RESUMO
With the advent of antiretroviral therapy, improved survival of people with HIV (PWH) is accompanied with increased prevalence of HIV-associated comorbidities. Chronic lung anomalies are recognized as one of the most devastating sequelae in PWH. The limited available data describing the lung complications in PWH with a history of opioid abuse warrants more research to better define the course of disease pathogenesis. The current study was conducted to investigate the progression of lung tissue remodeling in a morphine (Mor)-exposed rhesus macaque model of SIV infection. Pathologic features of lung remodeling, including histopathologic changes, oxidative stress, inflammation, and proliferation of fibroblasts, were investigated in archival lung tissues of SIVmac-251/macaque model with or without Mor dependence. Lungs of Mor-exposed, SIV-infected macaques exhibited significant fibrotic changes and collagen deposition in the alveolar and the bronchiolar region. There was increased oxidative stress, profibrotic transforming growth factor-ß, fibroblast proliferation and trans-differentiation, epithelial-mesenchymal transition, and matrix degradation in SIV-infected macaques, which was further exacerbated in the lungs of Mor-exposed macaques. Interestingly, there was decreased inflammation-associated remodeling in Mor-dependent SIV-infected macaques compared with SIV-infected macaques that did not receive Mor. Thus, the current findings suggest that SIV independently induces fibrotic changes in macaque lungs, which is further aggravated by Mor.
Assuntos
Infecções por HIV , Pneumonia , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Macaca mulatta , Infecções por HIV/patologia , Pulmão/patologia , Inflamação/patologia , Pneumonia/patologia , Fibrose , Derivados da MorfinaRESUMO
Brain metastasis (BrM) is one of the major causes of death in cancer patients and is associated with an estimated 10-40 % of total cancer cases. The survival rate of brain metastatic patients has not improved due to intratumor heterogeneity, the survival adaptations of brain homing metastatic cells, and the lack of understanding of underlying molecular mechanisms that limit the availability of effective therapies. The heterogeneous population of immune cells and tumor-initiating cells or cancer stem cells in the tumor microenvironment (TME) release various factors, such as chemokines that upon binding to their cognate receptors enhance tumor growth at primary sites and help tumor cells metastasize to the brain. Furthermore, brain metastatic sites have unique heterogeneous microenvironment that fuels cancer cells in establishing BrM. This review explores the crosstalk of chemokines with the heterogeneous TME during the progression of BrM and recognizes potential therapeutic approaches. We also discuss and summarize different targeted, immunotherapeutic, chemotherapeutic, and combinatorial strategies (with chemo-/immune- or targeted-therapies) to attenuate chemokines mediated BrM.
Assuntos
Neoplasias Encefálicas , Humanos , Neoplasias Encefálicas/prevenção & controle , Quimiocinas , Células-Tronco Neoplásicas , Encéfalo , Microambiente Tumoral , Metástase NeoplásicaRESUMO
Severe Acute Respiratory Coronavirus (SARS-CoV-2) has been emerging in the form of different variants since its first emergence in early December 2019. A new Variant of Concern (VOC) named the Omicron variant (B.1.1.529) was reported recently. This variant has a large number of mutations in the S protein. To date, there exists a limited information on the Omicron variant. Here we present the analyses of mutation distribution, the evolutionary relationship of Omicron with previous variants, and probable structural impact of mutations on antibody binding. Our analyses show the presence of 46 high prevalence mutations specific to Omicron. Twenty-three of these are localized within the spike (S) protein and the rest localized to the other 3 structural proteins of the virus, the envelope (E), membrane (M), and nucleocapsid (N). Phylogenetic analysis showed that the Omicron is closely related to the Gamma (P.1) variant. The structural analyses showed that several mutations are localized to the region of the S protein that is the major target of antibodies, suggesting that the mutations in the Omicron variant may affect the binding affinities of antibodies to the S protein.
Assuntos
Anticorpos Antivirais/imunologia , COVID-19/virologia , SARS-CoV-2/genética , Sítios de Ligação , COVID-19/imunologia , Humanos , Mutação , Filogenia , Estrutura Terciária de Proteína , Glicoproteína da Espícula de Coronavírus/genéticaRESUMO
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been rapidly evolving in the form of new variants. At least eleven known variants have been reported. The objective of this study was to delineate the differences in the mutational profile of Delta and Delta Plus variants. High-quality sequences (n = 1756) of Delta (B.1.617.2) and Delta Plus (AY.1 or B.1.617.2.1) variants were used to determine the prevalence of mutations (≥20 %) in the entire SARS-CoV-2 genome, their co-existence, and change in prevalence over a period of time. Structural analysis was conducted to get insights into the impact of mutations on antibody binding. A Sankey diagram was generated using phylogenetic analysis coupled with sequence-acquisition dates to infer the migration of the Delta Plus variant and its presence in the United States. The Delta Plus variant had a significant number of high-prevalence mutations (≥20 %) than in the Delta variant. Signature mutations in Spike (G142D, A222V, and T95I) existed at a more significant percentage in the Delta Plus variant than the Delta variant. Three mutations in Spike (K417N, V70F, and W258L) were exclusively present in the Delta Plus variant. A new mutation was identified in ORF1a (A1146T), which was only present in the Delta Plus variant with ~58 % prevalence. Furthermore, five key mutations (T95I, A222V, G142D, R158G, and K417N) were significantly more prevalent in the Delta Plus than in the Delta variant. Structural analyses revealed that mutations alter the sidechain conformation to weaken the interactions with antibodies. Delta Plus, which first emerged in India, reached the United States through England and Japan, followed by its spread to more than 20 the United States. Based on the results presented here, it is clear that the Delta and Delta Plus variants have unique mutation profiles, and the Delta Plus variant is not just a simple addition of K417N to the Delta variant. Highly correlated mutations may have emerged to keep the structural integrity of the virus.
Assuntos
COVID-19/genética , Evolução Molecular , Mutação de Sentido Incorreto , Filogenia , SARS-CoV-2/genética , Substituição de Aminoácidos , COVID-19/epidemiologia , COVID-19/transmissão , Humanos , Prevalência , SARS-CoV-2/metabolismoRESUMO
Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are chronic, progressive lung ailments that are characterized by distinct pathologies. Early detection biomarkers and disease mechanisms for these debilitating diseases are lacking. Extracellular vesicles (EVs), including exosomes, are small, lipid-bound vesicles attributed to carry proteins, lipids, and RNA molecules to facilitate cell-to-cell communication under normal and diseased conditions. Exosomal miRNAs have been studied in relation to many diseases. However, there is little to no knowledge regarding the miRNA population of bronchoalveolar lavage fluid (BALF) or the lung-tissue-derived exosomes in COPD and IPF. Here, we determined and compared the miRNA profiles of BALF- and lung-tissue-derived exosomes of healthy non-smokers, smokers, and patients with COPD or IPF in independent cohorts. Results: Exosome characterization using NanoSight particle tracking and TEM demonstrated that the BALF-derived exosomes were ~89.85 nm in size with a yield of ~2.95 × 1010 particles/mL in concentration. Lung-derived exosomes were larger in size (~146.04 nm) with a higher yield of ~2.38 × 1011 particles/mL. NGS results identified three differentially expressed miRNAs in the BALF, while there was one in the lung-derived exosomes from COPD patients as compared to healthy non-smokers. Of these, miR-122-5p was three- or five-fold downregulated among the lung-tissue-derived exosomes of COPD patients as compared to healthy non-smokers and smokers, respectively. Interestingly, there were a large number (55) of differentially expressed miRNAs in the lung-tissue-derived exosomes of IPF patients compared to non-smoking controls. Conclusions: Overall, we identified lung-specific miRNAs associated with chronic lung diseases that can serve as potential biomarkers or therapeutic targets.
Assuntos
Exossomos , Fibrose Pulmonar Idiopática , MicroRNAs , Doença Pulmonar Obstrutiva Crônica , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido da Lavagem Broncoalveolar , Exossomos/genética , Exossomos/metabolismo , Feminino , Humanos , Masculino , MicroRNAs/biossíntese , MicroRNAs/genética , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismoRESUMO
BACKGROUND: Ulcerative colitis (UC) is a Th2 inflammatory bowel disease characterized by increased IL-5 and IL-13 expression, eosinophilic/neutrophilic infiltration, decreased mucus production, impaired epithelial barrier, and bacterial dysbiosis of the colon. Acetylcholine and nicotine stimulate mucus production and suppress Th2 inflammation through nicotinic receptors in lungs but UC is rarely observed in smokers and the mechanism of the protection is unclear. METHODS: In order to evaluate whether acetylcholine can ameliorate UC-associated pathologies, we employed a mouse model of dextran sodium sulfate (DSS)-induced UC-like conditions, and a group of mice were treated with Pyridostigmine bromide (PB) to increase acetylcholine availability. The effects on colonic tissue morphology, Th2 inflammatory factors, MUC2 mucin, and gut microbiota were analyzed. RESULTS: DSS challenge damaged the murine colonic architecture, reduced the MUC2 mucin and the tight-junction protein ZO-1. The PB treatment significantly attenuated these DSS-induced responses along with the eosinophilic infiltration and the pro-Th2 inflammatory factors. Moreover, PB inhibited the DSS-induced loss of commensal Clostridia and Flavobacteria, and the gain of pathogenic Erysipelotrichia and Fusobacteria. CONCLUSIONS: Together, these data suggest that in colons of a murine model, PB promotes MUC2 synthesis, suppresses Th2 inflammation and attenuates bacterial dysbiosis therefore, PB has a therapeutic potential in UC.
Assuntos
Acetilcolinesterase/metabolismo , Anti-Inflamatórios/farmacologia , Inibidores da Colinesterase/farmacologia , Colite Ulcerativa/tratamento farmacológico , Colo/efeitos dos fármacos , Disbiose , Microbioma Gastrointestinal , Brometo de Piridostigmina/farmacologia , Animais , Colite Ulcerativa/enzimologia , Colite Ulcerativa/microbiologia , Colite Ulcerativa/patologia , Colo/enzimologia , Colo/microbiologia , Colo/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Proteínas Ligadas por GPI/metabolismo , Mediadores da Inflamação/metabolismo , Mucina-2/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/metabolismoRESUMO
Circadian oscillations are regulated at both central and peripheral levels to maintain physiological homeostasis. The central circadian clock consists of a central pacemaker in the suprachiasmatic nucleus that is entrained by light dark cycles and this, in turn, synchronizes the peripheral clock inherent in other organs. Circadian dysregulation has been attributed to dysregulation of peripheral clock and also associated with several diseases. Components of the molecular clock are disrupted in lung diseases like chronic obstructive pulmonary disease (COPD), asthma and IPF. Airway epithelial cells play an important role in temporally organizing magnitude of immune response, DNA damage response and acute airway inflammation. Non-coding RNAs play an important role in regulation of molecular clock and in turn are also regulated by clock components. Dysregulation of these non-coding RNAs have been shown to impact the expression of core clock genes as well as clock output genes in many organs. However, no studies have currently looked at the potential impact of these non-coding RNAs on lung molecular clock. This review focuses on the ways how these non-coding RNAs regulate and in turn are regulated by the lung molecular clock and its potential impact on lung diseases.
Assuntos
Relógios Circadianos/genética , Suscetibilidade a Doenças , Pneumopatias/etiologia , RNA não Traduzido/genética , Animais , Biomarcadores , Ritmo Circadiano/genética , Regulação da Expressão Gênica , Humanos , MicroRNAsRESUMO
Chronic airway inflammation from recurring exposures to noxious environmental stimuli results in a progressive and irreversible airflow limitation and the lung parenchymal damage that characterizes chronic obstructive pulmonary disease (COPD). The large variability observed in the onset and progression of COPD is primarily driven by complex gene-environment interactions. The transcriptomic and epigenetic memory potential of lung epithelial and innate immune cells drive responses, such as mucus hyperreactivity and airway remodeling, that are tightly regulated by various molecular mechanisms, for which several candidate susceptibility genes have been described. However, the recently described noncoding RNA species, in particular the long noncoding RNAs, may also have an important role in modulating pulmonary responses to chronic inhalation of toxic substances and the development of COPD. This review outlines the features of long noncoding RNAs that have been implicated in regulating the airway inflammatory responses to cigarette smoke exposure and their possible association with COPD pathogenesis. As COPD continues to debilitate the increasingly aging population and contribute to higher morbidity and mortality rates worldwide, the search for better biomarkers and alternative therapeutic options is pivotal.
Assuntos
Doença Pulmonar Obstrutiva Crônica/genética , RNA Longo não Codificante/fisiologia , Transcriptoma , Envelhecimento/genética , Envelhecimento/metabolismo , Poluentes Atmosféricos/efeitos adversos , Animais , Biomarcadores , Senescência Celular , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Interação Gene-Ambiente , Humanos , Imunidade Inata/genética , Inflamação/genética , Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/crescimento & desenvolvimento , Pulmão/metabolismo , Camundongos , Mitocôndrias/patologia , Modelos Animais , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/patologia , RNA Longo não Codificante/genética , Fumaça/efeitos adversos , Lesão por Inalação de Fumaça/complicações , Fumar/efeitos adversos , Fumar/genética , NicotianaRESUMO
Embryonic development is highly sensitive to xenobiotic toxicity and in utero exposure to environmental toxins affects physiological responses of the progeny. In the United States, the prevalence of allergic asthma (AA) is inexplicably rising and in utero exposure to cigarette smoke increases the risk of AA and bronchopulmonary dysplasia (BPD) in children and animal models. We reported that gestational exposure to sidestream cigarette smoke (SS), or secondhand smoke, promoted nicotinic acetylcholine receptor-dependent exacerbation of AA and BPD in mice. Recently, perinatal nicotine injections in rats were reported to induce peroxisome proliferator-activated receptor γ-dependent transgenerational transmission of asthma. Herein, we show that first generation and second generation progeny from gestationally SS-exposed mice exhibit exacerbated AA and BPD that is not dependent on the decrease in peroxisome proliferator-activated receptor γ levels. Lungs from these mice show strong eosinophilic infiltration, excessive Th2 polarization, marked airway hyperresponsiveness, alveolar simplification, decreased lung compliance, and decreased lung angiogenesis. At the molecular level, these changes are associated with increased RUNX3 expression, alveolar cell apoptosis, and the antiangiogenic factor GAX, and decreased expression of HIF-1α and proangiogenic factors NF-κB and VEGFR2 in the 7-d first generation and second generation lungs. Moreover, the lungs from these mice exhibit lower levels of microRNA (miR)-130a and increased levels of miR-16 and miR-221. These miRs regulate HIF-1α-regulated apoptotic, angiogenic, and immune pathways. Thus the intergenerational effects of gestational SS involve epigenetic regulation of HIF-1α through specific miRs contributing to increased incidence of AA and BPD in the progenies.
Assuntos
Asma/etiologia , Asma/genética , Displasia Broncopulmonar/etiologia , Epigênese Genética , Efeitos Tardios da Exposição Pré-Natal/imunologia , Fumaça/efeitos adversos , Poluição por Fumaça de Tabaco/efeitos adversos , Células Epiteliais Alveolares/patologia , Animais , Apoptose , Asma/imunologia , Asma/fisiopatologia , Displasia Broncopulmonar/imunologia , Displasia Broncopulmonar/fisiopatologia , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Feminino , Proteínas de Homeodomínio/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Pulmão/patologia , Camundongos , MicroRNAs/genética , Subunidade p50 de NF-kappa B/genética , Fatores de Crescimento Neural , Neuropeptídeos/genética , Nicotina/efeitos adversos , PPAR gama/genética , PPAR gama/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fumar/efeitos adversos , Células Th2/imunologiaRESUMO
OBJECTIVE: House dust mite (HDM) exposure is used to model experimental asthma in mice. However, a direct comparison of inflammatory responses following continuous versus intermittent HDM exposure has not been reported. Therefore, we investigated whether the HDM dose at sensitization or challenge affects extent of inflammation in mice that were either continuously or intermittently sensitized with HDM. MATERIALS AND METHODS: C57BL/6 mice received either 10 continuous exposures with 10 µg HDM per exposure or two intermittent HDM exposures over a period of two weeks and were subsequently challenged by three instillations with HDM during the third week. For the intermittent model, mice were sensitized with 1 or 10 µg HDM and challenged on three consecutive days with 1 or 10 µg HDM. Inflammatory cells in the bronchoalveolar lavage fluid and epithelial cell hyperplasia and mucous cell metaplasia were quantified. RESULTS: Significantly higher levels of inflammation and mucous cell metaplasia were observed when mice were sensitized intermittently compared with continuously. Intermittent sensitization and challenge with 10 µg HDM caused maximum inflammation, mucous cell metaplasia, and epithelial cell hyperplasia. However, sensitization with 1 µg HDM only also showed increased inflammation when challenged with 10 µg HDM. DISCUSSION: These findings suggest major differences in adaptive immunity, depending on the sensitization protocol. CONCLUSIONS: Because of significant differences, the HDM sensitization protocol should be carefully considered when designing studies to investigate the underlying mechanisms of immunity in mouse models of asthma.
Assuntos
Alérgenos/administração & dosagem , Hipersensibilidade/imunologia , Inflamação/imunologia , Pyroglyphidae/imunologia , Imunidade Adaptativa , Alérgenos/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Células Epiteliais/patologia , Hiperplasia/patologia , Hipersensibilidade/patologia , Inflamação/patologia , Pulmão/imunologia , Masculino , Camundongos Endogâmicos C57BLRESUMO
The purpose of this study was to determine whether expression of connective tissue growth factor (CTGF) protein in chronic obstructive pulmonary disease (COPD) is consistent in humans and animal models of COPD and to investigate the role of this protein in lung epithelial cells. CTGF in lung epithelial cells of ex-smokers with COPD was compared with ex-smokers without COPD by immunofluorescence. A total of twenty C57Bl/6 mice and sixteen non-human primates (NHPs) were exposed to cigarette smoke (CS) for 4 weeks. Ten mice of these CS-exposed mice and eight of the CS-exposed NHPs were infected with H3N2 influenza A virus (IAV), while the remaining ten mice and eight NHPs were mock-infected with vehicle as control. Both mRNA and protein expression of CTGF in lung epithelial cells of mice and NHPs were determined. The effects of CTGF overexpression on cell proliferation, p16 protein, and senescence-associated ß-galactosidase (SA-ß-gal) activity were examined in cultured human bronchial epithelial cells (HBECs). In humans, CTGF expression increased with increasing COPD severity. We found that protein expression of CTGF was upregulated in lung epithelial cells in both mice and NHPs exposed to CS and infected with IAV compared to those exposed to CS only. When overexpressed in HBECs, CTGF accelerated cellular senescence accompanied by p16 accumulation. Both CTGF and p16 protein expression in lung epithelia are positively associated with the severity of COPD in ex-smokers. These findings show that CTGF is consistently expressed in epithelial cells of COPD lungs. By accelerating lung epithelial senescence, CTGF may block regeneration relative to epithelial cell loss and lead to emphysema.
Assuntos
Senescência Celular , Fumar Cigarros/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Células Epiteliais/fisiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Mucosa Respiratória/metabolismo , Idoso , Animais , Biomarcadores/metabolismo , Linhagem Celular , Proliferação de Células , Senescência Celular/fisiologia , Fator de Crescimento do Tecido Conjuntivo/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Células Epiteliais/metabolismo , Feminino , Humanos , Vírus da Influenza A Subtipo H3N2 , Pulmão/metabolismo , Pulmão/patologia , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Infecções por Orthomyxoviridae/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Fumaça/efeitos adversos , Produtos do Tabaco , Regulação para Cima , beta-Galactosidase/metabolismoRESUMO
Influenza virus induces apoptosis in infected cells to promote viral replication by manipulating the host cell death signaling pathway. Although some Bcl-2 family proteins play a role in the replication of influenza A virus (IAV), the role of cell death pathways in the viral replication cycle is unclear. We investigated whether deficiency of the proapoptotic Bcl-2 family protein, Bik, plays a role in IAV replication. IAV replication was attenuated in mouse airway epithelial cells (MAECs) from bik(-/-) compared with bik(+/+) mice, as indicated by reduced viral titers. Bik(-/-) MAECs showed more stable transepithelial resistance after infection than did bik(+/+) MAECs, were less sensitive to infection-induced cell death, and released fewer copies of viral RNA. Similar results were obtained when Bik expression was suppressed in human airway epithelial cells (HAECs). Bik(+/+) mice lost weight drastically and died within 8 days of infection, whereas 75% of bik(-/-) mice survived infection for 14 days and were 10-fold less likely to die from infection compared with bik(+/+) mice. IAV infection activated caspase 3 in bik(+/+) but not in bik(-/-) MAECs. Cleavage of viral nucleoprotein and M2 proteins were inhibited in bik(-/-) MAECs and when caspase activation was inhibited in HAECs. Furthermore, Bik deficiency impaired cytoplasmic export of viral ribonucleoprotein. These studies suggest a link between Bik-mediated caspase activation and cleavage of viral proteins. Thus, inhibition of proapoptotic host factors such as Bik and downstream mediators of cell death may represent a novel approach to influenza treatment.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Caspase 3/metabolismo , Vírus da Influenza A/fisiologia , Influenza Humana/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Infecções por Orthomyxoviridae/metabolismo , Proteínas Virais/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Células Epiteliais Alveolares/virologia , Animais , Morte Celular , Embrião de Galinha , Citoplasma/metabolismo , Cães , Ativação Enzimática , Humanos , Influenza Humana/virologia , Células Madin Darby de Rim Canino , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/deficiência , Infecções por Orthomyxoviridae/virologia , Ribonucleoproteínas/metabolismo , Replicação ViralRESUMO
BACKGROUND: Airway epithelial cells (AECs) are crucial for mucosal and adaptive immunity but whether these cells respond in a memory-dependent manner is poorly studied. Previously, we have reported that LPS intratracheal instillation in rodents causes extensive neutrophilic inflammation and airway epithelial cell hyperplasia accompanied by mucous cell metaplasia (MCM). And the resolution process required a period of 40 d for the inflammation to subside and the lung epithelia to resemble the non-exposed condition. Therefore, the present study investigated the memory-dependent response of airway epithelial cells to a secondary LPS challenge after the initial inflammation was resolved. METHODS: Airway epithelial and mucous cells were assessed in response to a secondary LPS challenge in F344/N rats, and in C57BL/6 wild-type (Foxn1WT) and T cell-deficient athymic (Foxn1nu) mice that were instilled with LPS or saline 40 d earlier. Epithelial expression of TLR4, EGFR, and phosphorylated-ERK1/2 (pERK) were also analyzed. RESULTS: LPS-pretreated F344/N rats responded with elevated numbers of AECs after saline challenge and with 3-4-fold increased MCM following the LPS challenge in LPS- compared with saline-pretreated rats. LPS-pretreated rats showed 5-fold higher number of AECs expressing TLR4 apically than saline-pretreated rats. Also, the expression of EGFR was increased in LPS-pretreated rats along with the number of AECs with active or nuclear pERK, and the levels were further increased upon LPS challenge. LPS-pretreated Foxn1nu compared with Foxn1WT mice showed increased MCM and elevated levels of TLR4, EGFR, and nuclear pERK at 40 d after LPS instillation. LPS challenge further augmented MCM rapidly in Foxn1nu compared with Foxn1WT mice. CONCLUSION: Together, these data suggest that AECs preserve an 'innate memory' that drives a rapid mucous phenotype via spatiotemporal regulation of TLR4 and EGFR. Further, T cells may suppress the sustained elevated expression of TLR4 and EGFR and thereby the hyperactive epithelial response.
Assuntos
Células Epiteliais/imunologia , Imunidade nas Mucosas , Memória Imunológica , Pneumonia/imunologia , Mucosa Respiratória/imunologia , Linfócitos T/imunologia , Animais , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Receptores ErbB/imunologia , Receptores ErbB/metabolismo , Fatores de Transcrição Forkhead/deficiência , Fatores de Transcrição Forkhead/genética , Lipopolissacarídeos , Masculino , Metaplasia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Pneumonia/patologia , Ratos Endogâmicos F344 , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Transdução de Sinais , Linfócitos T/metabolismo , Linfócitos T/patologia , Fatores de Tempo , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismoRESUMO
Long-term cigarette smoking increases the risk for chronic obstructive pulmonary disease (COPD), characterized by irreversible expiratory airflow limitation. The pathogenesis of COPD involves oxidative stress and chronic inflammation. Various natural marine compounds possess both anti-oxidant and anti-inflammatory properties, but few have been tested for their efficacy in COPD models. In this study, we conducted an in vitro screening test to identify natural compounds isolated from various brown algae species that might provide protection against cigarette smoke extract (CSE)-induced cytotoxicity. Among nine selected natural compounds, apo-9'-fucoxanthinone (Apo9F) exhibited the highest protection against CSE-induced cytotoxicity in immortalized human bronchial epithelial cells (HBEC2). Furthermore, the protective effects of Apo9F were observed to be associated with a significant reduction in apoptotic cell death, DNA damage, and the levels of mitochondrial reactive oxygen species (ROS) released from CSE-exposed HBEC2 cells. These results suggest that Apo9F protects against CSE-induced DNA damage and apoptosis by regulating mitochondrial ROS production.
Assuntos
Apoptose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Nicotiana/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Rodófitas/química , Fumaça/efeitos adversos , Terpenos/farmacologia , Linhagem Celular , Dano ao DNA/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fumar/efeitos adversos , Terpenos/químicaAssuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Metabolômica , Pneumonia Viral/tratamento farmacológico , COVID-19 , Infecções por Coronavirus/virologia , Humanos , Metabolômica/métodos , Pandemias , Pneumonia Viral/virologia , SARS-CoV-2 , Tratamento Farmacológico da COVID-19RESUMO
Cigarette smoke contains numerous chemical compounds, including abundant reactive oxygen/nitrogen species and aldehydes, and many other carcinogens. Long-term cigarette smoking significantly increases the risk of various lung diseases, including chronic obstructive pulmonary disease and lung cancer, and contributes to premature death. Many in vitro and in vivo studies have elucidated mechanisms involved in cigarette smoke-induced inflammation, DNA damage, and autophagy, and the subsequent cell fates, including cell death, cellular senescence, and transformation. In this Translational Review, we summarize the known pathways underlying these processes in airway epithelial cells to help reveal future challenges and describe possible directions of research that could lead to better management and treatment of these diseases.
Assuntos
Células Epiteliais/efeitos dos fármacos , Pneumopatias/etiologia , Mucosa Respiratória/efeitos dos fármacos , Fumaça/efeitos adversos , Fumar/efeitos adversos , Animais , Morte Celular , Senescência Celular , Dano ao DNA , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Mediadores da Inflamação/metabolismo , Pneumopatias/metabolismo , Pneumopatias/patologia , Prognóstico , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Fatores de Risco , Transdução de Sinais/efeitos dos fármacosRESUMO
Bcl-2, a prosurvival protein, regulates programmed cell death during development and repair processes, and it can be oncogenic when cell proliferation is deregulated. The present study investigated what factors modulate Bcl-2 expression in airway epithelial cells and identified the pathways involved. Microarray analysis of mRNA from airway epithelial cells captured by laser microdissection showed that increased expression of IL-1ß and insulin-like growth factor-1 (IGF-1) coincided with induced Bcl-2 expression compared with controls. Treatment of cultured airway epithelial cells with IL-1ß and IGF-1 induced Bcl-2 expression by increasing Bcl-2 mRNA stability with no discernible changes in promoter activity. Silencing the IGF-1 expression using short hairpin RNA showed that intracellular IGF-1 (IC-IGF-1) was increasing Bcl-2 expression. Blocking epidermal growth factor receptor or IGF-1R activation also suppressed IC-IGF-1 and abolished the Bcl-2 induction. Induced expression and colocalization of IC-IGF-1 and Bcl-2 were observed in airway epithelial cells of mice exposed to LPS or cigarette smoke and of patients with cystic fibrosis and chronic bronchitis but not in the respective controls. These studies demonstrate that IC-IGF-1 induces Bcl-2 expression in epithelial cells via IGF-1R and epidermal growth factor receptor pathways, and targeting IC-IGF-1 could be beneficial to treat chronic airway diseases.
Assuntos
Células Epiteliais/imunologia , Regulação da Expressão Gênica/imunologia , Fator de Crescimento Insulin-Like I/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Mucosa Respiratória/imunologia , Animais , Doença Crônica , Fibrose Cística/imunologia , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Fibrose Cística/terapia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/imunologia , Receptores ErbB/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Ratos , Ratos Endogâmicos F344 , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Poluição por Fumaça de Tabaco/efeitos adversosAssuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Células Epiteliais/fisiologia , Interleucina-13/fisiologia , Proteínas Mitocondriais/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Alérgenos/imunologia , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Animais , Proteínas Reguladoras de Apoptose , Asma/tratamento farmacológico , Asma/imunologia , Células Cultivadas , Células Epiteliais/patologia , Humanos , Hiperplasia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucina-5AC/fisiologia , Ovalbumina/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Traqueia/citologiaRESUMO
[This corrects the article DOI: 10.1016/j.toxrep.2022.09.010.].
RESUMO
[This corrects the article DOI: 10.1016/j.toxrep.2022.08.007.].