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1.
Carcinogenesis ; 33(4): 859-67, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22287559

RESUMEN

Since recent evidence indicates a requirement for epithelial nuclear factor (NF)-κB signaling in lung tumorigenesis, we investigated the impact of the NF-κB inhibitor bortezomib on lung tumor promotion and growth. We used an experimental model in which wild-type mice or mice expressing an NF-κB reporter received intraperitoneal urethane (1 g/kg) followed by twice weekly bortezomib (1 mg/kg) during distinct periods of tumor initiation/progression. Mice were serially assessed for lung NF-κB activation, inflammation and carcinogenesis. Short-term proteasome inhibition with bortezomib did not impact tumor formation but retarded the growth of established lung tumors in mice via effects on cell proliferation. In contrast, long-term treatment with bortezomib resulted in significantly increased lung tumor number and size. This tumor-promoting effect of prolonged bortezomib treatment was associated with perpetuation of urethane-induced inflammation and chronic upregulation of interleukin-1ß and proinflammatory C-X-C motif chemokine ligands (CXCL) 1 and 2 in the lungs. In addition to airway epithelium, bortezomib inhibited NF-κB in pulmonary macrophages in vivo, presenting a possible mechanism of tumor amplification. In this regard, RAW264.7 macrophages exposed to bortezomib showed increased expression of interleukin-1ß, CXCL1 and CXCL2. In conclusion, although short-term bortezomib may exert some beneficial effects, prolonged NF-κB inhibition accelerates chemical lung carcinogenesis by perpetuating carcinogen-induced inflammation. Inhibition of NF-κB in pulmonary macrophages appears to play an important role in this adverse process.


Asunto(s)
Antineoplásicos/farmacología , Ácidos Borónicos/farmacología , Neoplasias Pulmonares/patología , FN-kappa B/antagonistas & inhibidores , Pirazinas/farmacología , Animales , Bortezomib , Línea Celular , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Endogámicos BALB C
2.
Am J Respir Crit Care Med ; 182(10): 1273-81, 2010 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-20595227

RESUMEN

RATIONALE: IL-5 is a T helper 2 cytokine important in the trafficking and survival of eosinophils. Because eosinophils can be found in malignant pleural effusions (MPE) from mice and humans, we asked whether IL-5 is involved in the pathogenesis of MPE. OBJECTIVES: To determine the role of IL-5 in MPE formation. METHODS: The effects of IL-5 on experimental MPE induced in C57BL/6 mice by intrapleural injection of syngeneic lung (Lewis lung cancer [LLC]) or colon (MC38) adenocarcinoma cells were determined using wild-type (il5(+/+)) and IL-5-deficient (il5⁻(/)⁻) mice, exogenous administration of recombinant mouse (rm) IL-5, and in vivo antibody-mediated neutralization of endogenous IL-5. The direct effects of rmIL-5 on LLC cell proliferation and gene expression in vitro were determined by substrate reduction and microarray. MEASUREMENTS AND MAIN RESULTS: Eosinophils and IL-5 were present in human and mouse MPE, but the cytokine was not detected in mouse (LLC) or human (A549) lung and mouse colon (MC38) adenocarcinoma-conditioned medium, suggesting production by host cells in MPE. Compared with il5(+/+) mice, il5⁻(/)⁻ mice showed markedly diminished MPE formation in response to both LLC and MC38 cells. Exogenous IL-5 promoted MPE formation in il5(+/+) and il5⁻(/)⁻ mice, whereas anti-IL-5 antibody treatment limited experimental MPE in il5(+/+) mice. Exogenous IL-5 had no effects on LLC cell proliferation and gene expression; however, IL-5 was found to be responsible for recruitment of eosinophils and tumor-promoting myeloid suppressor cells to MPE in vivo. CONCLUSIONS: Host-derived IL-5 promotes experimental MPE and may be involved in the pathogenesis of human MPE.


Asunto(s)
Adenocarcinoma/fisiopatología , Interleucina-5/fisiología , Neoplasias Pulmonares/fisiopatología , Derrame Pleural Maligno/fisiopatología , Adenocarcinoma/complicaciones , Animales , Carcinoma Pulmonar de Lewis/complicaciones , Carcinoma Pulmonar de Lewis/fisiopatología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Eosinófilos/fisiología , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Interleucina-5/análisis , Interleucina-5/biosíntesis , Interleucina-5/farmacología , Neoplasias Pulmonares/complicaciones , Ratones , Ratones Endogámicos C57BL , Derrame Pleural Maligno/inducido químicamente , Derrame Pleural Maligno/química , Derrame Pleural Maligno/citología
3.
BMC Pulm Med ; 11: 33, 2011 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-21627835

RESUMEN

BACKGROUND: Despite its widespread use in pulmonary fibrosis research, the bleomycin mouse model has not been thoroughly validated from a pulmonary functional standpoint using new technologies. Purpose of this study was to systematically assess the functional alterations induced in murine lungs by fibrogenic agent bleomycin and to compare the forced oscillation technique with quasi-static pressure-volume curves in mice following bleomycin exposure. METHODS: Single intratracheal injections of saline (50 µL) or bleomycin (2 mg/Kg in 50 µL saline) were administered to C57BL/6 (n=40) and Balb/c (n=32) mice. Injury/fibrosis score, tissue volume density (TVD), collagen content, airway resistance (RN), tissue damping (G) and elastance coefficient (H), hysteresivity (η), and area of pressure-volume curve (PV-A) were determined after 7 and 21 days (inflammation and fibrosis stage, respectively). Statistical hypothesis testing was performed using one-way ANOVA with LSD post hoc tests. RESULTS: Both C57BL/6 and Balb/c mice developed weight loss and lung inflammation after bleomycin. However, only C57BL/6 mice displayed cachexia and fibrosis, evidenced by increased fibrosis score, TVD, and collagen. At day 7, PV-A increased significantly and G and H non-significantly in bleomycin-exposed C57BL/6 mice compared to saline controls and further increase in all parameters was documented at day 21. G and H, but not PV-A, correlated well with the presence of fibrosis based on histology, TVD and collagen. In Balb/c mice, no change in collagen content, histology score, TVD, H and G was noted following bleomycin exposure, yet PV-A increased significantly compared to saline controls. CONCLUSIONS: Lung dysfunction in the bleomycin model is more pronounced during the fibrosis stage rather than the inflammation stage. Forced oscillation mechanics are accurate indicators of experimental bleomycin-induced lung fibrosis. Quasi-static PV-curves may be more sensitive than forced oscillations at detecting inflammation and fibrosis.


Asunto(s)
Bleomicina/efectos adversos , Pulmón/fisiopatología , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/fisiopatología , Mecánica Respiratoria/fisiología , Resistencia de las Vías Respiratorias/fisiología , Animales , Bleomicina/administración & dosificación , Colágeno/metabolismo , Modelos Animales de Enfermedad , Elasticidad/fisiología , Inyecciones , Pulmón/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Fibrosis Pulmonar/patología , Índice de Severidad de la Enfermedad , Tráquea
4.
Mol Cancer ; 9: 56, 2010 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-20219102

RESUMEN

BACKGROUND: We have previously shown that nuclear factor (NF)-kappaB activation of mouse Lewis lung carcinoma (LLC) specifically promotes the induction of malignant pleural effusions (MPE) by these cells. In the present studies we hypothesized that treatment of immunocompetent mice with bortezomib tailored to inhibit cancer cell NF-kappaB activation and not proliferation specifically inhibits MPE formation by LLC cells. RESULTS: Treatment of LLC cells with low concentrations of bortezomib (100 ng/ml) inhibited NF-kappaB activation and NF-kappaB-dependent transcription, but not cellular proliferation. Bortezomib treatment of immunocompetent C57BL/6 mice bearing LLC-induced subcutaneous tumors and MPEs significantly blocked tumor-specific NF-kappaB activation. However, bortezomib treatment did not impair subcutaneous LLC tumor growth, but was effective in limiting LLC-induced MPE. This specific effect was evidenced by significant reductions in effusion accumulation and the associated mortality and was observed with both preventive (beginning before MPE formation) and therapeutic (beginning after MPE establishment) bortezomib treatment. The favorable impact of bortezomib on MPE was associated with suppression of cardinal MPE-associated phenomena, such as inflammation, vascular hyperpermeability, and angiogenesis. In this regard, therapeutic bortezomib treatment had identical favorable results on MPE compared with preventive treatment, indicating that the drug specifically counteracts effusion formation. CONCLUSIONS: These studies indicate that proteasome inhibition tailored to block NF-kappaB activation of lung adenocarcinoma specifically targets the effusion-inducing phenotype of this tumor. Although the drug has limited activity against advanced solid lung cancer, it may prove beneficial for patients with MPE.


Asunto(s)
Ácidos Borónicos/uso terapéutico , Neoplasias Experimentales/tratamiento farmacológico , Derrame Pleural Maligno/tratamiento farmacológico , Pirazinas/uso terapéutico , Animales , Ácidos Borónicos/farmacología , Bortezomib , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Mediadores de Inflamación/metabolismo , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Neoplasias Experimentales/complicaciones , Neovascularización Patológica/complicaciones , Neovascularización Patológica/tratamiento farmacológico , Derrame Pleural Maligno/complicaciones , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma , Pirazinas/farmacología
5.
Respir Res ; 11: 118, 2010 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-20796309

RESUMEN

BACKGROUND: Although the relationship between allergic inflammation and lung carcinogenesis is not clearly defined, several reports suggest an increased incidence of lung cancer in patients with asthma. We aimed at determining the functional impact of allergic inflammation on chemical carcinogenesis in the lungs of mice. METHODS: Balb/c mice received single-dose urethane (1 g/kg at day 0) and two-stage ovalbumin during tumor initiation (sensitization: days -14 and 0; challenge: daily at days 6-12), tumor progression (sensitization: days 70 and 84; challenge: daily at days 90-96), or chronically (sensitization: days -14 and 0; challenge: daily at days 6-12 and thrice weekly thereafter). In addition, interleukin (IL)-5 deficient and wild-type C57BL/6 mice received ten weekly urethane injections. All mice were sacrificed after four months. Primary end-points were number, size, and histology of lung tumors. Secondary end-points were inflammatory cells and mediators in the airspace compartment. RESULTS: Ovalbumin provoked acute allergic inflammation and chronic remodeling of murine airways, evident by airspace eosinophilia, IL-5 up-regulation, and airspace enlargement. Urethane resulted in formation of atypical alveolar hyperplasias, adenomas, and adenocarcinomas in mouse lungs. Ovalbumin-induced allergic inflammation during tumor initiation, progression, or continuously did not impact the number, size, or histologic distribution of urethane-induced pulmonary neoplastic lesions. In addition, genetic deficiency in IL-5 had no effect on urethane-induced lung tumorigenesis. CONCLUSIONS: Allergic inflammation does not impact chemical-induced carcinogenesis of the airways. These findings suggest that not all types of airway inflammation influence lung carcinogenesis and cast doubt on the idea of a mechanistic link between asthma and lung cancer.


Asunto(s)
Modelos Animales de Enfermedad , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/inmunología , Pulmón/inmunología , Pulmón/patología , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/patología , Animales , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Pruebas de Carcinogenicidad/métodos , Pulmón/efectos de los fármacos , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Distribución Aleatoria , Uretano/toxicidad
6.
Neoplasia ; 13(12): 1143-51, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22241960

RESUMEN

Tumor necrosis factor (TNF) has been implicated in inflammation-associated tumor progression. Although multiple reports identified a role for TNF signaling in established cancers, few studies have assessed the impact of TNF blockade on early tumor formation promotion. We aimed at exploring the effects of TNF neutralization in a preclinical mouse model of lung carcinogenesis. For this, Balb/c mice (n = 42) received four weekly intraperitoneal urethane injections (1 g/kg) and twice-weekly intraperitoneal soluble TNF receptor (etanercept; 10 mg/kg) administered during tumor initiation/promotion, tumor progression, or continuously (months 1, 6, and 1-8 after urethane start, respectively). Lung oncogenesis was assessed after 8 months. In separate short-term studies, Balb/c mice (n = 21) received a single control or urethane injection followed by twice-weekly intraperitoneal control or sTNFR:Fc injections. Lung inflammation was assessed after 1 week. We found that sTNFR:Fc treatment during tumor initiation/promotion resulted in a significant reduction of tumor number but not dimensions. However, sTNFR:Fc administered during tumor progression did not impact tumor multiplicity but significantly decreased tumor diameter. Continued sTNFR:Fc administration was effective in halting both respiratory tumor formation and progression in response to urethane. This favorable impact was associated with impaired cellular proliferation and new vessel formation in lung tumors. In addition, TNF neutralization altered the lung inflammatory response to urethane, evidenced by reductions in TNF and macrophage and increases in interferon γ and interleukin 10 content of the air spaces. sTNFR:Fc treatment of RAW264.7 macrophages downregulated TNF and enhanced interferon γ and interleukin 10 expression. In conclusion, TNF neutralization is effective against urethane-induced lung oncogenesis in mice and could present a lung chemoprevention strategy worth testing clinically.


Asunto(s)
Transformación Celular Neoplásica/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Carcinógenos/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Etanercept , Inmunoglobulina G/administración & dosificación , Inmunoglobulina G/farmacología , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/farmacología , Interferón gamma/biosíntesis , Interleucina-10/biosíntesis , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos BALB C , Neovascularización Patológica/tratamiento farmacológico , Neumonía/inducido químicamente , Neumonía/tratamiento farmacológico , Receptores del Factor de Necrosis Tumoral/administración & dosificación , Receptores del Factor de Necrosis Tumoral/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Uretano/administración & dosificación
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