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Introduction. Antimicrobial peptides and proteins (AMPs) constitute the first line of defense against pathogenic microorganisms in the airway. The association between AMPs and chronic rhinosinusitis with nasal polyps (CRSwNP) requires further investigations. This study is aimed at investigating the expression and regulation of major dysregulated AMPs in the nasal mucosa of CRSwNP. Methods. The expression of AMPs was analyzed in nasal tissue from patients with eosinophilic (E) CRSwNP and nonECRSwNP and healthy subjects using RNA sequencing. The 10 most abundant AMPs expressed differentially in CRSwNP patients were verified by real-time PCR, and of these, the expression and regulation of secretory leukoprotease inhibitor (SLPI) and clusterin (CLU) were investigated further. Results. The 10 most abundant AMPs expressed differentially in CRSwNP compared to healthy control, regardless of subtypes, included BPIFA1, BPIFB1, BPIFB2, CLU, LTF, LYZ, and SLPI, which were downregulated, and S100A8, S100A9, and HIST1H2BC, which were upregulated. ELISA and immunofluorescence confirmed the decreased expression of SLPI and CLU levels in CRSwNP. SLPI is expressed in both nasal epithelial cells and glandular cells, whereas CLU is mainly expressed in glandular cells. AB/PAS staining further demonstrated that both SLPI and CLU were mainly produced by mucous cells in submucosal glands. Furthermore, the numbers of submucosal glands were significantly decreased in nasal polyp tissue of CRSwNP compared to nasal tissue of controls. SLPI was downregulated by TGF-β1 and IL-4 in cultured nasal tissues in vitro, while CLU expression was inhibited by TGF-β1. Glucocorticoid treatment for 2 weeks significantly increased the expression of all downregulated AMPs, but not LYZ. Additionally, budesonide significantly increased the expression of SLPI and CLU in cultured nasal tissues. Conclusion. The expression of major antimicrobial proteins is significantly decreased in nasal tissue of CRSwNP. The expression of SLPI and CLU is correlated with the numbers of submucosal glands and regulated by inflammatory cytokines and glucocorticoids.

Although biofilms have been implicated in the pathogenesis of chronic rhinosinusitis (CRS), there is little evidence that their presence or absence has any effect on the outcomes of endoscopic sinus surgery (ESS). The aim of this study was to investigate the effect of biofilms on postsurgical outcomes after ESS. A prospective, blinded study of 51 consecutive patients undergoing ESS for CRS was conducted. Preoperatively, patients assessed their symptoms using internationally accepted standardized symptom scoring systems and quality-of-life (QOL) measures, i.e., the 10-point Visual Analog Scale (VAS), Sino-Nasal-Outcome-Test 20, and global severity of CRS. Their sinonasal mucosa was graded using the Lund-Kennedy scale and the extent of radiological disease on computed tomography scans was scored using the Lund-McKay scale. Random sinonasal tissue samples were assessed for biofilm presence using confocal laser microscopy. At each postoperative visit, patients reassessed their sinus symptoms and completed QOL measures. Postsurgical state of their sinonasal mucosa was graded endoscopically. Bacterial biofilms were found in 36 of 51 (71%) CRS patients. Patients with biofilms presented with significantly worse preoperative radiology and nasendoscopy scores (p = 0.003 and 0.01, respectively). After a median follow-up period of 16 months postsurgery, biofilm-positive patients had statistically worse sinus symptoms (VAS, p = 0.002) and worse nasendoscopy scores (p = 0.026). They also required extra postoperative visits and multiple antibiotic treatments deviating from the standard postoperative care required by biofilm-negative patients. This study has shown that patients with biofilms have more severe disease preoperatively and persistence of postoperative symptoms, ongoing mucosal inflammation, and infections. This study strengthens the evidence for the role that biofilms may play in recalcitrant CRS.

Barrier tissue dysfunction is a fundamental feature of chronic human inflammatory diseases 1 . Specialized subsets of epithelial cells—including secretory and ciliated cells—differentiate from basal stem cells to collectively protect the upper airway 2 – 4 . Allergic inflammation can develop from persistent activation 5 of type 2 immunity 6 in the upper airway, resulting in chronic rhinosinusitis, which ranges in severity from rhinitis to severe nasal polyps 7 . Basal cell hyperplasia is a hallmark of severe disease 7 – 9 , but it is not known how these progenitor cells 2 , 10 , 11 contribute to clinical presentation and barrier tissue dysfunction in humans. Here we profile primary human surgical chronic rhinosinusitis samples (18,036 cells, n  = 12) that span the disease spectrum using Seq-Well for massively parallel single-cell RNA sequencing 12 , report transcriptomes for human respiratory epithelial, immune and stromal cell types and subsets from a type 2 inflammatory disease, and map key mediators. By comparison with nasal scrapings (18,704 cells, n  = 9), we define signatures of core, healthy, inflamed and polyp secretory cells. We reveal marked differences between the epithelial compartments of the non-polyp and polyp cellular ecosystems, identifying and validating a global reduction in cellular diversity of polyps characterized by basal cell hyperplasia, concomitant decreases in glandular cells, and phenotypic shifts in secretory cell antimicrobial expression. We detect an aberrant basal progenitor differentiation trajectory in polyps, and propose cell-intrinsic 13 , epigenetic 14 , 15 and extrinsic factors 11 , 16 , 17 that lock polyp basal cells into this uncommitted state. Finally, we functionally demonstrate that ex vivo cultured basal cells retain intrinsic memory of IL-4/IL-13 exposure, and test the potential for clinical blockade of the IL-4 receptor α-subunit to modify basal and secretory cell states in vivo. Overall, we find that reduced epithelial diversity stemming from functional shifts in basal cells is a key characteristic of type 2 immune-mediated barrier tissue dysfunction. Our results demonstrate that epithelial stem cells may contribute to the persistence of human disease by serving as repositories for allergic memories. Single-cell RNA sequencing is used to characterize cell types in nasal tissues from human patients with chronic rhinosinusitis, revealing a role for tissue stem cells in allergic inflammatory memory.

Inflammatory diseases are often chronic and recurrent, and current treatments do not typically remove underlying disease drivers 1 . T cells participate in a wide range of inflammatory diseases such as psoriasis 2 , Crohn’s disease 3 , oesophagitis 4 and multiple sclerosis 5 , 6 , and clonally expanded antigen-specific T cells may contribute to disease chronicity and recurrence, in part by forming persistent pathogenic memory. Chronic rhinosinusitis and asthma are inflammatory airway diseases that often present as comorbidities 7 . Chronic rhinosinusitis affects more than 10% of the general population 8 . Among these patients, 20–25% would develop nasal polyps, which often require repeated surgical resections owing to a high incidence of recurrence 9 . Whereas abundant T cells infiltrate the nasal polyps tissue 10 , 11 , T cell subsets that drive the disease pathology and promote recurrence are not fully understood. By comparing T cell repertoires in nasal polyp tissues obtained from consecutive surgeries, here we report that persistent CD8 + T cell clones carrying effector memory-like features colonize the mucosal tissue during disease recurrence, and these cells characteristically express the tryptase Granzyme K (GZMK). We find that GZMK cleaves many complement components, including C2, C3, C4 and C5, that collectively contribute to the activation of the complement cascade. GZMK-expressing CD8 + T cells participate in organized tertiary lymphoid structures, and tissue GZMK levels predict the disease severity and comorbidities better than well-established biomarkers such as eosinophilia and tissue interleukin-5. Using a mouse asthma model, we further show that GZMK-expressing CD8 + T cells exacerbate the disease in a manner dependent on the proteolytic activity of GZMK and complements. Genetic ablation or pharmacological inhibition of GZMK after the disease onset markedly alleviates tissue pathology and restores lung function. Our work identifies a pathogenic CD8 + memory T cell subset that promotes tissue inflammation and recurrent airway diseases by the effector molecule GZMK and suggests GZMK as a potential therapeutic target. Comparing T cells in nasal polyps from repeated surgeries shows that effector memory-like persistent clones colonize the mucosal tissue during disease recurrence and promote inflammation by producing Granzyme K, a complement-activating tryptase, which is a potential therapeutic target.

Objectives: Purified plant polysaccharide (HemoStase) is a plant-derived hemostatic agent that has not previously been used in sinus surgery. This study was conducted to evaluate the effectiveness of this novel agent in the control of nasal bleeding during endoscopic sinus surgery. The volume of bleeding during endoscopic sinus surgery was hypothesized to not be statistically significantly different between a control group (gelatin-thrombin matrix; FloSeal) and an experimental group (purified plant polysaccharide; HemoStase). Methods: Eighteen patients with a history of chronic rhinosinusitis in whom maximal medical therapy failed who underwent endoscopic sinus surgery were randomized into one of two groups (control FloSeal group or experimental HemoStase group). In the control group, sites in the nose that were actively bleeding during the operation were controlled with FloSeal. In the experimental group, sites in the nose that were actively bleeding during the operation were controlled with HemoStase. The main outcome measure was total operative blood loss. Blood loss was the sum of blood removed by suction during the surgery (recorded in milliliters) and blood on surgical sponges (weighed and converted to milliliters). Statistical analysis was performed with the t-test and the Mann-Whitney U test. Results: The amounts of blood loss (mean ± SEM) were not significantly different between the FloSeal (262 ± 15 mL) and HemoStase (265 ± 33 mL) groups (p = 0.93). Conclusions: The results of this study demonstrate the use of a novel product for the control of intraoperative bleeding during endoscopic sinus surgery.

Patients with allergic fungal rhinosinusitis (AFRS) are typically atopic and immunocompetent. Despite combined modality treatment based on surgery and immunomodulation, the potential for recidivism is well recognized. A study was conducted in a military hospital in India to identify the factors responsible for recidivism in AFRS and to suggest measures to overcome it. Sixty patients with AFRS (42 new cases and 18 cases that required revision surgery) were managed between January 2009 and July 2013. Patients underwent endoscopic, radiologic, and laboratory evaluation for AFRS followed by functional endoscopic sinus surgery. Each patient received oral prednisolone, 1 mg/kg/day, for 1 week preoperatively and 0.5 mg/kg/day for 4 weeks postoperatively. A randomly selected group of 30 patients (group A) received oral prednisolone 0.4 mg/kg/day for the next 4 weeks, tapered to 0.2 mg/kg/day for the next 2 months and to 0.1 mg/kg/day for the last 2 months. The drug was stopped after 6 months. In the remaining 30 patients (group B), oral prednisolone was tapered within 2 months. Topical steroid sprays were advised in all patients. Recidivism was observed in 12 of 42 (28.6%) patients presenting for the first time with AFRS: 9 patients from group B (30%) and 3 patients from group A (10%). Besides inadequate postoperative oral steroid therapy, suboptimal functional endoscopic sinus surgery, noncompliance with intranasal sprays, nonadherence to Kupferberg staging, inadequate follow-up, failure of surgeons to impart health education to patients, and unavailability of ENT consultation in rural belts were found to be factors causing recidivism.

Mice have lineage-negative IL-7Rα + (innate lymphoid) cells that contribute to type 2 immunity. Spits and colleagues identify a similar CRTH2 + CD161 + population in human lungs and gut that produces IL-13 after stimulation. Innate lymphoid cells (ILCs) are emerging as a family of effectors and regulators of innate immunity and tissue remodeling. Interleukin 22 (IL-22)- and IL-17-producing ILCs, which depend on the transcription factor RORγt, express CD127 (IL-7 receptor α-chain) and the natural killer cell marker CD161. Here we describe another lineage-negative CD127 + CD161 + ILC population found in humans that expressed the chemoattractant receptor CRTH2. These cells responded in vitro to IL-2 plus IL-25 and IL-33 by producing IL-13. CRTH2 + ILCs were present in fetal and adult lung and gut. In fetal gut, these cells expressed IL-13 but not IL-17 or IL-22. There was enrichment for CRTH2 + ILCs in nasal polyps of chronic rhinosinusitis, a typical type 2 inflammatory disease. Our data identify a unique type of human ILC that provides an innate source of T helper type 2 (T H 2) cytokines.

Sophisticated interactions between stromal and immune cells play crucial roles in various biological and pathological processes. In chronic rhinosinusitis with nasal polyps (CRSwNP), the upper airway inflammation in many patients is driven by T H 2, ILC2, and eosinophils, thus being treated with glucocorticoids and anti-type 2 inflammation biologics. The resistance to these therapies is often associated with neutrophilic inflammation, which has also been widely identified in CRSwNP, but the underlying mechanisms remain unclear. Using single-cell analysis, spatial transcriptomics, and T-cell receptor sequencing, we identify an increased presence of granzyme K + (GZMK + ) CD8 + T cells in NPs, which possess a phenotype distinct from the cytotoxic GZMB + effector CD8 + T subset. GZMK + CD8 + T cells are found to express CXCR4 and interact with CXCL12-secreting fibroblasts, inducing the latter to produce neutrophil chemoattractants in a manner uniquely mediated by GZMK but not other granzymes. This GZMK + CD8 + T cell-fibroblast crosstalk is also observed in other inflammatory diseases. Furthermore, GZMK + CD8 + T cells exhibit a selective expansion of clones that recognize Epstein-Barr virus. Here, we show that GZMK marks a phenotypically distinct subset of effector CD8 + T cells that promote neutrophilic inflammation. Chronic rhinosinusitis with nasal polyps generally has a type 2 inflammatory eosinophilic profile but can have a treatment resistant neutrophilic phenotype. Here the authors characterise nasal polyps using single cell sequencing and spatial transcriptomics and show granzyme K + CD8 + T cells associated with neutrophilic inflammation which promote release of neutrophilic chemoattractants from fibroblasts.

The pathophysiology of CRS is multifactorial and complex yet needs to be completed. Recent evidence emphasizes the crucial part played by epithelial cells in the development of CRS. The epithelial cells act as physical barriers and play crucial roles in host defense, including initiating and shaping innate and adaptive immune responses. This review aims to present a comprehensive understanding of the significance of nasal epithelial cells in CRS. New research suggests that epithelial dysfunction plays a role in developing CRS through multiple mechanisms. This refers to issues with a weakened barrier function, disrupted mucociliary clearance, and irregular immune responses. When the epithelial barrier is compromised, it can lead to the passage of pathogens and allergens, triggering inflammation in the body. Furthermore, impaired mucociliary clearance can accumulate pathogens and secretions of inflammatory mediators, promoting chronic inflammation. Epithelial cells can release cytokines and chemokines, which attract and activate immune cells. This can result in an imbalanced immune response that continues to cause inflammation. The interaction between nasal epithelial cells and various immune cells leads to the production of cytokines and chemokines, which can either increase or decrease inflammation. By comprehending the role of epithelial cells in CRS, we can enhance our understanding of the disease’s pathogenesis and explore new therapeutics.

Objectives: We assess the association between the presence of biofilms and cilial damage in patients with chronic rhinosinusitis (CRS), describe the microorganisms associated with samples that exhibited cilial loss and biofilms, and demonstrate the absence of ciliary injury and biofilms in similarly prepared “normal” controls. Methods: We examined samples of ethmoid mucosa obtained from 24 patients who underwent functional endoscopic sinus surgery for CRS. Samples from a control group (20 healthy subjects) were also examined. The specimens were divided into 2 fragments; the first was processed for bacterial cultures, and the second was subjected to scanning electron microscopy. Statistical analysis was performed. Results: All CRS samples had positive bacterial cultures. The scanning electron microscopy analysis showed bacterial biofilms in 10 of the 24 specimens. A marked destruction of the epithelium was observed in samples positive for biofilms (p < 0.001), and the presence of Haemophilus influenzae was associated with ciliary abnormalities (partial damage in 55.6% and absence of cilia in 50%; p = 0.041). Conclusions: The high percentage of biofilms in our specimens confirms the association between biofilms and CRS. Our data support the hypothesis that biofilm formation represents the latter phase of an inflammatory process that leads to complete epithelial destruction.