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Int J Mol Sci ; 22(14)2021 Jul 15.
Article in English | MEDLINE | ID: covidwho-1323264


The human paranasal sinuses are the major source of intrinsic nitric oxide (NO) production in the human airway. NO plays several roles in the maintenance of physiological homeostasis and the regulation of airway inflammation through the expression of three NO synthase (NOS) isoforms. Measuring NO levels can contribute to the diagnosis and assessment of allergic rhinitis (AR) and chronic rhinosinusitis (CRS). In symptomatic AR patients, pro-inflammatory cytokines upregulate the expression of inducible NOS (iNOS) in the inferior turbinate. Excessive amounts of NO cause oxidative damage to cellular components, leading to the deposition of cytotoxic substances. CRS phenotype and endotype classifications have provided insights into modern treatment strategies. Analyses of the production of sinus NO and its metabolites revealed pathobiological diversity that can be exploited for useful biomarkers. Measuring nasal NO based on different NOS activities is a potent tool for specific interventions targeting molecular pathways underlying CRS endotype-specific inflammation. We provide a comprehensive review of the functional diversity of NOS isoforms in the human sinonasal system in relation to these two major nasal disorders' pathologies. The regulatory mechanisms of NOS expression associated with the substrate bioavailability indicate the involvement of both type 1 and type 2 immune responses.

Nasal Mucosa/enzymology , Nitric Oxide Synthase/metabolism , Nitric Oxide/metabolism , Paranasal Sinuses/enzymology , Rhinitis, Allergic/physiopathology , Sinusitis/physiopathology , Animals , Chronic Disease , Humans , Isoenzymes , Rhinitis, Allergic/metabolism , Sinusitis/metabolism
J Laryngol Otol ; 135(9): 773-778, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1233677


OBJECTIVE: Severe acute respiratory syndrome coronavirus-2 uses angiotensin-converting enzyme-2 as a primary receptor for invasion. This study investigated angiotensin-converting enzyme-2 expression in the sinonasal mucosa of patients with chronic rhinosinusitis, as this could be linked to a susceptibility to severe acute respiratory syndrome coronavirus-2 infection. METHODS: Ethmoid sinus specimens were obtained from 27 patients with eosinophilic chronic rhinosinusitis, 18 with non-eosinophilic chronic rhinosinusitis and 18 controls. The angiotensin-converting enzyme-2 and other inflammatory cytokine and chemokine messenger RNA levels were assessed by quantitative reverse transcription polymerase chain reaction. Angiotensin-converting enzyme-2 positive cells were examined immunohistologically. RESULTS: The eosinophilic chronic rhinosinusitis patients showed a significant decrease in angiotensin-converting enzyme-2 messenger RNA expression. In the chronic rhinosinusitis patients, angiotensin-converting enzyme-2 messenger RNA levels were positively correlated with tumour necrosis factor-α and interleukin-1ß (r = 0.4971 and r = 0.3082, respectively), and negatively correlated with eotaxin-3 (r = -0.2938). Angiotensin-converting enzyme-2 immunoreactivity was mainly localised in the ciliated epithelial cells. CONCLUSION: Eosinophilic chronic rhinosinusitis patients with type 2 inflammation showed decreased angiotensin-converting enzyme-2 expression in their sinus mucosa. Angiotensin-converting enzyme-2 regulation was positively related to pro-inflammatory cytokines, especially tumour necrosis factor-α production, in chronic rhinosinusitis patients.

Angiotensin-Converting Enzyme 2/metabolism , Nasal Mucosa/enzymology , Rhinitis/enzymology , Sinusitis/enzymology , Adult , COVID-19/etiology , Chronic Disease , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Nasal Mucosa/metabolism , Nasal Mucosa/virology , Reverse Transcriptase Polymerase Chain Reaction , Rhinitis/complications , Rhinitis/metabolism , SARS-CoV-2/metabolism , Sinusitis/complications , Sinusitis/metabolism
Nat Commun ; 11(1): 5453, 2020 10 28.
Article in English | MEDLINE | ID: covidwho-894390


The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen.

Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Coronavirus Infections/pathology , Gene Expression/drug effects , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/pathology , Respiratory System/pathology , Age Factors , Angiotensin-Converting Enzyme 2 , COVID-19 , Cilia/metabolism , Coronavirus Infections/virology , Endothelial Cells , Goblet Cells/metabolism , Humans , Lung/pathology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Respiratory System/metabolism , Respiratory System/virology , Sex Factors , Sinusitis/metabolism , Smoking