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1.
Respir Res ; 18(1): 50, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28330488

RESUMO

BACKGROUND: Cigarette smoke (CS) is associated with lower numbers of circulating stem cells and might severely affect their mobilization, trafficking and homing. Our study was designed to demonstrate in an animal model of CS exposure whether CS affects the homing and functional capabilities of bone marrow-derived mesenchymal stem cells (BM-MSCs). METHODS: Guinea pigs (GP), exposed or sham-exposed to CS, were administered via tracheal instillation or by vascular administration with 2.5 × 106 BM-MSCs obtained from CS-exposed or sham-exposed animal donors. Twenty-four hours after cell administration, animals were sacrificed and cells were visualised into lung structures by optical microscopy. BM-MSCs from 8 healthy GP and from 8 GP exposed to CS for 1 month were isolated from the femur, cultured in vitro and assessed for their proliferation, migration, senescence, differentiation potential and chemokine gene expression profile. RESULTS: CS-exposed animals showed greater BM-MSCs lung infiltration than sham-exposed animals regardless of route of administration. The majority of BM-MSCs localized in the alveolar septa. BM-MSCs obtained from CS-exposed animals showed lower ability to engraft and lower proliferation and migration. In vitro, BM-MSCs exposed to CS extract showed a significant reduction of proliferative, cellular differentiation and migratory potential and an increase in cellular senescence in a dose dependent manner. CONCLUSION: Short-term CS exposure induces BM-MSCs dysfunction. Such dysfunction was observed in vivo, affecting the cell homing and proliferation capabilities of BM-MSCs in lungs exposed to CS and in vitro altering the rate of proliferation, senescence, differentiation and migration capacity. Additionally, CS induced a reduction in CXCL9 gene expression in the BM from CS-exposed animals underpinning a potential mechanistic action of bone marrow dysfunction.


Assuntos
Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Fumar Cigarros/efeitos adversos , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/patologia , Fumaça/efeitos adversos , Animais , Células da Medula Óssea/efeitos dos fármacos , Movimento Celular/imunologia , Cobaias , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Modelos Animais
2.
Eur Respir J ; 46(2): 346-54, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25929951

RESUMO

Sildenafil, a phosphodiesterase-5 inhibitor used to treat pulmonary hypertension, may have effects on pulmonary vessel structure and function. We evaluated the effects of sildenafil in a cigarette smoke (CS)-exposed model of chronic obstructive pulmonary disease (COPD).42 guinea-pigs were exposed to cigarette smoke or sham-exposed and treated with sildenafil or vehicle for 12 weeks, divided into four groups. Assessments included respiratory resistance, pulmonary artery pressure (PAP), right ventricle (RV) hypertrophy, endothelial function of the pulmonary artery and lung vessel and parenchymal morphometry.CS-exposed animals showed increased PAP, RV hypertrophy, raised respiratory resistance, airspace enlargement and intrapulmonary vessel remodelling. CS exposure also produced wall thickening, increased contractility and endothelial dysfunction in the main pulmonary artery. CS-exposed animals treated with sildenafil showed lower PAP and a trend to less RV hypertrophy than CS-exposed only animals. Furthermore, sildenafil preserved the intrapulmonary vessel density and attenuated the airspace enlargement induced by CS. No differences in gas exchange, respiratory resistance, endothelial function and vessel remodelling were observed.We conclude that in this experimental model of COPD, sildenafil prevents the development of pulmonary hypertension and contributes to preserve the parenchymal and vascular integrity, reinforcing the notion that the nitric oxide-cyclic guanosine monophosphate axis is perturbed by CS exposure.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Inibidores da Fosfodiesterase 5/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Citrato de Sildenafila/farmacologia , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Modelos Animais de Doenças , Cobaias , Hipertrofia Ventricular Direita/fisiopatologia , Masculino , Artéria Pulmonar/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/etiologia
3.
Am J Respir Crit Care Med ; 189(11): 1359-73, 2014 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-24738736

RESUMO

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a major cause of death worldwide. No therapy stopping progress of the disease is available. OBJECTIVES: To investigate the role of the soluble guanylate cyclase (sGC)-cGMP axis in development of lung emphysema and pulmonary hypertension (PH) and to test whether the sGC-cGMP axis is a treatment target for these conditions. METHODS: Investigations were performed in human lung tissue from patients with COPD, healthy donors, mice, and guinea pigs. Mice were exposed to cigarette smoke (CS) for 6 hours per day, 5 days per week for up to 6 months and treated with BAY 63-2521. Guinea pigs were exposed to CS from six cigarettes per day for 3 months, 5 days per week and treated with BAY 41-2272. Both BAY compounds are sGC stimulators. Gene and protein expression analysis were performed by quantitative real-time polymerase chain reaction and Western blotting. Lung compliance, hemodynamics, right ventricular heart mass alterations, and alveolar and vascular morphometry were performed, as well as inflammatory cell infiltrate assessment. In vitro assays of cell adhesion, proliferation, and apoptosis have been done. MEASUREMENTS AND MAIN RESULTS: The functionally essential sGC ß1-subunit was down-regulated in patients with COPD and in CS-exposed mice. sGC stimulators prevented the development of PH and emphysema in the two different CS-exposed animal models. sGC stimulation prevented peroxynitrite-induced apoptosis of alveolar and endothelial cells, reduced CS-induced inflammatory cell infiltrate in lung parenchyma, and inhibited adhesion of CS-stimulated neutrophils. CONCLUSIONS: The sGC-cGMP axis is perturbed by chronic exposure to CS. Treatment of COPD animal models with sGC stimulators can prevent CS-induced PH and emphysema.


Assuntos
Enfisema/prevenção & controle , Guanilato Ciclase/metabolismo , Hipertensão Pulmonar/prevenção & controle , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Receptores Citoplasmáticos e Nucleares/metabolismo , Fumar/efeitos adversos , Animais , Biomarcadores/metabolismo , Western Blotting , Modelos Animais de Doenças , Regulação para Baixo , Enfisema/enzimologia , Cobaias , Humanos , Hipertensão Pulmonar/enzimologia , Técnicas In Vitro , Camundongos , Doença Pulmonar Obstrutiva Crônica/enzimologia , Reação em Cadeia da Polimerase em Tempo Real , Fumar/metabolismo , Guanilil Ciclase Solúvel
4.
Am J Respir Cell Mol Biol ; 50(2): 337-46, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24032416

RESUMO

Long-acting muscarinic antagonists are widely used to treat chronic obstructive pulmonary disease (COPD). In addition to bronchodilation, muscarinic antagonism may affect pulmonary histopathological changes. The effects of long-acting muscarinic antagonists have not been thoroughly evaluated in experimental models of COPD induced by chronic exposure to cigarette smoke (CS). We investigated the effects of aclidinium bromide on pulmonary function, airway remodeling, and lung inflammation in a CS-exposed model of COPD. A total of 36 guinea pigs were exposed to CS and 22 were sham exposed for 24 weeks. Animals were nebulized daily with vehicle, 10 µg/ml, or 30 µg/ml aclidinium, resulting in six experimental groups. Pulmonary function was assessed weekly by whole-body plethysmography, determining the enhanced pause (Penh) at baseline, after treatment, and after CS/sham exposure. Lung changes were evaluated by morphometry and immunohistochemistry. CS exposure increased Penh in all conditions. CS-exposed animals treated with aclidinium showed lower baseline Penh than untreated animals (P = 0.02). CS induced thickening of all bronchial wall layers, airspace enlargement, and inflammatory cell infiltrate in airways and septa. Treatment with aclidinium abrogated the CS-induced smooth muscle enlargement in small airways (P = 0.001), and tended to reduce airspace enlargement (P = 0.054). Aclidinium also attenuated CS-induced neutrophilia in alveolar septa (P = 0.04). We conclude that, in guinea pigs chronically exposed to CS, aclidinium has an antiremodeling effect on small airways, which is associated with improved respiratory function, and attenuates neutrophilic infiltration in alveolar septa. These results indicate that, in COPD, aclidinium may exert beneficial effects on lung structure in addition to its bronchodilator action.


Assuntos
Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Nicotiana , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/farmacologia , Remodelação das Vias Aéreas/efeitos dos fármacos , Remodelação das Vias Aéreas/fisiologia , Animais , Modelos Animais de Doenças , Cobaias , Inflamação/tratamento farmacológico , Inflamação/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fumaça
5.
COPD ; 9(5): 473-84, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22708688

RESUMO

Cigarette smoke (CS) induces an inflammatory process in the lung that may underlie the development of chronic obstructive pulmonary disease (COPD). The nature and characteristics of this process have not been fully established in animal models. We aimed to evaluate the pulmonary inflammatory reaction and its involvement in structural changes in guinea pigs chronically exposed to CS. 19 Hartley guinea pigs were exposed to 7 cigarettes/day, during 3 or 6 months. 18 control guinea pigs were sham-exposed. Numbers of neutrophils, macrophages and eosinophils and lymphoid follicles were assessed in different lung structures. Airway and vessel morphometry, alveolar space size and collagen deposition were also quantified. After 6 months of exposure, CS-exposed guinea pigs showed increased numbers of neutrophils, macrophages and eosinophils in the airways, intrapulmonary vessels and alveolar septa, as well as lymphoid follicles. Increased numbers of muscularized intrapulmonary vessels were apparent at 3 months. After 6 months of exposure, the airway wall thickened and the alveolar space size increased. Collagen deposition was also apparent in airway walls and alveolar septa after 6 months' exposure. The magnitude of airway wall-thickening correlated with the number of infiltrating inflammatory cells, and the extension of collagen deposition correlated with alveolar space size. We conclude that in the guinea pig, 6 months of CS exposure induces inflammatory cell infiltrate in lung structures, at an intensity that correlates with airway remodelling. These changes resemble those observed in COPD, thus endorsing the pathogenic role of CS and the usefulness of this animal model for its study.


Assuntos
Remodelação das Vias Aéreas , Inflamação , Pulmão , Doença Pulmonar Obstrutiva Crônica , Fumar , Animais , Vasos Sanguíneos/patologia , Modelos Animais de Doenças , Granulócitos/citologia , Granulócitos/patologia , Cobaias , Inflamação/imunologia , Inflamação/patologia , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/patologia , Fumaça/efeitos adversos , Fumar/imunologia , Fumar/patologia , Nicotiana/efeitos adversos
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