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Gastrectomía , Laparoscopía , Escisión del Ganglio Linfático , Terapia Neoadyuvante , Estadificación de Neoplasias , Puntaje de Propensión , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patología , Gastrectomía/métodos , Gastrectomía/efectos adversos , Escisión del Ganglio Linfático/métodos , Laparoscopía/métodos , Laparoscopía/efectos adversos , Terapia Neoadyuvante/métodosRESUMEN
Metastasis is responsible for about 90 % of cancer deaths. Anti-metastatic drugs, termed as migrastatics, offer a distinctive therapeutic approach to address cancer migration and invasion. However, therapeutic exploitation of metastasis-specific targets remains limited, and the effective prevention and suppression of metastatic cancer continue to be elusive. Lysophosphatidic acid receptor 1 (LPA1) is activated by an endogenous lipid molecule LPA, leading to a diverse array of cellular activities. Previous studies have shown that the LPA/LPA1 axis supports the progression of metastasis for many types of cancer. In this study, we report the synthesis and biological evaluation of fluorine-containing triazole derivatives as potent LPA1 antagonists, offering potential as migrastatic drugs for triple negative breast cancer (TNBC). In particular, compoundâ 12 f, the most potent and highly selective in this series with an IC50 value of 16.0â nM in the cAMP assay and 18.4â nM in the calcium mobilization assay, inhibited cell survival, migration, and invasion in the TNBC cell line. Interestingly, the compound did not induce apoptosis in TNBCâ cells and demonstrated no cytotoxic effects. These results highlight the potential of LPA1 as a migrastatic target. Consequently, the LPA1 antagonists developed in this study hold promise as potential migrastatic candidates for TNBC.
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Purpose: This study aimed to explore the effect of Rapamycin (Rapa) in Staphylococcus aureus (S. aureus) pneumonia and clarify its possible mechanism. Methods: We investigated the effects of Rapa on S. aureus pneumonia in mouse models and in macrophages cultured in vitro. Two possible mechanisms were investigated: the mTOR-RPS6 pathway phosphorylation and phagocytosis. Furthermore, for the mechanism verification in vivo, mice with specific Mtor knockout in myeloid cells were constructed for pneumonia models. Results: Rapa exacerbated S. aureus pneumonia in mouse models, promoting chemokines secretion and inflammatory cells infiltration in lung. In vitro, Rapa upregulated the secretion of chemokines and cytokines in macrophages induced by S. aureus. Mechanistically, the mTOR-ribosomal protein S6 (RPS6) pathway in macrophages was phosphorylated in response to S. aureus infection, and the inhibition of RPS6 phosphorylation upregulated the inflammation level. However, Rapa did not increase the phagocytic activity. Accordingly, mice with specific Mtor knockout in myeloid cells experienced more severe S. aureus pneumonia. Conclusion: Rapa exacerbates S. aureus pneumonia by increasing the inflammatory levels of macrophages. Inhibition of mTOR-RPS6 pathway upregulates the expression of cytokines and chemokines in macrophages, thus increases inflammatory cells infiltration and exacerbates tissue damage.
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Major histocompatibility complex class II (MHC II) is an essential immune regulatory molecule that plays an important role in antigen presentation and T-cell development. Abnormal MHC II expression can lead to immunodeficiency, clinically termed as type II bare lymphocyte syndrome (BLS), which usually results from mutations in the MHC II transactivator (CIITA) and other coactivators. Here, we present a new paradigm for MHC II deficiency in mice that involves a spontaneous point mutation on H2-Aa. A significantly reduced population of CD4+ T cells was observed in mice obtained from the long-term homozygous breeding of autophagy-related gene microtubule-associated protein 1 light chain 3 ß (Map1lc3b, Lc3b) knockout mice; this phenotype was not attributed to the original knocked-out gene. MHC II expression was generally reduced, together with a marked deficiency of H2-Aa in the immune cells of these mice. Using cDNA and DNA sequencing, a spontaneous H2-Aa point mutation that led to false pre-mRNA splicing, deletion of eight bases in the mRNA, and protein frameshift was identified in these mice. These findings led to the discovery of a new type of spontaneous MHC II deficiency and provided a new paradigm to explain type II BLS in mice.
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Antígenos de Histocompatibilidad Clase II , Mutación Puntual , Animales , Linfocitos T CD4-Positivos , Ratones , Ratones Noqueados , Inmunodeficiencia Combinada Grave , Linfocitos TRESUMEN
Asthma is a chronic inflammatory disease of the lungs that poses a considerable health and socioeconomic burden. Several risk factors work synergistically to affect the progression of asthma. Lipid metabolism, especially in distinct cells such as T cells, macrophages, granulocytes, and non-immune cells, plays an essential role in the pathogenesis of asthma, as lipids are potent signaling molecules that regulate a multitude of cellular response. In this review, we focused on the metabolic pathways of lipid molecules, especially fatty acids and their derivatives, and summarized their roles in various cells during the pathogenesis of asthma along with the current pharmacological agents targeting lipid metabolism.
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Asma/metabolismo , Granulocitos/inmunología , Metabolismo de los Lípidos/inmunología , Macrófagos/inmunología , Linfocitos T/inmunología , Animales , Asma/tratamiento farmacológico , Asma/epidemiología , Ácidos Grasos/metabolismo , Humanos , Inmunidad Celular , Terapia Molecular Dirigida , Factores de Riesgo , Transducción de SeñalRESUMEN
INTRODUCTION: Acute lung injury (ALI) is a fatal but undertreated condition with severe neutrophilic inflammation, although little is known about the functions of eosinophils in the pathogenesis of ALI. Our objectives were to investigate the roles and molecular mechanisms of eosinophils in ALI. METHODS: Pulmonary eosinophils were identified by flow cytometry. Mice with abundant or deficient eosinophils were used. Cellularity of eosinophils and neutrophils in bronchoalveolar lavage fluid, inflammatory assessment, and survival rate were determined. Human samples were also used for validating experimental results. RESULTS: Blood eosinophils were increased in surviving patients with acute respiratory distress syndrome (ARDS) independent of corticosteroid usage. There existed homeostatic eosinophils in lung parenchyma in mice and these homeostatic eosinophils, originating from the bone marrow, were predominantly CD101-. More CD101- eosinophils could be recruited earlier than lipopolysaccharide (LPS)-initiated neutrophilic inflammation. Loss of eosinophils augmented LPS-induced pulmonary injury. Homeostatic CD101- eosinophils ameliorated, while allergic CD101+ eosinophils exacerbated, the neutrophilic inflammation induced by LPS. Likewise, CD101 expression in eosinophils from ARDS patients did not differ from healthy subjects. Mechanistically, CD101- eosinophils exhibited higher levels of Alox15 and Protectin D1. Administration of Protectin D1 isomer attenuated the neutrophilic inflammation. CONCLUSIONS: Collectively, our findings identify an uncovered function of native CD101- eosinophils in suppressing neutrophilic lung inflammation and suggest a potential therapeutic target for ALI.
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Lesión Pulmonar Aguda , Endotoxinas , Lesión Pulmonar Aguda/inducido químicamente , Animales , Líquido del Lavado Bronquioalveolar , Eosinófilos , Humanos , Lipopolisacáridos , Pulmón , RatonesRESUMEN
It is currently not understood whether cigarette smoke exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive chronic obstructive pulmonary disease (COPD)-associated pathologies.To address this question, mice were exposed to cigarette smoke for 2â weeks. Following a 2-week period of rest, mice were challenged intratracheally with elastin for 3â days or 1â month. Rag1-/- , Mmp12-/- , and Il17a-/- mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2â weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1â month resulted in airway remodelling, lung function decline and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6â months. Adoptive T cell transfer and studies in T cells deficient Rag1-/- mice conclusively implicated T cells in these processes. Mechanistically, cigarette smoke exposure-induced elastin-specific T cell responses were matrix metalloproteinase (MMP)12-dependent, while the ensuing immune inflammatory processes were interleukin 17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the cigarette smoke-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of cigarette smoke-induced autoimmune processes and may serve as a novel mouse model of COPD.
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Elastina , Enfermedad Pulmonar Obstructiva Crónica , Animales , Autoinmunidad , Modelos Animales de Enfermedad , Humanos , Pulmón , Ratones , Ratones Endogámicos C57BL , Humo/efectos adversos , Fumar/efectos adversosRESUMEN
Particulate matter (PM) is able to induce airway epithelial injury, while the detailed mechanisms remain unclear. Here we demonstrated that PM exposure inactivated MTOR (mechanistic target of rapamycin kinase), enhanced macroautophagy/autophagy, and impaired lysosomal activity in HBE (human bronchial epithelial) cells and in mouse airway epithelium. Genetic or pharmaceutical inhibition of MTOR significantly enhanced, while inhibition of autophagy attenuated, PM-induced IL6 expression in HBE cells. Consistently, club-cell-specific deletion of Mtor aggravated, whereas loss of Atg5 in bronchial epithelium reduced, PM-induced airway inflammation. Interestingly, the augmented inflammatory responses caused by MTOR deficiency were markedly attenuated by blockage of downstream autophagy both in vitro and in vivo. Mechanistically, the dysregulation of MTOR-autophagy signaling was partially dependent on activation of upstream TSC2, and interacted with the TLR4-MYD88 to orchestrate the downstream NFKB activity and to regulate the production of inflammatory cytokines in airway epithelium. Moreover, inhibition of autophagy reduced the expression of EPS15 and the subsequent endocytosis of PM. Taken together, the present study provides a mechanistic explanation for how airway epithelium localized MTOR-autophagy axis regulates PM-induced airway injury, suggesting that activation of MTOR and/or suppression of autophagy in local airway might be effective therapeutic strategies for PM-related airway disorders.Abbreviations: ACTB: actin beta; AKT: AKT serine/threonine kinase; ALI: air liquid interface; AP2: adaptor related protein complex 2; ATG: autophagy related; BALF: bronchoalveolar lavage fluid; COPD: chronic obstructive pulmonary disease; CXCL: C-X-C motif chemokine ligand; DOX: doxycycline; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; EPS15: epidermal growth factor receptor pathway substrate 15; HBE: human bronchial epithelial; H&E: hematoxylin & eosin; IKK: IKB kinase; IL: interleukin; LAMP2: lysosomal-associated membrane protein 2; LPS: lipopolysaccharide; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTEC: mouse tracheal epithelial cells; MTOR: mechanistic target of rapamycin kinase; MYD88: MYD88 innate immune signal transduction adaptor; NFKB: nuclear factor of kappa B; NFKBIA: NFKB inhibitor alpha; PM: particulate matter; PtdIns3K: phosphatidylinositol 3-kinase; Rapa: rapamycin; RELA: RELA proto-oncogene, NFKB subunit; SCGB1A1: secretoglobin family 1A member 1; siRNA: small interfering RNAs; SQSTM1: sequestosome 1; TEM: transmission electronic microscopy; TLR4: toll like receptor 4; TSC2: TSC complex subunit 2.
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Autofagia , Células Epiteliales/patología , Material Particulado/toxicidad , Neumonía/inducido químicamente , Neumonía/patología , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteína 5 Relacionada con la Autofagia/metabolismo , Bronquios/patología , Línea Celular , Citocinas/metabolismo , Endocitosis/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Eliminación de Gen , Humanos , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Ratones , Proteínas Asociadas a Microtúbulos/deficiencia , Proteínas Asociadas a Microtúbulos/metabolismo , Modelos Biológicos , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/metabolismo , Unión Proteica/efectos de los fármacos , Proto-Oncogenes Mas , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Proteína 2 del Complejo de la Esclerosis Tuberosa/metabolismoRESUMEN
Tissue factor (TF)-dependent coagulation contributes to lung inflammation and the pathogenesis of acute lung injury (ALI). In this study, we explored the roles of targeted endothelial anticoagulation in ALI using two strains of transgenic mice expressing either a membrane-tethered human tissue factor pathway inhibitor (hTFPI) or hirudin fusion protein on CD31+ cells, including vascular endothelial cells (ECs). ALI was induced by intratracheal injection of LPS, and after 24 h the expression of TF and protease-activated receptors (PARs) on EC in lungs were assessed, alongside the extent of inflammation and injury. The expression of TF and PARs on the EC in lungs was upregulated after ALI. In the two strains of transgenic mice, expression of either of hTFPI or hirudin by EC was associated with significant reduction of inflammation, as assessed by the extent of leukocyte infiltration or the levels of proinflammatory cytokines, and promoted survival after LPS-induced ALI. The beneficial outcomes were associated with inhibition of the expression of chemokine CCL2 in lung tissues. The protection observed in the CD31-TFPI-transgenic strain was abolished by injection of an anti-hTFPI antibody, but not by prior engraftment of the transgenic strains with WT bone marrow, confirming that the changes observed were a specific transgenic expression of anticoagulants by EC. These results demonstrate that the inflammation in ALI is TF and thrombin dependent, and that expression of anticoagulants by EC significantly inhibits the development of ALI via repression of leukocyte infiltration, most likely via inhibition of chemokine gradients. These data enhance our understanding of the pathology of ALI and suggest a novel therapeutic strategy for treatment.
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Lesión Pulmonar Aguda/metabolismo , Células Endoteliales/metabolismo , Hirudinas/metabolismo , Inflamación/metabolismo , Lipoproteínas/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Animales , Coagulación Sanguínea/fisiología , Quimiocinas/metabolismo , Quimiotaxis de Leucocito/fisiología , Hirudinas/genética , Humanos , Inflamación/inducido químicamente , Sanguijuelas/química , Lipopolisacáridos , Lipoproteínas/genética , Pulmón/patología , Ratones Endogámicos C57BL , Ratones Transgénicos , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/genética , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Pseudomonas aeruginosa/química , Receptores Proteinasa-Activados/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Trombina/metabolismo , Tromboplastina/metabolismoRESUMEN
Since the publication of the article, the authors became aware that Figs. 1c, 5k and 6m contained errors in representative image and PAS score in control groups. The corrected Figs. 1c, 5k, and 6m are given below, and the figure legends are the same as original.
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Particulate matter (PM) is a significant risk factor for airway injury. We have recently demonstrated a pivotal role of autophagy in mediating PM-induced airway injury. In the present study, we examined the possible effects of autophagy inhibitors spautin-1 and 3-Methyladenine (3-MA) in protection of PM-induced inflammatory responses. We observed that PM triggered autophagy in human bronchial epithelial (HBE) cells and in mouse airways. Spautin-1 or 3-MA inhibited PM-induced expression of inflammatory cytokines in HBE cells, and decreased the neutrophil influx and proinflammatory cytokines induced by PM in vivo. We further illustrated that autophagy inhibitors suppressed the inflammation responses via inhibition of the nuclear factor-кB (NF-кB) pathway. Thus, this study shows a paradigm that autophagy inhibitors effectively decrease the PM-induced airway inflammation via suppressing the NF-кB pathway, which may provide novel preventive and/or protective approaches for PM-related airway injury.
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Adenina/análogos & derivados , Autofagia/efectos de los fármacos , Bencilaminas/farmacología , Contaminantes Ambientales/toxicidad , Material Particulado/toxicidad , Quinazolinas/farmacología , Adenina/farmacología , Animales , Línea Celular , Citocinas/genética , Citocinas/metabolismo , Regulación de la Expresión Génica/fisiología , Humanos , Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BLRESUMEN
Pulmonary epithelial cells form the first line of defense of human airways against foreign irritants and also represent as the primary injury target of these pathogenic assaults. Autophagy is a revolutionary conserved ubiquitous process by which cytoplasmic materials are delivered to lysosomes for degradation when facing environmental and/or developmental changes, and emerging evidence suggests that autophagy plays pivotal but controversial roles in pulmonary epithelial injury. Here we review recent studies focusing on the roles of autophagy in regulating airway epithelial injury induced by various stimuli. Articles eligible for this purpose are divided into two groups according to the eventual roles of autophagy, either protective or deleterious. From the evidence summarized in this review, we draw several conclusions as follows: 1) in all cases when autophagy is decreased from its basal level, autophagy is protective; 2) when autophagy is deleterious, it is generally upregulated by stimulation; and 3) a plausible conclusion is that the endosomal/exosomal pathways may be associated with the deleterious function of autophagy in airway epithelial injury, although this needs to be clarified in future investigations.
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Autofagia/fisiología , Células Epiteliales/patología , Lesión Pulmonar/patología , Animales , Células Epiteliales/metabolismo , Humanos , Lesión Pulmonar/metabolismo , Lisosomas/metabolismo , Lisosomas/patología , Transducción de Señal/fisiologíaRESUMEN
Airway and lung inflammation is a fundamental hallmark of chronic obstructive pulmonary disease (COPD). Activating transcription factor 3 (ATF3) has been reported to negatively regulate many pro-inflammatory cytokines and chemokines. However, little is known about the impact of ATF3 on the inflammatory response of COPD. Since cigarette smoke (CS) is considered to be the most important risk factor in the etiology of COPD, we attempted to investigate the effects and molecular mechanisms of ATF3 in CS-induced inflammation. We observed an increase in the expression of ATF3 in the lung tissues of CS-exposed mice and CS extract (CSE)-treated human bronchial epithelial (HBE) cells. In vitro results indicated that ATF3 inhibition significantly increased the expression of proinflammatory cytokines interleukin 6 (IL6) and interleukin 8 (IL8) in CSE-stimulated HBE cells. Furthermore, in vivo data verified that CS induced inflammatory cell recruitment around the bronchus. In addition, neutrophil infiltration in bronchoalveolar lavage fluid (BALF) of CS-exposed Atf3-/- mice was markedly higher than in stimulated WT mice. Finally, ATF3 deficiency increased the in vitro and in vivo expression and phosphorylation of nuclear factor-κB (NF-κB), a positive mediator of inflammation. Thus, this study shows that ATF3 plays an important role in the negative regulation of CS-induced pro-inflammatory gene expression through downregulating NF-κB phosphorylation.
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Factor de Transcripción Activador 3/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , FN-kappa B/metabolismo , Fumar/efectos adversos , Factor de Transcripción Activador 3/genética , Animales , Bronquios/citología , Bronquios/efectos de los fármacos , Bronquios/metabolismo , Líquido del Lavado Bronquioalveolar , Línea Celular , Regulación hacia Abajo , Represión Epigenética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Humanos , Inflamación/etiología , Inflamación/genética , Interleucina-6/genética , Interleucina-8/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/antagonistas & inhibidores , FN-kappa B/genética , Infiltración Neutrófila/genética , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedad Pulmonar Obstructiva Crónica/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/aislamiento & purificación , Regulación hacia ArribaRESUMEN
Mucus hypersecretion is an important pathologic feature of chronic obstructive pulmonary disease. Activating transcription factor 3 (ATF3) is an adaptive-response gene that participates in various cellular processes. However, little is known about its role in cigarette smoke (CS)-induced mucus hyperproduction. This study aimed to investigate the role and molecular mechanisms of ATF3 in CS-induced Mucin 5AC (MUC5AC) expression. ATF3 was elevated in lung tissues of mice exposed to CS for 12 weeks. Treatment with CS extract significantly induced ATF3 expression and MUC5AC production in human bronchial epithelial cells, NCI-H292, and mouse tracheal epithelial cells. Interference of ATF3 significantly attenuated CS-induced MUC5AC expression in NCI-H292 and human bronchial epithelial cells. Mouse tracheal epithelial cells isolated from Atf3-/- mice also exhibited less MUC5AC production in response to CS extract treatment. In vivo, the Atf3-/- mice also displayed a significantly reduced mucus production relative to wild-type controls in response to chronic CS exposure. Furthermore, a chromatin immunoprecipitation assay revealed increased ATF3 binding to the MUC5AC promoter after CS treatment, and this transcriptional binding was significantly inhibited by knockdown of JUN, a subunit of activator protein-1. These results demonstrate that ATF3 may be involved in activator protein-1 signaling and transcriptional promotion of CS-induced MUC5AC expression in airway epithelial cells.
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Factor de Transcripción Activador 3/metabolismo , Mucina 5AC/biosíntesis , Mucosa Respiratoria/patología , Fumar/efectos adversos , Factor de Transcripción AP-1/metabolismo , Animales , Western Blotting , Inmunoprecipitación de Cromatina , Modelos Animales de Enfermedad , Humanos , Inmunohistoquímica , Ratones , Ratones Noqueados , Reacción en Cadena de la Polimerasa , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Mucosa Respiratoria/metabolismoRESUMEN
Mucus hypersecretion is a common pathological feature of chronic airway inflammatory diseases including chronic obstructive pulmonary disease (COPD). However, the molecular basis for this condition remains incompletely understood. We have previously demonstrated a critical role of autophagy in COPD pathogenesis through mediating apoptosis of lung epithelial cells. In this study, we aimed to investigate the function of autophagy as well as its upstream and downstream signals in cigarette smoke-induced mucus production in human bronchial epithelial (HBE) cells and in mouse airways. Cigarette smoke extract (CSE), as well as the classical autophagy inducers starvation or Torin-1, significantly triggered MUC5AC expression, and inhibition of autophagy markedly attenuated CSE-induced mucus production. The CSE-induced autophagy was mediated by mitochondrial reactive oxygen species (mitoROS), which regulated mucin expression through the JNK and activator protein-1 pathway. Epidermal growth factor receptor (EGFR) was also required for CSE-induced MUC5AC in HBE cells, but it exerted inconsiderable effects on the autophagy-JNK signaling cascade. Airways of mice with dysfunctional autophagy-related genes displayed a markedly reduced number of goblet cells and attenuated levels of Muc5ac in response to cigarette smoke exposure. These results altogether suggest that mitoROS-dependent autophagy is essential for cigarette smoke-induced mucus hyperproduction in airway epithelial cells, and reemphasize autophagy inhibition as a novel therapeutic strategy for chronic airway diseases.
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Autofagia/efectos de los fármacos , Mucina 5AC/genética , Mucosa Respiratoria/metabolismo , Fumar/metabolismo , Animales , Células Cultivadas , Receptores ErbB/metabolismo , Expresión Génica , Células Caliciformes , Humanos , Pulmón/metabolismo , Pulmón/patología , Ratones Noqueados , Mucina 5AC/metabolismo , Moco/metabolismo , Naftiridinas/farmacología , Mucosa Respiratoria/patología , Transducción de Señal , Nicotiana/química , Factor de Transcripción AP-1/metabolismoRESUMEN
Suhuang antitussive capsule (Suhuang), a traditional Chinese medication, is found effective in treating chronic cough and cough variant asthma (CVA). This study aimed to determine the possible effects and underlying mechanisms of Suhuang on chronic ovalbumin (OVA)-induced airway hyperresponsiveness (AHR), inflammation, and remodeling in mice. Mice were randomly assigned to six experimental groups: control, OVA model with or without Suhuang (low dose: 3.5 g/kg, middle dose: 7.0 g/kg, high dose: 14.0 g/kg), or dexamethasone (2.5 mg/kg). AHR, inflammatory cells, cytokines in bronchoalveolar lavage fluid (BALF), lung pathology, mucus production, and airway remodeling were examined. We found Suhuang treated at lower doses effectively inhibited OVA-induced AHR, airway inflammation, mucus production and collagen deposition around the airway. High dose of Suhuang reduced most of the inflammatory hallmarks while exerted inconsiderable effects on the number of macrophages in BALF and AHR. At all doses, Suhuang significantly reduced the levels of interlukin (IL) -13 and transforming growth factor (TGF)-ß1, but had little effects on IL-4, IL-5, IL-17A and interferon (IFN)-γ. Thus, Suhuang administration alleviates the pathological changes of chronic asthma likely through inhibition of IL-13 and TGF-ß1. Suhuang might be a promising therapy for patients with allergic asthma in the future.
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Asma/tratamiento farmacológico , Medicina Tradicional China , Preparaciones de Plantas/uso terapéutico , Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Animales , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Lamiaceae/metabolismo , Pulmón/patología , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Moco/metabolismo , OvalbúminaRESUMEN
Environmental ultrafine particulate matter (PM) is capable of inducing airway injury, while the detailed molecular mechanisms remain largely unclear. Here, we demonstrate pivotal roles of autophagy in regulation of inflammation and mucus hyperproduction induced by PM containing environmentally persistent free radicals in human bronchial epithelial (HBE) cells and in mouse airways. PM was endocytosed by HBE cells and simultaneously triggered autophagosomes, which then engulfed the invading particles to form amphisomes and subsequent autolysosomes. Genetic blockage of autophagy markedly reduced PM-induced expression of inflammatory cytokines, e.g. IL8 and IL6, and MUC5AC in HBE cells. Mice with impaired autophagy due to knockdown of autophagy-related gene Becn1 or Lc3b displayed significantly reduced airway inflammation and mucus hyperproduction in response to PM exposure in vivo. Interference of the autophagic flux by lysosomal inhibition resulted in accumulated autophagosomes/amphisomes, and intriguingly, this process significantly aggravated the IL8 production through NFKB1, and markedly attenuated MUC5AC expression via activator protein 1. These data indicate that autophagy is required for PM-induced airway epithelial injury, and that inhibition of autophagy exerts therapeutic benefits for PM-induced airway inflammation and mucus hyperproduction, although they are differentially orchestrated by the autophagic flux.
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Autofagia , Bronquios/patología , Epitelio/metabolismo , Inflamación/etiología , Inflamación/patología , Moco/metabolismo , Material Particulado/efectos adversos , Animales , Beclina-1/metabolismo , Citocinas/metabolismo , Endocitosis , Células Epiteliales/patología , Células Epiteliales/ultraestructura , Epitelio/patología , Humanos , Lisosomas/metabolismo , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/metabolismo , Modelos Biológicos , FN-kappa B/metabolismo , Tamaño de la Partícula , Factor de Transcripción AP-1/metabolismoRESUMEN
BACKGROUND AND OBJECTIVE: Nuclear erythroid 2 p45-related factor-2 (Nrf2) is known to play important roles in airway disorders, whereas little has been investigated about its direct role in airway mucus hypersecretion. The aim of this study is to determine whether this factor could protect pulmonary epithelium and mouse airway from cigarette-induced mucus overproduction. METHODS: Using genetic approaches, the role of Nrf2 on cigarette smoking extracts (CSE) induced MUC5AC expression was investigated in lung A549 cells. Nrf2 deficiency mice were smoked for various periods, and the airway inflammation and mucus production was characterized. RESULTS: Acute smoking exposure induced expression of MUC5AC and Nrf2 in both A549 cells and mouse lungs. Genetic ablation of Nrf2 augmented, whereas overexpression of this molecule ameliorated CSE-induced expression of MUC5AC. Nrf2 knockout mice, after exposure to cigarette smoking, displayed enhanced airway inflammation and mucus production. CONCLUSION: Nrf2 negatively regulated smoking-induced mucus production in vitro and in vivo, suggesting therapeutic potentials of this factor in airway diseases with hypersecreted mucus.
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Pulmón/fisiopatología , Moco/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Mucosa Respiratoria/fisiopatología , Fumar/efectos adversos , Animales , Línea Celular Tumoral , Regulación de la Expresión Génica , Humanos , Inflamación/etiología , Inflamación/metabolismo , Ratones , Ratones Endogámicos ICR , Ratones Noqueados , Mucina 5AC/genética , Mucina 5AC/metabolismo , Moco/metabolismo , Factor 2 Relacionado con NF-E2/genética , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The mammalian target of rapamycin (mTOR) is a central regulator of many major cellular processes including protein and lipid synthesis and autophagy, and is also implicated in an increasing number of pathological conditions. Emerging evidence suggests that both mTOR and autophagy are critically involved in the pathogenesis of pulmonary diseases including acute lung injury (ALI). However, the detailed mechanisms of these pathways in disease pathogenesis require further investigations. In certain cases within the same disease, the functions of mTOR and autophagy may vary from different cell types and pathogens. Here we review recent advances about the basic machinery of mTOR and autophagy, and their roles in ALI. We further discuss and propose the likelihood of cell type- and pathogen-dependent functions of these pathways in ALI pathogenesis.