Background The body of knowledge regarding rhinosinusitis(RS) continues to expand, with rapid growth in number of publications, yet substantial variability in the quality of those presentations. In an effort to both consolidate and critically appraise this information, rhinologic experts from around the world have produced the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR:RS). Methods Evidence-based reviews with recommendations(EBRRs) were developed for scores of topics, using previously reported methodology. Where existing evidence was insufficient for an EBRR, an evidence-based review (EBR)was produced. The sections were then synthesized and the entire manuscript was then reviewed by all authors for consensus. Results The resulting ICAR:RS document addresses multiple topics in RS, including acute RS (ARS), chronic RS (CRS)with and without nasal polyps (CRSwNP and CRSsNP), recurrent acute RS (RARS), acute exacerbation of CRS (AECRS), and pediatric RS. Conclusion As a critical review of the RS literature, ICAR:RS provides a thorough review of pathophysiology and evidence-based recommendations for medical and surgical treatment. It also demonstrates the significant gaps in our understanding of the pathophysiology and optimal management of RS. Too often the foundation upon which these recommendations are based is comprised of lower level evidence. It is our hope that this summary of the evidence in RS will point out where additional research efforts may be directed.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/alr.21695

International Consensus Statement on Allergy and Rhinology: Rhinosinusitis.

Interleukin 33 (IL-33) is a member of the IL-1 family of cytokines with a growing number of target cells and a plethora of biological functions. Although it has commonalities with other IL-1 cytokines, IL-33 exhibits some unique features. Here we review the biology of IL-33 and its receptor and develop a working model that describes two 'lives' for IL-33-one intracellular and one extracellular. Under healthy conditions, constitutively produced, intracellular IL-33 participates in maintaining barrier function by regulating gene expression as a nuclear protein. In parallel, nuclear IL-33 functions as a stored alarmin that is released when barriers are breached. Extracellular IL-33 coordinates immune defense and repair mechanisms while also initiating differentiation of helper T cells as the adaptive immune response is triggered.

Interleukin 33 is a guardian of barriers and a local alarmin

Clostridium perfringens enterotoxin fragment removes specific claudins from tight junction strands : Evidence for direct involvement of claudins in tight junction barrier

I. Executive summary BACKGROUND: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR-RS-2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence-based findings of the document. Methods ICAR-RS presents over 180 topics in the forms of evidence-based reviews with recommendations (EBRRs), evidence-based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results ICAR-RS-2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence-based management algorithm is provided. Conclusion This ICAR-RS-2021 executive summary provides a compilation of the evidence-based recommendations for medical and surgical treatment of the most common forms of RS.

International consensus statement on allergy and rhinology: rhinosinusitis 2021

The brain is well protected against microbial invasion by cellular barriers, such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). In addition, cells within the central nervous system (CNS) are capable of producing an immune response against invading pathogens. Nonetheless, a range of pathogenic microbes make their way to the CNS, and the resulting infections can cause significant morbidity and mortality. Bacteria, amoebae, fungi, and viruses are capable of CNS invasion, with the latter using axonal transport as a common route of infection. In this review, we compare the mechanisms by which bacterial pathogens reach the CNS and infect the brain. In particular, we focus on recent data regarding mechanisms of bacterial translocation from the nasal mucosa to the brain, which represents a little explored pathway of bacterial invasion but has been proposed as being particularly important in explaining how infection with Burkholderia pseudomallei can result in melioidosis encephalomyelitis.

/pdf/pathogens-penetrating-the-central-nervous-system-infection-284mobv2pn.pdf

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

The mucosal barrier of the upper respiratory tract including the nasal cavity, which is the first site of exposure to inhaled antigens, plays an important role in host defense in terms of innate immunity and is regulated in large part by tight junctions of epithelial cells. Tight junction molecules are expressed in both M cells and dendritic cells as well as epithelial cells of upper airway. Various antigens are sampled, transported, and released to lymphocytes through the cells in nasal mucosa while they maintain the integrity of the barrier. Expression of tight junction molecules and the barrier function in normal human nasal epithelial cells (HNECs) are affected by various stimuli including growth factor, TLR ligand, and cytokine. In addition, epithelial-derived thymic stromal lymphopoietin (TSLP), which is a master switch for allergic inflammatory diseases including allergic rhinitis, enhances the barrier function together with an increase of tight junction molecules in HNECs. Furthermore, respiratory syncytial virus infection in HNECs in vitro induces expression of tight junction molecules and the barrier function together with proinflammatory cytokine release. This paper summarizes the recent progress in our understanding of the regulation of tight junctions in the upper airway epithelium under normal, allergic, and RSV-infected conditions.

/pdf/regulation-of-tight-junctions-in-upper-airway-epithelium-1m8fm4ijbo.pdf

Regulation of Tight Junctions in Upper Airway Epithelium

Background
Pseudomonas aeruginosa causes chronic respiratory disease, and the elastase enzyme that it produces increases the permeability of airway epithelial cells owing to the disruption of tight junctions. P. aeruginosa is also implicated in prolonged chronic rhinosinusitis. However, the effects of P. aeruginosa elastase (PE) against the barrier formed by human nasal epithelial cells (HNECs) remain unknown.

/pdf/pseudomonas-aeruginosa-elastase-causes-transient-disruption-33c97uciue.pdf

Pseudomonas aeruginosa elastase causes transient disruption of tight junctions and downregulation of PAR-2 in human nasal epithelial cells.

Objectives/Hypothesis:

Epithelial-derived interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP) are critical regulators of innate and adaptive immune responses associated with Th2 cytokine-mediated inflammation, including allergic rhinitis. IL-33 and TSLP are expressed not only in epithelial cells but also fibroblasts, endothelial cells, and smooth muscle cells at nasal mucosal sites. However, the role and the regulation of IL-33 and TSLP in nasal fibroblasts remain unknown. We investigated the signal transduction regulation of IL-33 and TSLP induced by proinflammatory cytokines in nasal fibroblasts.



Study Design:

In vitro, prospective study.



Methods:

Nasal fibroblasts were derived from human nasal mucosa without allergic rhinitis. Expression of IL-33 and TSLP was examined in nasal fibroblasts treated with proinflammatory cytokines IL-1β or tumor necrosis factor (TNF)-α after pretreatment with or without various inhibitors of signal transduction pathways.



Results:

In nasal fibroblasts, both Western blotting and reverse transcriptase-polymerase chain reaction demonstrated that expression of mRNAs and proteins of IL-33 and TSLP was increased by treatment with IL-1β or TNF-α. Immunostaining revealed that IL-33–positive nuclei were markedly increased by the treatment with IL-1β or TNF-α. Enzyme-linked immunosorbent assay showed that fibroblast-released TSLP was significantly increased by treatment with IL-1β or TNF-α. The upregulation of both IL-33 and TSLP proteins by treatment with IL-1β was prevented by inhibitors of pan- protein kinase C (PKC), p38 mitogen-activated protein kinase, and nuclear factor (NF)-κB. In the cells treated with TNF-α, upregulation of IL-33 protein was prevented by inhibitors of phosphoinositide 3-kinase (PI3K), c-Jun N-terminal kinase (JNK), and NF-κB, whereas upregulation of TSLP protein was prevented by inhibitors of pan-PKC, PI3K, JNK, and NF-κB.



Conclusions:

Expression of IL-33 and TSLP in nasal fibroblasts was regulated via distinct signal transduction pathways including NF-κB.

Regulation of interleukin-33 and thymic stromal lymphopoietin in human nasal fibroblasts by proinflammatory cytokines

Objective: Intranasal insulin administration has therapeutic potential for Alzheimer's disease and in intranasal administration across the nasal mucosa, the paracellular pathway regulated by tight junctions is important. The C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) binds the tight junction protein claudin and disrupts the tight junctional barrier without a cytotoxic effect. The C-CPE mutant called C-CPE 194 binds only to claudin-4, whereas the C-CPE 194 mutant called C-CPE m19 binds not only to claudin-4 but also to claudin-1.Methods: In the present study, to investigate the effects of C-CPE mutants on the tight junctional functions of human nasal epithelial cells (HNECs) and on the permeability of human recombinant insulin across the cells, HNECs were treated with C-CPE 194 and C-CPE m19.Results: C-CPE 194 and C-CPE m19 disrupted the barrier and fence functions without changes in expression of claudin-1, -4, -7, and occludin or cytotoxicity, whereas they transiently incr...

https://www.tandfonline.com/doi/pdf/10.3109/10717544.2015.1050530

Claudin-binder C-CPE mutants enhance permeability of insulin across human nasal epithelial cells

Ranulas are conventionally treated by total resection, marsupialization or intracystic OK-432 injection. We clinically studied 16 such cases from 2000 to 2008—15 sublingual and 1 mixed. The ranula was excised in 7 cases with recurrence in 42.9%, marsupialized in 3 with 100% recurrence, the sublingual gland totally resected in 4 with no recurrence, and OK-432 injected intracystically in 2 with 50% recurrence. Our results thus suggest that total sublingual gland resection is an effective method for the treatment of ranula.

Takashi Keira

Papers

Regulation of Tight Junctions in Upper Airway Epithelium

Pseudomonas aeruginosa elastase causes transient disruption of tight junctions and downregulation of PAR-2 in human nasal epithelial cells.

Regulation of interleukin-33 and thymic stromal lymphopoietin in human nasal fibroblasts by proinflammatory cytokines

Claudin-binder C-CPE mutants enhance permeability of insulin across human nasal epithelial cells

A Clinical Study of 16 Cases of Ranula