RESUMO
Pequi is a Brazilian fruit used in folk medicine for pulmonary diseases treatment, but its oil presents bioavailability limitations. The use of nanocarriers can overcome this limitation. We developed nanoemulsions containing pequi oil (pequi-NE) and evaluated their effects in a lipopolysaccharide (LPS)-induced lung injury model. Free pequi oil or pequi-NE (20 mg/kg) was orally administered to A/J mice 16 and 4 h prior to intranasal LPS exposure, and the analyses were performed 24 h after LPS provocation. The physicochemical results revealed that pequi-NE comprised particles with mean diameter of 174-223 nm, low polydispersity index (0.11 ± 0.01), zeta potential of -7.13 ± 0.08 mV, and pH of 5.83 ± 0.12. In vivo evaluation showed that free pequi oil pretreatment reduced the influx of inflammatory cells into bronchoalveolar fluid (BALF), while pequi-NE completely abolished leukocyte accumulation. Moreover, pequi-NE, but not free pequi oil, reduced myeloperoxidase (MPO), TNF-α, IL-1ß, IL-6, MCP-1, and KC levels. Similar anti-inflammatory effects were observed when LPS-exposed animals were pre-treated with the nanoemulsion containing pequi or oleic acid. These results suggest that the use of nanoemulsions as carriers enhances the anti-inflammatory properties of oleic acid-containing pequi oil. Moreover, pequi's beneficial effect is likely due its high levels of oleic acid.
RESUMO
The co-existence with rhinitis limits the control of asthma. Compared with oral H1 receptor antagonists, intranasal corticosteroids have been demonstrated to provide greater relief of all symptoms of rhinitis and are recommended as first-line treatment for allergic rhinitis. Intrinsic limitations of nasal delivery, such as the presence of the protective mucous layer, the relentless mucociliary clearance, and the consequent reduced residence time of the formulation in the nasal cavity, limit budesonide efficacy to the treatment of local nasal symptoms. To overcome these limitations and to enable the treatment of asthma via nasal administration, we developed a budesonide-loaded lipid-core nanocapsule (BudNC) microagglomerate powder by spray-drying using a one-step innovative approach. BudNC was obtained, as a white powder, using L-leucine as adjuvant with 75 ± 6% yield. The powder showed a bimodal size distribution curve by laser diffraction with a principal peak just above 3 µm and a second one around 0.45 µm and a drug content determined by HPLC of 8.7 mg of budesonide per gram. In vivo after nasal administration, BudNC showed an improved efficacy in terms of reduction of immune cell influx; production of eotaxin-1, the main inflammatory chemokine; and arrest of airways remodeling when compared with a commercial budesonide product in both short- and long-term asthma models. In addition, data showed that the results in the long-term asthma model were more compelling than the results obtained in the short-term model. Graphical abstract.
Assuntos
Asma , Budesonida/administração & dosagem , Nanocápsulas , Administração Intranasal , Corticosteroides , Animais , Asma/tratamento farmacológico , Budesonida/uso terapêutico , Masculino , CamundongosRESUMO
We have previously shown that experimental infection caused by Trypanosoma cruzi is associated with changes in the hypothalamus-pituitary-adrenal axis. Increased glucocorticoid (GC) levels are believed to be protective against the effects of acute stress during infection but result in depletion of CD4(+)CD8(+) thymocytes by apoptosis, driving to thymic atrophy. However, very few data are available concerning prolactin (PRL), another stress-related hormone, which seems to be decreased during T. cruzi infection. Considering the immunomodulatory role of PRL upon the effects caused by GC, we investigated if intrathymic cross-talk between GC and PRL receptors (GR and PRLR, respectively) might influence T. cruzi-induced thymic atrophy. Using an acute experimental model, we observed changes in GR/PRLR cross-activation related with the survival of CD4(+)CD8(+) thymocytes during infection. These alterations were closely related with systemic changes, characterized by a stress hormone imbalance, with progressive GC augmentation simultaneously to PRL reduction. The intrathymic hormone circuitry exhibited an inverse modulation that seemed to counteract the GC-related systemic deleterious effects. During infection, adrenalectomy protected the thymus from the increase in apoptosis ratio without changing PRL levels, whereas an additional inhibition of circulating PRL accelerated the thymic atrophy and led to an increase in corticosterone systemic levels. These results demonstrate that the PRL impairment during infection is not caused by the increase of corticosterone levels, but the opposite seems to occur. Accordingly, metoclopramide (MET)-induced enhancement of PRL secretion protected thymic atrophy in acutely infected animals as well as the abnormal export of immature and potentially autoreactive CD4(+)CD8(+) thymocytes to the periphery. In conclusion, our findings clearly show that Trypanosoma cruzi subverts mouse thymus homeostasis by altering intrathymic and systemic stress-related endocrine circuitries with major consequences upon the normal process of intrathymic T cell development.
Assuntos
Doença de Chagas/imunologia , Homeostase , Hormônios/metabolismo , Interações Hospedeiro-Patógeno , Estresse Fisiológico , Timo/fisiologia , Trypanosoma cruzi/imunologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Timócitos/fisiologiaRESUMO
INTRODUCTION: Asthma is a common systemic disease occurring in infancy and adolescence, time periods that could encompass orthodontic treatment. Asthma is an inflammatory disease; therefore, it might interfere with orthodontic tooth movement. The purpose of the study was to analyze the histomorphologic aspects of the periodontal ligament of asthmatic Wistar rats in the initial period of orthodontic movement. METHODS: Thirty-two Wistar rats were divided into 4 groups: 2 control groups consisting of rats without induced allergic asthma, and 2 experimental groups consisting of rats with induced allergic asthma. The animals of the first control and experimental groups did not receive orthodontic forces, whereas those in the second control and experimental groups were subjected to mesial movement of the maxillary left first molar for 3 days. The samples were prepared for histomorphometric analysis of the periodontal ligament. The area of the periodontal ligament was calculated as a function of root length in the cervical and apical regions of the distal face of the maxillary first molar mesial root. The Student t test and the Welch correlation test were applied to the data obtained. RESULTS: There was a statistically significant difference (P <0.05) between the control and experimental groups. An enhanced response to orthodontic force was observed in the asthmatic animals: the periodontal ligament was more compressed at the pressure area and more stretched in the traction area. CONCLUSIONS: Our findings indicate that experimental allergic asthma seems to exacerbate orthodontic movement in rats.
Assuntos
Asma/patologia , Análise do Estresse Dentário , Ligamento Periodontal/anatomia & histologia , Técnicas de Movimentação Dentária , Animais , Asma/imunologia , Fenômenos Biomecânicos , Brônquios/patologia , Força Compressiva , Contagem de Leucócitos , Dente Molar , Ratos , Ratos Wistar , Resistência à Tração , Raiz Dentária/anatomia & histologiaRESUMO
Rats turned diabetic by alloxan treatment are refractory to systemic anaphylactic shock, in a direct association with reduced intestinal haemorrhage and tissue response to antigen challenge. As diabetic rats show reduction in mast cell numbers in different body compartments, this study was undertaken to investigate the influence of alloxan diabetes on mast cell population as well as the expression of the mast cell growth factor interleukin (IL)-3 in the small intestine of rats. We also analysed the putative involvement of endogenous insulin and glucocorticoid hormones in this phenomenon. There was a significant decrease in the number of mast cells present in the small intestine (ileum segment) of diabetic rats. Likewise, the immunohistochemical analysis revealed that IL-3 labelling was markedly attenuated in diabetic rats, as compared with normal animals, a phenomenon which paralleled with a decreased mRNA expression as attested by Reverse transcriptase-polymerase chain reaction technique. Treatment with insulin and with the steroid receptor antagonist RU 486 restored basal mast cell numbers, normal levels of IL-3 labelling and mRNA expression for IL-3 in the ileum of diabetic rats. In conclusion, our findings show that there is a causative relationship between down-regulation of mast cell numbers and the expression of IL-3 associated with diabetic state. In addition, as both parameters were suppressed by administration of insulin and RU 486, it indicates that an imbalance between the systemic levels of insulin and glucocorticoid hormones seems to be implicated in the reduction in intestinal mast cell population and refractoriness to antigen provocation in alloxan diabetes.
Assuntos
Diabetes Mellitus Experimental/patologia , Íleo/patologia , Interleucina-3/metabolismo , Mastócitos/patologia , Animais , Contagem de Células , Diabetes Mellitus Experimental/metabolismo , Regulação para Baixo/efeitos dos fármacos , Glucocorticoides/antagonistas & inibidores , Glucocorticoides/fisiologia , Antagonistas de Hormônios/farmacologia , Íleo/efeitos dos fármacos , Íleo/metabolismo , Insulina/farmacologia , Interleucina-3/genética , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Mifepristona/farmacologia , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodosRESUMO
This study was undertaken to investigate the putative mechanism(s) underlying the antispasmodic effect of 7-epiclusianone, a naturally occurring compound isolated from the plant Garcinia brasiliensis. Guinea pig tracheal rings were mounted in tissue baths filled with Krebs' solution, and the contractile response to distinct stimuli was measured in the presence or absence of 7-epiclusianone. We also tested the effect of 7-epiclusianone on methacholine-evoked airways obstruction in BALB/c mice using barometric plethysmography. 7-Epiclusianone (10 microM) inhibited epithelium-intact tracheal ring contraction induced by allergen, histamine, 5-hydroxytryptamine, or carbachol challenge. The relaxation effect was abrogated by epithelium removal, the presence of nitric-oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) (100 microM), or soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 microM). 7-Epiclusianone (1-100 microM) induced a dose-dependent increase in the intracellular cGMP levels of cultured tracheal rings. The relaxation effect of 7-epiclusianone was also inhibited by K(+) channel blockers tetraethylammonium (10 microM), glibenclamide (1 microM), or apamin (1 microM), but not by 9-(tetrahydro-2'-furyl)adenine (SQ22,536) (100 microM), an adenylate cyclase inhibitor. In epithelium-intact tracheal rings, 7-epiclusianone also inhibited Ca(2+)-induced contractions in K(+) (60 mM)-depolarized preparations, but it seemed ineffective in assays in which epithelium-denuded tracheal ring preparations were used. Oral administration of 7-epiclusinone (25-100 mg/kg) dose-dependently inhibited airway obstruction triggered by aerosolized methacholine (6-25 mg/ml), in a mechanism sensitive to L-NAME (20 mg/kg). In conclusion, the relaxation effect of 7-epiclusinone seems to be mediated by epithelium-, nitric oxide-, and cGMP-dependent mechanisms. Furthermore, oral administration of 7-epiclusianone reduces episodes of bronchial obstruction, warranting further research on this compound regarding a putative application in asthma therapy.
Assuntos
Benzofenonas/farmacologia , Benzoquinonas/farmacologia , GMP Cíclico/fisiologia , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Óxido Nítrico/fisiologia , Parassimpatolíticos/farmacologia , Transdução de Sinais , Traqueia/efeitos dos fármacos , Animais , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/fisiologia , Carbacol/farmacologia , Cricetinae , GMP Cíclico/análise , Epitélio/fisiologia , Feminino , Histamina/farmacologia , Técnicas In Vitro , Canais KATP/fisiologia , Masculino , Cloreto de Metacolina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Músculo Liso/fisiologia , Canais de Potássio Cálcio-Ativados/fisiologia , Traqueia/fisiologiaRESUMO
Prior studies have emphasized the anti-inflammatory and antioxidant properties of polyisoprenylated benzophenone derivatives, but their putative effect on allergic conditions has not yet been addressed. In the current study, the naturally occurring 7-epiclusianone, isolated from Garcinia brasiliensis, was investigated to check its effectiveness on allergen-evoked intestinal spasm. The standard antiallergic azelastine was used for comparison. We found that 7-epiclusianone and azelastine inhibited antigen-induced contractions of guinea pig ileum with similar IC (50) values (2.3 +/- 1.1 microM and 3.3 +/- 1.2 microM, respectively). A similar blockade of anaphylactic histamine release from the ileum was also noted. In contrast, azelastine was more potent than 7-epiclusianone to prevent spasms induced by histamine (IC (50) = 6.3 +/- 0.2 nM and 3.7 +/- 0.1 microM, respectively). These findings reveal that 7-epiclusianone is clearly active against the anaphylactic response and should be considered as a molecular template in drug discovery for allergic syndromes.
Assuntos
Antialérgicos/farmacologia , Benzofenonas/farmacologia , Benzoquinonas/farmacologia , Garcinia , Íleo/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Fitoterapia , Traqueia/efeitos dos fármacos , Alérgenos , Animais , Antialérgicos/administração & dosagem , Antialérgicos/uso terapêutico , Benzofenonas/administração & dosagem , Benzofenonas/uso terapêutico , Benzoquinonas/administração & dosagem , Benzoquinonas/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Frutas , Cobaias , Concentração Inibidora 50 , Masculino , Ftalazinas/farmacologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêuticoRESUMO
BACKGROUND: Prior reports show that nebulized lidocaine might be an effective treatment for asthma. OBJECTIVE: We sought to determine the anti-inflammatory and spasmolytic effects of lidocaine and its analogue, JMF2-1, which we have synthesized for reduced local anesthetic activity. METHODS: Blockade of Na(+) currents was assayed in cultured GH(3) cells by using the patch-clamp technique, whereas anesthesia was assessed in a cutaneous pinching test in rats. Lidocaine and its analogue were nebulized into sensitized rats for evaluation of their effectiveness on airways spasm and inflammation induced by methacholine and allergen, respectively. Tissue histamine release and tracheal spasm triggered by allergen challenge in the absence and presence of these treatments were also examined in vitro. RESULTS: The 50% inhibitory concentration values for blockade of Na(+) currents after treatment with JMF2-1 (25.4 mM) was remarkably higher than that of lidocaine (0.18 mM), which is consistent with the weak anesthetic capacity of this analogue. In contrast, JMF2-1 was more potent than lidocaine in inhibiting allergen-induced histamine release and tracheal spasm. In in vivo settings methacholine-induced increase in lung resistance (145%) significantly reduced to 72% and 47% after lidocaine and JMF2-1 treatment, respectively. Both treatments inhibited by about 81% allergen-evoked eosinophil accumulation into the lung tissue. CONCLUSION: Replacement of the 2,6-dimethyl radicals by the 2-trifluormethyl group on the benzene ring of lidocaine significantly reduces anesthetic activity, preserving its ability to prevent key aspects of the allergic inflammatory response in the lung. CLINICAL IMPLICATIONS: Nebulized JMF2-1 might be a means of achieving the antiasthmatic effects of lidocaine without the anesthetic effects.
Assuntos
Antiasmáticos/farmacologia , Anti-Inflamatórios/farmacologia , Lidocaína/análogos & derivados , Lidocaína/farmacologia , Hipersensibilidade Respiratória/tratamento farmacológico , Anestésicos/farmacologia , Animais , Linhagem Celular , Histamina/metabolismo , Contagem de Leucócitos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/fisiopatologia , Camundongos , Ovalbumina , Ratos , Ratos Wistar , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/fisiopatologia , Convulsões/induzido quimicamente , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/fisiologia , Traqueia/efeitos dos fármacos , Traqueia/fisiopatologiaRESUMO
It has been proposed that allergen provocation induces hyperalgesia but the involvement of immunoglobulin E and leukocytes remains poorly understood. Here, we have compared the profile of allergen-evoked thermal hyperalgesic response in both passively and actively sensitized rats, and investigated the role of leukocytes in allergen-evoked nociception. Wistar rats were passively sensitized with an intraplantar injection of immunoglobulin E anti-dinitrophenylated bovine serum albumin monoclonal antibody (0.5 microg/paw), and challenged with dinitrophenylated bovine serum albumin (0.5 microg/paw) 24 h later. Alternatively, the animals were actively sensitized with a mixture of Al(OH)3 and ovalbumin and challenged intraplantarly with ovalbumin (12 microg/paw) 14 days later. We found that the thermal hyperalgesic responses set in very rapidly and with comparable intensity in both passively and actively sensitized rats. However, while in the former group the response was shorter, peaking within 1 h and reducing thereafter, a marked plateau was observed from 1 to 6 h post-challenge in the latter group. Actively sensitized rats also had higher neutrophil influx in the plantar tissue, as attested by both myeloperoxidase activity and histological analysis. Treatment of actively sensitized rats with either fucoidin (10 mg/kg, i.v) or anti-rat neutrophil antiserum (i.p.) reduced neutrophil accumulation and the late hyperalgesic response noted from 3 to 6 h post-challenge. Thus, we conclude that though immunoglobulin E-mediated mechanisms can cause thermal hyperalgesia, components of the cellular immune reaction are crucial in order to amplify and sustain the immediate hyperalgesic response triggered by allergen, in a process dependent on neutrophil recruitment.
Assuntos
Alérgenos/imunologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/imunologia , Imunoglobulina E/imunologia , Infiltração de Neutrófilos/efeitos dos fármacos , Infiltração de Neutrófilos/imunologia , Alérgenos/administração & dosagem , Animais , Hiperalgesia/patologia , Masculino , Ratos , Ratos WistarRESUMO
Silicose é uma doença pulmonar crônica caracterizada por lesões fibróticas e granulomatosas pelo acúmulo de partículas de sílica inaladas. Os macrófagos alveolares são as primeiras células a entrar em contato com essas partículas e promovendo conseqüentemente sua ativação e liberação de diversas citocinas e outros mediadores, provocando o acúmulo de neutrófilos e linfócitos, estimulando aproliferação de fibroblastos com alteração da matriz extracelular. Os mecanismos patogênicos da silicose pulmonar ainda não estão totalmente claros.
Assuntos
Humanos , Animais , Macrófagos Alveolares , Fibrose Pulmonar , Dióxido de Silício , Silicose , Doenças ProfissionaisRESUMO
Mast cells are pivotal secretory cells primarily implicated in allergen-evoked inflammatory responses and are downregulated following experimental chemical diabetes. Here we tested the hypothesis that a decrease in the number and reactivity of mast cells would account for the hyporesponsiveness of diabetic rats to allergen-induced inflammation. We found that the anaphylactic release of histamine from sensitized ileum, trachea and skin tissues was clearly reduced in rats turned diabetic via intravenous administration of alloxan. Likewise, actively and passively sensitized diabetic rats mounted a weaker allergen-evoked pleural mast cell degranulation and protein extravasation, as compared to sensitized nondiabetic animals, which paralleled a marked reduction in the mast cell population in the pleural cavity. The number of mast cells enumerated in the mesentery from diabetic rats was also clearly reduced. The allergen-evoked plasma leakage in diabetic rats was restored by the transfer of mast cells from sensitized nondiabetic rats. Moreover, the adoptive transfer of sensitized mast cells from diabetics to naive animals led to a lower allergen-induced exudation as compared to the response noted after the transfer of sensitized naive mast cells. Purified mast cells from diabetic rats were hyporesponsive to antigen and compound 48/80 stimulation in vitro as attested by histamine release. Thus, our results show that the phenomenon of refractoriness of diabetic animals to allergen challenge appears to be accounted for by a reduction in the number and reactivity of mast cells.