Airways epithelial exposure to Streptococcus pneumoniae in the presence of the alarmin IL-33 induces a novel subset of pro-inflammatory ILC2s promoting a mixed inflammatory response.

BACKGROUND: We have previously shown that asthma-like airways inflammation may be induced by topical exposure to respiratory tract pathogens such as S. pneumoniae (SP) in concert with epithelial alarmins such as IL-33. Details of the pathogenesis of this murine surrogate remain however unexplored. METHODS: Airways inflammation was induced by repeated, intranasal exposure of Il-4-/-, Rag1-/- and Rag2-/-Il2rg-/- mice (in which B lymphocyte IgE switching, adaptive and innate immunity are respectively ablated) as well as wild type mice to inactivated SP, IL-33 or both. Airways pathological changes were analysed, and the subsets and functions of locally accumulated ILC2s investigated by single cell RNA sequencing and flow cytometry. RESULTS: In the presence of IL-33, repeated exposure of the airways to inactivated SP caused marked eosinophil- and neutrophil-rich inflammation and local accumulation of ILC2s, which was retained in the Il-4-/- and Rag1-/- deficient mice but abolished in the Rag2-/-Il2rg-/- mice, an effect partly reversed by adoptive transfer of ILC2s. Single cell sequencing analysis of ILC2s recruited following SP and IL-33 exposure revealed a Klrg1+Ly6a+subset, expressing particularly elevated quantities of the pro-inflammatory cytokine IL-6, type 2 cytokines (IL-5 and IL-13) and MHC class II molecules, promoting type 2 inflammation as well as involved in neutrophil-mediated inflammatory responses. CONCLUSION: Local accumulation of KLRG1+Ly6a+ ILC2s in the lung tissue is a critical aspect of the pathogenesis of airways eosinophilic and neutrophil-rich inflammation induced by repeated exposure to SP in the presence of the epithelial alarmin IL-33.

The role of histone deacetylases in inflammatory respiratory diseases: an update.

INTRODUCTION: Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysine residues of histones and other proteins, generally leading to a closed chromosomal configuration and transcriptional repression. Different HDACs have distinct substrate specificities and functions in different biological processes. Accumulating evidence indicates that HDACs play a key role in the pathogenesis of multiple respiratory diseases. AREAS COVERED: After an extensive search of the PubMed database, Web of Science and ClinicalTrials.gov, covering the period from 1992 to 2024, this review summarizes recent advances in understanding the role of HDACs in inflammatory respiratory diseases, including allergic rhinitis (AR), chronic rhinosinusitis (CRS), asthma and chronic obstructive pulmonary disease (COPD). We also examine recent progress on the efficacy and potential use of histone deacetylase inhibitors (HDACi) for the treatment of these diseases. EXPERT OPINION: Available data indicate that HDACs play an important role in the development of common inflammatory respiratory diseases, and HDACi have shown promise as treatments for these diseases. However, the exact roles and underlying mechanisms of specific HDACs in disease pathogenesis require further study. Additional work is necessary to develop novel potent HDACi with high isoform selectivity.

Decreased histone expression in chronic rhinosinusitis with nasal polyps.

Background: Histones have been associated with human diseases. However, the implication of extranuclear histone proteins and their potential mechanism in the pathophysiology of chronic rhinosinusitis (CRS) have not been thoroughly investigated. This study was designed to evaluate the role of histones in patients with CRS by comparing histone expression between patients and controls. Methods: Nasal polyp (NP) tissues were obtained, and their comprehensive gene expression profiles were investigated by microarray analysis. Differences in expression were verified by reverse transcriptase polymerase chain reaction and immunohistochemical staining. Cell culture and flow cytometry were used to evaluate the role of histones in the pathogenesis of polyps. Results: Significant differences in the microarray analysis were observed between the patient and control groups (P < 0.01). It was found by flow cytometry that the histone (H2BK) can promote cell apoptosis in NPs. Conclusion: Our results indicate that reduced expression of H2BK may contribute to the imbalance process of cell proliferation and apoptosis in CRS with NP.

Comparison of clinical traits for seasonal and perennial allergic rhinitis during allergen exposure.

Background: Allergic rhinitis (AR) is traditionally subdivided into seasonal AR (SAR) and perennial AR (PAR) according to the type of allergen and the occurrence of symptoms during the year. There are currently no reports on the comparison of trait profiles for SAR and PAR during the allergen exposure. Purpose: The purpose of this study was to analyze the clinical characteristics of SAR and PAR during respective allergen exposure periods to provide valuable information for the development of treatment strategies. Methods: This study was performed between August 1, 2021, and January 31, 2022, in the Department of Allergy, Beijing Tongren Hospital. We continuously included diagnosed SAR and PAR outpatients who volunteered to participate in the survey. A questionnaire with regard to medical history, severity of symptoms, and diagnosis and treatment status was collected. Results: A total of 296 patients with SAR and 448 with PAR were finally recruited. Patients with SAR had more severe rhinorrhea compared with patients with PAR (p < 0.001), whereas there was no statistically significant difference in the severity of itching, sneezing, and congestion between the two entities (p ≥ 0.05). Both the gritty and watery eyes of patients with SAR were noticeably more severe than those of patients with PAR (PTotal Ocular Symptom Score [PTOSS] < 0.001). AR symptom severity is mainly associated with the comorbid allergic conjunctivitis (odds ratio 1.94 [95% confidence interval, 1.21-3.09]). SAR patients and PAR patients show no statistically significant differences in terms of their frequency of visits, annual expenditure, and choice of medication treatment for AR (p > 0.05). The overall control under standard medication of both patients with PAR and those with SAR is not ideal, especially in SAR. Conclusion: The current cross-sectional study demonstrated that the patients with SAR exhibited more severe overall clinical symptoms than those with PAR, especially nasal rhinorrhea and gritty and watery eyes. Both of the two disease entities have poor control under standardized medication treatment, especially in SAR. Further multicenter longitudinal studies that involve larger and more diverse populations should be conducted to provide a more accurate and comprehensive understanding of the condition.

CircHIF1A induces cetuximab resistance in colorectal cancer by promoting HIF1α-mediated glycometabolism alteration.

Epidermal growth factor receptor (EGFR)-targeted therapy is an important treatment for RAS wild-type metastatic colorectal cancer (mCRC), but the resistance mechanism remains unclear. Here, the differential expression of circRNAs between Cetuximab sensitive and resistant cell lines was analyzed using whole-transcriptome sequencing. We identified that the expression of circHIF1A was significantly higher in LIM1215-R than in LIM1215. When treated with Cetuximab, downregulation of circHIF1A level weakened the proliferation and clonal formation ability of LIM1215-R, caused more cells to enter G0-G1 phase, and significantly reduced the basal respiration, ATP production, and maximal respiration, as well as the glycolytic capacity and glycolytic reserve. The response rate and prognosis of circHIF1A-positive patients were inferior to those of negative patients. Mechanistically, circHIF1A can upregulate the level of hypoxia-inducible factor 1 A (HIF1A) by competitively binding to miR-361-5p, inducing the overexpression of enzymes such as glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). In a xenograft model, inhibition of circHIF1A expression increased the sensitivity to Cetuximab treatment. In conclusion, circHIF1A can promote HIF1α-mediated glycometabolism alteration to induce Cetuximab resistance in CRC. It has the potential to become a screening indicator for the Cetuximab beneficial population in mCRC and a new therapeutic target for enhancing treatment efficacy.

Metabolomic profiles predict clinical severity in patients with obstructive sleep apnea hypopnea syndrome.

STUDY OBJECTIVES: Obstructive sleep apnea hypopnea syndrome (OSAHS) poses a significant health hazard, as intermittent hypoxia inflicts damage throughout the body and is considered a critical risk factor for metabolic disorders. The aim of this study was to establish a metabolic profile for patients with OSAHS using nontargeted metabolomics detection techniques, providing a basis for OSAHS diagnosis and novel biological marker identification. METHODS: Forty-five patients with OSAHS composed the OSAHS group, and 44 healthy volunteers composed the control group. Nontargeted metabolomics technology was used to analyze participants' urinary metabolites. Differentially abundant metabolites were screened and correlated through hierarchical clustering analysis. We constructed a composite metabolite diagnostic model using a random forest model. Simultaneously, we analyzed the relationships between 20 metabolites involved in model construction and OSAHS severity. RESULTS: The urinary metabolomics pattern of the OSAHS group exhibited significant changes, demonstrating noticeable differences in metabolic products. Urinary metabolite analysis revealed differences between the mild-moderate OSAHS and severe OSAHS groups. The composite metabolite model constructed in this study demonstrated excellent diagnostic performance not only in distinguishing healthy control participants from patients with mild-moderate OSAHS (AUC = 0.78) and patients with severe OSAHS (AUC = 0.78), but also in discriminating between patients with mild-moderate and severe OSAHS (AUC = 0.71). CONCLUSIONS: This study comprehensively analyzed the urinary metabolomic characteristics of patients with OSAHS. The established composite metabolite model provides robust support for OSAHS diagnosis and severity assessment. Twenty metabolites associated with OSAHS disease severity offer a new perspective for diagnosis.

First-In-Human Study on Pharmacokinetics, Safety, and Tolerability of Single and Multiple Escalating Doses of PA9159 Nasal Spray, a Highly Potent Glucocorticoid in Healthy Chinese Volunteers.

OBJECTIVE: PA9159 (previously named VSG159) is a structurally novel and highly potent glucocorticoid that plays a role in the late development of autoimmune and inflammatory diseases. The current first-in-human ascending-dose study of the PA9159 nasal spray was conducted in healthy Chinese volunteers to evaluate its pharmacokinetics, safety, and tolerability. In addition, the effects of PA9159 on serum cortisol secretion were investigated. METHODS: This was a double-blinded, randomized, placebo-controlled clinical study that included four single-dose groups in the single ascending dose cohort (SAD) and two multiple-dose groups in the multiple ascending dose cohort (MAD), with dose ranges of 10-80 µg and 20-40 µg, respectively. PA9159 was administered bilaterally via nasal spray once only or once daily for seven days. Pharmacokinetic, safety, and tolerability profiles were evaluated. RESULTS: A total of 60 participants completed the study. PA9159 doses of up to 80 µg in the SAD and up to 40 µg in the MAD were shown to be safe and tolerable. The most common treatment-related AEs were mild and transient local nasal AEs. Morning serum cortisol levels approximately remained unchanged in both the single-dose and multiple-dose groups. PA9159 was quantified in 41.8% (368/880) of the samples in all treatment groups, including 25.2% (105/416) of the SAD and 56.7% (263/464) of the MAD. The majority (>80.0%) of PA9159 plasma concentrations ranged from 0.5 to 2 pg/mL in determined samples. The mean AUC0-t of PA9159 in the SAD was 0.91, 1.39±0.68, 11.40±9.91, and 46.30±25.80 h*pg/mL in the 10 to 80 ug single group. The mean terminal half-life time (t1/2) was 8.43 h and 8.97±2.28 h in 40 ug and 80 ug single group, respectively. The mean AUCss of PA9159 in the MAD was 31.70±7.04, 44.20±20.60 h*pg /mL, and the t1/2 was 16.00±4.18 h, 21.20±10.20 h in the 20 ug and 40 ug multiple groups, respectively. The median Tmax was approximately 6 hours in both the SAD and MAD cohorts. CONCLUSIONS: The PA9159 nasal spray was generally safe and well tolerated, and the effects of PA9159 on serum cortisol levels were limited. The plasma concentration and systemic exposure to PA9159 were very low. These findings support the necessity for further clinical studies on PA9159 nasal spray in patients suffering from allergic rhinitis.

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.

Anti-thymic stromal lymphopoietin monoclonal antibody in patients with chronic rhinosinusitis with nasal polyps (DUBHE): Rationale and design of a multicenter, randomized, double-blind, placebo-controlled study.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) has a complex pathogenesis and is difficult to treat, which brings a huge economic burden to society. Despite all the progress in the treatment of CRSwNP, some patients with CRSwNP still experience recurrence. Therefore, there is an urgent need to develop novel drugs and treatments for CRSwNP. Thymic stromal lymphopoietin (TSLP) is produced by epithelial cells and mediates type 2 and nontype 2 inflammation through various downstream cellular immune and inflammatory pathways. Anti-TSLP treatment with tezepelumab has been proven to be effective in treating patients with uncontrolled asthma, regardless of their peripheral blood eosinophil levels being low or high. However, there is no relevant research on the usage of anti-TSLP monoclonal antibodies for the treatment of uncontrolled CRSwNP. Objective: This is the first phase Ib/IIa study for subjects with uncontrolled CRSwNP, aiming to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary efficacy of multiple ascending doses (MAD) of anti-TSLP monoclonal antibody. Methods: The DUBHE is a multicenter, randomized, double-blind, placebo-controlled, phase Ib/IIa clinical study. The study will be composed of 3 periods: a screening/run-in period of 4 weeks, a treatment period of 52 weeks (16 weeks of double-blind treatment period +36 weeks of open-label treatment period), and a safety follow-up period of 12 weeks. No more than 113 subjects with uncontrolled CRSwNP will be divided into 4 groups to receive different doses of CM326 or placebo treatments (55 mg every two weeks [Q2W] group, 110 mg Q2W group, 220 mg Q2W group, and 220 mg every four weeks [Q4W] group). Enrolled patients will be stratified by tissue eosinophil count (TEC). Results: The safety of the monoclonal antibody that targets TSLP in uncontrolled CRSwNP and its preliminary efficacy at 16 weeks of treatment. Conclusion: In this study, for the first time, the safety and preliminary efficacy of MAD of CM326 will be verified. The efficacy of CM326 in patients with eosinophilic CRSwNP (TEC ≥55/high power field [HPF]), as well as noneosinophilic CRSwNP (TEC <55/HPF) will be testified. Trial registration: NCT05324137.

Efficacy and safety of stapokibart (CM310) in uncontrolled seasonal allergic rhinitis (MERAK): an investigator-initiated, placebo-controlled, randomised, double-blind, phase 2 trial.

Background: There is no trial to assess the benefits of periodically using biologics during the pollen season in patients with uncontrolled seasonal allergic rhinitis (SAR), who have moderate-to-severe symptoms even after standard-of-care. This trial aimed to evaluate the efficacy and safety of the add-on administration of stapokibart, a humanised monoclonal antibody that targets interleukin-4 receptor alpha, in patients with uncontrolled SAR. Methods: In this investigator-initiated, randomised, double-blind, placebo-controlled trial, eligible patients received either stapokibart 600-300 mg weekly (QW), every 2 weeks (Q2W), or placebo QW for 4 weeks. All patients were given mometasone furoate nasal spray and loratadine throughout the trial. The primary endpoint was the mean change from baseline in daily reflective total nasal symptom score (rTNSS) during 2-week treatment. Secondary efficacy outcomes included: the mean change from baseline in daily rTNSS during 4-week treatment; the mean changes and the mean percentage changes from baseline during 2-week and 4-week treatment in 1) daily rTNSS and reflective total ocular symptom score (rTOSS), 2) morning (AM)/evening (PM) rTNSS and rTOSS, 3) AM instantaneous total nasal symptom score (iTNSS) and instantaneous total ocular symptom score (iTOSS), 4) individual nasal and ocular symptoms; the change from baseline in Rhinoconjunctivitis Quality of-Life Questionnaire score during 4-week treatment. Exploratory endpoints included the change of prespecified markers related to type 2 inflammation pre- and post-treatment. Safety, immunogenicity, and pharmacokinetics were also evaluated. This study is registered with www.clinicaltrials.gov (NCT05470647). Findings: Between August 17, 2022, and December 28, 2022, 92 patients with uncontrolled SAR were enrolled from 4 centres in China and randomly assigned to receive stapokibart 600-300 mg QW (n = 31), stapokibart 600-300 mg Q2W (n = 30), or placebo QW (n = 31), of whom 86 (93%) completed the study. Both stapokibart Q2W and QW did not significantly improve mean change from baseline in daily rTNSS compared with placebo in 2 weeks. The least-squares (LS) mean differences (97.5% confidence interval [CI]) compared with placebo were -1.0 (-2.3, 0.2) in stapokibart Q2W group (p = 0.065) and -0.2 (-1.5, 1.0) in stapokibart QW group (p = 0.67). For the secondary outcomes, compared with placebo, stapokibart Q2W presented significant improvements in the mean percentage change from baseline in daily rTNSS in 2 weeks (LS mean difference -12.9%, 95% CI -25.3%, -0.4%, p = 0.043), as well as AM iTNSS over 2 weeks (LS mean difference -17.4%, 95% CI -31.0%, -3.8%, p = 0.013) and 4 weeks (LS mean difference -15.4%, 95% CI -29.0%, -1.9%, p = 0.026). Additionally, the nasal congestion score was significantly lower in stapokibart Q2W than placebo during 2-week (LS mean difference -0.4, 95% CI -0.7, -0.1, p = 0.014) and 4-week (LS mean difference -0.4, 95% CI -0.7, -0.04, p = 0.028) treatment. Treatment-emergent adverse events (TEAEs) occurred in 48% (15/31), 33% (10/30), and 61% (19/31) of patients receiving stapokibart QW, Q2W, and placebo, respectively. Most reported TEAEs were sinus bradycardia, hyperlipidaemia, and blood uric acid increased. Interpretation: In this phase 2 trial, both stapokibart regimens had an acceptable safety and tolerability profile but did not significantly improve daily rTNSS in patients with uncontrolled SAR. The efficacy of stapokibart in patients with uncontrolled SAR is being further investigated in ongoing phase 3 trials (clinicaltrials.gov, NCT05908032). Funding: Ministry of Science and Technology of the People's Republic of China; Ministry of Education of the People's Republic of China; National Natural Science Foundation of China; Chinese Academy of Medical Sciences.

Expert consensus on odontogenic maxillary sinusitis multi-disciplinary treatment.

ABSTARCT: Odontogenic maxillary sinusitis (OMS) is a subtype of maxillary sinusitis (MS). It is actually inflammation of the maxillary sinus that secondary to adjacent infectious maxillary dental lesion. Due to the lack of unique clinical features, OMS is difficult to distinguish from other types of rhinosinusitis. Besides, the characteristic infectious pathogeny of OMS makes it is resistant to conventional therapies of rhinosinusitis. Its current diagnosis and treatment are thus facing great difficulties. The multi-disciplinary cooperation between otolaryngologists and dentists is absolutely urgent to settle these questions and to acquire standardized diagnostic and treatment regimen for OMS. However, this disease has actually received little attention and has been underrepresented by relatively low publication volume and quality. Based on systematically reviewed literature and practical experiences of expert members, our consensus focuses on characteristics, symptoms, classification and diagnosis of OMS, and further put forward multi-disciplinary treatment decisions for OMS, as well as the common treatment complications and relative managements. This consensus aims to increase attention to OMS, and optimize the clinical diagnosis and decision-making of OMS, which finally provides evidence-based options for OMS clinical management.

The mucosal concept in chronic rhinosinusitis: Focus on the epithelial barrier.

Chronic rhinosinusitis (CRS) is a common chronic nasal cavity and sinus disease affecting a growing number of individuals worldwide. Recent advances have shifted our understanding of CRS pathophysiology from a physical obstruction model of ventilation and drainage to a mucosal concept that recognizes the complexities of mucosal immunologic variations and cellular aberrations. A growing number of studies have demonstrated the alteration of the epithelial barrier during inflammatory states. Therefore, the current review has focused on the crucial role of epithelial cells within this mucosal framework in CRS, detailing the perturbed epithelial homeostasis, impaired epithelial cell barrier, dysregulated epithelial cell repair processes, and enhanced interactions between epithelial cells and immune cells. Notably, the utilization of novel technologies, such as single-cell transcriptomics, has revealed the novel functions of epithelial barriers, such as inflammatory memory and neuroendocrine functions. Therefore, this review also emphasizes the importance of epithelial inflammatory memory and the necessity of further investigations into neuroendocrine epithelial cells and neurogenic inflammation in CRS. We conclude by contemplating the prospective benefits of epithelial cell-oriented biological treatments, which are currently under investigation in rigorous randomized, double-blind clinical trials in patients with CRS with nasal polyps.

Microvessel barrier dysfunction in sinonasal inverted papilloma-associated squamous cell carcinoma and its manifestation in dynamic contrast-enhanced MRI.

BACKGROUND: To date, an effective means to preoperatively predict the malignant transformation of sinonasal inverted papilloma (SIP) remains lacking due to similarities in clinical appearance. This study aimed to retrospectively evaluate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters and microvessel structure in tumors with histologically confirmed SIP and inverted papilloma-associated squamous cell carcinoma (IP-SCC), as well as correlate DCE-MRI findings with angiogenesis biomarkers. METHODS: Absolute quantitative DCE-MRI parameters (Ktrans , Kep , Ve ) based on the Tofts model and model-free semi-quantitative indices (Tpeak , WR, MaxSlope) of SIP (n = 22) and IP-SCC (n = 20) were investigated. Regions of interest (ROIs) were oriented according to the tumor subsites in the surgical records. Micro-vessel density (MVD) counts and tight junction protein (claudin-5) expression were evaluated in tumor specimens obtained during surgery. Differences in the above data were compared between the two groups. Correlations between DCE-MRI parameters and angiogenic biomarkers were analyzed. RESULTS: Compared with SIP specimens, IP-SCC specimens were characterized by a significantly higher MVD and a leakier microvessel barrier. The values of Tpeak and Ve were significantly higher for SIP than those for IP-SCC, whereas WR, MaxSlope, and Kep were significantly lower, indicating early enhancement and a faster dispersion model in IP-SCC. MVD was positively correlated with WR and Kep and negatively correlated with Tpeak . Tpeak was slightly positively correlated to claudin-5 expression. CONCLUSION: DCE-MRI can serve as a noninvasive biomarker of angiogenesis in the malignant transformation from SIP to IP-SCC. DCE-MRI may assist in the differentiation of malignancies and treatment selection.

Matrix metalloproteinases in chronic rhinosinusitis.

INTRODUCTION: Matrix metalloproteinases (MMPs) are a group of enzymes that are essential in maintaining extracellular matrix (ECM) homeostasis, regulating inflammation and tissue remodeling. In chronic rhinosinusitis (CRS), the overexpression of certain MMPs can contribute to chronic nasal tissue inflammation, ECM remodeling, and tissue repair. AREAS COVERED: This review provides a comprehensive overview of the biological characteristics and functions of the MMP family, particularly focusing on the expression and activity of MMPs in patients with CRS, and delves into their role in the pathogenesis of CRS and their potential as therapeutic targets. EXPERT OPINION: MMPs are important in tissue remodeling and have been implicated in the pathophysiology of CRS. Previous studies have shown that the expression of MMPs is upregulated in the nasal mucosa of patients with CRS and positively correlates with the severity of CRS. However, there is still a large gap in the research content of MMP in CRS, and the specific expression and pathogenic mechanism of MMP still need to be clarified. The significance and value of the ratio of MMP to tissue inhibitors of metalloproteinase (TIMP) in diseases still need to be demonstrated. Moreover, further studies are needed to assess the efficacy and safety of biologics that target MMPs in patients with CRS.

Dynamic changes of nasal tight junctions in patients with convalescent COVID-19 with allergic rhinitis.

KEY POINTS: Nasal tight junction module score correlates negatively to allergy module score in COVID-19. Omicron variant may slow-down tight junction restoration in patients with AR.