RESUMO
BACKGROUND: Rhinoviruses (RVs) are the most common trigger for asthma exacerbations, and there are currently no targeted therapies for viral-induced asthma exacerbations. RV infection causes neutrophilic inflammation, which is often resistant to effects of glucocorticoids. IL-1 receptor antagonist (IL-1RA) treatment reduces neutrophilic inflammation in humans challenged with inhaled endotoxin and thus may have therapeutic potential for RV-induced asthma exacerbations. OBJECTIVE: We sought to test the hypothesis that IL-1RA treatment of airway epithelium reduces RV-mediated proinflammatory cytokine production, which is important for neutrophil recruitment. METHODS: Human bronchial epithelial cells from deceased donors without prior pulmonary disease were cultured at air-liquid interface and treated with IL-13 to approximate an asthmatic inflammatory milieu. Human bronchial epithelial cells were infected with human RV-16 with or without IL-1RA treatment. RESULTS: RV infection promoted the release of IL-1α and the neutrophil-attractant cytokines IL-6, IL-8, and CXCL10. Proinflammatory cytokine secretion was significantly reduced by IL-1RA treatment without significant change in IFN-ß release or RV titer. In addition, IL-1RA reduced MUC5B expression after RV infection without impacting MUC5AC. CONCLUSIONS: These data suggest that IL-1RA treatment significantly reduced proinflammatory cytokines while preserving the antiviral response. These results provide evidence for further investigation of IL-1RA as a novel targeted therapy against neutrophil-attractant cytokine release in RV-induced airway inflammatory responses.
Assuntos
Asma , Infecções por Enterovirus , Infecções por Picornaviridae , Humanos , Rhinovirus/fisiologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Receptores de Interleucina-1 , Asma/tratamento farmacológico , Citocinas/metabolismo , Epitélio/metabolismo , Células Epiteliais/metabolismo , Inflamação/tratamento farmacológico , Infecções por Picornaviridae/tratamento farmacológicoRESUMO
Cell pyroptosis has received increased attention due to the associations between innate immunity and disease, and it has become a major focal point recently due to in-depth studies of cancer. With increased research on pyroptosis, scientists have discovered that it has an essential role in viral infections, especially in the occurrence and development of some picornavirus infections. Many picornaviruses, including Coxsackievirus, a71 enterovirus, human rhinovirus, encephalomyocarditis virus, and foot-and-mouth disease virus induce pyroptosis to varying degrees. This review summarized the mechanisms by which these viruses induce cell pyroptosis, which can be an effective defense against pathogen infection. However, excessive inflammasome activation or pyroptosis also can damage the host's health or aggravate disease progression. Careful approaches that acknowledge this dual effect will aid in the exploration of picornavirus infections and the mechanisms that produce the inflammatory response. This information will promote the development of drugs that can inhibit cell pyroptosis and provide new avenues for future clinical treatment.
Assuntos
Enterovirus , Infecções por Picornaviridae , Picornaviridae , Viroses , Animais , Humanos , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Infecções por Picornaviridae/tratamento farmacológico , Piroptose , Replicação ViralRESUMO
Prematurity and bronchopulmonary dysplasia (BPD) increase the risk of asthma later in life. Supplemental oxygen therapy is a risk factor for chronic respiratory symptoms in infants with BPD. Hyperoxia induces cell injury and release of damage-associated molecular patterns (DAMPs). Cytoskeletal filamentous actin (F-actin) is a DAMP which binds Clec9a, a C-type lectin selectively expressed on CD103+ dendritic cells (DCs). Co-stimulation of Clec9a and TLR3 induces maximal proinflammatory responses. We have shown that neonatal hyperoxia (a model of BPD) increases lung IL-12+Clec9a+CD103+ DCs, pro-inflammatory responses and airway hyperreactivity following rhinovirus (RV) infection. CD103+ DCs and Clec9a are required for these responses. Hyperoxia increases F-actin levels in bronchoalveolar lavage fluid (BALF). We hypothesized that the F-actin severing protein gelsolin attenuates neonatal hyperoxia-induced Clec9a+CD103+ DC-dependent pro-inflammatory responses to RV and preserves alveolarization. We exposed neonatal mice to hyperoxia and treated them with gelsolin intranasally. Subsequently we inoculated the mice with RV intranasally. Alternatively, we inoculated normoxic neonatal mice with BALF from hyperoxia-exposed mice (hyperoxic BALF), RV and gelsolin. We analyzed lung gene expression two days after RV infection. For in vitro studies, lung CD11c+ cells were isolated from C57BL/6J or Clec9agfp-/- mice and incubated with hyperoxic BALF and RV. Cells were analyzed by flow cytometry. In neonatal mice, gelsolin blocked hyperoxia-induced Il12p40, TNF-α and IFN-γ mRNA and protein expression in response to RV infection. Similar effects were observed when gelsolin was co-administered with hyperoxic BALF and RV. Gelsolin decreased F-actin levels in hyperoxic BALF in vitro and inhibited hyperoxia-induced D103lo DC expansion and inflammation in vivo. Gelsolin also attenuated hyperoxia-induced hypoalveolarization. Further, incubation of lung CD11c+ cells from WT and Clec9agfp-/- mice with hyperoxic BALF and RV, showed Clec9a is required for maximal hyperoxic BALF and RV induced IL-12 expression in CD103+ DCs. Finally, in tracheal aspirates from mechanically ventilated human preterm infants the F-actin to gelsolin ratio positively correlates with FiO2, and gelsolin levels decrease during the first two weeks of mechanical ventilation. Collectively, our findings demonstrate a promising role for gelsolin, administered by inhalation into the airway to treat RV-induced exacerbations of BPD and prevent chronic lung disease.
Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Gelsolina/administração & dosagem , Hiperóxia/fisiopatologia , Lectinas Tipo C/metabolismo , Infecções por Picornaviridae/tratamento farmacológico , Receptores Imunológicos/metabolismo , Administração por Inalação , Animais , Animais Recém-Nascidos/metabolismo , Antígenos CD/metabolismo , Displasia Broncopulmonar/virologia , Feminino , Humanos , Recém-Nascido , Cadeias alfa de Integrinas/metabolismo , Interleucina-12/metabolismo , Lectinas Tipo C/genética , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxigenoterapia/efeitos adversos , Infecções por Picornaviridae/virologia , Receptores Imunológicos/genética , Testes de Função Respiratória , Rhinovirus/isolamento & purificaçãoRESUMO
OBJECTIVE: The maintenance of tight junction integrity contributes significantly to epithelial barrier function. If barrier function is destroyed, cell permeability increases and the movement of pathogens is promoted, further increasing the susceptibility to secondary infection. Here, we examined the protective effects of wogonin on rhinovirus (RV)-induced tight junction disruption. Additionally, we examined the signaling molecules responsible for anti-inflammatory activities in human nasal epithelial (HNE) cells. METHODS AND RESULTS: Primary HNE cells grown at an air-liquid interface and RPMI 2650 cells were infected apically with RV. Incubation with RV resulted in disruption of tight junction proteins (ZO-1, E-cadherin, claudin-1, and occludin) in the HNE cells. Cell viability of wogonin-treated HNE cells was measured using the MTT assay. Pretreatment with wogonin decreased RV-induced disruption of tight junctions in HNE cells. Furthermore, wogonin significantly decreased RV-induced phosphorylation of Akt/NF-κB and ERK1/2. Additionally, RV-induced generation of reactive oxygen species and RV-induced up-regulation of the production of inflammatory cytokines IL-8 and IL-6 were diminished by wogonin in HNE cells. CONCLUSION: Wogonin inhibits HRV-induced tight junction disruption via the suppression of inflammatory responses and phosphorylation of Akt/NF-κB and ERK1/2 in HNE cells. These finds will facilitate the development of novel therapeutic strategies.
Assuntos
Flavanonas , Proteína Quinase 3 Ativada por Mitógeno , NF-kappa B , Proteínas Proto-Oncogênicas c-akt , Rhinovirus , Junções Íntimas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Flavanonas/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Infecções por Picornaviridae/tratamento farmacológico , Infecções por Picornaviridae/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rhinovirus/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/patologiaRESUMO
Human rhinovirus (RV) is a major risk factor for chronic obstructive pulmonary disease (COPD) and asthma exacerbations. The exploration of RV pathogenesis has been hampered by a lack of disease-relevant model systems. We performed a detailed characterization of host responses to RV infection in human lung tissue ex vivo and investigated whether these responses are disease relevant for patients with COPD and asthma. In addition, impact of the viral replication inhibitor rupintrivir was evaluated. Human precision-cut lung slices (PCLS) were infected with RV1B with or without rupintrivir. At Days 1 and 3 after infection, RV tissue localization, tissue viability, and viral load were determined. To characterize host responses to infection, mediator and whole genome analyses were performed. RV successfully replicated in PCLS airway epithelial cells and induced both antiviral and proinflammatory cytokines such as IFNα2a, CXCL10, CXCL11, IFN-γ, TNFα, and CCL5. Genomic analyses revealed that RV not only induced antiviral immune responses but also triggered changes in epithelial cell-associated pathways. Strikingly, the RV response in PCLS was reflective of gene expression changes described in patients with COPD and asthma. Although RV-induced host immune responses were abrogated by rupintrivir, RV-triggered epithelial processes were largely refractory to antiviral treatment. Detailed analysis of RV-infected human PCLS and comparison with gene signatures of patients with COPD and asthma revealed that the human RV PCLS model represents disease-relevant biological mechanisms that can be partially inhibited by a well-known antiviral compound and provide an outstanding opportunity to evaluate novel therapeutics.
Assuntos
Asma/genética , Interações Hospedeiro-Patógeno/genética , Pulmão/virologia , Infecções por Picornaviridae/genética , Doença Pulmonar Obstrutiva Crônica/genética , Idoso , Antivirais/farmacologia , Asma/patologia , Brônquios/patologia , Brônquios/fisiologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Feminino , Perfilação da Expressão Gênica , Genoma Humano , Humanos , Isoxazóis/farmacologia , Pulmão/fisiologia , Masculino , Pessoa de Meia-Idade , Fenilalanina/análogos & derivados , Fenilalanina/farmacologia , Infecções por Picornaviridae/tratamento farmacológico , Infecções por Picornaviridae/patologia , Doença Pulmonar Obstrutiva Crônica/patologia , Pirrolidinonas/farmacologia , Rhinovirus/patogenicidade , Valina/análogos & derivados , Valina/farmacologiaRESUMO
Virus-induced respiratory tract infections are a major health burden in childhood, and available treatments are supportive rather than disease modifying. Rhinoviruses (RVs), the cause of approximately 80% of common colds, are detected in nearly half of all infants with bronchiolitis and the majority of children with an asthma exacerbation. Bronchiolitis in early life is a strong risk factor for the development of asthma. Here, we found that RV infection induced the expression of miRNA 122 (miR-122) in mouse lungs and in human airway epithelial cells. In vivo inhibition specifically in the lung reduced neutrophilic inflammation and CXCL2 expression, boosted innate IFN responses, and ameliorated airway hyperreactivity in the absence and in the presence of allergic lung inflammation. Inhibition of miR-122 in the lung increased the levels of suppressor of cytokine signaling 1 (SOCS1), which is an in vitro-validated target of miR-122. Importantly, gene silencing of SOCS1 in vivo completely reversed the protective effects of miR-122 inhibition on RV-induced lung disease. Higher miR-122 expression in nasopharyngeal aspirates was associated with a longer time on oxygen therapy and a higher rate of treatment failure in 87 infants hospitalized with moderately severe bronchiolitis. These results suggest that miR-122 promotes RV-induced lung disease via suppression of its target SOCS1 in vivo. Higher miR-122 expression was associated with worse clinical outcomes, highlighting the potential use of anti-miR-122 oligonucleotides, successfully trialed for treatment of hepatitis C, as potential therapeutics for RV-induced bronchiolitis and asthma exacerbations.
Assuntos
Bronquite/terapia , Pneumopatias/virologia , MicroRNAs/genética , Infecções por Picornaviridae/genética , Proteína 1 Supressora da Sinalização de Citocina/genética , Animais , Antagomirs/farmacologia , Bronquite/virologia , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Feminino , Humanos , Lactente , Pneumopatias/genética , Pneumopatias/terapia , Masculino , Camundongos Endogâmicos BALB C , Nasofaringe/virologia , Infecções por Picornaviridae/tratamento farmacológico , Rhinovirus/fisiologia , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Falha de Tratamento , Replicação ViralRESUMO
Human rhinovirus (HRV) infection is one of the main causes of respiratory injury. Recently, calcitriol has been reported to have protective effect against respiratory infections. In this paper, we aimed to explore the effects and mechanisms of calcitriol on HRV-induced respiratory infection. Participants including pediatric patients diagnosed with HRV-induced respiratory infection (n = 50) and paired healthy controls (n = 40) were recruited at the Weifang People's Hospital between May 2019 and May 2020. The serum 25(OH)D3 level was measured in participants using ELISA kit. The HRV-induced respiratory infection model in human nasal mucosal epithelial cells (hNECs) was adapted, in vitro. HRV infection was measured by real-time PCR analysis of HRV expression. After HRV infection and treatment with calcitriol, the changes of cell viability were detected by MTT assay, the expression of ER stress-induced apoptosis and AMPK-mTOR related proteins by western blot, and the cell apoptosis by flow cytometry assay. In order to confirm whether AMPK-mTOR signal pathway was involved in the ER stress-induced apoptosis of hNECs, cells were pretreated with compound C which was a AMPK inhibitor. The 25-(OH)D3 concentration in serum collected in HRV-infected children was lower than that in controls. In vitro experiments showed that HRV infection decreased cell viability, and this effect was reversed when treated with calcitriol. Additionally, HRV increased levels of apoptosis and ER stress markers (including cleaved-caspase3, Bax, CHOP, nATF6, and BiP), while calcitriol significantly reversed these effects. Furthermore, calcitriol played a protective role by increasing p-AMPK and decreasing p-mTOR level. However, the protective effects of calcitriol could be abolished by compound C. Calcitriol protected HRV-infected hNECs by inhibiting the ER stress-induced apoptosis through the AMPK-mTOR signaling pathway. These protective effects of calcitriol against HRV-induced respiratory infection may provide an experimental basis for the clinical application.
Assuntos
Antivirais/farmacologia , Calcifediol/sangue , Calcitriol/farmacologia , Células Epiteliais/efeitos dos fármacos , Lesão Pulmonar/sangue , Infecções por Picornaviridae/sangue , Infecções Respiratórias/sangue , Rhinovirus , Vitaminas/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Criança , Pré-Escolar , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Feminino , Humanos , Lesão Pulmonar/tratamento farmacológico , Masculino , Mucosa Nasal/citologia , Infecções por Picornaviridae/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismoRESUMO
In this review, we discuss the latest developments in research pertaining to virus-induced asthma exacerbations and consider recent advances in treatment options. Asthma is a chronic disease of the airways that continues to impose a substantial clinical burden worldwide. Asthma exacerbations, characterised by an acute deterioration in respiratory symptoms and airflow obstruction, are associated with significant morbidity and mortality. These episodes are most commonly triggered by respiratory virus infections. The mechanisms underlying the pathogenesis of virus-induced exacerbations have been the focus of extensive biomedical research. Developing a robust understanding of the interplay between respiratory viruses and the host immune response will be critical for developing more efficacious, targeted therapies for exacerbations. CONCLUSION: There has been significant recent progress in our understanding of the mechanisms underlying virus-induced airway inflammation in asthma and these advances will underpin the development of future clinical therapies.
Assuntos
Antiasmáticos/uso terapêutico , Antivirais/uso terapêutico , Asma/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Viroses/tratamento farmacológico , Infecções por Adenovirus Humanos/tratamento farmacológico , Infecções por Adenovirus Humanos/imunologia , Infecções por Adenovirus Humanos/fisiopatologia , Administração por Inalação , Asma/imunologia , Asma/fisiopatologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Progressão da Doença , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/imunologia , Influenza Humana/fisiopatologia , Interferon beta/uso terapêutico , Macrolídeos/uso terapêutico , Omalizumab/uso terapêutico , Infecções por Paramyxoviridae/tratamento farmacológico , Infecções por Paramyxoviridae/imunologia , Infecções por Paramyxoviridae/fisiopatologia , Infecções por Picornaviridae/tratamento farmacológico , Infecções por Picornaviridae/imunologia , Infecções por Picornaviridae/fisiopatologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/fisiopatologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/fisiopatologia , Viroses/imunologia , Viroses/fisiopatologiaAssuntos
Parechovirus/isolamento & purificação , Infecções por Picornaviridae/sangue , Infecções por Picornaviridae/diagnóstico , Ampicilina/uso terapêutico , Antibacterianos/uso terapêutico , Cefotaxima/uso terapêutico , Feminino , Humanos , Lactente , Recém-Nascido , Linfo-Histiocitose Hemofagocítica/epidemiologia , Masculino , Infecções por Picornaviridae/tratamento farmacológico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Resultado do TratamentoRESUMO
BACKGROUND: Viral infection is the main cause of asthma and COPD (chronic obstructive pulmonary disease) exacerbation and accumulate inflammatory cells to airway tissue. We have reported poly I:C, a mimic product of the virus and ligand of toll-like receptor 3 (TLR3), induced inflammatory chemokines from airway epithelial cells and found prior incubation with corticosteroids diminishes the effect of TLR3 activation. In clinical practice, mild asthma is recommended as-needed budesonide (BUD) when symptoms occur following a viral infection, etc. However, many questions still surround BUD's usefulness if taken after a virus has already infected airway tissue. OBJECTIVE: The aim of this study was to investigate the inhibitory effects of BUD on inflammatory cytokines induced by viral infection. Methods: Normal human bronchial epithelial (NHBE) cells were stimulated with poly I:C or infected with human rhinovirus-16 (HRV16) and BUD was added after the initial stimulation. Expression of both thymic stromal lymphopoietin (TSLP) and CCL26/eotaxin-3 was quantified by real-time RT-PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Knockdown study was performed. Results: Pre-or post-incubation with BUD inhibited both poly I:C- and HRV16-induced mRNAs and proteins of both thymic stromal lymphopoietin (TSLP) and CCL26 with significance. Knockdown of the glucocorticoid receptor diminished these effects of BUD. Under the same conditions of BUD's experiment, post-incubation with neither fluticasone propionate nor dexamethasone suppressed expression of both TSLP and CCL26, which induced by poly I:C. CONCLUSION: Post-addition of BUD inhibited the virus-induced TSLP and CCL26 from the airway epithelial cells. These results suggest that inhalation of BUD after viral infection has beneficial effects on asthma. CONCLUSION: Late addition of BUD may benefit among patient with viral infection and type 2 allergic airway disease such as asthma.
Assuntos
Broncodilatadores/farmacologia , Budesonida/farmacologia , Citocinas/efeitos dos fármacos , Infecções por Picornaviridae/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Rhinovirus , Técnicas de Cultura de Células , Quimiocina CCL26/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Humanos , Infecções por Picornaviridae/virologia , Mucosa Respiratória/citologia , Mucosa Respiratória/virologia , Infecções Respiratórias/virologiaRESUMO
Bronchial epithelial cells are the first target cell for rhinovirus infection. The course of viral infections in patients with acute bronchitis, asthma and COPD can be improved by oral application of Pelargonium sidoides radix extract; however, the mechanism is not well understood. This study investigated the in vitro effect of Pelargonium sidoides radix extract (EPs 7630) on the expression of virus binding cell membrane and host defence supporting proteins on primary human bronchial epithelial cells (hBEC). Cells were isolated from patients with severe asthma (n = 6), moderate COPD (n = 6) and non-diseased controls (n = 6). Protein expression was determined by Western-blot and immunofluorescence. Rhinovirus infection was determined by immunofluorescence as well as by polymerase chain reaction. Cell survival was determined by manual cell count after live/death immunofluorescence staining. All parameters were determined over a period of 3 days. The results show that EPs 7630 concentration-dependently and significantly increased hBEC survival after rhinovirus infection. This effect was paralleled by decreased expression of the inducible co-stimulator (ICOS), its ligand ICOSL and cell surface calreticulin (C1qR). In contrast, EPs 7630 up-regulated the expression of the host defence supporting proteins ß-defensin-1 and SOCS-1, both in rhinovirus infected and un-infected hBEC. The expression of other virus interacting cell membrane proteins such as MyD88, TRL2/4 or ICAM-1 was not altered by EPs 7630. The results indicate that EPs 7630 may reduce rhinovirus infection of human primary BEC by down-regulating cell membrane docking proteins and up-regulating host defence proteins.
Assuntos
Antivirais/farmacologia , Brônquios , Células Epiteliais , Pelargonium/química , Infecções por Picornaviridae , Extratos Vegetais/farmacologia , Rhinovirus/metabolismo , Adulto , Idoso , Antivirais/química , Asma/tratamento farmacológico , Asma/metabolismo , Asma/patologia , Asma/virologia , Brônquios/metabolismo , Brônquios/fisiologia , Sobrevivência Celular , Células Cultivadas , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Células Epiteliais/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Picornaviridae/tratamento farmacológico , Infecções por Picornaviridae/metabolismo , Infecções por Picornaviridae/patologia , Extratos Vegetais/química , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/virologiaRESUMO
Human rhinovirus (RV), the major cause of the common cold, triggers the majority of acute airway exacerbations in patients with asthma and chronic obstructive pulmonary disease. Nitric oxide, and the related metabolite S-nitrosoglutathione, are produced in the airway epithelium via nitric oxide synthase (NOS) 2 and have been shown to function in host defense against RV infection. We hypothesized that inhibitors of the S-nitrosoglutathione-metabolizing enzyme, S-nitrosoglutathione reductase (GSNOR), might potentiate the antiviral properties of airway-derived NOS2. Using in vitro models of RV-A serotype 16 (RV-A16) and mNeonGreen-H1N1pr8 infection of human airway epithelial cells, we found that treatment with a previously characterized GSNOR inhibitor (4-[[2-[[(3-cyanophenyl)methyl]thio]-4-oxothieno-[3,2-d]pyrimidin-3(4H)-yl]methyl]-benzoic acid; referred to as C3m) decreased RV-A16 replication and expression of downstream proinflammatory and antiviral mediators (e.g., RANTES [regulated upon activation, normal T cell expressed and secreted], CXCL10, and Mx1), and increased Nrf2 (nuclear factor erythroid 2-related factor 2)-dependent genes (e.g., SQSTM1 and TrxR1). In contrast, C3m had no effect on influenza virus H1N1pr8 replication. Moreover, a structurally dissimilar GSNOR inhibitor (N6022) did not alter RV replication, suggesting that the properties of C3m may be specific to rhinovirus owing to an off-target effect. Consistent with this, C3m antiviral effects were not blocked by either NOS inhibition or GSNOR knockdown but appeared to be mediated by reduced intercellular adhesion molecule 1 transcription and increased shedding of soluble intercellular adhesion molecule 1 protein. Collectively these data show that C3m has novel antirhinoviral properties that may synergize with, but are unrelated to, its GSNOR inhibitor activity.
Assuntos
Aldeído Oxirredutases/antagonistas & inibidores , Brônquios/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Células Epiteliais/efeitos dos fármacos , Inflamação/tratamento farmacológico , Infecções por Picornaviridae/tratamento farmacológico , Rhinovirus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Benzamidas/farmacologia , Brônquios/metabolismo , Brônquios/virologia , Células Cultivadas , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Humanos , Inflamação/metabolismo , Inflamação/virologia , Óxido Nítrico Sintase Tipo II/metabolismo , Infecções por Picornaviridae/metabolismo , Infecções por Picornaviridae/virologia , Pirróis/farmacologiaRESUMO
Human rhinovirus (RV) infections are a significant risk factor for exacerbations of asthma and chronic obstructive pulmonary disease. Thus, approaches to prevent RV infection in such patients would give significant benefit. Through RNA interference library screening, we identified lanosterol synthase (LSS), a component of the cholesterol biosynthetic pathway, as a novel regulator of RV replication in primary normal human bronchial epithelial cells. Selective knock down of LSS mRNA with short interfering RNA inhibited RV2 replication in normal human bronchial epithelial cells. Small molecule inhibitors of LSS mimicked the effect of LSS mRNA knockdown in a concentration-dependent manner. We further demonstrated that the antiviral effect is not dependent on a reduction in total cellular cholesterol but requires a 24-hour preincubation with the LSS inhibitor. The rank order of antiviral potency of the LSS inhibitors used was consistent with LSS inhibition potency; however, all compounds showed remarkably higher potency against RV compared with the LSS enzyme potency. We showed that LSS inhibition led to an induction of 24(S),25 epoxycholesterol, an important regulator of the sterol pathway. We also demonstrated that LSS inhibition led to a profound increase in expression of the innate antiviral defense protein, IFN-ß. We found LSS to be a novel regulator of RV replication and innate antiviral immunity and identified a potential molecular mechanism for this effect, via induction of 24(S),25 epoxycholesterol. Inhibition of LSS could therefore be a novel therapeutic target for prevention of RV-induced exacerbations.
Assuntos
Antivirais/farmacologia , Brônquios/imunologia , Células Epiteliais/imunologia , Imunidade Inata/imunologia , Transferases Intramoleculares/metabolismo , Infecções por Picornaviridae/imunologia , Rhinovirus/imunologia , Replicação Viral/imunologia , Brônquios/efeitos dos fármacos , Brônquios/virologia , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Humanos , Imunidade Inata/efeitos dos fármacos , Transferases Intramoleculares/antagonistas & inibidores , Transferases Intramoleculares/genética , Infecções por Picornaviridae/tratamento farmacológico , Infecções por Picornaviridae/virologia , RNA Interferente Pequeno/genética , Rhinovirus/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
Acute exacerbations are the major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Rhinovirus, which causes acute exacerbations may also accelerate progression of lung disease in these patients. Current therapies reduces the respiratory symptoms and does not treat the root cause of exacerbations effectively. We hypothesized that quercetin, a potent antioxidant and anti-inflammatory agent with antiviral properties may be useful in treating rhinovirus-induced changes in COPD. Mice with COPD phenotype maintained on control or quercetin diet and normal mice were infected with sham or rhinovirus, and after 14 days mice were examined for changes in lung mechanics and lung inflammation. Rhinovirus-infected normal mice showed no changes in lung mechanics or histology. In contrast, rhinovirus-infected mice with COPD phenotype showed reduction in elastic recoiling and increase in lung inflammation, goblet cell metaplasia, and airways cholinergic responsiveness compared to sham-infected mice. Interestingly, rhinovirus-infected mice with COPD phenotype also showed accumulation of neutrophils, CD11b+/CD11c+ macrophages and CD8+ T cells in the lungs. Quercetin supplementation attenuated rhinovirus-induced all the pathologic changes in mice with COPD phenotype. Together these results indicate that quercetin effectively mitigates rhinovirus-induced progression of lung disease in a mouse model of COPD. Therefore, quercetin may be beneficial in the treatment of rhinovirus-associated exacerbations and preventing progression of lung disease in COPD.
Assuntos
Infecções por Picornaviridae/complicações , Infecções por Picornaviridae/virologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Quercetina/farmacologia , Rhinovirus , Animais , Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , Biópsia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Neutrófilos/patologia , Fenótipo , Infecções por Picornaviridae/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Rhinovirus/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologiaRESUMO
Rhinovirus, a major causative agent of the common cold, is associated with exacerbation of asthma and chronic obstructive pulmonary disease. Currently, there is no antiviral treatment or vaccine for human rhinovirus (HRV). Gemcitabine (2',2'-difluorodeoxycytidine, dFdC) is a deoxycytidine analog with antiviral activity against rhinovirus, as well as enterovirus 71, in vitro. However, the antiviral effects of gemcitabine in vivo have not been investigated. In the current study, we assessed whether gemcitabine mediated antiviral effects in the murine HRV infection model. Intranasal administration of gemcitabine significantly lowered pulmonary viral load and inflammation by decreasing proinflammatory cytokines, including TNF-α and IL-1ß, and reduction in the number of lung-infiltrating lymphocytes. Interestingly, we found that the addition of UTP and CTP significantly attenuated the antiviral activity of gemcitabine. Thus the limitation of UTP and CTP by the addition of gemcitabine may inhibit the viral RNA synthesis. These results suggest that gemcitabine, an antineoplastic drug, can be repositioned as an antiviral drug to inhibit HRV infection.
Assuntos
Antivirais/farmacologia , Antivirais/uso terapêutico , Desoxicitidina/análogos & derivados , Infecções por Picornaviridae/tratamento farmacológico , Rhinovirus/efeitos dos fármacos , Animais , Citocinas/biossíntese , Citocinas/imunologia , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Humanos , Inflamação , Pulmão/imunologia , Camundongos , Infecções por Picornaviridae/imunologia , Infecções por Picornaviridae/virologia , RNA Viral , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , GencitabinaRESUMO
The principal target organ of duck hepatitis A virus type 1 (DHAV-1) is duckling liver, which is an energy-intensive organ and plays important roles in body's energy metabolism and conversion. As the "power house" of the hepatocytes, mitochondria provide more than 90% of the energy. However, mitochondria are much vulnerable to the oxidative stress for their rich in polyunsaturated fatty acids. Although previous researches have demonstrated that DHAV-1 could induce the oxidative stress in the serum of the infected ducklings, no related study on the mitochondria during the pathological process of DVH has been reported by far. To address this issue, we examined the HE stained tissue pathological slices, detected the hepatic SOD, CAT and GPX activities and MDA contents and analyzed the ATP content, mitochondrial ultrastructure and the mitochondrial SOD, GPX activities and MDA content in the liver tissues. The results showed that the hepatic redox status was significantly disturbed so that causing the mitochondrial dysfunction, ATP depletion and mitochondrial oxidative stress during the process of the DHAV-1 infection, and a prescription formulated with Hypericum japonicum flavone, Radix Rehmanniae Recens polysaccharide and Salvia plebeia flavone (HRS), which had been demonstrated with good anti-oxidative activity in serum, could effectively alleviate the hepatic injury and the oxidative stress in liver tissue induced by DHAV-1 thus alleviating the mitochondrial injury and oxidative stress. In a word, this research discovers the oxidative stress induced mitochondrial dysfunction and oxidative stress during the DVH pathological process and demonstrates HRS exerts good anti-oxidative activity in liver tissue to protect mitochondria against reactive oxygen species (ROS).
Assuntos
Antivirais/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Vírus da Hepatite do Pato , Hepatite Viral Animal/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Infecções por Picornaviridae/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Animais , Patos , Flavonas/farmacologia , Glutationa Peroxidase/metabolismo , Hepatite Viral Animal/metabolismo , Hepatite Viral Animal/mortalidade , Hepatite Viral Animal/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Malondialdeído/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Infecções por Picornaviridae/metabolismo , Infecções por Picornaviridae/mortalidade , Infecções por Picornaviridae/patologia , Polissacarídeos/farmacologia , Distribuição Aleatória , Superóxido Dismutase/metabolismo , Resultado do TratamentoRESUMO
Although bacteria have historically been considered to play a major role in cystic fibrosis (CF) airway damage, a strong impact of respiratory viral infections (RVI) is also now recognized. Emerging evidence confirms that respiratory viruses are associated with deterioration of pulmonary function and exacerbation and facilitation of bacterial colonization in CF patients. The aim of this review is to provide an overview of the current knowledge on respiratory viruses in CF airways, to discuss the resulting inflammation and RVI response, to determine how to detect the viruses, and to assess their clinical consequences, prevalence, and interactions with bacteria. The most predominant are Rhinoviruses (RVs), significantly associated with CF exacerbation. Molecular techniques, and especially multiplex PCR, help to diagnose viral infections, and the coming rise of metagenomics will extend knowledge of viral populations in the complex ecosystem of CF airways. Prophylaxis and vaccination are currently available only for Respiratory syncytial and Influenza virus (IV), but antiviral molecules are being tested to improve CF patients' care. All the points raised in this review highlight the importance of taking account of RVIs and their potential impact on the CF airway ecosystem.
Assuntos
Fibrose Cística/virologia , Influenza Humana/patologia , Infecções por Picornaviridae/patologia , Infecções por Vírus Respiratório Sincicial/patologia , Infecções Respiratórias/virologia , Antivirais/uso terapêutico , Fibrose Cística/imunologia , Humanos , Inflamação/patologia , Influenza Humana/tratamento farmacológico , Orthomyxoviridae/imunologia , Infecções por Picornaviridae/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sinciciais Respiratórios/imunologia , Infecções Respiratórias/tratamento farmacológico , Rhinovirus/imunologiaRESUMO
INTRODUCTION: Respiratory viruses (influenza, parainfluenza, respiratory syncytial virus, coronavirus, human metapneumovirus, and rhinovirus) represent the most common causes of respiratory viral infections in immunocompromised patients. Also, these infections may be more severe in immunocompromised patients than in the general population. Early diagnosis and treatment of viral infections continue to be of paramount importance in immunocompromised patients; because once viral replication and invasive infections are evident, prognosis can be grave. Areas covered: The purpose of this review is to provide an overview of the main antiviral agents used for the treatment of respiratory viral infections in immunocompromised patients and review of the new agents in the pipeline. Expert commentary: Over the past decade, important diagnostic advances, specifically, the use of rapid molecular testing has helped close the gap between clinical scenarios and pathogen identification and enhanced early diagnosis of viral infections and understanding of the role of prolonged shedding and viral loads. Advancements in novel antiviral therapeutics with high resistance thresholds and effective immunization for preventable infections in immunocompromised patients are needed.
Assuntos
Antivirais/uso terapêutico , Hospedeiro Imunocomprometido , Infecções Respiratórias/tratamento farmacológico , Ácidos Carbocíclicos , Amantadina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Ciclopentanos/uso terapêutico , Guanidinas/uso terapêutico , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/imunologia , Influenza Humana/virologia , Oseltamivir/uso terapêutico , Palivizumab/uso terapêutico , Infecções por Paramyxoviridae/tratamento farmacológico , Infecções por Paramyxoviridae/imunologia , Infecções por Paramyxoviridae/virologia , Infecções por Picornaviridae/tratamento farmacológico , Infecções por Picornaviridae/imunologia , Infecções por Picornaviridae/virologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/virologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologia , Ribavirina/uso terapêutico , Zanamivir/uso terapêuticoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ficus religiosa L. is one of the most relevant members of the family of Moraceae. It is the most sacred tree of South Asia, and it is used in traditional Ayurvedic and Unani medicine to cure respiratory disorders like cough, wheezing and asthma. Some studies were performed to investigate the anti-asthmatic potential of F. religiosa bark, leaves and fruit extracts but none of them tested their antiviral activity against viruses responsible for the exacerbation of wheezing and asthma. AIM OF THE STUDY: The present study was undertaken to investigate the antiviral activity of F. religiosa L. extracts against respiratory viruses such as human respiratory syncytial virus (RSV) and human rhinovirus (HRV). MATERIALS AND METHODS: The antiviral activity of F. religiosa L. was tested in vitro by plaque reduction and virus yield assays and the major mechanism of action was investigated by virus inactivation and time-of-addition assays. RESULTS: F. religiosa L. methanol bark extract was the most active against HRV with an EC50 of 5.52 µg/mL. This extract likely inhibited late steps of replicative cycle. Water bark extract was the most active against RSV with an EC50 between 2.23 and 4.37 µg/mL. Partial virus inactivation and interference with virus attachment were both found to contribute to the anti-RSV activity. Replication of both viruses was inhibited in viral yield reduction assays. CONCLUSIONS: The results of the present study demonstrate that F. religiosa L. is endowed with antiviral activity against RSV and HRV in vitro. Further work remains to be done to identify the active components and to assess the therapeutic potential in vivo.
Assuntos
Antivirais/farmacologia , Ficus , Extratos Vegetais/farmacologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Rhinovirus/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Infecções por Picornaviridae/tratamento farmacológico , Casca de Planta , Folhas de Planta , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sincicial Respiratório Humano/fisiologia , Rhinovirus/fisiologia , Ligação Viral/efeitos dos fármacos , Inativação de Vírus/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacosRESUMO
BACKGROUND: Acute rhinosinusitis is a frequent inflammatory disease of the mucosa of the nose and paranasal sinuses, usually associated with substantial morbidity having considerable socioeconomic impact. A new herbal drug based on a dry extract of a combination of 5 medicinal drugs (Sinupret® extract Dragees) was tested in a confirmatory trial in patients with acute viral rhinosinusitis. METHODS: 386 patients with symptomatic acute viral rhinosinusitis have been treated with the herbal drug combination (daily dosage 3 × 160 mg) or placebo in a double-blind, randomised, placebo-controlled clinical trial for 15 days. Primary efficacy endpoint was the investigator assessed symptom score at the end of therapy (Major Symptom Score, MSSINV). RESULTS: Treatment with verum lead to a statistically significant, clinically relevant improvement of the symptom score (2.07 ± 0.18 [SEM] vs. 3.47 ± 0.28 score points, p = 0.0001; PP: N = 300) compared to placebo at visit 5. The Number Needed to Treat (NNT) was 7 (PP). Adverse events occurred in 9.8% of the patients treated with verum and 14.1% of the patients treated with placebo. No serious adverse event was observed. The investigators assessed the tolerability of the herbal drug combination predominantly as good and very good (96.4% verum, 95.3% placebo). CONCLUSION: The results prove the efficacy and tolerability of the herbal drug in the indication acute viral rhinosinusitis. Especially due to the favorable benefit-risk ratio the drug represents a suitable treatment alternative.