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1.
Sci Adv ; 8(14): eabh2445, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35394843

RESUMO

Nasopharyngeal cancer (NPC) is an Epstein-Barr virus (EBV)-positive epithelial malignancy with an extensive inflammatory infiltrate. Traditional RNA-sequencing techniques uncovered only microenvironment signatures, while the gene expression of the tumor epithelial compartment has remained a mystery. Here, we use Smart-3SEQ to prepare transcriptome-wide gene expression profiles from microdissected NPC tumors, dysplasia, and normal controls. We describe changes in biological pathways across the normal to tumor spectrum and show that fibroblast growth factor (FGF) ligands are overexpressed in NPC tumors, while negative regulators of FGF signaling, including SPRY1, SPRY2, and LGALS3, are down-regulated early in carcinogenesis. Within the NF-κB signaling pathway, the critical noncanonical transcription factors, RELB and NFKB2, are enriched in the majority of NPC tumors. We confirm the responsiveness of EBV-positive NPC cell lines to targeted inhibition of these pathways, reflecting the heterogeneity in NPC patient tumors. Our data comprehensively describe the gene expression landscape of NPC and unravel the mysteries of receptor tyrosine kinase and NF-κB pathways in NPC.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Linhagem Celular Tumoral , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/patologia , Fatores de Crescimento de Fibroblastos/metabolismo , Expressão Gênica , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Transdução de Sinais , Microambiente Tumoral
2.
Am J Physiol Lung Cell Mol Physiol ; 322(5): L712-L721, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35318858

RESUMO

Accumulating evidence has confirmed that chronic obstructive pulmonary disease (COPD) is a risk factor for development of severe pathological changes in the peripheral lungs of patients with COVID-19. However, the underlying molecular mechanisms remain unclear. Because bronchiolar club cells are crucial for maintaining small airway homeostasis, we sought to explore whether the altered susceptibility to SARS-CoV-2 infection of the club cells might have contributed to the severe COVID-19 pneumonia in COPD patients. Our investigation on the quantity and distribution patterns of angiotensin-converting enzyme 2 (ACE2) in airway epithelium via immunofluorescence staining revealed that the mean fluorescence intensity of the ACE2-positive epithelial cells was significantly higher in club cells than those in other epithelial cells (including ciliated cells, basal cells, goblet cells, neuroendocrine cells, and alveolar type 2 cells). Compared with nonsmokers, the median percentage of club cells in bronchiolar epithelium and ACE2-positive club cells was significantly higher in COPD patients. In vitro, SARS-CoV-2 infection (at a multiplicity of infection of 1.0) of primary small airway epithelial cells, cultured on air-liquid interface, confirmed a higher percentage of infected ACE2-positive club cells in COPD patients than in nonsmokers. Our findings have indicated the role of club cells in modulating the pathogenesis of SARS-CoV-2-related severe pneumonia and the poor clinical outcomes, which may help physicians to formulate a novel therapeutic strategy for COVID-19 patients with coexisting COPD.


Assuntos
COVID-19 , Doença Pulmonar Obstrutiva Crônica , Enzima de Conversão de Angiotensina 2 , Células Epiteliais , Humanos , Pulmão , Peptidil Dipeptidase A , SARS-CoV-2
4.
Allergy ; 2022 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-35274302

RESUMO

BACKGROUND: Human rhinoviruses (HRVs) are frequently associated with asthma exacerbations, and have been found in the airways of asthmatic patients. While HRV-induced acute infection is well-documented, it is less clear whether the nasal epithelium sustains prolonged HRV infections along with the associated activation of host immune responses. OBJECTIVE: To investigate sustainably regulated host responses of human nasal epithelial cells (hNECs) during HRV persistence. METHODS: Using a time-course study, HRV16 persistence and viral replication dynamics were established using an in vitro infection model of hNECs. RNA sequencing was performed on hNECs in the early and late stages of infection at 3 and 14 days post-infection (dpi), respectively. The functional enrichment of differentially expressed genes (DEGs) was evaluated using gene ontology (GO) and Ingenuity pathway analysis. RESULTS: HRV RNA and protein expression persisted throughout prolonged infections, even after decreased production of infectious virus progeny. GO analysis of unique DEGs indicated altered regulation of pathways related to ciliary function and airway remodeling at 3 dpi and serine-type endopeptidase activity at 14 dpi. The functional enrichment of shared DEGs between the two time-points was related to interferon (IFN) and cytoplasmic pattern recognition receptor (PRR) signaling pathways. Validation of the sustained regulation of candidate genes confirmed the persistent expression of RIG-I and revealed its close co-regulation with interferon-stimulated genes (ISGs) during HRV persistence. CONCLUSIONS: The persistence of HRV RNA does not necessarily indicate an active infection during prolonged infection. The sustained expression of RIG-I and ISGs in response to viral RNA persistence highlights the importance of assessing how immune-activating host factors can change during active HRV infection and the immune regulation that persists thereafter.

5.
Mil Med Res ; 9(1): 7, 2022 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-35093168

RESUMO

BACKGROUND: Airway inflammation is the core pathological process of asthma, with the key inflammatory regulators incompletely defined. Recently, fibroblast growth factor 2 (FGF2) has been reported to be an inflammatory regulator; however, its role in asthma remains elusive. This study aimed to investigate the immunomodulatory role of FGF2 in asthma. METHODS: First, FGF2 expression was characterised in clinical asthma samples and the house dust mite (HDM)-induced mouse chronic asthma model. Second, recombinant mouse FGF2 (rm-FGF2) protein was intranasally delivered to determine the effect of FGF2 on airway inflammatory cell infiltration. Third, human airway epithelium-derived A549 cells were stimulated with either HDM or recombinant human interleukin-1ß (IL-1ß) protein combined with or without recombinant human FGF2. IL-1ß-induced IL-6 or IL-8 release levels were determined using enzyme-linked immunosorbent assay, and the involved signalling transduction was explored via Western blotting. RESULTS: Compared with the control groups, the FGF2 protein levels were significantly upregulated in the bronchial epithelium and alveolar areas of clinical asthma samples (6.70 ± 1.79 vs. 16.32 ± 2.40, P = 0.0184; 11.20 ± 2.11 vs. 21.00 ± 3.00, P = 0.033, respectively) and HDM-induced asthmatic mouse lung lysates (1.00 ± 0.15 vs. 5.14 ± 0.42, P < 0.001). Moreover, FGF2 protein abundance was positively correlated with serum total and anti-HDM IgE levels in the HDM-induced chronic asthma model (R2 = 0.857 and 0.783, P = 0.0008 and 0.0043, respectively). Elevated FGF2 protein was mainly expressed in asthmatic bronchial epithelium and alveolar areas and partly co-localised with infiltrated inflammatory cell populations in HDM-induced asthmatic mice. More importantly, intranasal instillation of rm-FGF2 aggravated airway inflammatory cell infiltration (2.45 ± 0.09 vs. 2.88 ± 0.14, P = 0.0288) and recruited more subepithelial neutrophils after HDM challenge [(110.20 ± 29.43) cells/mm2 vs. (238.10 ± 42.77) cells/mm2, P = 0.0392] without affecting serum IgE levels and Th2 cytokine transcription. In A549 cells, FGF2 was upregulated through HDM stimulation and promoted IL-1ß-induced IL-6 or IL-8 release levels (up to 1.41 ± 0.12- or 1.44 ± 0.14-fold change vs. IL-1ß alone groups, P = 0.001 or 0.0344, respectively). The pro-inflammatory effect of FGF2 is likely mediated through the fibroblast growth factor receptor (FGFR)/mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) pathway. CONCLUSION: Our findings suggest that FGF2 is a potential inflammatory modulator in asthma, which can be induced by HDM and acts through the FGFR/MAPK/NF-κB pathway in the airway epithelial cells.


Assuntos
Asma , NF-kappa B , Animais , Asma/metabolismo , Asma/patologia , Células Epiteliais/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Inflamação/metabolismo , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo
7.
mBio ; : e0343621, 2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35038898

RESUMO

The dynamics of SARS-CoV-2 infection in COVID-19 patients are highly variable, with a subset of patients demonstrating prolonged virus shedding, which poses a significant challenge for disease management and transmission control. In this study, the long-term dynamics of SARS-CoV-2 infection were investigated using a human well-differentiated nasal epithelial cell (NEC) model of infection. NECs were observed to release SARS-CoV-2 virus onto the apical surface for up to 28 days postinfection (dpi), further corroborated by viral antigen staining. Single-cell transcriptome sequencing (sc-seq) was utilized to explore the host response from infected NECs after short-term (3-dpi) and long-term (28-dpi) infection. We identified a unique population of cells harboring high viral loads present at both 3 and 28 dpi, characterized by expression of cell stress-related genes DDIT3 and ATF3 and enriched for genes involved in tumor necrosis factor alpha (TNF-α) signaling and apoptosis. Remarkably, this sc-seq analysis revealed an antiviral gene signature within all NEC cell types even at 28 dpi. We demonstrate increased replication of basal cells, absence of widespread cell death within the epithelial monolayer, and the ability of SARS-CoV-2 to replicate despite a continuous interferon response as factors likely contributing to SARS-CoV-2 persistence. This study provides a model system for development of therapeutics aimed at improving viral clearance in immunocompromised patients and implies a crucial role for immune cells in mediating viral clearance from infected epithelia. IMPORTANCE Increasing medical attention has been drawn to the persistence of symptoms (long-COVID syndrome) or live virus shedding from subsets of COVID-19 patients weeks to months after the initial onset of symptoms. In vitro approaches to model viral or symptom persistence are needed to fully dissect the complex and likely varied mechanisms underlying these clinical observations. We show that in vitro differentiated human NECs are persistently infected with SARS-CoV-2 for up to 28 dpi. This viral replication occurred despite the presence of an antiviral gene signature across all NEC cell types even at 28 dpi. This indicates that epithelial cell intrinsic antiviral responses are insufficient for the clearance of SARS-CoV-2, implying an essential role for tissue-resident and infiltrating immune cells for eventual viral clearance from infected airway tissue in COVID-19 patients.

9.
Handb Exp Pharmacol ; 268: 151-170, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34085123

RESUMO

Chronic rhinosinusitis (CRS) is a clinical syndrome stemming from persistent inflammation of the sinonasal mucosa. Phenotypically, it is traditionally and widely described according to the presence or absence of polyps. While this distinction is simple to use, it has little bearing on prognosis and treatment, for CRS is essentially an inflammatory disease resulting from dysregulated interaction between a multitude of host and environmental factors. Allergy is merely one of them and, like many of the proposed aetiologies, has been subject to much debate which will be discussed here. As our understanding of CRS continues to evolve, previous so-called conventional wisdom about phenotypes (e.g. CRS with nasal polyps is associated with Type 2 inflammation) is being challenged, and new phenotypes are also emerging. In addition, there is growing interest in defining the endotypes of CRS to deliver precise and personalised treatment, especially pertaining to the development of biologics for the group of severe, difficult-to-treat CRS patients. A proposed model of precision medicine tailored to management of CRS will also be introduced to readers, which can be continually modified to adapt to new discoveries about this exciting condition.


Assuntos
Hipersensibilidade , Pólipos Nasais , Rinite , Sinusite , Doença Crônica , Humanos , Pólipos Nasais/tratamento farmacológico , Medicina de Precisão , Rinite/diagnóstico , Rinite/tratamento farmacológico , Rinite/etiologia , Sinusite/diagnóstico , Sinusite/tratamento farmacológico , Sinusite/etiologia
10.
Viruses ; 13(11)2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34835030

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of coronavirus disease 2019 (COVID-19). It is known as a respiratory virus, but SARS-CoV-2 appears equally, or even more, infectious for the olfactory epithelium (OE) than for the respiratory epithelium in the nasal cavity. In light of the small area of the OE relative to the respiratory epithelium, the high prevalence of olfactory dysfunctions (ODs) in COVID-19 has been bewildering and has attracted much attention. This review aims to first examine the cytological and molecular biological characteristics of the OE, especially the microvillous apical surfaces of sustentacular cells and the abundant SARS-CoV-2 receptor molecules thereof, that may underlie the high susceptibility of this neuroepithelium to SARS-CoV-2 infection and damages. The possibility of SARS-CoV-2 neurotropism, or the lack of it, is then analyzed with regard to the expression of the receptor (angiotensin-converting enzyme 2) or priming protease (transmembrane serine protease 2), and cellular targets of infection. Neuropathology of COVID-19 in the OE, olfactory bulb, and other related neural structures are also reviewed. Toward the end, we present our perspectives regarding possible mechanisms of SARS-CoV-2 neuropathogenesis and ODs, in the absence of substantial viral infection of neurons. Plausible causes for persistent ODs in some COVID-19 convalescents are also examined.


Assuntos
Anosmia/epidemiologia , Anosmia/etiologia , COVID-19/complicações , Mucosa Olfatória/virologia , SARS-CoV-2/fisiologia , Tropismo Viral , Enzima de Conversão de Angiotensina 2/metabolismo , Anosmia/fisiopatologia , COVID-19/patologia , COVID-19/virologia , Humanos , Bulbo Olfatório/patologia , Bulbo Olfatório/virologia , Mucosa Olfatória/metabolismo , Mucosa Olfatória/ultraestrutura , Prevalência , Receptores de Coronavírus/metabolismo
11.
Int J Mol Sci ; 22(21)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34769038

RESUMO

Tetraspanins are transmembrane glycoproteins that have been shown increasing interest as host factors in infectious diseases. In particular, they were implicated in the pathogenesis of both non-enveloped (human papillomavirus (HPV)) and enveloped (human immunodeficiency virus (HIV), Zika, influenza A virus, (IAV), and coronavirus) viruses through multiple stages of infection, from the initial cell membrane attachment to the syncytium formation and viral particle release. However, the mechanisms by which different tetraspanins mediate their effects vary. This review aimed to compare and contrast the role of tetraspanins in the life cycles of HPV, HIV, Zika, IAV, and coronavirus viruses, which cause the most significant health and economic burdens to society. In doing so, a better understanding of the relative contribution of tetraspanins in virus infection will allow for a more targeted approach in the treatment of these diseases.


Assuntos
Interações Hospedeiro-Patógeno/fisiologia , Tetraspaninas/fisiologia , Viroses/metabolismo , Regulação Viral da Expressão Gênica , HIV-1/patogenicidade , Humanos , Vírus da Influenza A/patogenicidade , Papillomaviridae/patogenicidade , SARS-CoV-2/patogenicidade , Viroses/genética , Viroses/virologia , Internalização do Vírus , Zika virus/patogenicidade
12.
Expert Rev Respir Med ; 15(12): 1517-1523, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34613861

RESUMO

INTRODUCTION: Upper respiratory tract infection (URTI) is an illness caused by an acute infection by viruses or bacteria of the nose, sinuses, pharynx, and larynx. Most URTIs are short, mild, and self-limiting, but some can lead to serious complications, resulting in heavy social and economic burden on individuals and society. AREAS COVERED: This article presents the management guidelines and consensus established through the Delphi method during an expert roundtable conducted in November 2020 and results of a targeted literature review. EXPERT OPINION: The current acute URTI management strategies aim toward symptom alleviation and prevention of URTI virus transmission. The effectiveness of these strategies is highly increased with early intervention, administered prior to the peaking of viral shedding. This reduces the chances of developing a full-blown acute URTI, decreases symptom severity, and reduces viral transmission. Mucoadhesive gel nasal sprays have shown promising results for early intervention of acute URTI. They act by creating a barrier that can trap virus particles, thereby preventing invasion of the mucosa by the virus. Additionally, they deliver broad spectrum activity that is effective against a wide variety of pathogens that cause acute URTI. Acute URTI warrants greater attention and proactive management in reducing its burden.


Assuntos
Infecções Respiratórias , Humanos , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/tratamento farmacológico
13.
Mil Med Res ; 8(1): 47, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465396

RESUMO

SARS-CoV-2 is a newly identified member of the coronavirus family that has caused the Coronavirus disease 2019 (COVID-19) pandemic. This rapidly evolving and unrelenting SARS-CoV-2 has disrupted the lives and livelihoods of millions worldwide. As of 23 August 2021, a total of 211,373,303 COVID-19 cases have been confirmed globally with a death toll of 4,424,341. A strong understanding of the infection pathway of SARS-CoV-2, and how our immune system responds to the virus is highly pertinent for guiding the development and improvement of effective treatments. In this review, we discuss the current understanding of neutralising antibodies (NAbs) and their implications in clinical practice. The aspects include the pathophysiology of the immune response, particularly humoral adaptive immunity and the roles of NAbs from B cells in infection clearance. We summarise the onset and persistence of IgA, IgM and IgG antibodies, and we explore their roles in neutralising SARS-CoV-2, their persistence in convalescent individuals, and in reinfection. Furthermore, we also review the applications of neutralising antibodies in the clinical setting-from predictors of disease severity to serological testing to vaccinations, and finally in therapeutics such as convalescent plasma infusion.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , COVID-19/terapia , Imunidade Humoral , SARS-CoV-2/imunologia , Anticorpos Neutralizantes/imunologia , COVID-19/epidemiologia , COVID-19/imunologia , Humanos , Imunização Passiva , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Pandemias , Glicoproteína da Espícula de Coronavírus/imunologia
14.
J Inflamm Res ; 14: 2769-2780, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234504

RESUMO

BACKGROUND: Epithelial cytokines including IL-25, IL-33 and thymic stromal lymphopoietin (TLSP) are recently established as drivers of type 2 chronic inflammatory diseases such as chronic rhinosinusitis with nasal polyps (CRSwNP). Here, we further confirmed the increased expression of IL-25 in CRSwNP and investigated potential contributors of IL-25 in CRSwNP epithelium. METHODS: Sixty CRSwNP, 25 CRSsNP and 15 healthy control tissues were examined for IL-25 expression and for the accompanying type 2 inflammatory cytokines. We then tested different respiratory virus infections on human nasal epithelial cells (hNECs) for their ability to trigger IL-25 expression. In addition, we subjected hNECs generated from CRSwNP tissues to pretreatment with recombinant interferon-alpha (IFN-α) prior to viral infection to evaluate IFN effects on IL-25 induction. RESULTS: We confirmed that significantly enhanced levels of IL-25 were observed in CRSwNP tissues, and that IL-25 expression correlated with type 2 inflammatory cytokine expression. In vitro, we observed significantly elevated IL-25 in hNECs infected with influenza A virus as early as 24 hours post-infection (hpi), regardless of tissue origin, and IL-25 correlated positively with viral load. While other respiratory viruses exhibited increasing trends of IL-25, these were not significant at the time-points tested. IFN-α treatment of CRSwNP epithelium was found to exert bimodal effects, ie IFN-α treatment alone induced moderate IL-25 expression, whereas IFN-α pretreatment of hNECs before influenza infection significantly diminished IL-25 induction by active influenza virus infection. CONCLUSION: We have authenticated the observation of elevated IL-25 in CRSwNP, which is correlated with type 2 inflammatory cytokines. Notably, we identified influenza virus infection as a potential contributor of IL-25 in both control and CRSwNP epithelium during active infection. This IL-25 induction can be abated by IFN-α pretreatment which ameliorated active influenza infection. TRIAL REGISTRATION: Chictr.org.cn ChiCTR-BON-16010179, Registered 18 December 2016, http://www.chictr.org.cn/showproj.aspx?proj=17331. The authors agree on the sharing of deidentified participant data where it pertains to request directly related to the data in this article when contacted (Haiyu Hong; honghy@mail.sysu.edu.cn).

15.
Commun Biol ; 4(1): 832, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215830

RESUMO

Sialyl-Lewis x (sLex, CD15s) is a tetra-saccharide on the surface of leukocytes required for E-selectin-mediated rolling, a prerequisite for leukocytes to migrate out of the blood vessels. Here we show using flow cytometry that sLex expression on basophils and mast cell progenitors depends on fucosyltransferase 6 (FUT6). Using genetic association data analysis and qPCR, the cell type-specific defect was associated with single nucleotide polymorphisms (SNPs) in the FUT6 gene region (tagged by rs17855739 and rs778798), affecting coding sequence and/or expression level of the mRNA. Heterozygous individuals with one functional FUT6 gene harbor a mixed population of sLex+ and sLex- basophils, a phenomenon caused by random monoallelic expression (RME). Microfluidic assay demonstrated FUT6-deficient basophils rolling on E-selectin is severely impaired. FUT6 null alleles carriers exhibit elevated blood basophil counts and a reduced itch sensitivity against insect bites. FUT6-deficiency thus dampens the basophil-mediated allergic response in the periphery, evident also in lower IgE titers and reduced eosinophil counts.


Assuntos
Basófilos/metabolismo , Fucosiltransferases/genética , Expressão Gênica , Antígeno Sialil Lewis X/biossíntese , Sequência de Bases , Basófilos/citologia , Células Cultivadas , Estudos de Coortes , Selectina E/metabolismo , Fucosiltransferases/deficiência , Perfilação da Expressão Gênica/métodos , Humanos , Contagem de Leucócitos , Migração e Rolagem de Leucócitos/genética , Migração e Rolagem de Leucócitos/fisiologia , Polimorfismo de Nucleotídeo Único , Homologia de Sequência do Ácido Nucleico
16.
J Inflamm Res ; 14: 2979-2991, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262323

RESUMO

BACKGROUND: Nasal inverted papilloma (NIP) is defined based on its histological characteristic of inverted epithelium growth into the stroma. The inversion can result in epithelial growth in the underlying connective tissue stroma when the basement membrane completely separates from the epithelial layer. To date, such inversion mechanism underlying NIP's pathological phenomenon is unknown. Therefore, we hypothesized that mediators and soluble proteins released by neutrophils, the most predominant infiltrating cells in NIP, is vital in causing the epithelial changes and pathogenesis of NIP. METHODS: We collected 37 NIP tissues from patients who underwent surgical removal of NIP and performed hematoxylin-eosin (HE), immunohistochemical, and immunofluorescence staining to analyze in-depth the basic characteristics of NIP, including detecting the expression and distribution of MMPs and associated factors in NIP. Western blotting and quantitative real-time PCR were further performed to analyze the protein and mRNA expression levels of specific factors including MMPs, HIF-1α, and tissue inhibitors of metalloproteinases (TIMPs). RESULTS: We observed finger-like projections that insert into the epithelium in NIP tissue as its main characteristics. The projections contain fibroblasts, extracellular matrix, capillaries, and infiltrating inflammatory cells. We found abundant neutrophils clustered at the finger-like projection of NIP, and also noted MMP-1 and MMP-9 were up-regulated in NIP (p<0.05), whereas TIMP-1/3 was decreased. The expression level of HIF-1α was also found to be increased in NIP tissue. We further showed that MMP-9 and HIF-1α were mainly expressed by neutrophils and were predominantly observed in the finger-like projections that contribute to the NIP pathology. CONCLUSION: Upregulation and release of MMP-9 and HIF-1α from infiltrating neutrophils may cause damage to the epithelial basement membrane and epithelial clefts, forming finger-like projections with angiogenesis and fibroblasts insertion, resulting in epithelial growth in the tissue stroma, a typical histo-pathological characteristic in NIP.

17.
Curr Allergy Asthma Rep ; 21(6): 38, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34259961

RESUMO

PURPOSE OF REVIEW: Increasing knowledge of the pathogenesis of the SARS-CoV-2 infection and the complex interaction between host and viral factors have allowed clinicians to stratify the severity of COVID-19 infection. Epidemiological data has also helped to model viral carriage and infectivity. This review presents a comprehensive summary of the pathophysiology of COVID-19, the mechanisms of action of the SARS-CoV-2 virus, and the correlation with the clinical and biochemical characteristics of the disease. RECENT FINDINGS: ACE2 and TMPRSS2 receptors have emerged as a key player in the mechanism of infection of SARS-CoV-2. Their distribution throughout the body has been shown to impact the organ-specific manifestations of COVID-19. The immune-evasive and subsequently immunoregulative properties of SARS-CoV-2 are also shown to be implicated in disease proliferation and progression. Information gleaned from the virological properties of SARS-CoV-2 is consistent with and reflects the clinical behavior of the COVID-19 infection. Further study of specific clinical phenotypes and severity classes of COVID-19 may assist in the development of targeted therapeutics to halt progression of disease from mild to moderate-severe. As the understanding of the pathophysiology and mechanism of action of SARS-CoV-2 continues to grow, it is our hope that better and more effective treatment options continue to emerge.


Assuntos
COVID-19/fisiopatologia , SARS-CoV-2/patogenicidade , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/virologia , Progressão da Doença , Humanos , Evasão da Resposta Imune , Especificidade de Órgãos , SARS-CoV-2/imunologia , Serina Endopeptidases/metabolismo , Índice de Gravidade de Doença , Internalização do Vírus
18.
Biomaterials ; 274: 120876, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34034027

RESUMO

Rapid diagnostics of adventitious agents in biopharmaceutical/cell manufacturing release testing and the fight against viral infection have become critical. Quantitative real-time PCR and CRISPR-based methods rapidly detect DNA/RNA in 1 h but suffer from inter-site variability. Absolute quantification of DNA/RNA by methods such as digital PCR reduce this variability but are currently too slow for wider application. Here, we report a RApid DIgital Crispr Approach (RADICA) for absolute quantification of nucleic acids in 40-60 min. Using SARS-CoV-2 as a proof-of-concept target, RADICA allows for absolute quantification with a linear dynamic range of 0.6-2027 copies/µL (R2 value > 0.99), high accuracy and low variability, no cross-reactivity to similar targets, and high tolerance to human background DNA. RADICA's versatility is validated against other targets such as Epstein-Barr virus (EBV) from human B cells and patients' serum. RADICA can accurately detect and absolutely quantify EBV DNA with similar dynamic range of 0.5-2100 copies/µL (R2 value > 0.98) in 1 h without thermal cycling, providing a 4-fold faster alternative to digital PCR-based detection. RADICA therefore enables rapid and sensitive absolute quantification of nucleic acids which can be widely applied across clinical, research, and biomanufacturing areas.


Assuntos
COVID-19 , Infecções por Vírus Epstein-Barr , Ácidos Nucleicos , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Herpesvirus Humano 4/genética , Humanos , SARS-CoV-2 , Sensibilidade e Especificidade
19.
Allergy ; 76(11): 3349-3358, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33948955

RESUMO

Chronic rhinosinusitis (CRS) is a complex upper airway inflammatory disease with a broad spectrum of clinical variants. As our understanding of the disease pathophysiology evolves, so too does our philosophy towards the approach and management of CRS. Endotyping is gaining favour over phenotype-based classifications, owing to its potential in prognosticating disease severity and delivering precision treatment. Endotyping is especially useful in challenging CRS with nasal polyposis cases, for whom novel treatment options such as biologicals are now available. The latest European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS2020) reflects these changes with updated rhinosinusitis classifications and new integrated care pathways. With the coronavirus disease 2019 (COVID-19) pandemic, physicians and rhinologists have to balance the responsibility of managing their patients' upper airway while adequately protecting themselves from droplet and aerosol transmission. This review summarises the key updates from EPOS2020, endotype-based classification and biomarkers. The role of biologicals in CRS and the lessons we can draw from their use in severe asthma will be examined. Finally, the principles of CRS management during COVID-19 will also be discussed.


Assuntos
COVID-19 , Pólipos Nasais , Rinite , Sinusite , Doença Crônica , Humanos , Pólipos Nasais/diagnóstico , Pólipos Nasais/terapia , Rinite/diagnóstico , Rinite/terapia , SARS-CoV-2 , Sinusite/diagnóstico , Sinusite/terapia
20.
Inflammation ; 44(5): 1937-1948, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33999330

RESUMO

Mucus secretion and its composition are vital in the maintenance of airway health, among which hypoxia-inducible factors (HIFs) are thought to be involved in the regulation of mucin synthesis and regulation. Nasal mucus composition difference between healthy individuals and chronic rhinosinusitis (CRS) patients may contribute to the pathology of chronic nasal diseases, but so far, their role has yet to be completely understood. Nasal biopsy specimens were obtained from 24 healthy subjects and 99 patients with CRS without (CRSsNP, n=36) or with (CRSwNP, n=63) nasal polyps. Immunohistochemical (IHC) and immunofluorescent (IF) staining, quantitative real-time PCR, and western blot were performed to compare the nasal mucus composition between the subjects. Areas of the serous gland and mucous gland were both significantly increased in CRSsNP patients. In CRSwNP patients, a decrease in submucosal gland density and a marked increase in goblet cells were observed. The major gel-forming mucins in the sinonasal mucosa of CRSsNP and CRSwNP are MUC5B and MUC5AC respectively. Mucous cells are found in a higher proportion in both CRSsNP and CRSwNP. The proportion of MUC5AC-positive goblet cells was increased in CRSwNP. The mRNA level of HIF-2α was significantly increased in CRS, and both HIF-1α and HIF-2α were expressed in serous cell but not mucous cell. Over secretion and altered composition of mucus are observed in sinonasal mucosa of CRS, which was mainly associated with glandular hyperplasia in CRSsNP and goblet cell hyperplasia in CRSwNP. Mucus abnormality compromised both non-specific and specific antimicrobial capabilities in the sinonasal mucosa. HIF expression may contribute to differences in mucin synthesis and serous gland regulation, which needs further investigation to understand the pathology of CRS.


Assuntos
Muco , Mucosa Nasal/patologia , Pólipos Nasais/patologia , Rinite/patologia , Sinusite/patologia , Adulto , Células Cultivadas , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Muco/metabolismo , Mucosa Nasal/metabolismo , Pólipos Nasais/metabolismo , Rinite/metabolismo , Sinusite/metabolismo , Adulto Jovem
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