Formation of nasal polyps: The roles of innate type 2 inflammation and deposition of fibrin

doi:10.1016/j.jaci.2020.01.027

Journal of Allergy and Clinical Immunology

Volume 145, Issue 3, March 2020, Pages 740-750

https://doi.org/10.1016/j.jaci.2020.01.027 Get rights and content

Chronic rhinosinusitis (CRS) is one of the most common chronic diseases worldwide. It is a heterogeneous disease, and geographical or ethnic differences in inflammatory pattern in nasal mucosa are major issues. Tissue eosinophilia in CRS is highly associated with extensive sinus disease, recalcitrance, and a higher nasal polyp (NP) recurrence rate after surgery. The prevalence of eosinophilic CRS (ECRS) is increasing in Asian countries within the last 2 decades, and this trend appears to be occurring across the world. International consensus criteria for ECRS are required for the accurate understanding of disease pathology and precision medicine. In a multicenter large-scale epidemiological survey, the “Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis study,” ECRS was definitively defined when the eosinophil count in nasal mucosa is greater than or equal to 70 eosinophils/hpf (magnification, ×400), and this study proposed an algorithm that classifies CRS into 4 groups according to disease severity. The main therapeutic goal with ECRS is to eliminate or diminish the bulk of NP tissue. NPs are unique abnormal lesions that grow from the lining of the nasal and paranasal sinuses, and type 2 inflammation plays a critical role in NP development in patients with ECRS. An imbalance between protease and endogenous protease inhibitors might play a pivotal role in the initiation and exacerbation of type 2 inflammation in ECRS. Intraepithelial mast cells in NPs, showing a tryptase+, chymase− phenotype, may also enhance type 2 inflammation. Intense edema and reduced fibrosis are important histological features of eosinophilic NPs. Mucosal edema mainly consists of exuded plasma protein, and excessive fibrin deposition would be expected to contribute to the retention of proteins from capillaries and thereby perpetuate mucosal edema that may play an etiological role in NPs. Upregulation of the coagulation cascade and downregulation of fibrinolysis strongly induce abnormal fibrin deposition in nasal mucosa, and type 2 inflammation plays a central role in the imbalance of coagulation and fibrinolysis.

Section snippets

Heterogeneity and disease severity of CRS

Tissue eosinophilia in CRS is highly associated with extensive sinus disease, recalcitrance, and a higher NP recurrence rate after endoscopic sinus surgery.²⁰^,²¹ To our knowledge, Okuda⁵ was the first to report the differences in the inflammation pattern of CRS nasal mucosa between European and Asian (in this case, Japanese) patients. The prevalence of eosinophilic CRSwNP is increasing in Asian countries within the last 2 decades however, and this trend appears to be occurring across the world,

Establishment of type 2 inflammation in ECRS

Regardless of ethnicity and geographic region, eosinophilia in patients with CRS strongly correlates with type 2 inflammatory response and generally demonstrates severe symptoms and high recurrence rate, and high prevalence and severity of asthma.⁶ Therefore, understanding the mechanisms of establishing type 2 inflammation in nasal and paranasal sinus mucosa is therapeutically important. It is clear that type 2 cytokines, especially IL-5 and IL-13 but possibly also IL-4, play important roles

Nature of NP and fibrin deposition

NPs are painless benign lesions that originate from around the middle nasal meatus or paranasal sinus cavity, and unlike polyps in the digestive tract or bladder, malignant transformation is extremely rare. NPs have a semitranslucent pale gray appearance, resembling a cystic lesion; nonetheless, the content is mostly a jelly-like solid. Striking histological features of NPs include intense edematous stroma filled with plasma proteins, mainly albumin, and less collagen production and fibrosis.⁶⁴^,

Increases in levels of coagulation factors in NPs

Tissue factor (TF) initiates the extrinsic coagulation cascade and subsequent fibrin deposition. Leakage of coagulation factors contained in the exuded plasma into tissues facilitates factor VIIa binding to TF on cell surfaces, and the formed complex activates factor Xa, which in turn leads to thrombin generation and subsequent fibrin clot formation. Eosinophils were found to express TF, which initiates the extrinsic coagulation cascade and subsequent fibrin deposition, and significant positive

Fibrinolytic impairment causes abnormal fibrin deposition in NPs

The serine protease plasmin is responsible for the degradation of cross-linked fibrin (ie, fibrinolysis) to prevent or reverse excess fibrin deposition in tissue. Plasmin is generated through cleavage of the proenzyme plasminogen by 2 physiological plasminogen activators, urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA). The activities of uPA and tPA are inhibited by plasminogen activator inihibitor-1.

We have previously found that NPs from patients with CRSwNP have

Summary and conclusions

CRS is a heterogeneous disease, and geographical or racial differences in inflammatory pattern in nasal mucosa are major issues. Although it was believed that eosinophilic NPs are most common in Western countries and neutrophilic NPs are most common in Asian countries, recent studies reported that the prevalence of eosinophilic NPs is increasing in Asian countries within the last 2 decades, and this trend will possibly be seen throughout the world. International consensus criteria for CRS are

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Chronic rhinosinusitis (CRS) is heterogeneous and contains diverse pathogenesis including type 1, type 2, and/or type 3 inflammation. For severe type 2 CRS especially CRS with nasal polyps (CRSwNP), biologics that target inflammatory molecules have recently been applied along with further changes in the treatment algorithm for CRS. Currently, a completed phase 3 clinical trial for biologics for severe CRSwNP with inadequate response to surgery and/or intranasal corticosteroids, including omalizumab (anti-IgE), mepolizumab (anti-IL-5), benralizumab (anti-IL-5Rα), and dupilumab (anti-IL-4Rα), have all shown efficacy. Similar phase 3 clinical trials for tezepelumab (anti-TSLP) and etokimab (anti-IL-33) are now underway and completed, respectively. Further studies need to evaluate how to optimally and cost-effectively use biologics for CRS and determine if any biomarkers are indicative of which biologics should be administered. A definition of complete and/or clinical remission of CRS is also needed to determine when to reduce or discontinue biologics. In addition, more precise basic research on CRS, such as endotyping and genotyping, will need to be undertaken in order to determine novel targets for biologics.
Middle meatus microbiome in patients with eosinophilic chronic rhinosinusitis in a Japanese population
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Chronic rhinosinusitis (CRS) is a common chronic inflammatory disease and is subdivided into eosinophilic and noneosinophilic forms. There are few reports investigating the nasal microbiome and its pathological functions in patients with CRS.
We sought to analyze factors contributing to variations of the nasal microbiome in CRS, and on the basis of these factors, to elucidate whether the bacterial metabolites were related to the pathogenesis.
Nasal swabs were collected, and the V3 to V4 variable region of the 16S ribosomal RNA gene was amplified and sequenced. Factors contributing to variations of the nasal microbiome in patients with CRS were compared. The most influential factor was whether CRS was eosinophilic, and we compared α- and β-diversity, bacterial species, and predictive bacterial functions between the 2 patient groups. In addition, the metabolites of the key bacteria were extracted, and we evaluated the predicted bacterial functions in airway epithelial cells.
In total, 110 patients with CRS and 33 control subjects were enrolled. On the basis of the factors of variation, it was found that patients with eosinophilic CRS (n = 65) had different microbiomes with weighted UniFrac β-diversity and lower α-diversity compared with those with noneosinophilic CRS (n = 45). A higher abundance of Fusobacterium nucleatum and an increased LPS pathway were observed in patients with noneosinophilic CRS compared with those with eosinophilic CRS. In airway epithelial cells, LPS derived from F nucleatum suppressed the expression levels of ALOX15 induced by T_H2 cytokines.
The differences in the nasal microbiome may play a key role in the pathophysiology of CRS.
Differences in the expression of multidrug resistance proteins in chronic rhinosinusitis according to endotype
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Chronic rhinosinusitis is a common disease of the nasal cavity and is classified into two major endotypes, which are neutrophilic and eosinophilic. Some patients with neutrophilic and eosinophilic chronic rhinosinusitis are refractory to treatment, and the mechanism of drug resistance is not completely understood.
Nasal polyp samples were collected from patients with non-eosinophilic chronic rhinosinusitis (nECRS) and eosinophilic chronic rhinosinusitis (ECRS). Transcriptomic and proteomic analyses were performed simultaneously. Gene Ontology (GO) analysis was conducted to extract genes involved in drug resistance. Then, GO analysis results were validated via real-time polymerase chain reaction and immunohistochemistry analysis.
The nasal polyps of patients with ECRS were enriched with 110 factors in the genes and 112 in the proteins, unlike in those of patients with nECRS. GO analysis on the combined results of both showed that the factors involved in extracellular transportation were enriched. Our analysis focused on multidrug resistance protein 1–5 (MRP1–5). Real-time polymerase chain reaction revealed that the MRP4 expression was significantly upregulated in ECRS polyps. Immunohistochemical staining showed that the MRP3 and MRP4 expressions significantly increased in nECRS and ECRS, respectively. MRP3 and MRP4 expressions were positively correlated with the number of neutrophil and eosinophil infiltrates in polyps and associated with the tendency to relapse in patients with ECRS.
MRP is associated with treatment resistance and is expressed in nasal polyps. The expression pattern had different features based on chronic rhinosinusitis endotype. Therefore, drug resistance factors can be associated with therapeutic outcomes.
Macroarray expression analysis of cytokines and prostaglandin metabolism–related genes in chronic rhinosinusitis
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Chronic rhinosinusitis (CRS) can be divided into endotypes by functional or pathophysiologic findings.
The aim of this study was to analyze the expression of cytokines, prostaglandin (PG) synthases, and their receptors related to the pathogenesis of CRS, especially those contributing to nasal polyp (NP) formation.
NPs and uncinate tissue (UT) samples were collected from 90 patients who underwent endoscopic sinus surgery. They included 75 patients with CRS (including 45 with eosinophilic CRS [eCRS] and 30 with non-eCRS) and 15 patients without CRS. A total of 30 genes were selected for our original DNA array plate to analyze the levels of expression of 10 cytokines (IFN-γ, IL-4, IL-5, IL-10, IL-13, IL-17A, IL-22, IL-25, IL-33, and TSLP), 4 prostaglandin synthases (prostaglandin D₂ [PGD₂] synthase, prostaglandin E₂ synthase, COX-1, and COX-2), and their 16 receptors. Clustering analysis was performed according to the expression results, and clinical findings of patients from each cluster were investigated.
The samples could be divided into 3 clusters. Cluster 1 showed elevated levels of expression of IL4, IL5, IL13, TSLP, IL1RL1 (ST2 [an IL-33 receptor]), HPGDS, and GPR44 (CRTH2, a PGD₂ receptor); cluster 2 showed elevated levels of expression of IL17A and PTGES; and cluster 3 showed an elevated level of expression of IL25. Regarding clinical features, the main characteristics of each cluster were as follows: NPs from patients with eCRS for cluster 1, NPs and/or UT samples from patients with non-eCRS for cluster 2, and UTs from patients with non-CRS for cluster 3.
The results suggest that there are associations between type 2 inflammation/PGD₂ and eCRS and also between type 3 inflammation/prostaglandin E₂ and non-eCRS.
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Aspirin-exacerbated respiratory disease (AERD) is a unique and often clinically severe disease affecting a subgroup of adults with asthma and chronic rhinosinusitis with nasal polyposis. Works published in 2021-2022 confirmed the critical role of lipid mediator dysregulation and mast cell activation and expanded our understanding of basophils, macrophages, fibrin dysregulation, and the 15-lipoxygenase pathway in disease pathogenesis. Translational studies established inflammatory heterogeneity in the upper and lower airway at baseline and during aspirin-induced respiratory reactions. Clinical cohorts provided insights into the mechanistic actions of frequently utilized biologic therapies in AERD. These advances are already changing clinical care delivery and affecting patient outcomes. Despite this, further work is needed to improve clinical tools to reliably diagnose AERD and identify factors that could prevent development of the disease altogether. Additionally, the impact of inflammatory heterogeneity on clinical trajectories and the utility and safety of combination biologic and daily aspirin therapies remains unanswered.
The development of nasal polyps involves early middle meatus mucous remodeling via TGF-β1 mediated PAI-1 reduction
2023, Brazilian Journal of Otorhinolaryngology
Our study aimed to elucidate the effect of PAI-1 (Plasminogen Activator Inhibitor-1) and t-PA (Tissue-type Plasminogen Activator) in tissue remodeling in nasal polyps patients.
Samples were streamed as early Nasal Polyps (eNP, n = 10) and inferior tissue from the same patient, mature Nasal Polyps (mNP, n = 14), and Control group (n = 15), respectively. Immunohistochemistry and immunofluorescence were applied to detect localization. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Western blot were used to measure different levels among three groups. The mNP tissue was cultured in vitro and treated with TGF-β1 (Transforming Growth Factor-beta 1) activator, TGF-β1 inhibitor (SB431542), and PAI-1 inhibitor (TM5275); then Western blot, qRT-PCR, and ELISA were used to assess changes.
The immunohistochemistry and immunofluorescence showed that PAI-1 expression decreased in eNP and mNP, mainly in epithelium and glands. The transcriptional expression and protein level of TGF-β1/t-PA/PAI-1/Collagen1 were lower in eNP than IT while mNP group demonstrated lower mRNA expression and protein level of TGF-β1/t-PA/PAI-1/Collagen1 than Control group. In mNP tissue culture in vitro, TGF-β1 activator elevated t-PA, PAI-1, and Collagen1 with higher release of PAI-1 and Collagen1 in supernatant, whereas SB431542 suppressed above reactions; TM5275 lowered transcriptional and protein level of Collagen1 in supernatant.
Early Nasal polyps’ formation in middle meatus mucous is related with fibrillation system PAI-1/t-PA and tissue remodeling; moreover, nasal polyps’ development is regulated by TGF-β1-mediated PAI-1 reduction.
3b.

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: This research was supported in part by a Grant-in-Aid for Scientific Research (KAKENHI) (C) grant number 16K11207. R. P. Schleimer was supported in part by grants AI137174 on AERD and PO1AI145818 (Chronic Rhinosinusitis Integrative Studies Program 2 [CRISP2]) from the NIH and by The Ernest S. Bazley Charitable Fund.

: Terms in boldface and italics are detailed in the glossary on page 741.

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Reviews and feature articleFormation of nasal polyps: The roles of innate type 2 inflammation and deposition of fibrin

Section snippets

Heterogeneity and disease severity of CRS

Establishment of type 2 inflammation in ECRS

Nature of NP and fibrin deposition

Increases in levels of coagulation factors in NPs

Fibrinolytic impairment causes abnormal fibrin deposition in NPs

Summary and conclusions

J Allergy Clin Immunol

Allergol Int

J Allergy Clin Immunol

J Allergy Clin Immunol

Allergol Int

Curr Opin Allergy Clin Immunol

Allergol Int

Allergol Int

Ann Allergy Asthma Immunol

Auris Nasus Larynx

Allergol Int

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Respir Med

J Allergy Clin Immunol

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Trends Immunol

Mucosal Immunol

J Biol Chem

J Allergy Clin Immunol

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Blood

Allergol Int

J Crohns Colitis

J Allergy Clin Immunol

Thromb Res

Pharmacol Ther

Neuropharmacology

Allergol Int

J Allergy Clin Immunol

EPOS2020: development strategy and goals for the latest European Position Paper on Rhinosinusitis

Rhinology

International Consensus Statement on Allergy and Rhinology: Rhinosinusitis

Int Forum Allergy Rhinol

Immunopathogenesis of chronic rhinosinusitis and nasal polyposis

Annu Rev Pathol

[Differences in chronic rhinitis with reference to its incidence and type in Chiba and Vienna]

Monatsschr Ohrenheilkd Laryngorhinol

Eosinophilic chronic rhinosinusitis in East Asians

World J Clin Cases

Changes in the clinical and histological characteristics of Chinese chronic rhinosinusitis with nasal polyps over 11 years

Int Forum Allergy Rhinol

Changes in histological features of nasal polyps in a Korean population over a 17-year period

Otolaryngol Head Neck Surg

Inflammatory patterns in upper airway disease in the same geographical area may change over time

Am J Rhinol Allergy

Analysis of comorbidities and objective parameters in refractory chronic rhinosinusitis

Laryngoscope

Nasal polyps in patients with asthma: prevalence, impact, and management challenges

J Asthma Allergy

Diagnosis and management of NSAID-exacerbated respiratory disease (N-ERD)—a EAACI position paper

Allergy

The effect of functional endoscopic sinus surgery on patients with asthma and CRS with nasal polyps

Rhinology

A clinical study of endoscopic sinus surgery for sinusitis in patients with bronchial asthma

Int Arch Allergy Immunol

Reviews and feature article
Formation of nasal polyps: The roles of innate type 2 inflammation and deposition of fibrin