RESUMEN
BACKGROUND & AIMS: Inflammation in the gastrointestinal tract may lead to the development of cancer. Dicarbonyl electrophiles, such as isolevuglandins (isoLGs), are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. Thus, we sought to determine the role of dicarbonyl electrophiles in inflammation-associated carcinogenesis. METHODS: The formation of isoLG adducts was analyzed in the gastric tissues of patients infected with Helicobacter pylori from gastritis to precancerous intestinal metaplasia, in human gastric organoids, and in patients with colitis and colitis-associated carcinoma (CAC). The effect on cancer development of a potent scavenger of dicarbonyl electrophiles, 5-ethyl-2-hydroxybenzylamine (EtHOBA), was determined in transgenic FVB/N insulin-gastrin (INS-GAS) mice and Mongolian gerbils as models of H pylori-induced carcinogenesis and in C57BL/6 mice treated with azoxymethane-dextran sulfate sodium as a model of CAC. The effect of EtHOBA on mutations in gastric epithelial cells of H pylori-infected INS-GAS mice was assessed by whole-exome sequencing. RESULTS: We show increased isoLG adducts in gastric epithelial cell nuclei in patients with gastritis and intestinal metaplasia and in human gastric organoids infected with H pylori. EtHOBA inhibited gastric carcinoma in infected INS-GAS mice and gerbils and attenuated isoLG adducts, DNA damage, and somatic mutation frequency. Additionally, isoLG adducts were elevated in tissues from patients with colitis, colitis-associated dysplasia, and CAC as well as in dysplastic tumors of C57BL/6 mice treated with azoxymethane-dextran sulfate sodium. In this model, EtHOBA significantly reduced adduct formation, tumorigenesis, and dysplasia severity. CONCLUSIONS: Dicarbonyl electrophiles represent a link between inflammation and somatic genomic alterations and are thus key targets for cancer chemoprevention.
Asunto(s)
Transformación Celular Neoplásica/inmunología , Neoplasias Asociadas a Colitis/inmunología , Lípidos/inmunología , Lesiones Precancerosas/inmunología , Neoplasias Gástricas/inmunología , Animales , Bencilaminas/farmacología , Bencilaminas/uso terapéutico , Núcleo Celular/metabolismo , Transformación Celular Neoplásica/efectos de los fármacos , Neoplasias Asociadas a Colitis/microbiología , Neoplasias Asociadas a Colitis/patología , Neoplasias Asociadas a Colitis/prevención & control , Modelos Animales de Enfermedad , Células Epiteliales , Mucosa Gástrica/citología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/inmunología , Mucosa Gástrica/patología , Gastritis/inmunología , Gastritis/microbiología , Gastritis/patología , Gerbillinae , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/inmunología , Helicobacter pylori/aislamiento & purificación , Humanos , Lípidos/antagonistas & inhibidores , Metaplasia/inmunología , Metaplasia/microbiología , Metaplasia/patología , Ratones , Ratones Transgénicos , Organoides , Lesiones Precancerosas/tratamiento farmacológico , Lesiones Precancerosas/microbiología , Lesiones Precancerosas/patología , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Neoplasias Gástricas/prevención & controlRESUMEN
BACKGROUND & AIMS: Severe injury to the lining of the stomach leads to changes in the epithelium (reprogramming) that protect and promote repair of the tissue, including development of spasmolytic polypeptide-expressing metaplasia (SPEM) and tuft and foveolar cell hyperplasia. Acute gastric damage elicits a type-2 inflammatory response that includes production of type-2 cytokines and infiltration by eosinophils and alternatively activated macrophages. Stomachs of mice that lack interleukin 33 (IL33) or interleukin 13 (IL13) did not undergo epithelial reprogramming after drug-induced injury. We investigated the role of group 2 innate lymphoid cells (ILC2s) in gastric epithelial repair. METHODS: Acute gastric injury was induced in C57BL/6J mice (wild-type and RAG1 knockout) by administration of L635. We isolated ILC2s by flow cytometry from stomachs of mice that were and were not given L635 and performed single-cell RNA sequencing. ILC2s were depleted from wild-type and RAG1-knockout mice by administration of anti-CD90.2. We assessed gastric cell lineages, markers of metaplasia, inflammation, and proliferation. Gastric tissue microarrays from patients with gastric adenocarcinoma were analyzed by immunostaining. RESULTS: There was a significant increase in the number of GATA3-positive ILC2s in stomach tissues from wild-type mice after L635-induced damage, but not in stomach tissues from IL33-knockout mice. We characterized a marker signature of gastric mucosal ILC2s and identified a transcription profile of metaplasia-associated ILC2s, which included changes in expression of Il5, Il13, Csf2, Pd1, and Ramp3; these changes were validated by quantitative polymerase chain reaction and immunocytochemistry. Depletion of ILC2s from mice blocked development of metaplasia after L635-induced injury in wild-type and RAG1-knockout mice and prevented foveolar and tuft cell hyperplasia and infiltration or activation of macrophages after injury. Numbers of ILC2s were increased in stomach tissues from patients with SPEM compared with patients with normal corpus mucosa. CONCLUSIONS: In analyses of stomach tissues from mice with gastric tissue damage and patients with SPEM, we found evidence of type 2 inflammation and increased numbers of ILC2s. Our results suggest that ILC2s coordinate the metaplastic response to severe gastric injury.
Asunto(s)
Mucosa Gástrica/patología , Inmunidad Innata , Subgrupos Linfocitarios/inmunología , Animales , Modelos Animales de Enfermedad , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/inmunología , Humanos , Interleucina-33/genética , Metaplasia/inducido químicamente , Metaplasia/genética , Metaplasia/inmunología , Ratones , Ratones NoqueadosRESUMEN
BACKGROUND & AIMS: Chronic atrophic gastritis can lead to gastric metaplasia and increase risk of gastric adenocarcinoma. Metaplasia is a precancerous lesion associated with an increased risk for carcinogenesis, but the mechanism(s) by which inflammation induces metaplasia are poorly understood. We investigated transcriptional programs in mucous neck cells and chief cells as they progress to metaplasia mice with chronic gastritis. METHODS: We analyzed previously generated single-cell RNA-sequencing (scRNA-seq) data of gastric corpus epithelium to define transcriptomes of individual epithelial cells from healthy BALB/c mice (controls) and TxA23 mice, which have chronically inflamed stomachs with metaplasia. Chronic gastritis was induced in B6 mice by Helicobacter pylori infection. Gastric tissues from mice and human patients were analyzed by immunofluorescence to verify findings at the protein level. Pseudotime trajectory analysis of scRNA-seq data was used to predict differentiation of normal gastric epithelium to metaplastic epithelium in chronically inflamed stomachs. RESULTS: Analyses of gastric epithelial transcriptomes revealed that gastrokine 3 (Gkn3) mRNA is a specific marker of mouse gastric corpus metaplasia (spasmolytic polypeptide expressing metaplasia, SPEM). Gkn3 mRNA was undetectable in healthy gastric corpus; its expression in chronically inflamed stomachs (from TxA23 mice and mice with Helicobacter pylori infection) identified more metaplastic cells throughout the corpus than previously recognized. Staining of healthy and diseased human gastric tissue samples paralleled these results. Although mucous neck cells and chief cells from healthy stomachs each had distinct transcriptomes, in chronically inflamed stomachs, these cells had distinct transcription patterns that converged upon a pre-metaplastic pattern, which lacked the metaplasia-associated transcripts. Finally, pseudotime trajectory analysis confirmed the convergence of mucous neck cells and chief cells into a pre-metaplastic phenotype that ultimately progressed to metaplasia. CONCLUSIONS: In analyses of tissues from chronically inflamed stomachs of mice and humans, we expanded the definition of gastric metaplasia to include Gkn3 mRNA and GKN3-positive cells in the corpus, allowing a more accurate assessment of SPEM. Under conditions of chronic inflammation, chief cells and mucous neck cells are plastic and converge into a pre-metaplastic cell type that progresses to metaplasia.
Asunto(s)
Células Principales Gástricas/patología , Gastritis Atrófica/inmunología , Infecciones por Helicobacter/inmunología , Lesiones Precancerosas/diagnóstico , Neoplasias Gástricas/prevención & control , Animales , Biomarcadores/análisis , Biomarcadores/metabolismo , Carcinogénesis/genética , Carcinogénesis/inmunología , Proteínas Portadoras/análisis , Proteínas Portadoras/metabolismo , Células Principales Gástricas/inmunología , Modelos Animales de Enfermedad , Femenino , Gastritis Atrófica/microbiología , Gastritis Atrófica/patología , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/inmunología , Humanos , Masculino , Proteínas de la Membrana/análisis , Proteínas de la Membrana/metabolismo , Metaplasia/diagnóstico , Metaplasia/genética , Metaplasia/inmunología , Metaplasia/patología , Ratones , Lesiones Precancerosas/genética , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/patología , RNA-Seq , Análisis de la Célula Individual , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND & AIMS: The association between chronic inflammation and gastric carcinogenesis is well established, but it is not clear how immune cells and cytokines regulate this process. We investigated the role of interleukin 27 (IL27) in the development of gastric atrophy, hyperplasia, and metaplasia (preneoplastic lesions associated with inflammation-induced gastric cancer) in mice with autoimmune gastritis. METHODS: We performed studies with TxA23 mice (control mice), which express a T-cell receptor against the H+/K+ adenosine triphosphatase α chain and develop autoimmune gastritis, and TxA23xEbi3-/- mice, which develop gastritis but do not express IL27. In some experiments, mice were given high-dose tamoxifen to induce parietal cell atrophy and spasmolytic polypeptide-expressing metaplasia (SPEM). Recombinant IL27 was administered to mice with mini osmotic pumps. Stomachs were collected and analyzed by histopathology and immunofluorescence; we used flow cytometry to measure IL27 and identify immune cells that secrete IL27 in the gastric mucosa. Single-cell RNA sequencing was performed on immune cells that infiltrated stomach tissues. RESULTS: We identified IL27-secreting macrophages and dendritic cell in the corpus of mice with chronic gastritis (TxA23 mice). Mice deficient in IL27 developed more severe gastritis, atrophy, and SPEM than control mice. Administration of recombinant IL27 significantly reduced the severity of inflammation, atrophy, and SPEM in mice with gastritis. Single-cell RNA sequencing showed that IL27 acted almost exclusively on stomach-infiltrating CD4+ T cells to suppress expression of inflammatory genes. CONCLUSIONS: In studies of mice with autoimmune gastritis, we found that IL27 is an inhibitor of gastritis and SPEM, suppressing CD4+ T-cell-mediated inflammation in the gastric mucosa.
Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Mucosa Gástrica/patología , Gastritis/tratamiento farmacológico , Interleucinas/administración & dosificación , Lesiones Precancerosas/prevención & control , Animales , Atrofia/inmunología , Atrofia/patología , Atrofia/prevención & control , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Enfermedad Crónica/tratamiento farmacológico , Modelos Animales de Enfermedad , Femenino , Mucosa Gástrica/citología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/inmunología , Gastritis/diagnóstico , Gastritis/inmunología , Gastritis/patología , Humanos , Masculino , Metaplasia/inmunología , Metaplasia/patología , Metaplasia/prevención & control , Ratones , Ratones Noqueados , Antígenos de Histocompatibilidad Menor/genética , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/patología , Receptores de Citocinas/genética , Proteínas Recombinantes/administración & dosificación , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that invades surrounding structures and metastasizes rapidly. Although inflammation is associated with tumor formation and progression, little is known about the mechanisms of this connection. We investigate the effects of interleukin (IL) 22 in the development of pancreatic tumors in mice. METHODS: We performed studies with Pdx1-Cre;LSL-KrasG12D;Trp53+/-;Rosa26EYFP/+ (PKCY) mice, which develop pancreatic tumors, and PKCY mice with disruption of IL22 (PKCY Il22-/-mice). Pancreata were collected at different stages of tumor development and analyzed by immunohistochemistry, immunoblotting, real-time polymerase chain reaction, and flow cytometry. Some mice were given cerulean to induce pancreatitis. Pancreatic cancer cell lines (PD2560) were orthotopically injected into C57BL/6 mice or Il22-/-mice, and tumor development was monitored. Pancreatic cells were injected into the tail veins of mice, and lung metastases were quantified. Acini were collected from C57BL/6 mice and resected human pancreata and were cultured. Cell lines and acini cultures were incubated with IL22 and pharmacologic inhibitors, and protein levels were knocked down with small hairpin RNAs. We performed immunohistochemical analyses of 26 PDACs and 5 nonneoplastic pancreas specimens. RESULTS: We observed increased expression of IL22 and the IL22 receptor (IL22R) in the pancreas compared with other tissues in mice; IL22 increased with pancreatitis and tumorigenesis. Flow cytometry indicated that the IL22 was produced primarily by T-helper 22 cells. PKCY Il22-/-mice did not develop precancerous lesions or pancreatic tumors. The addition of IL22 to cultured acinar cells increased their expression of markers of ductal metaplasia; these effects of IL22 were prevented with inhibitors of Janus kinase signaling to signal transducer and activator of transcription (STAT) (ruxolitinib) or mitogen-activated protein kinase kinase (MEK) (trametinib) and with STAT3 knockdown. Pancreatic cells injected into Il22-/- mice formed smaller tumors than those injected into C57BL/6. Incubation of IL22R-expressing PDAC cells with IL22 promoted spheroid formation and invasive activity, resulting in increased expression of stem-associated transcription factors (GATA4, SOX2, SOX17, and NANOG), and increased markers of the epithelial-mesenchymal transition (CDH1, SNAI2, TWIST1, and beta catenin); ruxolitinib blocked these effects. Human PDAC tissues had higher levels of IL22, phosphorylated STAT3, and markers of the epithelial-mesenchymal transition than nonneoplastic tissues. An increased level of STAT3 in IL22R-positive cells was associated with shorter survival times of patients. CONCLUSIONS: We found levels of IL22 to be increased during pancreatitis and pancreatic tumor development and to be required for tumor development and progression in mice. IL22 promotes acinar to ductal metaplasia, stem cell features, and increased expression of markers of the epithelial-mesenchymal transition; inhibitors of STAT3 block these effects. Increased expression of IL22 by PDACs is associated with reduced survival times.
Asunto(s)
Células Acinares/patología , Carcinoma Ductal Pancreático/inmunología , Transformación Celular Neoplásica/inmunología , Interleucinas/metabolismo , Neoplasias Pancreáticas/inmunología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/inmunología , Células Acinares/inmunología , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral/trasplante , Plasticidad de la Célula/efectos de los fármacos , Plasticidad de la Célula/inmunología , Transformación Celular Neoplásica/efectos de los fármacos , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/inmunología , Femenino , Células HEK293 , Humanos , Interleucinas/inmunología , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Masculino , Metaplasia/inmunología , Metaplasia/patología , Ratones , Ratones Noqueados , Nitrilos , Páncreas/citología , Páncreas/inmunología , Páncreas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pancreatitis/inmunología , Pancreatitis/patología , Pirazoles/farmacología , Piridonas/farmacología , Pirimidinas , Pirimidinonas/farmacología , ARN Interferente Pequeño/metabolismo , Receptores de Interleucina/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia , Interleucina-22RESUMEN
The premalignant process preceding squamous cell lung cancer is not inevitable; it can stop at any of the bronchial lesions: basal cell hyperplasia (BCH), squamous metaplasia (SM), and dysplasia and then progress or regress. At present, the mechanisms underlying the progression of the bronchial lesions remain undefined. Previously, we hypothesized that bronchial lesions that presented individually or combined with each other in the bronchi of lung cancer patients mirror the different "scenarios" of the premalignant process: individual BCH-the stoppage at the stage of hyperplasia, BCH plus SM-the progression of hyperplasia to metaplasia, and SM plus dysplasia-the progression of metaplasia to dysplasia. In this study, we analyzed gene expression profiles of BCH, SM, and dysplasia depending on their cooccurrence in the bronchi of lung cancer patients. The immune response gene expression was found to be a key difference between the individual BCH and BCH combined with SM lesions and a potential mechanism that determines the progression of hyperplasia to metaplasia. Upregulation of the cell cycle and downregulation of the cilium assembly genes mainly distinguished SM that copresented with dysplasia from SM that copresented with BCH and is a probable mechanism of the progression of metaplasia to dysplasia. Dysplasia showed mainly overexpression of the cell division genes and underexpression of the inflammation genes. Thus, this study demonstrates the significant gene expression differences between the premalignant lesions depending on their cooccurrence in the bronchi and sheds light on the mechanisms of the precancerous process preceding squamous cell lung cancer.
Asunto(s)
Bronquios/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Hiperplasia/metabolismo , Metaplasia/metabolismo , Lesiones Precancerosas/metabolismo , Bronquios/citología , Bronquios/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , División Celular/genética , Biología Computacional , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Ontología de Genes , Humanos , Hiperplasia/genética , Hiperplasia/inmunología , Hiperplasia/patología , Inmunohistoquímica , Inflamación/genética , Inflamación/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Metaplasia/genética , Metaplasia/inmunología , Metaplasia/patología , Familia de Multigenes , Análisis de Secuencia por Matrices de Oligonucleótidos , Lesiones Precancerosas/genéticaRESUMEN
BACKGROUND/AIM: Kita-Kyushu lung cancer antigen-1 (KK-LC-1) is a known cancer/testis antigen. Our group has previously shown KK-LC-1 gene expression in gastric cancer. However, could not be detected the KK-LC-1 protein due to the lack of an appropriate antibody. Here, we assessed our original monoclonal antibody (Kmab34B3) and, using it, assessed the expression of KK-LC-1 in gastric cancer. PATIENTS AND METHODS: We evaluated an original monoclonal antibody against KK-LC-1 (Kmab34B3), and used this antibody to compare KK-LC-1 protein expression in tumour and non-tumour stomach cells from gastric cancer patients. RESULTS: Kmab34B3 stained testicular germ cells, and tumour cells in nine out of 11 (82%) specimens. In non-tumorous areas, Kmab34B3 stained 13 out of 29 (45%) pyloric gland specimens. Furthermore, Kmab34B3 also stained intestinal metaplasia positive and negative areas. CONCLUSION: Kmab34B3 was able to detect KK-LC-1 protein within tumour cells and the pyloric gland where the gene has been shown to be expressed. Therefore, it might be an attractive tool for detecting KK-LC-1 expression in precancerous and cancerous stomach cells.
Asunto(s)
Anticuerpos Monoclonales , Antígenos de Neoplasias/análisis , Neoplasias Gástricas/inmunología , Estómago/inmunología , Antígenos de Neoplasias/genética , Expresión Génica , Humanos , Metaplasia/inmunología , Lesiones Precancerosas/inmunología , Píloro/inmunologíaRESUMEN
Conjugated bile acids (CBAs), such as tauroursodeoxycholic acid (TUDCA), are known to resolve the inflammatory and unfolded protein response (UPR) in inflammatory diseases, such as asthma. Whether CBAs exert their beneficial effects on allergic airway responses via 1 arm or several arms of the UPR, or alternatively through the signaling pathways for conserved bile acid receptor, remains largely unknown. We used a house dust mite-induced (HDM-induced) murine model of asthma to evaluate and compare the effects of 5 CBAs and 1 unconjugated bile acid in attenuating allergen-induced UPR and airway responses. Expression of UPR-associated transcripts was assessed in airway brushings from human patients with asthma and healthy subjects. Here we show that CBAs, such as alanyl ß-muricholic acid (AßM) and TUDCA, significantly decreased inflammatory, immune, and cytokine responses; mucus metaplasia; and airway hyperresponsiveness, as compared with other CBAs in a model of allergic airway disease. CBAs predominantly bind to activating transcription factor 6α (ATF6α) compared with the other canonical transducers of the UPR, subsequently decreasing allergen-induced UPR activation and resolving allergic airway disease, without significant activation of the bile acid receptors. TUDCA and AßM also attenuated other HDM-induced ER stress markers in the lungs of allergic mice. Quantitative mRNA analysis of airway epithelial brushings from human subjects demonstrated that several ATF6α-related transcripts were significantly upregulated in patients with asthma compared with healthy subjects. Collectively, these results demonstrate that CBA-based therapy potently inhibits the allergen-induced UPR and allergic airway disease in mice via preferential binding of the canonical transducer of the UPR, ATF6α. These results potentially suggest a novel avenue to treat allergic asthma using select CBAs.
Asunto(s)
Alérgenos/inmunología , Asma/inmunología , Inflamación/inmunología , Hipersensibilidad Respiratoria/inmunología , Respuesta de Proteína Desplegada/inmunología , Animales , Ácidos y Sales Biliares/efectos adversos , Quimiocinas , Citocinas/metabolismo , Femenino , Humanos , Hipersensibilidad , Pulmón/inmunología , Pulmón/metabolismo , Metaplasia/inmunología , Metaplasia/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Deficiencias en la Proteostasis , Pyroglyphidae/inmunología , Receptores Acoplados a Proteínas G/metabolismo , Hipersensibilidad Respiratoria/tratamiento farmacológico , Ácido Tauroquenodesoxicólico/farmacología , Respuesta de Proteína Desplegada/efectos de los fármacosRESUMEN
AIM: To clarify the role of serum anti-Helicobacter pylori (H. pylori) antibody titers in gastric cancer. METHODS: In this cross-sectional study, the effect of patients' baseline characteristics and endoscopic findings on their serum antibody titers were assessed. We evaluated consecutive patients who underwent esophagogastroduodenoscopy and their first evaluation for H. pylori infection using a serum antibody test. We excluded patients with a history of eradication therapy. The participants were divided into four groups according to their E-plate serum antibody titer. Patients with serum antibody titers < 3, 3-9.9, 10-49.9, and ≥ 50 U/mL were classified into groups A, B, C, and D, respectively. RESULTS: In total, 874 participants were analyzed with 70%, 16%, 8.7%, and 5.1% of them in the groups A, B, C, and D, respectively. Patients in group C were older than patients in groups A and B. Gastric open-type atrophy, intestinal metaplasia, enlarged folds, diffuse redness, and duodenal ulcers were associated with a high titer. Regular arrangements of collecting venules, fundic gland polyps, superficial gastritis, and gastroesophageal reflux disease were related to a low titer. Multivariate analysis revealed that nodularity (P = 0.0094), atrophy (P = 0.0076), and age 40-59 years (vs age ≥ 60 years, P = 0.0090) were correlated with a high serum antibody titer in H. pylori-infected patients. Intestinal metaplasia and atrophy were related to age ≥ 60 years in group C and D. CONCLUSION: Serum antibody titer changes with age, reflects gastric mucosal inflammation, and is useful in predicting the risk of gastric cancer.
Asunto(s)
Anticuerpos/sangre , Mucosa Gástrica/patología , Infecciones por Helicobacter/sangre , Helicobacter pylori/inmunología , Mucosa Intestinal/patología , Adulto , Factores de Edad , Anciano , Atrofia/sangre , Atrofia/diagnóstico por imagen , Atrofia/inmunología , Atrofia/microbiología , Estudios Transversales , Endoscopía del Sistema Digestivo , Femenino , Mucosa Gástrica/diagnóstico por imagen , Mucosa Gástrica/microbiología , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/aislamiento & purificación , Humanos , Mucosa Intestinal/diagnóstico por imagen , Mucosa Intestinal/microbiología , Masculino , Metaplasia/sangre , Metaplasia/diagnóstico por imagen , Metaplasia/inmunología , Metaplasia/microbiología , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Pruebas SerológicasRESUMEN
Sonic hedgehog (SHH) is abundantly expressed and critical for morphogenesis in embryonic lungs; however, SHH expression drops to a much lower level in mice from E17.5 and in humans from the 21st gestational week. We find that SHH expression is robustly upregulated in the airway epithelia of children with asthma or mouse models with allergic airway disease. Specifically, airway-specific SMO loss of function significantly suppresses allergen-induced goblet cell phenotypes, whereas an airway-specific SMO gain of function markedly enhances the goblet cell phenotypes in mouse models with allergic airway disease. Notably, intratracheal administration with SHH-neutralizing antibody or cyclopamine robustly attenuates goblet cell phenotypes in mouse models with allergic airway disease. Finally, we identify that Muc5AC gene encoding MUC5AC mucin serves as a direct target of GLI transcriptional factors in response to SHH, whereas the SAM-pointed domain-containing ETS transcription factor and Forkhead box A2, critical transcriptional factors for goblet cell phenotypes, both function as the effectors of GLIs in response to SHH stimulation. Together, the upregulation of SHH expression in allergic bronchial epithelia contributes to goblet cell metaplasia; thus, blockage of SHH signaling is a rational approach in a therapeutic intervention of epithelial remodeling in chronic airway diseases.
Asunto(s)
Expresión Génica/genética , Células Caliciformes/patología , Proteínas Hedgehog/genética , Hipersensibilidad/genética , Metaplasia/genética , Animales , Anticuerpos Neutralizantes/inmunología , Asma/genética , Asma/inmunología , Asma/patología , Niño , Preescolar , Células Epiteliales/inmunología , Células Epiteliales/patología , Femenino , Células Caliciformes/inmunología , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/patología , Masculino , Metaplasia/inmunología , Metaplasia/patología , Ratones , Ratones Endogámicos C57BL , Mucina 5AC/genética , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/patología , Factores de Transcripción/genética , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunologíaRESUMEN
Introduction: Although aspirin/NSAIDs may have potential preventive effects on several cancers, it remains unclear on gastric cancer. The purpose of this study is to compare the risk of developing gastric cancer and the histologic changes of intestinal metaplasia and neutrophil infiltration, between aspirin/NSAID users and nonusers.Methods: Using an electronic endoscopy database in two hospitals from 1996 to 2017, we analyzed the data from patients with chronic gastritis who received aspirin or NSAIDs prior to upper gastrointestinal endoscopy. One-to-one propensity score matching was performed to compare the proportion of gastric cancer, intestinal metaplasia, and neutrophil infiltration between these drug users and nonusers.Results: We analyzed 2,082 aspirin users and 2,082 nonusers as well as 898 NSAID users and 898 nonusers. Six diffuse-type and 19 intestinal-type gastric cancer, 1,243 intestinal metaplasia, and 1,503 neutrophil infiltration patients were identified. The proportion of diffuse-type gastric cancer (0.05%) was 80% lower in aspirin users compared with the nonusers (0.24%), and there was no case of diffuse-type cancer in patients who took aspirin for more than 2 years. In contrast, intestinal-type gastric cancer incidence was significantly higher in aspirin users (0.72%) compared with nonusers (0.14%). No significant differences in the incidence of gastric cancer were found between NSAID use and nonusers. NSAID use was significantly associated with decreased proportion of neutrophil infiltration compared with nonusers.Conclusion: Aspirin may have distinct effects between intestinal-type and diffuse-type gastric cancer development. Cancer Prev Res; 11(5); 279-86. ©2018 AACR.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Aspirina/administración & dosificación , Gastritis/diagnóstico por imagen , Metaplasia/epidemiología , Neoplasias Gástricas/epidemiología , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Femenino , Estudios de Seguimiento , Mucosa Gástrica/diagnóstico por imagen , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/inmunología , Mucosa Gástrica/patología , Gastritis/inmunología , Gastritis/patología , Humanos , Incidencia , Masculino , Metaplasia/diagnóstico por imagen , Metaplasia/inmunología , Metaplasia/patología , Persona de Mediana Edad , Neutrófilos/inmunología , Puntaje de Propensión , Estudios Retrospectivos , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patologíaRESUMEN
Early-life respiratory viral infection is a risk factor for asthma development. Rhinovirus (RV) infection of 6-d-old mice, but not mature mice, causes mucous metaplasia and airway hyperresponsiveness that are associated with the expansion of lung type 2 innate lymphoid cells (ILC2s) and are dependent on IL-13 and the innate cytokine IL-25. However, contributions of the other innate cytokines, IL-33 and thymic stromal lymphopoietin (TSLP), to the observed asthma-like phenotype have not been examined. We reasoned that IL-33 and TSLP expression are also induced by RV infection in immature mice and are required for maximum ILC2 expansion and mucous metaplasia. We inoculated 6-d-old BALB/c (wild-type) and TSLP receptor-knockout mice with sham HeLa cell lysate or RV. Selected mice were treated with neutralizing Abs to IL-33 or recombinant IL-33, IL-25, or TSLP. ILC2s were isolated from RV-infected immature mice and treated with innate cytokines ex vivo. RV infection of 6-d-old mice increased IL-33 and TSLP protein abundance. TSLP expression was localized to the airway epithelium, whereas IL-33 was expressed in epithelial and subepithelial cells. RV-induced mucous metaplasia, ILC2 expansion, airway hyperresponsiveness, and epithelial cell IL-25 expression were attenuated by anti-IL-33 treatment and in TSLP receptor-knockout mice. Administration of intranasal IL-33 and TSLP was sufficient for mucous metaplasia. Finally, TSLP was required for maximal ILC2 gene expression in response to IL-25 and IL-33. The generation of mucous metaplasia in immature RV-infected mice involves a complex interplay among the innate cytokines IL-25, IL-33, and TSLP.
Asunto(s)
Citocinas/inmunología , Interleucina-33/inmunología , Interleucinas/inmunología , Activación de Linfocitos , Linfocitos/fisiología , Metaplasia/inmunología , Infecciones por Picornaviridae/inmunología , Rhinovirus/inmunología , Factores de Edad , Animales , Asma/inmunología , Asma/virología , Citocinas/genética , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Células Epiteliales/virología , Inmunoglobulinas/genética , Inmunoglobulinas/inmunología , Inmunoglobulinas/metabolismo , Interleucina-33/genética , Interleucinas/genética , Linfocitos/inmunología , Metaplasia/patología , Metaplasia/virología , Ratones , Ratones Noqueados , Membrana Mucosa/inmunología , Membrana Mucosa/patología , Infecciones por Picornaviridae/virología , Receptores de Citocinas/genética , Receptores de Citocinas/inmunología , Receptores de Citocinas/metabolismo , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/virología , Linfopoyetina del Estroma TímicoRESUMEN
Goblet cell metaplasia and excessive mucus secretion associated with asthma, cystic fibrosis, and chronic obstructive pulmonary disease contribute to morbidity and mortality worldwide. We performed a high-throughput screen to identify small molecules targeting a transcriptional network critical for the differentiation of goblet cells in response to allergens. We identified RCM-1, a nontoxic small molecule that inhibited goblet cell metaplasia and excessive mucus production in mice after exposure to allergens. RCM-1 blocked the nuclear localization and increased the proteasomal degradation of Forkhead box M1 (FOXM1), a transcription factor critical for the differentiation of goblet cells from airway progenitor cells. RCM-1 reduced airway resistance, increased lung compliance, and decreased proinflammatory cytokine production in mice exposed to the house dust mite and interleukin-13 (IL-13), which triggers goblet cell metaplasia. In cultured airway epithelial cells and in mice, RCM-1 reduced IL-13 and STAT6 (signal transducer and activator of transcription 6) signaling and prevented the expression of the STAT6 target genes Spdef and Foxa3, which are key transcriptional regulators of goblet cell differentiation. These results suggest that RCM-1 is an inhibitor of goblet cell metaplasia and IL-13 signaling, providing a new therapeutic candidate to treat patients with asthma and other chronic airway diseases.
Asunto(s)
Alérgenos/toxicidad , Proteína Forkhead Box M1/antagonistas & inhibidores , Células Caliciformes/inmunología , Interleucina-13/inmunología , Factor de Transcripción STAT6/inmunología , Animales , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/inmunología , Células Caliciformes/patología , Factor Nuclear 3-gamma del Hepatocito/genética , Factor Nuclear 3-gamma del Hepatocito/inmunología , Interleucina-13/genética , Metaplasia/inducido químicamente , Metaplasia/genética , Metaplasia/inmunología , Metaplasia/patología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Proto-Oncogénicas c-ets/inmunología , Factor de Transcripción STAT6/genéticaRESUMEN
Allergic asthma is a chronic inflammatory disease of the conducting airways characterized by the presence of allergen-specific IgE, Th2 cytokine production, eosinophilic airway inflammation, bronchial hyperreactivity, mucus overproduction, and structural changes in the airways. Investigators have tried to mimic these features of human allergic asthma in murine models. Whereas the surrogate allergen ovalbumin has been extremely valuable for unravelling underlying mechanisms of the disease, murine asthma models depend nowadays on naturally occurring allergens, such as house dust mite (HDM), cockroach, and Alternaria alternata. Here we describe a physiologically relevant model of acute allergic asthma based on sensitization and challenge with HDM extracts, and compare it with the ovalbumin/alum-induced asthma model. Moreover, we propose a detailed readout of the asthma phenotype, determining the degree of eosinophilia in bronchoalveolar lavage fluids by flow cytometry, visualizing goblet cell metaplasia, and measuring Th cytokine production by lung-draining mediastinal lymph node cells restimulated with HDM. © 2016 by John Wiley & Sons, Inc.
Asunto(s)
Asma/inmunología , Modelos Animales de Enfermedad , Ratones , Enfermedad Aguda , Compuestos de Alumbre/farmacología , Animales , Asma/etiología , Asma/parasitología , Líquido del Lavado Bronquioalveolar/química , Citocinas/metabolismo , Eosinofilia/etiología , Eosinofilia/inmunología , Citometría de Flujo , Células Caliciformes/patología , Humanos , Metaplasia/etiología , Metaplasia/inmunología , Ovalbúmina/farmacología , Pyroglyphidae/química , Células Th2/metabolismoRESUMEN
IL-13 and IL-17A, produced mainly by Th2 and Th17 cells, respectively, have an influential role in asthma pathogenesis. We examined the role of IL-13 and IL-17A in mediating airway hyperresponsiveness (AHR), lung inflammation, and mucus metaplasia in a dual Th2/Th17 model of asthma. IL-13 and/or IL-17A were neutralized using mAbs. Th2/Th17 adoptive transfer induced a mixed asthma phenotype characterized by elevated eosinophilia and neutrophilia, tissue inflammation, mucus metaplasia, and AHR that were partially reversible with steroid treatment. Pulmonary inflammation and quasi-static lung compliance were largely unaffected by neutralization of IL-13 and/or IL-17A. However, neutralization of IL-13 alone or in combination with IL-17A significantly attenuated AHR and mucus metaplasia. Further, STAT6 activation was attenuated following IL-13 and IL-13/IL-17A Ab treatment. We next assessed the role of STAT6 in Th2/Th17-mediated allergic airway disease using STAT6(-/-) mice. STAT6(-/-) mice adoptively transferred with Th2/Th17 cells had decreased AHR compared with controls. These data suggest that IL-13 drives AHR and mucus metaplasia in a STAT6-dependent manner, without directly contributing to airway or tissue inflammation. IL-17A independently contributes to AHR, but it only partially mediates inflammation and mucus metaplasia in a mixed Th2/Th17 model of steroid-resistant asthma.
Asunto(s)
Asma/inmunología , Interleucina-13/inmunología , Interleucina-17/inmunología , Hipersensibilidad Respiratoria/inmunología , Traslado Adoptivo , Animales , Asma/patología , Modelos Animales de Enfermedad , Resistencia a Medicamentos , Immunoblotting , Metaplasia/inmunología , Metaplasia/patología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones SCID , Ratones Transgénicos , Moco/inmunología , Reacción en Cadena de la Polimerasa , Hipersensibilidad Respiratoria/patología , Células Th17/inmunología , Células Th2/inmunología , TranscriptomaRESUMEN
Geographic differences have been reported to affect the morphological and molecular features of papillary thyroid carcinomas (PTCs). The area around Chernobyl is well-known to be iodine-deficient in contrast to Japan, an iodine-rich country. We reviewed histological differences in adult PTC between Ukraine and Japan. In total, 112 PTCs from age- and sex-matched adults (Ukraine 56, Japan 56) were evaluated histologically for several factors including tumor size, capsulation, tumor components (papillary, follicular, solid, trabecular), lymph node metastasis, extrathyroid invasion, lymphocytic infiltration, oxyphilic metaplasia, and MIB-1 index. We demonstrated that tumors were smaller (1.56 vs. 2.13 cm, p<0.05) and more solid and that lymph node metastasis was less frequent (14.3% vs. 48.2%, p<0.001) in Ukrainian cases. PTC subtype distribution was significantly different between the two groups. Solid variant (8.9% vs. 1.8%) and mixed subtypes with solid components were more frequent in Ukrainian patients. In contrast, classical papillary carcinomas were more frequent in Japanese cases (10.7% vs. 50.0%, p<0.001). Marked oxyphilic metaplasia was more common in Ukrainian cases (33.9 % vs. 8.9 %, p<0.001). MIB-1 index was significantly higher in Ukrainian cases (2.9% vs. 1.8%, p<0.001). However, the frequencies of tumor capsule formation and background lymphoid follicle formation around the tumor were similar between groups. Morphological differences in adult PTCs were similar to those in pediatric PTCs as reported previously, suggesting that morphogenesis of PTC is influenced by environmental factors, especially dietary iodine, as well as genetic factors.
Asunto(s)
Carcinoma Papilar/patología , Carcinoma/patología , Glándula Tiroides/patología , Neoplasias de la Tiroides/patología , Adulto , Carcinoma/complicaciones , Carcinoma/epidemiología , Carcinoma/inmunología , Carcinoma Papilar/complicaciones , Carcinoma Papilar/epidemiología , Carcinoma Papilar/inmunología , Carcinoma Papilar Folicular/complicaciones , Carcinoma Papilar Folicular/epidemiología , Carcinoma Papilar Folicular/inmunología , Carcinoma Papilar Folicular/patología , Proliferación Celular , Accidente Nuclear de Chernóbil , Enfermedades Carenciales/complicaciones , Femenino , Humanos , Incidencia , Yodo/deficiencia , Japón/epidemiología , Metástasis Linfática , Linfocitos/inmunología , Linfocitos/patología , Masculino , Metaplasia/inmunología , Metaplasia/patología , Persona de Mediana Edad , Invasividad Neoplásica/inmunología , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Prevalencia , Cáncer Papilar Tiroideo , Glándula Tiroides/inmunología , Neoplasias de la Tiroides/complicaciones , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/inmunología , Carga Tumoral , Ucrania/epidemiologíaRESUMEN
The emergence of nanotechnology has produced a multitude of engineered nanomaterials such as carbon nanotubes (CNTs), and concerns have been raised about their effects on human health, especially for susceptible populations such as individuals with asthma. Multiwalled CNTs (MWCNTs) have been shown to exacerbate ovalbumin (OVA)-induced airway remodeling in mice. Moreover, cyclooxygenase-2 (COX-2) has been described as a protective factor in asthma. We postulated that COX-2-deficient (COX-2(-/-)) mice would be susceptible to MWCNT-induced exacerbations of allergen-induced airway remodeling, including airway inflammation, fibrosis, and mucus-cell metaplasia (i.e., the formation of goblet cells). Wild-type (WT) or COX-2(-/-) mice were sensitized to OVA to induce allergic airway inflammation before a single dose of MWCNTs (4 mg/kg) delivered to the lungs by oropharyngeal aspiration. MWCNTs significantly increased OVA-induced lung inflammation and mucus-cell metaplasia in COX-2(-/-) mice compared with WT mice. However, airway fibrosis after exposure to allergen and MWCNTs was no different between WT and COX-2(-/-) mice. Concentrations of certain prostanoids (prostaglandin D2 and thromboxane B2) were enhanced by OVA or MWCNTs in COX-2(-/-) mice. No differences in COX-1 mRNA concentrations were evident between WT and COX-2(-/-) mice treated with OVA and MWCNTs. Interestingly, MWCNTs significantly enhanced allergen-induced cytokines involved in Th2 (IL-13 and IL-5), Th1 (CXCL10), and Th17 (IL-17A) inflammatory responses in COX-2(-/-) mice, but not in WT mice. We conclude that exacerbations of allergen-induced airway inflammation and mucus-cell metaplasia by MWCNTs are enhanced by deficiencies in COX-2, and are associated with the activation of a mixed Th1/Th2/Th17 immune response.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias)/fisiología , Alérgenos/inmunología , Ciclooxigenasa 2/inmunología , Nanotubos de Carbono , Remodelación de las Vías Aéreas (Respiratorias)/genética , Remodelación de las Vías Aéreas (Respiratorias)/inmunología , Animales , Ciclooxigenasa 1/genética , Ciclooxigenasa 1/inmunología , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Citocinas/inmunología , Femenino , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/metabolismo , Metaplasia/genética , Metaplasia/inmunología , Metaplasia/metabolismo , Ratones , Ratones Endogámicos C57BL , Moco/inmunología , Moco/metabolismo , Ovalbúmina/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
Mucous cell metaplasia is a hallmark of asthma, and may be mediated by signal transducers and activators of transcription (STAT)-6 signaling. IL-17A is increased in the bronchoalveolar lavage fluid of patients with severe asthma, and IL-17A also increases mucus production in airway epithelial cells. Asthma therapeutics are being developed that inhibit STAT6 signaling, but the role of IL-17A in inducing mucus production in the absence of STAT6 remains unknown. We hypothesized that IL-17A induces mucous cell metaplasia independent of STAT6, and we tested this hypothesis in two murine models in which increased IL-17A protein expression is evident. In the first model, ovalbumin (OVA)-specific D011.10 Th17 cells were adoptively transferred into wild-type (WT) or STAT6 knockout (KO) mice, and the mice were challenged with OVA or PBS. WT-OVA and STAT6 KO-OVA mice demonstrated increased airway IL-17A and IL-13 protein expression and mucous cell metaplasia, compared with WT-PBS or STAT6 KO-PBS mice. In the second model, WT, STAT1 KO, STAT1/STAT6 double KO (DKO), or STAT1/STAT6/IL-17 receptor A (RA) triple KO (TKO) mice were challenged with respiratory syncytial virus (RSV) or mock viral preparation, and the mucous cells were assessed. STAT1 KO-RSV mice demonstrated increased airway mucous cell metaplasia compared with WT-RSV mice. STAT1 KO-RSV and STAT1/STAT6 DKO-RSV mice also demonstrated increased mucous cell metaplasia, compared with STAT1/STAT6/IL17RA TKO-RSV mice. We also treated primary murine tracheal epithelial cells (mTECs) from WT and STAT6 KO mice. STAT6 KO mTECs showed increased periodic acid-Schiff staining with IL-17A but not with IL-13. Thus, asthma therapies targeting STAT6 may increase IL-17A protein expression, without preventing IL-17A-induced mucus production.
Asunto(s)
Interleucina-17/metabolismo , Metaplasia/patología , Moco/metabolismo , Factor de Transcripción STAT6/metabolismo , Activación Transcripcional , Traslado Adoptivo , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Femenino , Interleucina-13/metabolismo , Interleucina-17/genética , Pulmón/inmunología , Pulmón/patología , Metaplasia/inmunología , Metaplasia/virología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Neutrófilos/metabolismo , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/inmunología , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/inmunología , Receptores de Interleucina-17/metabolismo , Infecciones por Virus Sincitial Respiratorio/inmunología , Infecciones por Virus Sincitial Respiratorio/patología , Virus Sincitiales Respiratorios/inmunología , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT6/genética , Células Th17/inmunologíaRESUMEN
Chronic inflammation is a major risk factor for cancer, including gastric cancers and other gastrointestinal cancers. For example, chronic inflammation caused by autoimmune gastritis (AIG) is associated with an increased risk of gastric polyps, gastric carcinoid tumors, and possibly adenocarcinomas. In this study, we characterized the progression of gastric cancer in a novel mouse model of AIG. In this model, disease was caused by CD4(+) T cells expressing a transgenic T-cell receptor specific for a peptide from the H(+)/K(+) ATPase proton pump, a protein expressed by parietal cells in the stomach. AIG caused epithelial cell aberrations that mimicked most of those seen in progression of human gastric cancers, including chronic gastritis followed by oxyntic atrophy, mucous neck cell hyperplasia, spasmolytic polypeptide-expressing metaplasia, dysplasia, and ultimately gastric intraepithelial neoplasias. Our work provides the first direct evidence that AIG supports the development of gastric neoplasia and provides a useful model to study how inflammation drives gastric cancer.
Asunto(s)
Enfermedades Autoinmunes/etiología , Linfocitos T CD4-Positivos/inmunología , Gastritis/complicaciones , ATPasa Intercambiadora de Hidrógeno-Potásio/inmunología , Inflamación/complicaciones , Receptores de Antígenos de Linfocitos T/fisiología , Neoplasias Gástricas/etiología , Adenocarcinoma/etiología , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Western Blotting , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Mucosa Gástrica/inmunología , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Gastritis/inmunología , Gastritis/patología , Humanos , Técnicas para Inmunoenzimas , Inflamación/inmunología , Inflamación/patología , Interferón gamma/metabolismo , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Metaplasia/complicaciones , Metaplasia/inmunología , Metaplasia/patología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
Chronic airway disorders, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma, are associated with persistent pulmonary inflammation and goblet cell metaplasia and contribute to significant morbidity and mortality worldwide. While the molecular pathogenesis of these disorders is actively studied, little is known regarding the transcriptional control of goblet cell differentiation and mucus hyperproduction. Herein, we demonstrated that pulmonary allergen sensitization induces expression of FOXM1 transcription factor in airway epithelial and inflammatory cells. Conditional deletion of the Foxm1 gene from either airway epithelium or myeloid inflammatory cells decreased goblet cell metaplasia, reduced lung inflammation, and decreased airway resistance in response to house dust mite allergen (HDM). FOXM1 induced goblet cell metaplasia and Muc5AC expression through the transcriptional activation of Spdef. FOXM1 deletion reduced expression of CCL11, CCL24, and the chemokine receptors CCR2 and CX3CR1, resulting in decreased recruitment of eosinophils and macrophages to the lung. Deletion of FOXM1 from dendritic cells impaired the uptake of HDM antigens and decreased cell surface expression of major histocompatibility complex II (MHC II) and costimulatory molecule CD86, decreasing production of Th2 cytokines by activated T cells. Finally, pharmacological inhibition of FOXM1 by ARF peptide prevented HDM-mediated pulmonary responses. FOXM1 regulates genes critical for allergen-induced lung inflammation and goblet cell metaplasia.