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1.
Parasitol Res ; 119(11): 3719-3728, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32955617

RESUMO

This study aimed to evaluate the effects of early-life exposure to different extracts of Angiostrongylus cantonensis (A. cantonensis) on airway inflammation in an allergic asthma model. The total soluble extract (TE) and the soluble extracts of the digestive (AcD), reproductive (AcR), and cuticle (AcC) systems of A. cantonensis were used for immunisation before ovalbumin (OVA)-sensitisation/challenge in an OVA-induced allergic asthma model. The initial hypothesis of the study was that some soluble extract of the systems (AcD, AcR, or AcC) could be more potent to the modulation of inflammation than the TE. Our data, however, shows that immunisation with the TE is more promising because it decreased the high influx of inflammatory cells on airways and promoted an increase of interferon-γ (IFN-ɣ) and interleukin-10 (IL-10) levels. Besides this, the immunisation with the TE also led to a reduction of goblet cells and mucus overproduction in the lung tissue of asthmatic mice. We believe that the extracts have a distinct capacity to modulate the immune system, due to the TE possessing a greater variability of molecules, which together leads to control of airway inflammation. In conclusion, this is the first study to reveal that the TE of A. cantonensis adult worms has a greater potential for developing a novel therapeutic for allergic asthma.


Assuntos
Angiostrongylus cantonensis/metabolismo , Asma/imunologia , Imunomodulação , Angiostrongylus cantonensis/anatomia & histologia , Animais , Asma/induzido quimicamente , Asma/prevenção & controle , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Imunização , Inflamação , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/efeitos adversos , Mucosa Respiratória/metabolismo
2.
Inflammation ; 41(5): 1987-2001, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29995294

RESUMO

Pulmonary fibrosis is a specific form of interstitial pneumonia. In addition to the idiopathic cause, it may be caused by drugs such as bleomycin (BLM)-used in the treatment of tumors. Fructose-1,6-bisphosphate (FBP) is a high-energy endogenous glycolytic compound that has antifibrotic, anti-inflammatory, and immunomodulatory effects. The aim of this study was to investigate the effects of FBP on both BLM-induced pulmonary fibrosis in mice and in a human embryonic lung fibroblast (MRC-5) culture system. C57BL/6 mice were divided into four groups: control, FBP, BLM, and BLM plus FBP. A single dose of bleomycin (7.5 U/kg) was administered intratracheally, and survival, body weight, Ashcroft score, and histological analysis were evaluated. Pulmonary function and bronchoalveolar lavage fluid (BALF) were also evaluated after a single dose of bleomycin (1.2 U/kg-intratracheally). Treatment with FBP (500 mg/kg) was given on day 0 intraperitoneally. Fibroblasts (MRC-5 cells) were used to access the effect of FBP in vitro. In vivo, FBP increased the survival rate and reduced body weight loss (BLM vs. BLM plus FBP-p < 0.05). FBP also prevented BLM-induced loss of pulmonary function and decreased BALF inflammatory cells, level of fibrosis, and superficial collagen density (p < 0.05). In vitro, FBP (0.62 and 1.25 mM) had inhibitory activity on MRC-5 cells and was able to induce senescence in fibroblasts. These results showed that FBP has the potential of reducing the toxic effects of BLM and may provide supportive therapy for conventional methods used for the treatment of cancer.


Assuntos
Fibroblastos/patologia , Frutosedifosfatos/farmacologia , Fibrose Pulmonar/prevenção & controle , Animais , Bleomicina/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Frutosedifosfatos/uso terapêutico , Humanos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Taxa de Sobrevida , Redução de Peso/efeitos dos fármacos
3.
Physiol Behav ; 165: 358-64, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27568231

RESUMO

Adversities faced during the prenatal period can be related to the onset of diseases in adulthood. However, little is known about the effects on the respiratory system. This study aimed to evaluate the effects of prenatal stress in two different time-points during pregnancy on pulmonary function and on the inflammatory profile of mice exposed to an asthma model. Male and female BALB/c mice were divided into 3 groups: control (CON), prenatal stress from the second week of pregnancy (PNS1) and prenatal stress on the last week of pregnancy (PNS2). Both PNS1 and PNS2 pregnant females were submitted to restraint stress. As adults, fear/anxiety behaviors were assessed, and animals were subjected to an asthma model induced by ovalbumin. Pulmonary function, inflammatory parameters in bronchoalveolar lavage (BAL) and histology were evaluated. There was a significant decrease in the number of entries and time spent in the central quadrant on the open field test for the PNS1 animals. Females (PNS1) showed improved pulmonary function (airway resistance, tissue damping and pulmonary elastance), significant increase in the percentage of neutrophils and lymphocytes and a decrease in eosinophils when compared to controls. There was a significant decrease in inflammatory cytokines in BAL of both males (IL-5 and IL-13) and females (IL-4, IL-5 and IL-13) from PNS1 and PNS2 when compared to the CON group. Prenatal stress starting from the beginning of pregnancy reduces the impact of asthma development in adult female mice, showing an improved pulmonary function and a lower inflammatory response in the lungs.


Assuntos
Asma/etiologia , Asma/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Caracteres Sexuais , Estresse Fisiológico/fisiologia , Fatores Etários , Análise de Variância , Animais , Ansiedade/fisiopatologia , Peso Corporal , Lavagem Broncoalveolar/métodos , Corticosterona/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Eosinófilos/patologia , Comportamento Exploratório/fisiologia , Medo/psicologia , Feminino , Linfócitos/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/toxicidade , Gravidez , Testes de Função Respiratória
4.
Exp Lung Res ; 42(2): 66-74, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27070484

RESUMO

PURPOSE: Asthma is a highly prevalent chronic inflammatory lung disease characterized by airway hyperresponsiveness to allergens, airway edema, and increased mucus secretion. Such mucus can be liquefied by recombinant human deoxyribonuclease (rhDNase), in which efficacy of rhDNase has been well documented in patients with cystic fibrosis, but little studied in asthma. In the present study, we investigated whether rhDNase intranasal administration improved inflammation and pulmonary function in an experimental model of asthma. METHODS: Mice were sensitized by two subcutaneous injections of ovalbumin (OVA), on days 0 and 7, followed by three intranasal challenges with OVA on days 14, 15, and 16. A control group, replacing OVA by DPBS, was included. On days 15 and 16, after 2 hours of OVA challenge, mice received 1 mg/mL of intranasal rhDNase. RESULTS: We showed that rhDNase decreased significantly the airway resistance and reduced EETs formation and globet cells hyperplasia. CONCLUSIONS: Our results suggest that extracellular DNA in mucus play a role in lower airways obstruction in OVA asthma protocol and that the treatment with rhDNase improved lung function and DNA extracellular traps, with no direct cellular anti-inflammatory effects.


Assuntos
Resistência das Vias Respiratórias/efeitos dos fármacos , Asma/tratamento farmacológico , DNA/metabolismo , Desoxirribonucleases/farmacologia , Armadilhas Extracelulares/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Administração Intranasal/métodos , Obstrução das Vias Respiratórias/tratamento farmacológico , Obstrução das Vias Respiratórias/metabolismo , Alérgenos/farmacologia , Animais , Asma/metabolismo , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/metabolismo , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Armadilhas Extracelulares/metabolismo , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Muco/efeitos dos fármacos , Muco/metabolismo , Ovalbumina/farmacologia
5.
Asia Pac Allergy ; 6(1): 48-55, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26844220

RESUMO

BACKGROUND: Tyrophagus putrescentiae (Tp) is a source of aeroallergen that causes allergic diseases. OBJECTIVE: To describe an acute and chronic murine model of allergic asthma with Tp extract with no systemic sensitization and no use of adjuvant. METHODS: Mites from dust sample were cultured and a raw extract was produced. Female BALB/c mice (6-8 weeks) were challenged intranasally with Tp extract or Dulbecco's phosphate-buffered saline, for 10 consecutive days (acute protocol) or for 6 weeks (chronic protocol). Twenty-four hours after the last intranasal challenge, bronchoalveolar lavage fluid (BALF) was performed for total and differential cells count, cytokine analysis, and eosinophil peroxidase activity. Lung tissue was also removed for histopathologic analysis. RESULTS: Tp extract has shown a significant increase in total cells count from BALF as well as an increase in absolute eosinophils count, eosinophil peroxidase activity, interleukin (IL)-5 and IL-13 levels, in both acute and chronic protocols. Peribronchovascular infiltrate, goblet cells hyperplasia and collagen deposition were shown in the airways of acute and chronic Tp-exposed mice. CONCLUSION: Our data suggest that the intranasal exposure to Tp extract, with no systemic sensitization and no use of adjuvants, induces a robust allergic inflammation in the lungs of mice, in both acute and chronic models. Our Tp extract seems to be a potent allergen extract which may be used in asthma model studies.

6.
Mol Cell Biochem ; 413(1-2): 47-55, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26738487

RESUMO

The inflammatory cells infiltrating the airways produce several mediators, such as reactive oxygen species (ROS). ROS and the oxidant-antioxidant imbalance might play an important role in the modulation of airways inflammation. In order to avoid the undesirable effects of ROS, various endogenous antioxidant strategies have evolved, incorporating both enzymatic and non-enzymatic mechanisms. Recombinant human deoxyribonuclease (rhDNase) in clinical studies demonstrated a reduction in sputum viscosity, cleaving extracellular DNA in the airways, and facilitating mucus clearance, but an antioxidant effect was not studied so far. Therefore, we evaluated whether the administration of rhDNase improves oxidative stress in a murine model of asthma. Mice were sensitized by two subcutaneous injections of ovalbumin (OVA), on days 0 and 7, followed by three lung challenges with OVA on days 14, 15, and 16. On days 15 and 16, after 2 h of the challenge with OVA, mice received 1 mg/mL of rhDNase in the lungs. Bronchoalveolar lavage fluid and lung tissue were obtained on day 17, for inflammatory and oxidative stress analysis. We showed that rhDNase did not alter the population of inflammatory cells, such as eosinophil cells, in OVA-treated rhDNase group but significantly improved oxidative stress in lung tissue, by decreasing oxygen reactive species and increasing superoxide dismutase/catalase ratio, glutathione peroxidase activity, and thiol content. Our data provide the first evidence that rhDNase decreases some measures of oxidative stress and antioxidant status in a murine model of asthma, with a potential antioxidant effect to be further studied in human asthma.


Assuntos
Asma/imunologia , Desoxirribonucleases/administração & dosagem , Eosinófilos/metabolismo , Pulmão/imunologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Asma/induzido quimicamente , Asma/metabolismo , Líquido da Lavagem Broncoalveolar/química , Desoxirribonucleases/genética , Desoxirribonucleases/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Ovalbumina/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
7.
J Bras Pneumol ; 38(5): 595-604, 2012.
Artigo em Inglês, Português | MEDLINE | ID: mdl-23147052

RESUMO

OBJECTIVE: To determine whether a short-term protocol using subcutaneous sensitization with ovalbumin, without the use of adjuvants, would induce an eosinophilic response in the lungs of mice similar to that observed in previous, well-established protocols. METHODS: Adult female BALB/c mice were randomized and divided into groups according to the number of sensitizations with ovalbumin and the number/dosage of intranasal ovalbumin challenges. The short-term protocol (10 days) consisted of one sensitization with ovalbumin and three ovalbumin challenges (100 µg). Total and differential cell counts in BAL fluid, levels of eosinophil peroxidase in lung tissue, and histopathological examination of the lungs were performed 24 h after the last ovalbumin challenge. RESULTS: No significant differences were found among the groups regarding the variables studied. The short-term protocol, as well as the other protocols studied, induced an eosinophilic response similar to that obtained in the positive control. CONCLUSIONS: Subcutaneous sensitization with ovalbumin and without the use of adjuvants resulted in a significant allergic response in the lungs of mice, even in the short-term protocol group. Our findings suggest that this short-term protocol can be used as a first-line pre-clinical test for the study of new medications, reducing the costs and observation periods.


Assuntos
Asma/patologia , Hiper-Reatividade Brônquica/patologia , Peroxidase de Eosinófilo/metabolismo , Pulmão/patologia , Ovalbumina , Eosinofilia Pulmonar/imunologia , Doença Aguda , Animais , Asma/enzimologia , Hiper-Reatividade Brônquica/enzimologia , Testes de Provocação Brônquica , Líquido da Lavagem Broncoalveolar/citologia , Modelos Animais de Doenças , Feminino , Pulmão/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Eosinofilia Pulmonar/patologia , Distribuição Aleatória
8.
J. bras. pneumol ; 38(5): 595-604, set.-out. 2012. ilus
Artigo em Português | LILACS | ID: lil-656011

RESUMO

OBJETIVO: Determinar se um protocolo curto de sensibilização com ovalbumina subcutânea, sem adjuvante, induziria uma resposta pulmonar eosinofílica em pulmões de camundongos similar àquela encontrada em protocolos previamente estabelecidos. MÉTODOS: Fêmeas adultas de camundongos BALB/c foram randomizadas e divididas em grupos de acordo com o número de sensibilizações com ovalbumina e o número/dosagem de provocação intranasal. O protocolo curto (10 dias) consistiu de uma sensibilização e três provocações com ovalbumina (100 µg). A contagem total e diferencial de células no lavado broncoalveolar, o nível de peroxidase eosinofílica no tecido pulmonar e o exame histopatológico dos pulmões foram realizados 24 h após a última provocação. RESULTADOS: Não houve diferenças significativas entre os grupos em relação às variáveis estudadas. O protocolo curto, assim como os outros protocolos estudados, induziu uma resposta eosinofílica pulmonar semelhante àquela do grupo controle positivo. CONCLUSÕES: A sensibilização por ovalbumina subcutânea sem o uso de adjuvante resultou em uma significativa resposta pulmonar alérgica em ratos, mesmo no grupo de protocolo curto. Nossos achados sugerem que esse protocolo curto pode ser utilizado como teste pré-clínico de primeira linha para a pesquisa de novos fármacos, reduzindo custos e o tempo de observação.


OBJECTIVE: To determine whether a short-term protocol using subcutaneous sensitization with ovalbumin, without the use of adjuvants, would induce an eosinophilic response in the lungs of mice similar to that observed in previous, well-established protocols. METHODS: Adult female BALB/c mice were randomized and divided into groups according to the number of sensitizations with ovalbumin and the number/dosage of intranasal ovalbumin challenges. The short-term protocol (10 days) consisted of one sensitization with ovalbumin and three ovalbumin challenges (100 µg). Total and differential cell counts in BAL fluid, levels of eosinophil peroxidase in lung tissue, and histopathological examination of the lungs were performed 24 h after the last ovalbumin challenge. RESULTS: No significant differences were found among the groups regarding the variables studied. The short-term protocol, as well as the other protocols studied, induced an eosinophilic response similar to that obtained in the positive control. CONCLUSIONS: Subcutaneous sensitization with ovalbumin and without the use of adjuvants resulted in a significant allergic response in the lungs of mice, even in the short-term protocol group. Our findings suggest that this short-term protocol can be used as a first-line pre-clinical test for the study of new medications, reducing the costs and observation periods.


Assuntos
Animais , Feminino , Camundongos , Asma/patologia , Hiper-Reatividade Brônquica/patologia , Peroxidase de Eosinófilo/metabolismo , Pulmão/patologia , Ovalbumina , Eosinofilia Pulmonar/imunologia , Doença Aguda , Asma/enzimologia , Testes de Provocação Brônquica , Hiper-Reatividade Brônquica/enzimologia , Líquido da Lavagem Broncoalveolar/citologia , Modelos Animais de Doenças , Pulmão/enzimologia , Camundongos Endogâmicos BALB C , Eosinofilia Pulmonar/patologia , Distribuição Aleatória
9.
Sci. med ; 22(2): 71-80, abr-jun. 2012.
Artigo em Português | LILACS | ID: lil-661318

RESUMO

Objetivos: Testar alternativas de protocolos com modelos animais de asma aguda e crônica que apresentem características mais próximas da doença em humanos, utilizando ovalbumina livre de adjuvante.Métodos: Foram utilizadas fêmeas adultas de camundongos BALB/c, divididas em grupos de acordo com as sensibilizações com ovalbumina. O modelo agudo utilizou duas doses de ovalbumina subcutânea, sem adjuvante, com intervalo de sete dias, com posterior desafio intranasal durante três dias, comparado ao protocolo padrão que utiliza três doses de ovalbumina intraperitoneal, no período de sensibilização. O modelo crônico também utilizou ovalbumina subcutânea livre de adjuvante para sensibilização, com intervalo de 14 dias e posterior desafio intranasal, três vezes por semana, durante oito semanas. Contagem total e diferencial de células no lavado broncoalveolar e análise histológica dos pulmões foram realizadas 24 horas após o último desafio com ovalbumina.Resultados: Nos dois modelos estudados, agudo e crônico, observou-se uma resposta eosinofílica pulmonar semelhante entre os grupos. A contagem de células e a análise histológica do tecido pulmonar não apresentaram diferença significativa entre os grupos estudados.Conclusões: O uso de sensibilização subcutânea em modelo murino com ovalbumina, sem adjuvante (alum), resulta em significativa resposta inflamatória pulmonar alérgica, com predomínio de eosinófilos, podendo ser uma opção futura para experimentos mais próximos ao modelo humano, tanto na fase aguda, como na fase crônica da doença.


Aims: To test alternative protocols using animal models of acute and chronic asthma, with features closer to human disease, using ovalbumin without adjuvant. Methods: Adult female BALB/c mice were used and divided into groups according to sensitization with ovalbumin. The acute model used two doses of ovalbumin subcutaneously without adjuvant, on days 0 and 7, and after intranasal challenge for consecutives three days, compared with a standard protocol using three doses of ovalbumin for sensitization. The chronic model also used ovalbumin subcutaneously for sensitization, adjuvant-free, on days 0 and 14, and after intranasal challenge, for eight consecutive weeks. Total and differential cell counts from bronchoalveolar lavage and histopathology of the lungs were performed 24 hours after the last ovalbumin challenge. Results: In both models of protocols studied, acute and chronic, we have observed similar allergic pulmonary response between the groups. Cell counts and histological analysis of lung tissue showed no significant difference between groups. Conclusions: Use of sensitization in murine model with ovalbumin subcutaneously, with no adjuvant (alum), resulted in an expected allergic pulmonary response, with predominant eosinophils. These protocols may be a future option to animal models of asthma closer to the human disease, both in the acute and chronic patterns.


Assuntos
Camundongos , Modelos Animais , Asma , Hipersensibilidade , Ovalbumina
10.
Sci. med ; 20(3)jul. 2010. ilus
Artigo em Português | LILACS | ID: lil-583399

RESUMO

Objetivos: discutir as vantagens e limitações de pesquisas com modelos murinos em asma e suas aplicações mais imediatas.Fonte de Dados: foi realizada revisão da literatura no PubMed. Os descritores utilizados foram: mice, asthma, animal model e murine model. Síntese dos Dados: modelos experimentais murinos têm sido muito utilizados para elucidar a fisiopatogenia da asma brônquica e para avaliar novos alvos terapêuticos. Diversas críticas surgiram nos últimos anos em relação aos modelos utilizados. Os modelos animais diferem bastante da asma em humanos, particularmente em relação à utilização de adjuvante, via de administração e dose dos alergenos, além do tipo de resposta inflamatória pulmonar.Conclusões: novos modelos experimentais devem reproduzir da forma mais próxima possível as características da asma em humanos. Embora o modelo murino apresente inúmeras vantagens em relação a outros modelos animais, as limitações inerentes a esse tipo de estudo devem ser levadas em consideração no momento da extrapolação dos resultados para a doença em humanos.


Aims: To discuss the advantages and limitations of studies using murine models in asthma and the most immediate applications. Source of Data: A review of the literature using PubMed database was performed. The keywords used were: mice, asthma, animal model and murine model. Summary of Findings: Experimental models have been used to elucidate the pathophysiology of asthma and to evaluate new therapeutic targets. Several limitations related to the models currently used have emerged in recent years. Animal models are very different from the human asthma, particularly regarding to the use of adjuvant, administration route, dose of allergen and the type of pulmonary inflammatory response. Conclusions: New experimental models must reproduce the characteristics of human asthma as close as possible. Although murine models show several advantages in relation to other animals, the inherent limitations of this type of study must be considered before the extrapolation of results to human pathology.


Assuntos
Camundongos , Modelos Animais , Asma/fisiopatologia , Muridae
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