RESUMO
BACKGROUND: Inhaled nanoparticles can deposit in the deep lung where they interact with pulmonary cells. Despite numerous studies on pulmonary nanotoxicity, detailed molecular mechanisms of specific nanomaterial-induced lung injury have yet to be identified. RESULTS: Using whole-body dynamic inhalation model, we studied the interactions between aluminum oxide nanoparticles (Al2O3 NPs) and the pulmonary system in vivo. We found that seven-day-exposure to Al2O3 NPs resulted in emphysema and small airway remodeling in murine lungs, accompanied by enhanced inflammation and apoptosis. Al2O3 NPs exposure led to suppression of PTPN6 and phosphorylation of STAT3, culminating in increased expression of the apoptotic marker PDCD4. Rescue of PTPN6 expression or application of a STAT3 inhibitor, effectively protected murine lungs from inflammation and apoptosis, as well as, in part, from the induction of chronic obstructive pulmonary disease (COPD)-like effects. CONCLUSION: In summary, our studies show that inhibition of PTPN6 plays a critical role in Al2O3 NPs-induced COPD-like lesions.
Assuntos
Óxido de Alumínio/toxicidade , Pulmão/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Fator de Transcrição STAT3/metabolismo , Células A549 , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Progressão da Doença , Relação Dose-Resposta a Droga , Humanos , Mediadores da Inflamação/metabolismo , Exposição por Inalação/efeitos adversos , Pulmão/enzimologia , Pulmão/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Fosforilação , Pneumonia/induzido quimicamente , Pneumonia/enzimologia , Pneumonia/patologia , Doença Pulmonar Obstrutiva Crônica/enzimologia , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/enzimologia , Enfisema Pulmonar/patologia , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de TempoRESUMO
INTRODUCTION: Emphysema has been associated with decreased VEGF and VEGFR-2 expression and the presence of high numbers of apoptotic alveolar cells. Keratinocyte growth factor stimulates VEGF synthesis which in turn confers normal lung structure maintenance via the Akt pathway. In this study the potential role of rHuKGF in the improvement of deregulated Akt mediated cell survival pathway in emphysematous mice was investigated. METHODS: Three experimental groups, i.e., emphysema, treatment and control groups, were prepared. Lungs of mice were treated on 3 occasions by oropharyngeal instillation of 10mg rHuKGF per kg body weight after induction of emphysema with porcine pancreatic elastase. Subsequently, lung tissues from mice were collected for histopathology and molecular biology studies. RESULTS AND DISCUSSION: Histopathology photomicrographs and destructive index analysis have shown that elastase-induced airspace enlargement and loss of alveoli recovered in the treatment group. rHuKGF stimulates VEGF production which in turn induces the Akt mediated cell survival pathway in emphysematous lungs. mRNA expression of VEGF, VEGFR, PI3K and Akt was significantly increased while Pten, Caspase-9 and Bad was notably decreased in treatment group when compared with emphysema group, being comparable with the control group. Moreover, VEGF protein expression was in accordance with that found for mRNA. CONCLUSION: Therapeutic rHuKGF supplementation improves the deregulated Akt pathway in emphysema, resulting in alveolar cell survival through activation of the endogenous VEGF-dependent cell survival pathway. Hence rHuKGF may prove to be a potential drug in the treatment of emphysema.
Assuntos
Fator 7 de Crescimento de Fibroblastos/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/fisiologia , Enfisema Pulmonar/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Caspase 9/biossíntese , Caspase 9/genética , Sobrevivência Celular , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Fator 7 de Crescimento de Fibroblastos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Instilação de Medicamentos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PTEN Fosfo-Hidrolase/biossíntese , PTEN Fosfo-Hidrolase/genética , Elastase Pancreática/toxicidade , Fosfatidilinositol 3-Quinases/biossíntese , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/biossíntese , Proteínas Proto-Oncogênicas c-akt/genética , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/enzimologia , Enfisema Pulmonar/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Distribuição Aleatória , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Proteína de Morte Celular Associada a bcl/biossíntese , Proteína de Morte Celular Associada a bcl/genéticaRESUMO
OBJECTIVE: To investigate the effect of spearmint oil on emphysema-like changes and the expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta(IL-1beta), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-9) in lipopolysaccharide (LPS) treated rats. METHOD: Emphysematous changes model was induced by intratracheal instillation of LPS once a week for up to 8 weeks in rats. Rats were divided into control, dexamethasone (0.3 mg x kg(-1)), and spearmint oil (10, 30,100 mg x kg(-1)) groups. Each group was treated with saline, dexamethasone, and spearmint of oil respectively for 4 weeks. Then total and different white blood cell counts in bronchoalveolar lavage fluid(BALF) were carried out. The pathologic changes of lung tissue such as alveolar structure, airway inflammation, and goblet cell metaplasia were observed by HE and AB-PAS staining. Expression of TNF-alpha, IL-1beta, TIMP-1 and MMP-9 were measured. RESULT: Both spearmint and dexamethasone decreased the destruction of pulmonary alveolus. The total and different white blood cell counts in BALF including neutrophile and lymphocyte of spearmint oil 100 mg x kg(-1) and dexamethasone group were significantly reduced, and the goblet cell metaplasia was also inhibited. Dexamethasone had inhibitory effect on the expression of TNF-alpha, IL-1beta, TIMP-1 and MMP-9. Spearmint oil 30, 100 mg x kg(-1) significantly reduced TNF-alpha and IL-1beta respectively. Spearmint oil 10, 30 and 100 mg x kg(-1) had no effect on the expression of TIMP-1, but could decrease the expression of MMP-9 significantly in lung tissues. CONCLUSION: Spearmint oil has protective effect on rats with emphysematous changes, since it improves alveolar destruction, pulmonary inflammation, and goblet cell metaplasia. The mechanism may include reducing TNF-alpha, IL-1beta content and inhibiting overexpression of matrix metalloproteinase-9 in lung tissues.
Assuntos
Metaloproteinase 9 da Matriz/efeitos dos fármacos , Mentha spicata/química , Fitoterapia , Óleos de Plantas/uso terapêutico , Enfisema Pulmonar/tratamento farmacológico , Enfisema Pulmonar/enzimologia , Animais , Compostos Azo/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Células Caliciformes/efeitos dos fármacos , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Lipopolissacarídeos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaplasia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/patologia , Ratos , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/patologia , Inibidor Tecidual de Metaloproteinase-1/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
RATIONALE: Oxidants are believed to play a major role in the development of emphysema. OBJECTIVES: This study aimed to determine if the expression of human copper-zinc superoxide dismutase (CuZnSOD) within the lungs of mice protects against the development of emphysema. METHODS: Transgenic CuZnSOD and littermate mice were exposed to cigarette smoke (6 h/d, 5 d/wk, for 1 yr) and compared with nonexposed mice. A second group was treated with intratracheal elastase to induce emphysema. MEASUREMENTS: Lung inflammation was measured by cell counts and myeloperoxidase levels. Oxidative damage was assessed by immunofluorescence for 3-nitrotyrosine and 8-hydroxydeoxyguanosine and lipid peroxidation levels. The development of emphysema was determined by measuring the mean linear intercept (Lm). MAIN RESULTS: Smoke exposure caused a fourfold increase in neutrophilic inflammation and doubled lung myeloperoxidase activity. This inflammatory response did not occur in the smoke-exposed CuZnSOD mice. Similarly, CuZnSOD expression prevented the 58% increase in lung lipid peroxidation products that occurred after smoke exposure. Most important, CuZnSOD prevented the onset of emphysema in both the smoke-induced model (Lm, 68 exposed control vs. 58 exposed transgenic; p < 0.04) and elastase-generated model (Lm, 80 exposed control vs. 63 exposed transgenic; p < 0.03). These results demonstrate for the first time that antioxidants can prevent smoke-induced inflammation and can counteract the proteolytic cascade that leads to emphysema formation in two separate animal models of the disease. CONCLUSIONS: These findings indicate that strategies aimed at enhancing or supplementing lung antioxidants could be effective for the prevention and treatment of this disease.
Assuntos
Enfisema Pulmonar/prevenção & controle , Fumar , Superóxido Dismutase/biossíntese , Animais , Biomarcadores/metabolismo , Contagem de Células , Modelos Animais de Doenças , Progressão da Doença , Peroxidação de Lipídeos , Pulmão/enzimologia , Pulmão/patologia , Macrófagos Alveolares/enzimologia , Macrófagos Alveolares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Elastase Pancreática/toxicidade , Peroxidase/metabolismo , Enfisema Pulmonar/enzimologia , Enfisema Pulmonar/etiologia , Fumar/efeitos adversos , Superóxido Dismutase/genéticaRESUMO
Hyperbaric oxygen may provoke lesions in various organs and tissues depending on the dose and application time. The toxic action mechanisms of oxygen are manifold. The pulmonary lesions that occur in mice submitted to various oxygen pressures are investigated. Anatomo-pathological examination revealed numerous alterations of various kinds depending on pressure used. Emphysema, pulmonary oedema and enormous inflammatory processes in the lung are the most frequent findings encountered in research.