Role of Innate Immunity in the Pathogenesis of Chronic Rhinosinusitis: Progress and New Avenues

Chronic rhinosinusitis is a heterogeneous and multifactorial disease with unknown etiology. Aberrant responses to microorganisms have been suggested to play a role in the pathophysiology of the disease. Research has focused on the presence, detection, response to, and eradication of these potential threats. Main topics seem to center on the contribution of structural cells such as epithelium and fibroblasts, on the consequences of activation of pattern-recognition receptors, and on the role of antimicrobial agents. This research should be viewed not only in the light of a comparison between healthy and diseased individuals, but also in a comparison between patients who do or do not respond to treatment. New players that could play a role in the pathophysiology seem to surface at regular intervals, adding to our understanding (and the complexity) of the disease and opening new avenues that may help fight this incapacitating disease

Polymorphisms in RYBP and AOAH Genes Are Associated with Chronic Rhinosinusitis in a Chinese Population: A Replication Study

BACKGROUND: The development of CRS is believed to be the result of combined interactions between the genetic background of the affected subject and environmental factors. OBJECTIVES: To replicate and extend our recent findings from genetic association studies in chronic rhinosinusitis (CRS) performed in a Canadian Caucasian population in a Chinese population. METHODS: In a case-control replication study, DNA samples were obtained from CRS with (n  = 306; CRSwNP) and without (n = 332; CRSsNP) nasal polyps, and controls (n = 315) in a Chinese population. A total of forty-nine single nucleotide polymorphisms (SNPs) selected from previous identified SNPs associated with CRS in Canadian population, and SNPs from the CHB HapMap dataset were individually genotyped. RESULTS: We identified two SNPs respectively in RYBP (rs4532099, p = 2.15E-06, OR = 2.59) and AOAH (rs4504543, p = 0.0001152, OR = 0.58) significantly associated with whole CRS cohort. Subgroup analysis for the presence of nasal polyps (CRSwNP and CRSsNP) displayed significant association in CRSwNP cohorts regarding to one SNP in RYBP (P = 3.24(E)-006, OR = 2.76). Evidence of association in the CRSsNP groups in terms of 2 SNPs (AOAH_rs4504543 and RYBP_rs4532099) was detected as well. Stratifying analysis by gender demonstrated that none of the selected SNPs were associated with CRSwNP as well as CRSsNP. Meanwhile 3 SNPs (IL1A_rs17561, P = 0.005778; IL1A_rs1800587, P = 0.009561; IRAK4_rs4251513, P = 0.03837) were associated with serum total IgE level. CONCLUSIONS: These genes are biologically plausible, with roles in regulation of transcription (RYBP) and inflammatory response (AOAH). The present data suggests the potential common genetic basis in the development of CRS in Chinese and Caucasian population

The Ser82 RAGE variant affects lung function and serum RAGE in smokers and sRAGE production in vitro

Introduction: Genome-Wide Association Studies have identified associations between lung function measures and Chronic Obstructive Pulmonary Disease (COPD) and chromosome region 6p21 containing the gene for the Advanced Glycation End Product Receptor (AGER, encoding RAGE). We aimed to (i) characterise RAGE expression in the lung, (ii) identify AGER transcripts, (iii) ascertain if SNP rs2070600 (Gly82Ser C/T) is associated with lung function and serum sRAGE levels and (iv) identify whether the Gly82Ser variant is functionally important in altering sRAGE levels in an airway epithelial cell model. Methods: Immunohistochemistry was used to identify RAGE protein expression in 26 human tissues and qPCR was used to quantify AGER mRNA in lung cells. Gene expression array data was used to identify AGER expression during lung development in 38 fetal lung samples. RNA-Seq was used to identify AGER transcripts in lung cells. sRAGE levels were assessed in cells and patient serum by ELISA. BEAS2B-R1 cells were transfected to overexpress RAGE protein with either the Gly82 or Ser82 variant and sRAGE levels identified. Results: Immunohistochemical assessment of 6 adult lung samples identified high RAGE expression in the alveoli of healthy adults and individuals with COPD. AGER/RAGE expression increased across developmental stages in human fetal lung at both the mRNA (38 samples) and protein levels (20 samples). Extensive AGER splicing was identified. The rs2070600T (Ser82) allele is associated with higher FEV1, FEV1/FVC and lower serum sRAGE levels in UK smokers. Using an airway epithelium model overexpressing the Gly82 or Ser82 variants we found that HMGB1 activation of the RAGE-Ser82 receptor results in lower sRAGE production. Conclusions: This study provides new information regarding the expression profile and potential role of RAGE in the human lung and shows a functional role of the Gly82Ser variant. These findings advance our understanding of the potential mechanisms underlying COPD particularly for carriers of this AGER polymorphism

Cutaneous lesions of the nose

Skin diseases on the nose are seen in a variety of medical disciplines. Dermatologists, otorhinolaryngologists, general practitioners and general plastic and dermatologic surgeons are regularly consulted regarding cutaneous lesions on the nose. This article is the second part of a review series dealing with cutaneous lesions on the head and face, which are frequently seen in daily practice by a dermatologic surgeon. In this review, we focus on those skin diseases on the nose where surgery or laser therapy is considered a possible treatment option or that can be surgically evaluated

Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial Phagocytosis and Efferocytosis by Macrophages in COPD

Pulmonary inflammation and bacterial colonization are central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Defects in macrophage phagocytosis of both bacteria and apoptotic cells contribute to the COPD phenotype. Small molecule inhibitors with anti-inflammatory activity against p38 mitogen activated protein kinases (MAPKs), phosphatidyl-inositol-3 kinase (PI3K) and Rho kinase (ROCK) are being investigated as novel therapeutics in COPD. Concerns exist, however, about off-target effects. We investigated the effect of p38 MAPK inhibitors (VX745 and SCIO469), specific inhibitors of PI3K α (NVS-P13K-2), δ (NVS-P13K-3) or γ (NVS-P13K-5) and a ROCK inhibitor PF4950834 on macrophage phagocytosis, early intracellular killing of bacteria and efferocytosis of apoptotic neutrophils. Alveolar macrophages (AM) obtained from broncho-alveolar lavage (BAL) or monocyte-derived macrophages (MDM) from COPD patients (GOLD stage II/III) enrolled from a well characterized clinical cohort (MRC COPD-MAP consortium) or from healthy ex-smoker controls were studied. Both COPD AM and MDM exhibited lower levels of bacterial phagocytosis (using Streptococcus pneumoniae and non-typeable Haemophilus influenzae) and efferocytosis than healthy controls. None of the inhibitors altered bacterial internalization or early intracellular bacterial killing in AM or MDM. Conversely PF4950834, but not other inhibitors, enhanced efferocytosis in COPD AM and MDM. These results suggest none of these inhibitors are likely to exacerbate phagocytosis-related defects in COPD, while confirming ROCK inhibitors can enhance efferocytosis in COPD

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

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

Analysis of Olfaction after Bilateral Nasoseptal Rescue Flap Transsphenoidal Approach with Olfactory Mucosal Preservation.

OBJECTIVE: To ascertain the impact of septal olfactory strip preservation and bilateral rescue flap elevation on the incidence of olfactory dysfunction. STUDY DESIGN: Case series with chart review of patients undergoing endoscopic endonasal skull base surgery (2012-2014). SETTING: Providence Saint John\u27s Health Center and John Wayne Cancer Institute. SUBJECTS AND METHODS: The incidences of postoperative epistaxis, hyposmia, and anosmia were analyzed using the Brief Smell Identification Test (B-SIT), which was completed in 110 of the 165 patients. RESULTS: Seventy-eight patients required extended approaches. Bilateral nasoseptal rescue flaps were elevated in 144 patients (87.3%) and pedicled nasoseptal or middle turbinate flaps in 21 patients (12.7%). The neurovascular pedicles were preserved in all patients, and there were no episodes of postoperative arterial epistaxis. Normal olfaction was noted in 95 patients (86%), with new hyposmia noted in 5 patients (5.5%). Within the rescue flap cohort, new hyposmia occurred in 6.3% ( CONCLUSIONS: Superior olfactory strip preservation during elevation of reconstructive flaps preserves olfactory function and maintains adequate surgical exposure. In addition, rescue flaps have significantly diminished the rate of arterial postoperative epistaxis while maintaining the ability to harvest nasoseptal flaps for future reconstruction