Pericyte loss leads to microvessel remodeling and nasal polyp formation.

BACKGROUND: Chronic rhinosinusitis (CRS) may be caused by increased vascular permeability and inflammatory cell leakage in the subepithelial tissue. AIMS/OBJECTIVES: The aim of this study is to clarify the role of pericytes in tissue edema, microvessel dysfunction and vascular remodeling mechanisms in patients of CRS with nasal polyps (CRSwNP). MATERIAL AND METHODS: A total of 63 tissue samples were collected, including 42 CRSwNP samples (22 eosinophilic CRSwNP (eCRSwNP) and 20 non-eosinophilic CRSwNP (non-eCRSwNP) samples) and 21 samples of CRS without nasal polyps (CRSsNP). The samples were stained by immunofluorescence to measure microvessel density (MVD) and microvessel pericyte coverage index (MPI). RESULTS: We found that the albumin expression in the eCRSwNP group was significantly increased (p < .05). The MPI was significantly decreased (p <.05). There was a significant negative correlation between the MPI and the plasma albumin level (r=-0.82, p < .05). The MPI was negatively correlated with eosinophilic count (r=-0.77, p < .05). In the eCRSwNP group, the expressions of IL-4, Ang-1 and Ang-2 were increased compared with those in the control group. CONCLUSIONS AND SIGNIFICANCE: Pericyte loss may induce microvessel dysfunction, affect the development of interstitial edema and eosinophilic exosmosis in eCRSwNP, and contribute to the formation and maintenance of nasal polyps.

Recent advances in understanding the effects of T lymphocytes on mucosal barrier function in allergic rhinitis.

Allergic rhinitis is a non-infectious chronic inflammatory disease of the nasal mucosa that affects T cells and their cytokines. T cells play significant roles in the development of allergic inflammatory diseases by orchestrating mechanisms underlying innate and adaptive immunity. Although many studies on allergic rhinitis have focused on helper T cells, molecular makeup, and pathogenesis-related transduction pathways, pathological mechanisms have not yet been completely explored. Recent studies have suggested that T cell status may play an important role in the interaction between T cells and the nasal mucosal barrier in allergic rhinitis. This study aimed to explore the interactions between T cells and nasal mucosal barriers in allergic rhinitis and to review the therapeutic modalities of pertinent biological agents involving T cells.

A Decade of Pathogenesis Advances in Non-Type 2 Inflammatory Endotypes in Chronic Rhinosinusitis: 2012-2022.

Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by localized inflammation of the upper airways. CRS includes two main phenotypes, namely, CRS with nasal polyps and CRS without nasal polyps. The phenotype-based classification method cannot reflect the pathological mechanism. The endotype-based classification method has been paid more and more attention by researchers. It is mainly divided into type 2 and non-type 2 endotypes. The mechanism driving the pathogenesis of non-type 2 inflammation is currently unknown. In this review, the PubMed and Web of Science databases were searched to conduct a critical analysis of representative literature works on the pathogenesis of non-type 2 inflammation in CRS published in the past decade. This review summarizes the latest evidence that may lead to the pathogenesis of non-type 2 inflammation. It is the main method that analyzing the pathogenesis from the perspective of immunology. Genomics and proteomics technique provide new approaches to the study of the pathogenesis. Due to differences in race, environment, geography, and living habits, there are differences in the occurrence of non-type 2 inflammation, which increase the difficulty of understanding the pathogenesis of non-type 2 inflammation in CRS. Studies have confirmed that non-type 2 endotype is more common in Asian patients. The emergence of overlap and unclassified endotypes has promoted the study of heterogeneity in CRS. In addition, as the source of inflammatory cells and the initiation site of the inflammatory response, microvessels and microlymphatic vessels in the nasal mucosal subepithelial tissue participate in the inflammatory response and tissue remodeling. It is uncertain whether CRS patients affect the risk of infection with SARS-CoV-2. In addition, the pathophysiological mechanism of non-type 2 CRS combined with COVID-19 remains to be further studied, and it is worth considering how to select the befitting biologics for CRS patients with non-type 2 inflammation.

Clinical and upper airway characteristics of 3715 patients with the Omicron variant of SARS-Cov-2 in Changchun, China.

OBJECTIVE: The spread of the novel SARS-Cov-2 variant Omicron created a challenging public health situation in a number of countries. In March 2022, Omicron emerged in Changchun, China, and the number of patients infected rapidly increased. The prevalence of Omicron infection symptoms differs from that of Delta, with more upper airway clinical symptoms apparent. This study aimed to investigate the clinical and upper airway characteristics of the Omicron variant. MATERIALS AND METHODS: In this retrospective study, we collected data from participants in Changchun who had tested positive for Omicron with quantitative polymerase chain reaction between 10 March and 30 May 2022 using telephone interviews. The questionnaire was designed by the research team based on the number of upper airway symptoms using the visual analogue scale. We also considered age, sex, vaccination status, general symptoms, and cure period. RESULTS: A total of 3715 patients (2056 males and 1659 females) with mild COVID-19 from the Omicron variant were included. The patients had a mean age of 38.63 ( ± 13.97) years (range 2-86 years). The vaccine uptake rate was 91.33 % (8.66 %, 4.58 %, 65.33 %, and 21.43 % had received zero, one, two, and three doses, respectively). The incidence of upper airway symptoms, including throat and nasal symptoms, was 54.21 %. Throat symptoms were the most common during Omicron infection (49.12 %). Nasal symptoms were also common (20.08 %). The incidence of lower airway symptoms was 25.60 %, and gastrointestinal symptoms was 10.87 %. The incidence of general symptoms was 55.26 %. The cure period ranged from three to 37 days, with a mean of 10.24 ± 4.69 days. We compared the upper airway symptom severity for Omicron among different vaccination statuses and found no differences. CONCLUSIONS: The main clinical characteristics of the SARS-Cov-2 Omicron variant are upper airway symptoms and general symptoms. Fever remains the most common symptom, followed by mild dry cough. There was no association between Omicron infection and COVID-19 vaccines, and the vaccination status might have been ineffective against upper airway symptom severity by Omicron.

Mechanism of Lower Airway Hyperresponsiveness Induced by Allergic Rhinitis.

Allergic rhinitis is a global illness that puzzles many researchers. Most patients with allergic rhinitis also have lower airway hyperresponsiveness, and an allergic rhinitis attack can increase lower airway hyperresponsiveness. However, the mechanism of the effect of allergic rhinitis on the lower airways is still unclear. In this paper, the effects of allergic rhinitis on the lower airways are studied in terms of epidemiology, anatomy, pathophysiology, nasal function loss, inflammation drainage, nasobronchial reflex, and whole-body circulatory flow to determine the mechanism involved and provide ideas for future diagnosis, treatment, and experiments.

The Role of Small Extracellular Vesicles and MicroRNAs in the Diagnosis and Treatment of Allergic Rhinitis and Nasal Polyps.

Allergic rhinitis and nasal polyps are common otorhinolaryngological diseases. Small extracellular vesicles and microRNAs have recently become major research topics of interest due to their key regulatory roles in cancer, inflammation, and various diseases. Although very detailed and in-depth studies on the pathogenesis and pathophysiology of allergic rhinitis and nasal polyps have been conducted, few studies have assessed the regulatory effects of exosomes and microRNAs on allergic rhinitis and nasal polyps. This paper reviews the studies on small extracellular vesicles and microRNAs in allergic rhinitis and nasal polyps conducted in recent years and focuses on the regulation of small extracellular vesicles and microRNAs in allergic rhinitis and nasal polyps with the aim of providing insights for the future diagnosis and treatment of allergic rhinitis and nasal polyps.

Organoid Models for Salivary Gland Biology and Regenerative Medicine.

The salivary gland is composed of an elegant epithelial network that secrets saliva and maintains oral homeostasis. While cell lines and animal models furthered our understanding of salivary gland biology, they cannot replicate key aspects of the human salivary gland tissue, particularly the complex architecture and microenvironmental features that dictate salivary gland function. Organoid cultures provide an alternative system to recapitulate salivary gland tissue in vitro, and salivary gland organoids have been generated from pluripotent stem cells and adult stem/progenitor cells. In this review, we describe salivary gland organoids, the advances and limitations, and the promising potential for regenerative medicine.

Contribution of Regulatory T Cell Methylation Modifications to the Pathogenesis of Allergic Airway Diseases.

Regulatory T (Treg) cells are a subtype of CD4+ T cells that play a significant role in the protection from autoimmunity and the maintenance of immune tolerance via immune regulation. Epigenetic modifications of Treg cells (i.e., cytosine methylation at the promoter region of the transcription factor, Forkhead Box P3) have been found to be closely associated with allergic diseases, including allergic rhinitis, asthma, and food allergies. In this study, we highlighted the recent evidence on the contribution of epigenetic modifications in Treg cells to the pathogenesis of allergic diseases. Moreover, we also discussed directions for future clinical treatment approaches, with a particular emphasis on Treg cell-targeted therapies for allergic disorders.

Mesenchymal Stem Cell-Based Therapy for Allergic Rhinitis.

Allergic rhinitis (AR) is a prevalent disorder that causes a significant and often underestimated health burden for individuals and society. The current drug treatment cannot essentially deal with the regulation of the allergic reaction, while the allergic symptoms could be alleviated. Mesenchymal stem cells (MSCs) bear a variety of properties, such as the ability to differentiate into various cell lineages, to secrete soluble factors crucial for cell survival and proliferation, to migrate to the exact site of injury, and to modulate the immune response. Clinical studies have been extensively conducted in MSCs as the models for varieties of diseases such as neurological diseases. Due to their immunomodulatory properties, the MSCs have gradually been believed to become one of the promising strategies for AR treatments although so far the MSCs-mediated treatment for AR is still at animal experiments stage. Fully understanding the roles and mechanisms of MSCs immunomodulatory effects serves as the prerequisite that will be beneficial to the application of MSCs-based AR clinical treatment methods. In this review article, we highlighted the recent research advances and give a brief perspective in the future study of the MSCs-mediated therapeutic application in AR treatments.

Chinese Society of Allergy and Chinese Society of Otorhinolaryngology-Head and Neck Surgery Guideline for Chronic Rhinosinusitis.

The current document is based on a consensus reached by a panel of experts from the Chinese Society of Allergy and the Chinese Society of Otorhinolaryngology-Head and Neck Surgery, Rhinology Group. Chronic rhinosinusitis (CRS) affects approximately 8% of Chinese adults. The inflammatory and remodeling mechanisms of CRS in the Chinese population differ from those observed in the populations of European descent. Recently, precision medicine has been used to treat inflammation by targeting key biomarkers that are involved in the process. However, there are no CRS guidelines or a consensus available from China that can be shared with the international academia. The guidelines presented in this paper cover the epidemiology, economic burden, genetics and epigenetics, mechanisms, phenotypes and endotypes, diagnosis and differential diagnosis, management, and the current status of CRS in China. These guidelines-with a focus on China-will improve the abilities of clinical and medical staff during the treatment of CRS. Additionally, they will help international agencies in improving the verification of CRS endotypes, mapping of eosinophilic shifts, the identification of suitable biomarkers for endotyping, and predicting responses to therapies. In conclusion, these guidelines will help select therapies, such as pharmacotherapy, surgical approaches and innovative biotherapeutics, which are tailored to each of the individual CRS endotypes.

P-FN12, an H4R-Based Epitope Vaccine Screened by Phage Display, Regulates the Th1/Th2 Balance in Rat Allergic Rhinitis.

Allergic rhinitis (AR) involves antigen-specific immune-inflammation of the nasal mucosa. Classical therapy for AR targets the histamine pathway, e.g., histamine receptor blockers. Histamine H4 receptor (H4R) was suggested as a novel therapeutic target due to its wide expression on almost all immune-related cells. A 12-mer random peptide library was used to select the specific epitope of the H4R. The phage clone showing the highest degree of activation was verified and translated to the corresponding peptide. The peptide FNKWMDCLSVTH, designated as P-FN12, was bound by H4R monoclonal antibody (mcAb) with high affinity. Moreover, the P-FN12 + CTB@Lipo-formulated vaccine, used as nasal drops, decreased allergic symptoms such as sneezing and nasal rubbing in a rat model. The level of ovalbumin (OVA)-specific immunoglobulin E (IgE) decreased significantly after vaccine administration. It also elicited increased levels of interferon (IFN)-γ and interleukin-2 (IL-2) but a decreased level of IL-4, and it elevated the T helper type 1 (Th1):T helper type 2 (Th2) cell ratio in peripheral blood mononuclear cell cultures. Our results indicated that the reduction of allergic inflammation by P-FN12-based vaccine was related to a decrease in production of OVA-specific IgE, Th2 immunity, and tissue eosinophilia. P-FN12 + CTB@Lipo is a promising vaccine that could suppress Th2 response and enhance the induction of Th1 cells in an AR model.

Hypoxia regulates IL-17A secretion from nasal polyp epithelial cells.

Hypoxia creates a microenvironment conducive to polypogenesis by regulating immune responses of the nasal polyp (NP) epithelium. We explored the immunocompetence of NP and control epithelial cells in response to hypoxia, to investigate potential relationships with polypogenesis. Three groups of tissue samples were collected: inferior turbinate (IT)and NP from individuals with chronic rhinosinusitis with NPs (CRSwNP), and control IT. A positive relationship was detected between HIF1α, HIF2α protein expression in epithelial cells and endoscope score in NP samples, while there was a negative correlation between HIF1α expression and degree of eosinophil infiltration. Epithelial IL-17A expression was lower in NPs than in IT samples from either controls or patients with CRSwNP. Primary human nasal epithelial cells were cultured under hypoxic or normoxic conditions. Enzyme-linked immunosorbent assays demonstrated decreased IL-17A expression upon prolonged exposure to hypoxia in both IT and NP samples from patients with CRSwNP, while IL-17A increased in control IT epithelial cells; correlation and time-dependency were observed between HIF1α and IL-17A expression in both IT and NP samples from patients with CRSwNP. These observations suggest that hypoxia is involved in the pathogenesis of NPs through regulation of IL-17A secretion and HIF1α and HIF2α expression in the NP epithelium.

Correlation of Serum ß-Endorphin and the Quality of Life in Allergic Rhinitis.

Background. Allergic rhinitis (AR) significantly impairs the quality of life of the patients; however, a questionnaire alone is an insufficient and subjective measure of this condition. Obtaining an objective clinical assessment of the level of impairment will be valuable for its treatment. ß-Endorphin is one of the most important mediators of both mental state and specific immunity. Thus, we investigated the possibility of using ß-endorphin as a biomarker for evaluating the impairment level in AR. Methods. This study included 48 patients with AR and 32 healthy volunteers. The serum ß-endorphin level was determined by enzyme immunoassay, and the serum-specific IgE and total IgE levels were determined by immunoblot assay. The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) was used to assess the impairment level in the symptom duration. Results. The ß-endorphin concentration was significantly decreased in AR patients compared to the healthy controls (p = 0.000, p < 0.05). There was significant negative correlation between the impairment level and serum ß-endorphin level (correlation coefficient: -0.468; p = 0.001; p < 0.05), but there was no association between the serum ß-endorphin and total IgE levels (p = 0.947, p > 0.05). Conclusion. ß-Endorphin is a systemic biomarker that has the potential to assess the impairment level in AR and may therefore be a novel therapeutic target for the treatment of AR.

[The inhibiting role of recombinant plasmid PGCsi-AQP1 on laryngeal carcinoma in vivo].

OBJECTIVE: To construct a kind of recombinant plasmid PGCsi-AQP1 delivery with DOPC and explore the inhibit effect of laryngeal carcinoma by RNAi targeting AQP1 in vivo. METHOD: Male BALB/c mice, 6 weeks of age transplanted with laryngeal carcinoma cell line Hep-2, four groups were divided randomly: Tail vein injection group (TVIG), Carcinoma around injection group (CAIG), negative control group (NCG) and blank control group (BCG). The recombinant plasmid PGCsi-AQP1 delivery with DOPC were inject into tail vein or surrounding tumor. HE pathological slides and tumor size were observed and inhibitory rate was figured up. The level of AQP1 protein expression and high microvessel density were detected by Immunohistochemical staining (IHC). RESULT: We constructed BALB/c mice models of laryngeal carcinoma successfully (1) HE staining: cell putrescence, nuclear pyknosis and apoptotic bodies were more in the tumor tissues of experimental groups than two control groups. (2) The total volumes of tumor in experimental group were both smaller than in two control groups (P < 0.01). The inhibition rate of TVIG and CAIG were 52.4% and 53.5% respectively and there was no significant difference (P > 0.05). (3) IHC: the AQP1 positive cells and microvessel density in TVIG and CAIG were both less than in two control groups (P < 0.01). CONCLUSION: Neutral lipsomes DOPC could help carriaging the recombinant plasmid PGCsi-AQP1 to tumor and then play an inhibit role in laryngeal carcinoma tissue by RNAi targeting AQP1 in vivo.

The expression and significance of immunoglobulin free light chain in the patients with allergic rhinitis and nonallergic rhinitis.

BACKGROUND: Inflammation has been shown to be an integral component of allergic rhinitis (AR). However, there is no noteworthy debate regarding this fact in nonallergic rhinitis (NAR). Some studies have suggested that exclusion of inflammation is indicative of NAR and other studies have indicated that most of the NAR patients have some degree of inflammation. Recently, it has been shown that the level of immunoglobulin free light chains (IgFLCs) in serum is increased in some autoimmune diseases and airway inflammation. This study was designed to show whether IgFLC is associated with non-IgE-mediated rhinitis to reveal the relationship between the expression of IgFLC and activation of mast cells and eosinophils. METHODS: Thirty patients with IgE-mediated AR and 30 patients with NAR and 30 healthy persons as control were involved this study. The total IgE, IgFLC, eosinophil cationic protein (ECP) and mast cell tryptase (MCT) in serum, and nasal secretions were assayed, respectively. For identifying the expression cells of IgFLC in nasal mucosa, the immunohistochemical (IHC) staining for kappa-FLC, gamma-FLC, ECP, and MCT were performed on 30 specimens. Meanwhile, the mRNA expression of kappa-FLC, gamma-FLC, and MCT was determined by real-time quantitative polymerase chain reaction. RESULTS: IgFLCs (kappa/lambda) levels in serum and nasal secretion were significantly increased in AR patients and NAR patients. The ECP and MCT levels in serum and nasal secretion were significantly enhanced in AR and NAR patients when compared with healthy control subjects (p < 0.01). There was a positive correlation between IgFLC (kappa/lambda) and MCT in nasal secretion of patients with NAR, but only IgFLC (kappa-FLC was associated with MCT in AR. There was no correlation between IgFLC and ECP in nasal secretion. In serum expression level, there was a positive correlation between IgFLC (kappa) and ECP in AR or IgFLCs (lambda) and ECP in NAR. IHC staining showed that FLC(+) cells were significantly increased in AR and NAR mucosa, kappa-FLC was mainly expressed in epithelial cells, and lambda-FLC was mainly expressed in subepithelial cells. Double immunofluorescence staining showed that the expression of lambda-FLC was mainly localized in mast cells in NAR nasal mucosa (45%). CONCLUSION: These findings suggest strongly that IgFLC may play an important role in inducing local nasal mucosa inflammation especially those in AR and NAR.

[Efficacy and safety analysis with standardized mite allergen subcutaneous immunotherapy in 90 patients with allergic rhinitis].

OBJECTIVE: To evaluate the three-year efficacy and safety with standardized dust mite subcutaneous immunotherapy in patients with allergic rhinitis. METHODS: Ninety patients who were diagnosed as allergic to mite by skin prick test and serum IgE were include in the standardized allergen-specific dose-escalation regimen. Nasal symptom score (0-3) were collected before treatment and three years after treatment; VAS (visual analogue scale, 0-10) of all nasal symptoms and drug use score were collected every four months; frequency of local and systemic reactions were recorded in the duration of dose escalation and maintenance. RESULTS: Nasal blocking, sneeze, rhinorrhea and nasal itch were significantly improved after 3 years treatment (before treatment: 2[2;3], 2[2;3], 2[2;3], 2[1;2] ; after treatment: all were 0[0;0]; Z value were -8.310, -8.408, -8.377, -8.287, all P were 0.000). VAS of all nasal symptoms and drug use score decreased dramatically after escalation period (before treatment: 8.00[7.00;8.85], 2.00[1.50;2.00]; after treatment: 1.00[1.00;1.50], 0 [0;0]; Z value were -8.287, -8.248, P value 0.086, 0.744), and maintained afterwards (F value were 2.483, 0.296; P value were 0.086, 0.744). Ninety-eight case times (64.47%) local reactions mainly happened in maintenance period; the frequency of systemic reactions was 2.54%. CONCLUSION: The standardized specific allergen immunotherapy for allergic rhinitis is safe and effective.