External nasal valve dysfunction (ENVD) is a common cause of nasal obstruction. Although many techniques are described to help correct ENVD, evidence of the objective changes in the airway achieved by these interventions is mainly unknown. OBJECTIVE: To document the airway changes in patients with ENVD by comparing subjective and objective measures obtained before and after rhinoplasty. DESIGN, SETTING, AND PARTICIPANTS: Prospective case series with validated subjective and objective outcomes at a tertiary rhinologic center in Sydney, Australia. We included 19 patients with nasal obstruction and clinically diagnosed ENVD from January 2012 to May 2013. INTERVENTIONS: Functional reconstructive rhinoplasty involving lateral crural underlay strut grafts using costal cartilage or lateral crural cephalic turn-in maneuvers performed to correct ENVD. MAIN OUTCOMES AND MEASURES: Objective assessment included nasal peak inspiratory flow, nasal airway resistance, and minimum cross-sectional area. Subjective assessment included a visual analog scale for nasal obstruction, the 22-item Sinonasal Outcome Test, the Nasal Obstruction Symptom Evaluation Scale, and the 36-Item Short Form Health Survey, version 2. A 13-point Likert scale was also used to assess overall function and cosmesis. Objective data and visual analog scale scores were obtained before and after decongestion at baseline and 6 months after surgery. RESULTS: Mean (SD) age of the patients undergoing assessment was 33.3 (12.4) years; 13 patients (68%) were female. Significant improvement was observed in scores for the Sinonasal Outcome Test (mean [SD] change, 0.85 [0.96]), Nasal Obstruction Symptom Evaluation Scale (mean [SD] change, 30.53 [26.14]), and overall function (median [25th-75th percentiles] change, -6.5 [-7.0 to 1.0]) and cosmesis (median [25th-75th percentiles] change, -4.0 [-8.0 to -1.0]) (P < .01). The mean (SD) nasal peak inspiratory flow increased from 102.6 (45.6) to 124.0 (52.9) L/min (P < .01). Median (25th-75th percentiles) nasal airway resistance showed no significant change (from 0.296 [0.237-0.414] to 0.292 [0.267-0.371] Pa/cm3/s; P = .92). The minimum cross-sectional area also showed no significant change (mean [SD], from 1.188 [0.407] to 1.229 [0.336] cm2; P = .69). CONCLUSIONS AND RELEVANCE: Contrary to common belief, successful rhinoplasty had little effect on structural shape or resistance in ENVD, but symptoms improved with changes in collapsibility as defined by the nasal peak inspiratory flow. The need to reconstruct lateral wall support is reinforced by the data presented. LEVEL OF EVIDENCE: 4.

Cellular comparison of sinus mucosa vs polyp tissue from a single sinus cavity in chronic rhinosinusitis.

BACKGROUND: Nasal polyposis is a common development in chronic rhinosinusitis (CRS), and sinus mucosa and polyp tissue have been used interchangeably in studies investigating CRS. However, potential differences may exist between these 2 tissue types, which have not been entirely characterized. METHODS: A cross-sectional study of CRS with nasal polyposis (CRSwNP) patients undergoing endoscopic sinus surgery was conducted. Sinus mucosal biopsies and corresponding polyp tissue were obtained from the same sinus cavity via flow cytometry, single-cell suspensions identified type 2 innate lymphoid cells (ILC2s), CD4 and CD8 T cells, activated CD4 and CD8 T cells, plasma cells, plasmacytoid dendritic cells (pDCs), regulatory T cells, T follicular helper cells, B cells, and immunoglobulin A (IgA)(+) and IgG(+) B cells. Cells were measured as a percentage of CD45(+) cells. Paired nonparametric comparisons between sinus and polyp tissue were performed. RESULTS: Ten patients (50% female; age 48 ± 16 years) were recruited. Significantly elevated ILC2 levels were found in polyp tissue compared to sinus mucosa (0.12 [0.07 to 0.23] vs 0.07 [0.04 to 0.16], p = 0.02), as well as plasma cells (2.25 [0.84 to 3.68] vs 1.18 [0.74 to 2.41], p = 0.01); pDCs (0.15 [0.12 to 0.50[ vs 0.04 [0.02 to 0.17], p = 0.03); activated CD8 T cells (29.22 [17.60 to 41.43] vs 16.32 [10.07 to 36.16], p = 0.04) and IgG(+) B cells (6.96 [0.06 to 11.82] vs 1.51 [0.38 to 5.13], p = 0.04). Other cell populations showed no significant differences. CONCLUSION: Polyps have a similar cellular composition to that of mucosa. Higher levels of ILC2s, plasma cells, pDCs, activated CD8 T cells, and IgG(+) B cells in polyp tissue may be reflective of cell populations driving nasal polyp development. The cellular machinery of CRS is present in polyps and representative of the disease process. This pilot study strongly suggests that a larger study would provide significant insights into the relationship of sinus mucosa to pathogenesis of nasal polyps.