Advantages of the co2 laser use in the rare condition of nasal mucosa squamous cell carcinoma surgery in dogs-a clinical prospective study.

Nasal mucosa tumors are an uncommon process and very dificult to work on with surgery. Radiotherapy associated or not with chemotherapy is the standard method to treat the disease. However, its access it is in the majority of the case not possible, making the surgery the best choice to try to achieve the patient's control. The anatomy of the region makes the complete surgical resection very difficult to achieve using the common and conventional blade scalpel surgery. The study features the advantages of using a CO2 laser to perform nasal mucosa carcinoma surgery in 6 dogs (N = 6). For the work we used an Aesculigth CO2 surgical laser model -Vetscalpel®, with the settings of 12Watts in a Superpulse mode, and a 0.25-0.4 mm focus to dissect the nasal mucosa, and a 1.5 mm focus for vaporization of the area. All the masses were histopathologically characterized as squamous cells carcinoma. The CO2 surgical laser allow us to work in a bloodless region promoting a more accurate dissection of the nasal mucosa sparing therefore the underlying and adjacent tissues and being less invasive. Also, it was possible to do the vaporization of the entire surgical area interviened. None of the patients presented relapse of clinical signs. Only 2 individuals were alive at the end of the study, presenting a survival rate of 420 and 514 days, which is in the same line of literature results of the treatment with radiotherapy combined with chemotherapy wich shows a median of 474-580 days. The study demonstrates successful outcomes with CO2 laser surgery in treating nasal mucosa SCC in dogs, with patients experiencing improved survival rates compared to traditional treatment methods. This highlights the efficacy and potential of CO2 laser surgery as a valuable tool in managing aggressive nasal tumors in veterinary oncology.

SerpinB3/B4 Abates Epithelial Cell-Derived CXCL8/IL-8 Expression in Chronic Rhinosinusitis with Nasal Polyps.

Background: Serine proteinase inhibitors, clade B, member 3 (SerpinB3) and B4 are highly similar in amino acid sequences and associated with inflammation regulation. We investigated SerpinB3 and B4 expression and their roles in chronic rhinosinusitis with nasal polyps (CRSwNP). Methods: The expression of SerpinB3 and B4 in nasal mucosa tissues, brush cells, and secretions from CRSwNP patients was measured, and their regulation by inflammatory cytokines were investigated. Their functions were also analyzed using air-liquid interface (ALI)-cultured primary human nasal epithelial cells (HNECs) and transcriptomic analysis. Results: Both SerpinB3 and B4 expression was higher in nasal mucosa, brush cells, and secretions from eosinophilic (E) CRSwNP and nonECRSwNP patients than in healthy controls. Immunofluorescence staining indicated that SerpinB3 and B4 were primarily expressed in epithelial cells and their expression was higher in CRSwNP patients. SerpinB3 and B4 expression was upregulated by interleukin-4 (IL-4), IL-5, IL-6, and IL-17a. Transcriptomic analysis identified differentially expressed genes (DEGs) in response to recombinant SerpinB3 and B4 stimulation. Both the DEGs of SerpinB3 and B4 were associated with disease genes of nasal polyps and inflammation in DisGeNET database. Pathway enrichment indicated that downregulated DEGs of SerpinB3 and B4 were both enriched in cytokine-cytokine receptor interactions, with CXCL8 as the hub gene in the protein-protein interaction networks. Furthermore, CXCL8/IL-8 expression was downregulated by recombinant SerpinB3 and B4 protein in ALI-cultured HNECs, and upregulated when knockdown of SerpinB3/B4. Conclusion: SerpinB3/B4 expression is upregulated in nasal mucosa of CRSwNP patients. SerpinB3/B4 may play an anti-inflammatory role in CRSwNP by inhibiting the expression of epithelial cell-derived CXCL8/IL-8.

Association between maxillary sinus floor perforation by dental implants and mucosal thickening: A cone-beam computed tomography study.

OBJECTIVE: To investigate the association of perforation of the maxillary sinus floor by dental implants with mucosal thickening and to describe its characteristics in perforated cases. STUDY DESIGN: One-hundred and twenty-nine maxillary sinuses of 93 patients presenting 202 dental implants in the maxillary posterior region were retrospectively assessed in cone-beam computed tomography scans and classified according to maxillary sinus perforation, bone graft, mucosal thickening, and mucosal appearance. Logistic regression determined the chance of mucosal thickening in perforated maxillary sinuses. The chi-square test compared categorical variables between maxillary sinus perforated or not by implants and maxillary sinus with or without mucosal thickening. The significance level assumed was 5 % (α = 0.05). RESULTS: There was perforation of 60 maxillary sinuses floor (46.5 %) by 74 dental implants. The chance of mucosal thickening was higher when the implant tip was trespassing on the maxillary sinus floor (p < 0.001). There was a significant association between maxillary sinus mucosal thickening and perforation by a dental implant with the tip trespassing the maxillary sinus floor (p < 0.05). CONCLUSION: Maxillary sinus mucosal thickening is associated with sinus floor perforation by dental implants and does not depend on the number of implants perforating it. CLINICAL RELEVANCE: There is an association between dental implants' perforation of the maxillary sinus floor and the thickening of the maxillary sinus. In those cases, the appearance of the mucosa thickening may be irregular, local, or total opacification of the sinus cavity.

miR-224-5p Attenuates Allergic Responses in Mice with Allergic Rhinitis by Modulating the Th1/Th2 Response.

Background: Allergic rhinitis (AR) is a common chronic respiratory disease that has become a global health problem. miRNAs play an important role in multiple immune and inflammatory diseases, including AR. In this work, the mechanism by which miR-224-5p regulates AR in vivo and in vitro was examined. Methods: Human nasal epithelial cells (HNEpCs) were used to establish an AR cell model induced by Der P1, and C57BL/6 mice were used to establish an AR animal model induced by OVA (ovalbumin). RT-qPCR was used to determine the level of miR-224-5p; western blot analysis was used to determine GATA3; ELISA was used to determine the levels of OVA-specific IgE, IFN-γ, IL-4, IL-5, and IL-13; flow cytometry was used to determine the differentiation of Th1 and Th2 cells; and HE and PAS staining was used to observe the histopathological alterations in the mouse nasal mucosa and spleen. Results: miR-224-5p was downregulated in nasal mucosa from mice with AR and an AR cell model. Overexpressed miR-224-5p can improve AR development and attenuate AR symptoms by regulating GATA3-mediated Th1/Th2 responses. Conclusion: miR-224-5p attenuates allergic reactions in mice with AR by regulating the Th1/Th2 response.

The study of the role of purified anti-mouse CD193 (CCR3) antibody in allergic rhinitis mouse animal models.

The pathogenesis of allergic asthma is similar to that of allergic rhinitis, with inflammation cells producing and releasing inflammatory mediators and cytokines closely related to CCR3.Based on the theory of "one airway, one disease", the use of CCR3 monoclonal antibody may have a similar effect on allergic rhinitis. However, there are few studies on CCR3 monoclonal antibody in allergic rhinitis. Therefore, the aim of this study was to investigate the effective concentration of CCR3 monoclonal antibody, to compare the effects of different methods of administration, and to examine the lung condition of allergic mice to investigate whether antibody treatment protects the lungs. In this study, we constructed a mouse model of allergic rhinitis and intraperitoneally injected different doses of CCR3 monoclonal antibody (5, 10, and 20 uL/mg) to observe its therapeutic effect: observing changes in tissue morphology of nasal mucosa, infiltration of inflammation, and using ELISA to detect changes in relevant inflammatory mediators and cytokines, studying the role of CCR3 mAb in inhibiting CCR3-related actions on the nasal mucosa of allergic rhinitis mice. Furthermore, In addition, the therapeutic effects of intraperitoneal injection (i.p.) and intranasal administration (i.n.) were studied on the basis of effective concentrations.

Levels of nasal nitric oxide and nitric oxide synthase expression in chronic rhinosinusitis with nasal polyposis.

KEY POINTS: CRSwNP patients had decreased nNO and increased SNOT-22, endoscopy, and CT scores. CRSwNP patients exhibited decreased nNO despite elevated iNOS and eNOS mRNA expression. The mechanism behind lowered nNO in CRSwNP may not be related to NOS expression.

The Effect of Rosmarinic Acid on Wound Healing of Nasal Mucosa in the Rats.

BACKGROUND: The nose can be damaged by environmental pollutants and foreign bodies, as well as a result of trauma, infection or surgical interventions. Proper healing of the damaged nasal mucosa is important for health. OBJECTIVE: There is no study in the literature investigating the effects of rosmarinic acid on mucosal healing. The aim of this study was to investigate the effect of rosmarinic acid on nasal mucosal healing. METHODS: 21 male, adult Spraque Dawley albino rats were divided into three groups as the control group, the local treatment group in which rosmarinic acid was applied locally to the nasal mucosa, and the systemic treatment group in which rosmarinic acid was injected intraperitoneally. The wound area was obtained by creating a trauma area by inserting a 10 mm interdental brush through the right nasal nostril into the right nasal cavities of all animals. For the following 15 days, the treatment agent was applied as indicated once a day and on the 15th day the animals were decapitated and tissue samples taken from the nasal mucosa were prepared for histopathological examination. The preparations were examined in terms of cellular hyperplasia, goblet cell hypertrophy and degeneration, leukocyte infiltration, cilia loss and degeneration, edema and vascular dilatation, and they have been classified into four categories as mild (+), moderate (++), severe (+++) and very severe (++++). RESULTS: There was a significant difference between the groups in terms of all parameters evaluated, and there is a decrease in the intensity of the parameters with transition from the control group to the local group and from there to the systemic group. CONCLUSION: Systemic rosmarinic acid administration showed an enhancing effect on the healing of experimentally induced nasal mucosal injury due to its possible anti-inflammatory effect.

[Pathogenetic approach in the treatment of inflammatory diseases of the nose and paranasal sinuses]. / Patogeneticheskii podkhod v terapii vospalitel'nykh zabolevanii nosa i okolonosovykh pazukh.

In recent years, inflammatory diseases of the nose and paranasal sinuses have been on the rise. In addition to infectious diseases, in the modern world a large percentage of the population suffers from allergic diseases. The approach to therapy and the choice of a drug should take into account the pathogenesis of the inflammatory reaction in the nasal cavity and paranasal sinuses. By exerting its effect, the drug should reduce hyperemia and swelling of the nasal mucosa, reduce the level of mucus secretion, improve the drainage of the paranasal sinuses, i.e. possess vasoconstrictive and anti-allergic properties. As such a drug, you can use the combined intranasal spray Frinozol, which basically contains cetirizine and phenylephrine. The use of Frinozol in the complex treatment of inflammation of the mucous membrane of the nasal cavity and paranasal sinuses contributes to the rapid and pronounced weakening of the symptoms of the disease, and is also the key to successful therapy.

The destruction of mucosal barriers, epithelial remodeling, and impaired mucociliary clearance: possible pathogenic mechanisms of Pseudomonas aeruginosa and Staphylococcus aureus in chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is a pathological condition characterized by persistent inflammation in the upper respiratory tract and paranasal sinuses. The epithelium serves as the first line of defense against potential threats and protects the nasal mucosa. The fundamental mechanical barrier is formed by the cell-cell contact and mucociliary clearance (MCC) systems. The physical-mechanical barrier is comprised of many cellular structures, including adhesion junctions and tight junctions (TJs). To this end, different factors, such as the dysfunction of MCC, destruction of epithelial barriers, and tissue remodeling, are related to the onset and development of CRS. Recently published studies reported the critical role of different microorganisms, such as Staphylococcus aureus and Pseudomonas aeruginosa, in the induction of the mentioned factors. Bacteria could result in diminished ciliary stimulation capacity, and enhance the chance of CRS by reducing basal ciliary beat frequency. Additionally, bacterial exoproteins have been demonstrated to disrupt the epithelial barrier and induce downregulation of transmembrane proteins such as occludin, claudin, and tricellulin. Moreover, bacteria exert an influence on TJ proteins, leading to an increase in the permeability of polarized epithelial cells. Noteworthy, it is evident that the activation of TLR2 by staphylococcal enterotoxin can potentially undermine the structural integrity of TJs and the epithelial barrier through the induction of pro-inflammatory cytokines. The purpose of this article is an attempt to investigate the possible role of the most important microorganisms associated with CRS and their pathogenic mechanisms against mucosal surfaces and epithelial barriers in the paranasal sinuses. Video Abstract.

Effects of Differentially Expressed mRNAs Screened Based on GEO Database on Inflammatory Infiltration of Nasal Mucosa in Mice with Allergic Rhinitis.

Objective: To identify messenger RNAs (mRNAs) with differential expression in allergic rhinitis (AR) based on an online database, Gene Expression Omnibus (GEO), to provide a new research direction for future diagnosis and treatment of AR. Methods: The GSE44037 dataset from the CEO database was selected to obtain differentially expressed mRNAs (DEmRNAs) in AR. The keywords involved in these DEmRNAs were enriched and analyzed, and ECM1 and CCL2 were selected for subsequent analysis. In addition, BALB/c mice were purchased and randomized to control (normal feeding), model (AR modeling), si-CCL2 (AR modeling + CCL2 suppression by lentivirus vector), nc-CCL2 (AR modeling + CCL2 empty vector), si-ECM1 (AR modeling + ECM1 suppression by lentivirus vector), and nc-ECM1 (AR modeling + ECM1 empty vector) groups. The frequencies of sneezing and nasal rubbing were recorded in each group. Besides, levels of CCL2, ECM1, interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and high sensitivity C-reactive protein (hs-CRP) were quantified, and the inflammatory infiltration of nasal mucosa (NM) was observed. Results: Twenty-six DEmRNAs were acquired from the GSE44037 dataset, among which only CCL2 and ECM1 were found to be associated with keywords such as "immune response" and "inflammatory response" through enrichment analysis. In animal experiments, CCL2 presented lower mRNA expression in model mice than in control mice, while ECM1 showed higher mRNA expression (P < .05). The frequencies of sneezing and nose rubbing and the levels of inflammatory factors were significantly increased in si-CCL2 mice compared with model mice, while were significantly decreased in si-ECM1 mice (P < .05). The NM inflammatory infiltration was serious in the si-CCL2 group and significantly improved in the si-ECM1 group. Conclusions: Low expression of CCL2 and high expression of ECM1 in AR are strongly linked to the pathological progression of AR, and these two genes are expected to be new research directions for AR diagnosis and treatment.

Cigarette Smoke Mediates Nasal Epithelial Barrier Dysfunction via TNF-α.

BACKGROUND: Extensive data suggest that exposure to cigarette smoke can induce pulmonary epithelial barrier dysfunction. However, the effects of cigarette smoke on the nasal epithelial barrier are still unclear. Here, we investigated the consequence and mechanism of cigarette smoke on the nasal epithelial barrier. METHODS: Sprague Dawley rats were exposed to cigarette smoke for 3 or 6 months, and changes in inflammatory markers and nasal barrier function were evaluated. Moreover, underlying mechanisms were explored. Finally, normal human bronchial epithelial cells were cultured with or without tumor necrosis factor-alpha (TNF-α) in vitro, and the levels of continuity and tight junction-associated proteins were measured. RESULTS: In vivo experiments showed that the nasal mucosal barrier function of rats exposed to cigarette smoke was disturbed. Indeed, proteins associated with tight junctions were decreased, and the levels of inflammatory factors, such as IL-8, IL-6, and TNF-α, were dramatically increased in comparison to those of control animals. In vitro, TNF-α was shown to disrupt the continuity of proteins associated with tight junctions and to downregulate the expression of these proteins in bronchial epithelial cells. CONCLUSIONS: We found that cigarette smoke disrupted the nasal mucosal barrier, and the extent of the damage was correlated with the duration of cigarette smoke exposure. We showed that TNF-α can disrupt the continuity and attenuate the expression of tight junction proteins in human bronchial epithelial cells. Therefore, cigarette smoke may induce nasal epithelial barrier dysfunction through TNF-α.

Pathophysiology and management of Staphylococcus aureus in nasal polyp disease.

INTRODUCTION: Staphylococcus aureus (S. aureus) is a common pathogen that frequently colonizes the sinonasal cavity. Recent studies demonstrated the essential role of Staphylococcus aureus in the pathophysiology of uncontrolled severe chronic rhinosinusitis with nasal polyps (NP) by initiating an immune response to the germ and its products, resulting in type 2 inflammation. AREAS COVERED: This review aims to summarize the evidence for the role of S. aureus in the development of NP disease including S. aureus-related virulence factors, the pathophysiologic mechanisms used by S. aureus, and the synergistic effects of S. aureus and other pathogens. It also describes the current management of S. aureus associated with NPs as well as potential therapeutic strategies that are used in clinical practice. EXPERT OPINION: S. aureus is able to damage the nasal mucosal epithelial barrier, impair the clearance of the host immune system, and trigger adaptive and innate immune reactions which lead to the formation of inflammation and nasal polyp growth. Further studies should focus on the development of novel therapeutic strategies, such as biologics, bacteriophages, probiotics, and nanomedicine, which could be used to treat S. aureus and its immunological consequences in the future.

MiR-29a-3p promotes nasal epithelial barrier dysfunction via direct targeting of CTNNB1-VCL module in allergic rhinitis.

Allergic rhinitis (AR) is resulted from immunoglobulin E (IgE)-mediated reactions to inhaled allergens which elicit mucosal inflammation and impair epithelial barrier integrity. However, whether miR-29a-3p as an epigenetic regulator that can contribute to epithelial barrier dysfunction in the pathogenesis of AR, and its underlying mechanism remians unclear. In this study, we discovered that miR-29a-3p was upregulated in AR patients and preferentially expressed in epithelial and glandular cells of nasal mucosa. VCL and CTNNB1, candidate target genes of miR-29a-3p, were predicted with several databases, including miRDB, miRanda, microT-CDS and TargetScan, and were validated through dual-luciferase reporter assay system. These two proteins were strongly associated with adherens junction (AJ) and tight junction (TJ) of nasal mucosa epithelial cells, in which played vital roles in mucosal integrity and nasal epithelial barrier function stability. Results for HNEpC culture and in vitro treatment experiments showed that expression of VCL and CTNNB1 were inhibited by miR-29a-3p mimic and were enhanced by miR-29a-3p inhibitor. In OVA-induced AR mice model, the expression pattern of miR-29a-3p and its target genes (Vcl and Ctnnb1) were consistent with the aforementioned quantitative results in AR patients, and miR-29a-3p antagomir could partially alleviate the symptom of OVA-induced AR in mice, restoring mucosal integrity and paracellular barrier function. In conclusion, our findings indicate that miR-29a-3p targets CTNNB1 and VCL to regulate nasal epithelial permeability and barrier function integrity, which may serve as a potential novel therapeutic target for the treatment of AR.

Azithromycin Mechanisms of Action in CRS Include Epithelial Barrier Restoration and Type 1 Inflammation Reduction.

OBJECTIVE: Previous in vitro transcriptomic profiling suggests azithromycin exerts its effects in patients with chronic rhinosinusitis (CRS) via modulation of type 1 inflammation and restoration of epithelial barrier function. We wished to verify these postulated effects using in vitro models of epithelial repair and in vivo transcriptional profiling. STUDY DESIGN: Functional effects of azithromycin in CRS were verified using in vitro models of wounding. The mechanism of the effect of azithromycin was assessed in vivo using transcriptomic profiling. SETTING: Academic medical center. METHODS: Effects of azithromycin on the speed of epithelial repair were verified in a wounding model using primary nasal epithelial cells (pNEC) from CRS patients. Nasal brushings collected pre-and posttreatment during a placebo-controlled trial of azithromycin for CRS patients unresponsive to surgery underwent transcriptomic profiling to identify implicated pathways. RESULTS: Administration of azithromycin improved the wound healing rates in CRS pNECs and prevented the negative effect of Staphylococcus aureus on epithelial repair. In vivo, response to azithromycin was associated with downregulation in pathways of type 1 inflammation, and upregulation of pathways implicated in the restoration of the cell cycle. CONCLUSION: Restoration of healthy epithelial function may represent a major mode of action of azithromycin in CRS. In vitro models show enhanced epithelial repair, while in vivo transcriptomics shows downregulation of pathways type 1 inflammation accompanied by upregulation of DNA repair and cell-cycle pathways. The maximal effect in patients with high levels of type 1-enhanced inflammation suggests that azithromycin may represent a novel therapeutic option for surgery-unresponsive CRS patients.

Alpha-linolenic acid improves nasal mucosa epithelial barrier function in allergic rhinitis by arresting CD4+ T cell differentiation via IL-4Rα-JAK2-STAT3 pathway.

BACKGROUND: Allergic rhinitis (AR) defined as inflammation and tissue remodeling of the nasal mucosa in atopic individuals after allergen exposure. Alpha-linolenic acid [cis-9, cis-12, cis-15-octadecatrienoic acid (18:3)] (ALA) as dietary supplementation can reduce inflammation and allergic symptoms. OBJECTIVE: To evaluate the potential therapeutic effect and mechanism of ALA in AR mouse model. METHODS: Ovalbumin sensitized AR mouse model were challenged with oral ALA administration. Nasal symptoms, tissue pathology, immune cell infiltration and goblet cell hyperplasia were investigated. Levels of IgE, TNF-ß, IFN-γ, IL-2, IL-4, IL-5, IL-12, IL-13 and IL-25 were determined by ELISA in serum and nasal fluid. Quantitative RT-PCR and immunofluorescence were performed for occludin and zonula occludens-1 expression. CD3+CD4+ T-cells from peripheral blood and splenic lymphocytes were isolated and Th1/Th2 ratio were determined. Mouse naive CD4+ T cell were isolated and Th1/Th2 ratio, IL-4Rα expression, and IL5/IL13 secretion were determined. IL-4Rα-JAK2-STAT3 pathway change in AR mice were performed by western blot. RESULTS: Ovalbumin induced AR, nasal symptoms, pathological performance, IgE, and cytokine production. ALA treated mice showed reduced nasal symptoms, nasal inflammation, nasal septum thickening, goblet cell hyperplasia, and eosinophil infiltration. In serum and nasal fluid of ovalbumin challenged mice, ALA decreased IgE, IL-4 levels, and the increase of Th2-cells. ALA prevented the disruption of the epithelial cell barrier in ovalbumin-challenged AR mice. Simultaneously, ALA prevents IL-4 induced barrier disruption. ALA treatment of AR by affecting the differentiation stage of CD4+T cells and block IL-4Rα-JAK2-STAT3 pathway. CONCLUSION: This study suggests that ALA has the potential therapeutic effect to ovalbumin-induced AR. ALA can affect the differentiation stage of CD4+T cells and improve epithelial barrier functions through IL-4Rα-JAK2-STAT3 pathways. CLINICAL IMPLICATION: ALA might be considered as drug candidate for improving epithelial barrier function through Th1/Th2 ratio recovery in AR.

Study of nasal mucosa histopathological changes in patients with hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is an interstitial lung disease that develops after inhalation of a variety antigens in susceptible individuals. The nasal mucosa is constantly exposed to these antigens that can irritate the respiratory mucosa. So, the purpose of this study was to study nasal histopathological changes in order to identify any shared pathological changes between the upper airways and the well-known pathological features of HP. 40 HP patients diagnosed at the Chest Department, Kasr Alainy hospital following ATS/JRS/ALAT guidelines were included. Patients were subjected to thorough history, high-resolution computed tomography, spirometry, cough evaluation test (CET), sinonasal outcome test-22 (SNOT-22), sinonasal examination and nasal mucosal biopsy by an otolaryngologist under visualization by a rigid nasal endoscope. The mean age of the patients was 46.2 ± 13.5 (85% were females and 15% were males). 90% of patients presented with cough and the mean CET was 17.15 ± 5.59.77.5% of patients suffered from sinonasal symptoms and the mean SNOT-22 was 12.18 ± 3.8. There was a significant correlation between the burden of sinonasal symptoms represented by the SNOT-22 and the severity of the cough represented by CET (r 0.40, p 0.01). 87.5% of HP patients had chronic inflammation of the nasal mucosa with predominant lymphocytic infiltration in 72.5% of patients. 77.5% of HP patients had a high burden of sinonasal symptoms which is positively associated with cough severity. 72.5% of patients had predominately lymphocytic infiltration of the nasal mucosa.Trial registration: retrospectively registered, registration number is NCT05723796, date of registration 13/02/2023.

BMP-2 and IL-1ß as Markers of Nasal Mucosa Inflammation in Rhinosinusitis with Nasal Polyps.

Rhinosinusitis with nasal polyps is characterized by chronic inflammation and hyperplasia of the nasal mucosa. The key mechanism for polyp formation is the expression of molecules that regulate proliferation and inflammation. We studied immunolocalization of bone morphogenetic protein-2 (BMP-2) and IL-1ß in the nasal mucosa in patients aged 35-70 years (n=70, mean age 57.4±1.52 years). The typology of polyps was determined depending on the distribution of inflammatory cells, subepithelial edema, the presence of fibrosis and cysts. The immunolocalization of BMP-2 and IL-1ß had the same pattern in edematous, fibrous, and eosinophilic (allergic) polyps. Goblet and connective tissue cells, microvessels and terminal sections of the glands were positively stained. BMP-2+ and IL-1ß+ cells predominated in polyps of the eosinophilic type. BMP-2/IL-1ß can be considered as a specific marker of inflammatory remodeling of the nasal mucosa in refractory rhinosinusitis with nasal polyps.

IL-13-associated epithelial remodeling correlates with clinical severity in nasal polyposis.

BACKGROUND: Epithelial remodeling is a histopathologic feature of chronic inflammatory airway diseases including chronic rhinosinusitis (CRS). Cell-type shifts and their relationship to CRS endotypes and severity are incompletely described. OBJECTIVE: We sought to understand the relationship of epithelial cell remodeling to inflammatory endotypes and disease outcomes in CRS. METHODS: Using cell-type transcriptional signatures derived from epithelial single-cell sequencing, we analyzed bulk RNA-sequencing data from sinus epithelial brushings obtained from patients with CRS with and without nasal polyps in comparison to healthy controls. RESULTS: The airway epithelium in nasal polyposis displayed increased tuft cell transcripts and decreased ciliated cell transcripts along with an IL-13 activation signature. In contrast, CRS without polyps showed an IL-17 activation signature. IL-13 activation scores were associated with increased tuft cell, goblet cell, and mast cell scores and decreased ciliated cell scores. Furthermore, the IL-13 score was strongly associated with a previously reported activated ("polyp") tuft cell score and a prostaglandin E2 activation signature. The Lund-Mackay score, a computed tomographic metric of sinus opacification, correlated positively with activated tuft cell, mast cell, prostaglandin E2, and IL-13 signatures and negatively with ciliated cell transcriptional signatures. CONCLUSIONS: These results demonstrate that cell-type alterations and prostaglandin E2 stimulation are key components of IL-13-induced epithelial remodeling in nasal polyposis, whereas IL-17 signaling is more prominent in CRS without polyps, and that clinical severity correlates with the degree of IL-13-driven epithelial remodeling.

Role of Nasal Fibroblasts in Airway Remodeling of Chronic Rhinosinusitis: The Modulating Functions Reexamined.

Chronic rhinosinusitis (CRS) is a multifactorial inflammatory disease of the nose and sinuses that affects more than 10% of the adult population worldwide. Currently, CRS is classified into endotypes according to the inflammatory response (Th1, Th2, and Th17) or the distribution of immune cells in the mucosa (eosinophilic and non-eosinophilic). CRS induces mucosal tissue remodeling. Extracellular matrix (ECM) accumulation, fibrin deposition, edema, immune cell infiltration, and angiogenesis are observed in the stromal region. Conversely, epithelial-to-mesenchymal transition (EMT), goblet cell hyperplasia, and increased epithelial permeability, hyperplasia, and metaplasia are found in the epithelium. Fibroblasts synthesize collagen and ECM, which create a structural skeleton of tissue and play an important role in the wound-healing process. This review discusses recent knowledge regarding the modulation of tissue remodeling by nasal fibroblasts in CRS.

Blocking Notch signalling reverses miR-155-mediated inflammation in allergic rhinitis.

Although recent studies have shown that the Notch signalling pathway induces the production of Th2-related immune factors, the exact mechanism through which Notch signalling exacerbates allergic rhinitis (AR) remains unknown. To investigate the roles of Notch in AR, serum, nasal mucosa and spleen samples were isolated from BALB/c mice. Paraffin sections were stained with haematoxylin and eosin (H&E) or periodic acid-Schiff (PAS) to assess inflammation. Flow cytometry was performed to detect group 2 innate lymphoid cells (ILC2s) in the serum samples, and cytokine levels were measured by enzyme-linked immunosorbent assays (ELISAs). The mRNA expression levels of the Notch signalling pathway components and miR-155 were measured by quantitative real-time PCR (qRT-PCR). In addition, human nasal epithelial cells (HNEpCs) were cultured to investigate the functional consequences of Notch pathway inhibition. The findings demonstrated that symptomatology and pathology were substantially altered, and AR model mice were established. In vivo stimulation with ovalbumin (OVA) significantly increased the Th2-type immune responses and the expression of OVA-sIgE, IL-4, GATA3, NF-κB and miR-155. However, the Notch signalling pathway was significantly deteriorated in AR, and this effect was accompanied by reduced Notch1, Notch2, RBPj and Hes1 levels. These effects were abrogated by gamma-secretase inhibitor IX (DAPT) treatment, and DAPT inhibited the wound healing and proliferation of HNEpCs in a dose-dependent manner. Therefore, our results suggest that blocking the Notch pathway may alleviate miR-155-mediated inflammation via the regulation of immune homeostasis in AR.