RESUMO
Changes in extracellular matrix (ECM) components in the lungs are associated with the progression of respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS). Experimental and clinical studies have revealed that structural changes in ECM components occur under chronic inflammatory conditions, and these changes are associated with impaired lung function. In bronchial asthma, elastic and collagen fiber remodeling, mostly in the airway walls, is associated with an increase in mucus secretion, leading to airway hyperreactivity. In COPD, changes in collagen subtypes I and III and elastin, interfere with the mechanical properties of the lungs, and are believed to play a pivotal role in decreased lung elasticity, during emphysema progression. In ARDS, interstitial edema is often accompanied by excessive deposition of fibronectin and collagen subtypes I and III, which can lead to respiratory failure in the intensive care unit. This review uses experimental models and human studies to describe how inflammatory conditions and ECM remodeling contribute to the loss of lung function in these respiratory diseases.
Assuntos
Remodelação das Vias Aéreas , Asma/fisiopatologia , Matriz Extracelular/patologia , Pulmão/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Síndrome do Desconforto Respiratório/fisiopatologia , Animais , Hiper-Reatividade Brônquica/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo II/metabolismo , Modelos Animais de Doenças , Fibronectinas/metabolismo , HumanosRESUMO
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/farmacologiaRESUMO
BACKGROUND AND PURPOSE: A long-term imbalance between pro- and anti-inflammatory mediators leads to airway remodelling, which is strongly correlated to most of the symptoms, severity and progression of chronic lung inflammation. The Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor axis of the renin-angiotensin system is associated with attenuation of acute and chronic inflammatory processes. In this study, we investigated the effects of Ang-(1-7) treatment in a model of chronic allergic lung inflammation. EXPERIMENTAL APPROACH: Mice were sensitized to ovalbumin (OVA; 4 injections over 42 days, 14 days apart) and were challenged three times per week (days 21-46). These mice received Ang-(1-7) (1 µg·h(-1) , s.c.) by osmotic mini-pumps, for the last 28 days. Histology and morphometric analysis were performed in left lung and right ventricle. Airway responsiveness to methacholine, analysis of Ang-(1-7) levels (RIA), collagen I and III (qRT-PCR), ERK1/2 and JNK (Western blotting), IgE (elisa), cytokines and chemokines (elisa multiplex), and immunohistochemistry for Mas receptors were performed. KEY RESULTS: Infusion of Ang-(1-7) in OVA-sensitized and challenged mice decreased inflammatory cell infiltration and collagen deposition in the airways and lung parenchyma, and prevented bronchial hyperresponsiveness. These effects were accompanied by decreased IgE and ERK1/2 phosphorylation, and decreased pro-inflammatory cytokines. Mas receptors were detected in the epithelium and bronchial smooth muscle, suggesting a site in the lung for the beneficial actions of Ang-(1-7). CONCLUSIONS AND IMPLICATIONS: Ang-(1-7) exerted beneficial attenuation of three major features of chronic asthma: lung inflammation, airway remodelling and hyperresponsiveness. Our results support an important protective role of Ang-(1-7) in lung inflammation.
Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Angiotensina I/farmacologia , Anti-Inflamatórios/farmacologia , Hiper-Reatividade Brônquica/prevenção & controle , Broncoconstrição/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Pneumonia/prevenção & controle , Hipersensibilidade Respiratória/prevenção & controle , Animais , Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/fisiopatologia , Colágeno/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Hipertrofia Ventricular Direita/induzido quimicamente , Hipertrofia Ventricular Direita/fisiopatologia , Hipertrofia Ventricular Direita/prevenção & controle , Imunoglobulina E/sangue , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Camundongos Endogâmicos BALB C , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Ovalbumina , Fosforilação , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Pneumonia/fisiopatologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/agonistas , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/fisiopatologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Bronchial hyperresponsiveness is a hallmark of asthma and many factors modulate bronchoconstriction episodes. A potential correlation of formaldehyde (FA) inhalation and asthma has been observed; however, the exact role of FA remains controversial. We investigated the effects of FA inhalation on Ovalbumin (OVA) sensitisation using a parameter of respiratory mechanics. The involvement of nitric oxide (NO) and cyclooxygenase-derived products were also evaluated. The rats were submitted, or not, to FA inhalation (1%, 90 min/day, 3 days) and were OVA-sensitised and challenged 14 days later. Our data showed that previous FA exposure in allergic rats reduced bronchial responsiveness, respiratory resistance (Rrs) and elastance (Ers) to methacholine. FA exposure in allergic rats also increased the iNOS gene expression and reduced COX-1. L-NAME treatment exacerbated the bronchial hyporesponsiveness and did not modify the Ers and Rrs, while Indomethacin partially reversed all of the parameters studied. The L-NAME and Indomethacin treatments reduced leukotriene B4 levels while they increased thromboxane B2 and prostaglandin E2. In conclusion, FA exposure prior to OVA sensitisation reduces the respiratory mechanics and the interaction of NO and PGE2 may be representing a compensatory mechanism in order to protect the lung from bronchoconstriction effects.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Hiper-Reatividade Brônquica/tratamento farmacológico , Modelos Animais de Doenças , Eicosanoides/metabolismo , Óxido Nítrico/metabolismo , Insuficiência Respiratória/prevenção & controle , Mucosa Respiratória/efeitos dos fármacos , Administração por Inalação , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/fisiopatologia , Broncoconstritores/farmacologia , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Dinoprostona/agonistas , Dinoprostona/metabolismo , Formaldeído/administração & dosagem , Formaldeído/toxicidade , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Leucotrieno B4/antagonistas & inibidores , Leucotrieno B4/metabolismo , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Wistar , Insuficiência Respiratória/etiologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/fisiopatologia , Tromboxano B2/agonistas , Tromboxano B2/metabolismoRESUMO
Female sex hormones (FSHs) exert profound regulatory effects on the course of lung inflammation due to allergic and non-allergic immune responses. As pollution is one of the pivotal factors to induce lung dysfunction, in this study we investigated the modulatory role of FSHs on lung inflammation after a formaldehyde (FA) exposure. For this purpose, lung and systemic inflammatory responses were evaluated in terms of leukocytes countings in bronchoalveolar lavage (BAL), peripheral blood and bone marrow lavage from 7-day ovariectomized (OVx) and Sham-OVx rats subjected to FA inhalation for 3 consecutive days. The hypothesized link between effects of FSHs on expression of adhesion molecules and mast cells degranulation was also studied. Once exposed to FA, Sham-OVx rats increased the number of total cells recovered in BAL and of leukocytes in peripheral blood, and decreased the counts in bone marrow. By contrast, in OVx rats upon FA exposure there was a reduction of the total cells counts in BAL and of blood leukocytes; lung expressions of ICAM-1 and Mac-1 were depressed, but the number of bone marrow cells did not vary. Estradiol treatment of OVx rats increased the total cells in BAL and decreased the number of blood leukocytes, whereas the number of bone marrow cell remained unaltered. Progesterone treatment, in turn increased the total cells in BAL and blood leukocytes, but decreased the number of bone marrow cells. OVx rats exposed to FA developed tracheal hyperresponsiveness to methacholine (MCh). A similarly altered response was found between the tracheal segments of Sham-OVx rats after FA exposure and that found in tracheae of naïve rats. Estradiol treatment prevented FA-induced tracheal hyperresponsiveness to MCh whereas progesterone was ineffective in this regard. In addition, OVx rats upon FA exposure significantly increased both, the ability of mast cell degranulation and serum corticosterone levels. In conclusion, it was found that FSHs act by distinct control mechanisms on FA-induced lung inflammation and tracheal hyperresponsiveness, since at low circulating levels of FSHs (such as those after OVx) there is some resistance to the development of a lung inflammatory response, but the cholinergic tracheal responsiveness is exacerbated. Our data also help to understand the involvement of FSHs on mast cells activity after pollutants exposure and add information regarding the role of FSHs on the mechanisms related to endothelium-leukocyte interactions.
Assuntos
Hiper-Reatividade Brônquica/induzido quimicamente , Estradiol/metabolismo , Formaldeído/toxicidade , Pulmão/efeitos dos fármacos , Progesterona/metabolismo , Traqueia/efeitos dos fármacos , Poluentes Atmosféricos/toxicidade , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Hiper-Reatividade Brônquica/sangue , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Moléculas de Adesão Celular/metabolismo , Degranulação Celular/efeitos dos fármacos , Corticosterona/sangue , Feminino , Técnicas In Vitro , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/metabolismo , Leucócitos/patologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Ativação Linfocitária/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/metabolismo , Mastócitos/fisiologia , Especificidade de Órgãos , Ovariectomia , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pneumonia/metabolismo , Pneumonia/patologia , Ratos , Ratos Wistar , Traqueia/imunologia , Traqueia/metabolismoRESUMO
There is evidence that sex and sex hormones influence the severity of asthma. Airway and lung parenchyma remodeling and the relationship of ultrastructural changes to airway responsiveness and inflammation in male, female, and oophorectomized mice (OVX) were analyzed in experimental chronic allergic asthma. Seventy-two BALB/c mice were randomly divided into three groups (n=24/each): male, female, and OVX mice, whose ovaries were removed 7 days before the start of sensitization. Each group was further randomized to be sensitized and challenged with ovalbumin (OVA) or saline. Twenty-four hours after the last challenge, collagen fiber content in airways and lung parenchyma, the volume proportion of smooth muscle-specific actin in alveolar ducts and terminal bronchiole, the amount of matrix metalloproteinase (MMP)-2 and MMP-9, and the number of eosinophils and interleukin (IL)-4, IL-5, and transforming growth factor (TGF)-ß levels in bronchoalveolar lavage fluid were higher in female than male OVA mice. The response of OVX mice was similar to that of males, except that IL-5 remained higher. Nevertheless, after OVA provocation, airway responsiveness to methacholine was higher in males compared with females and OVX mice. In conclusion, sex influenced the remodeling process, but the mechanisms responsible for airway hyperresponsiveness seemed to differ from those related to remodeling.
Assuntos
Asma/metabolismo , Hiper-Reatividade Brônquica/metabolismo , Matriz Extracelular/metabolismo , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Pneumonia/metabolismo , Animais , Asma/imunologia , Asma/patologia , Asma/fisiopatologia , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/patologia , Hiper-Reatividade Brônquica/fisiopatologia , Testes de Provocação Brônquica , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Broncodilatadores/administração & dosagem , Doença Crônica , Colágeno/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Pulmão/imunologia , Pulmão/fisiopatologia , Pulmão/ultraestrutura , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Cloreto de Metacolina/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Ovariectomia , Pneumonia/imunologia , Pneumonia/patologia , Pneumonia/fisiopatologia , Fatores Sexuais , Fatores de Tempo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Helminths and their products have a profound immunomodulatory effect upon the inductive and effector phases of inflammatory responses, including allergy. We have demonstrated that PAS-1, a protein isolated from Ascaris suum worms, has an inhibitory effect on lung allergic inflammation due to its ability to down-regulate eosinophilic inflammation, Th2 cytokine release and IgE antibody production. Here, we investigated the role of IL-12, IFN-gamma and IL-10 in the PAS-1-induced inhibitory mechanism using a murine model of asthma. Wild type C57BL/6, IL-12(-/-), IFN-gamma(-/-) and IL-10(-/-) mice were immunized with PAS-1 and/or OVA and challenged with the same antigens intranasally. The suppressive effect of PAS-1 was demonstrated on the cellular influx into airways, with reduction of eosinophil number and eosinophil peroxidase activity in OVA+PAS-1-immunized wild type mice. This effect well correlated with a significant reduction in the levels of IL-4, IL-5, IL-13 and eotaxin in BAL fluid. Levels of IgE and IgG1 antibodies were also impaired in serum from these mice. The inhibitory activity of PAS-1 was also observed in IL-12(-/-) mice, but not in IFN-gamma(-/-) and IL-10(-/-) animals. These data show that IFN-gamma and IL-10, but not IL-12, play an important role in the PAS-1 modulatory effect.
Assuntos
Ascaris suum/imunologia , Hiper-Reatividade Brônquica/imunologia , Proteínas de Helminto/metabolismo , Interferon gama/imunologia , Interleucina-10/imunologia , Animais , Formação de Anticorpos/imunologia , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/metabolismo , Movimento Celular/imunologia , Imunoglobulina G/imunologia , Interferon gama/deficiência , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-10/deficiência , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-12/deficiência , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-12/metabolismo , Leucócitos/citologia , Leucócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
We have used a pharmacological approach to study the mechanisms underlying the rat lung injury and the airway reactivity changes induced by inhalation of formaldehyde (FA) (1% formalin solution, 90 min once a day, 4 days). The reactivity of isolated tracheae and intrapulmonary bronchi were assessed in dose-response curves to methacholine (MCh). Local and systemic inflammatory phenomena were evaluated in terms of leukocyte countings in bronchoalveolar lavage (BAL) fluid, blood, bone marrow lavage and spleen. Whereas the tracheal reactivity to MCh did not change, a significant bronchial hyporesponsiveness (BHR) was found after FA inhalation as compared with naive rats. Also, FA exposure significantly increased the total cell numbers in BAL, in peripheral blood and in the spleen, but did not modify the counts in bone marrow. Capsaicin hindered the increase of leukocyte number recovered in BAL fluid after FA exposure. Both compound 48/80 and indomethacin were able to prevent the lung neutrophil influx after FA, but indomethacin had no effect on that of mononuclear cells. Following FA inhalation, the treatment with sodium cromoglycate (SCG), but not with the nitric oxide (NO) synthase inhibitor L-NAME, significantly reduced the total cell number in BAL. Compound 48/80, L-NAME and SCG significantly prevented BHR to MCh after FA inhalation, whereas capsaicin was inactive in this regard. On the other hand, indomethacin exacerbated BHR. These data suggest that after FA inhalation, the resulting lung leukocyte influx and BHR may involve nitric oxide, airway sensory fibers and mast cell-derived mediators. The effect of NO seemed to be largely restricted to the bronchial tonus, whereas neuropeptides appeared to be linked to the inflammatory response, therefore indicating that the mechanisms responsible for the changes of airway responsiveness caused by FA may be separate from those underlying its inflammatory lung effects.