RESUMO
Pulmonary remodeling is an important feature of asthma physiopathology that can contribute to irreversible changes in lung function. Although neurokinins influence lung inflammation, their exact role in the extracellular matrix (ECM) remodeling remains to be determined. Our objective was to investigate whether inactivation of capsaicin-sensitive nerves modulates pulmonary ECM remodeling in animals with chronic lung inflammation. After 14 days of capsaicin (50 mg/kg, sc) or vehicle administration, male Hartley guinea pigs weighing 250-300 g were submitted to seven inhalations of increasing doses of ovalbumin (1, 2.5, and 5 mg/mL) or saline for 4 weeks. Seventy-two hours after the seventh inhalation, animals were anesthetized and mechanically ventilated and the lung mechanics and collagen and elastic fiber content in the airways, vessels and lung parenchyma were evaluated. Ovalbumin-exposed animals presented increasing collagen and elastic fiber content, respectively, in the airways (9.2 ± 0.9; 13.8 ± 1.2), vessels (19.8 ± 0.8; 13.4 ± 0.5) and lung parenchyma (9.2 ± 0.9; 13.8 ± 1.2) compared to control (P < 0.05). Capsaicin treatment reduced collagen and elastic fibers, respectively, in airways (1.7 ± 1.1; 7.9 ± 1.5), vessels (2.8 ± 1.1; 4.4 ± 1.1) and lung tissue (2.8 ± 1.1; 4.4 ± 1.1) of ovalbumin-exposed animals (P < 0.05). These findings were positively correlated with lung mechanical responses to antigenic challenge (P < 0.05). In conclusion, inactivation of capsaicin-sensitive nerve fibers reduces pulmonary remodeling, particularly collagen and elastic fibers, which contributes to the attenuation of pulmonary functional parameters.
Assuntos
Animais , Cobaias , Masculino , Remodelação das Vias Aéreas/efeitos dos fármacos , Asma/patologia , Capsaicina/farmacologia , Colágeno/efeitos dos fármacos , Tecido Elástico/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Asma/metabolismo , Doença Crônica , Colágeno/metabolismo , Denervação , Tecido Elástico/metabolismo , Matriz Extracelular/metabolismo , Pulmão/patologia , OvalbuminaRESUMO
Pulmonary remodeling is an important feature of asthma physiopathology that can contribute to irreversible changes in lung function. Although neurokinins influence lung inflammation, their exact role in the extracellular matrix (ECM) remodeling remains to be determined. Our objective was to investigate whether inactivation of capsaicin-sensitive nerves modulates pulmonary ECM remodeling in animals with chronic lung inflammation. After 14 days of capsaicin (50 mg/kg, sc) or vehicle administration, male Hartley guinea pigs weighing 250-300 g were submitted to seven inhalations of increasing doses of ovalbumin (1, 2.5, and 5 mg/mL) or saline for 4 weeks. Seventy-two hours after the seventh inhalation, animals were anesthetized and mechanically ventilated and the lung mechanics and collagen and elastic fiber content in the airways, vessels and lung parenchyma were evaluated. Ovalbumin-exposed animals presented increasing collagen and elastic fiber content, respectively, in the airways (9.2 ± 0.9; 13.8 ± 1.2), vessels (19.8 ± 0.8; 13.4 ± 0.5) and lung parenchyma (9.2 ± 0.9; 13.8 ± 1.2) compared to control (P < 0.05). Capsaicin treatment reduced collagen and elastic fibers, respectively, in airways (1.7 ± 1.1; 7.9 ± 1.5), vessels (2.8 ± 1.1; 4.4 ± 1.1) and lung tissue (2.8 ± 1.1; 4.4 ± 1.1) of ovalbumin-exposed animals (P < 0.05). These findings were positively correlated with lung mechanical responses to antigenic challenge (P < 0.05). In conclusion, inactivation of capsaicin-sensitive nerve fibers reduces pulmonary remodeling, particularly collagen and elastic fibers, which contributes to the attenuation of pulmonary functional parameters.
Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Asma/patologia , Capsaicina/farmacologia , Colágeno/efeitos dos fármacos , Tecido Elástico/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Animais , Asma/metabolismo , Doença Crônica , Colágeno/metabolismo , Denervação , Tecido Elástico/metabolismo , Matriz Extracelular/metabolismo , Cobaias , Pulmão/patologia , Masculino , OvalbuminaRESUMO
BACKGROUND: Leukotriene receptor antagonists have been demonstrated in several studies to possess bronchodilating and anti-inflammatory properties in asthma. However, there are few experimental studies performed to compare the effects of anti-leukotrienes and glucocorticoids, most used anti-inflammatory agents in asthma. In the present study, we evaluated the effects of treatment with dexamethasone or montelukast on eosinophil and mononuclear cell recruitment in an experimental model of allergen-induced chronic airway inflammation in guinea-pigs (GP). METHODS: GP were submitted to increasing concentrations of aerosols of ovalbumin (OVA) twice a week for 4 weeks. After 2 weeks, animals were treated daily with dexamethasone, montelukast or saline solution. After this period, GP were anaesthetized, tracheostomized, mechanically ventilated and challenged with OVA aerosol. RESULTS: Maximal changes of respiratory system resistance and elastance induced by OVA challenge were attenuated by dexamethasone (P<0.001), but not by montelukast treatment. Neither dexamethasone nor montelukast significantly influenced bronchial oedema formation. Dexamethasone but not montelukast induced a decrease in mononuclear cells in airways (P<0.001). Eosinophil infiltration in the bronchial wall was reduced by both dexamethasone and montelukast (P<0.005). Only dexamethasone treatment reduced the levels of exhaled nitric oxide (P<0.025). CONCLUSION: Although leukotriene receptor antagonist treatment reduces eosinophil accumulation induced by multiple antigen challenges, glucocorticoid treatment attenuates both eosinophil and mononuclear cell infiltration.
Assuntos
Acetatos/uso terapêutico , Asma/tratamento farmacológico , Dexametasona/uso terapêutico , Glucocorticoides/uso terapêutico , Antagonistas de Leucotrienos/uso terapêutico , Quinolinas/uso terapêutico , Animais , Asma/imunologia , Doença Crônica , Ciclopropanos , Eosinófilos/imunologia , Cobaias , Contagem de Leucócitos , Pulmão/imunologia , Masculino , SulfetosRESUMO
The elastic system fibers were studied at the light microscopic level by using Weigert's resorcin-fuchsin method after oxidation. This study was designed to describe the distribution of these fibers in intrapulmonary guinea-pig airways and to characterize their conformational changes during bronchoconstriction induced by methacholine aerosol. Airways present a palisade of elastic system fibers just beneath the epithelial basement membrane; these fibers are also present in the adventitial connective tissue. Thin fibers link the fibers located in the palisade among themselves and also connect them to those fibers located in the bronchial adventitial tissue, by traversing the airway smooth muscle. During bronchoconstriction, the fibers located beneath the epithelial basement membrane are divided into two components: one follows the epithelial invaginations towards airway lumen, while the other population remains attached through airway smooth muscle to the fibers located in the adventitial connective tissue. At the ultrastructural level, the findings corroborated those of the light microscopy and in addition, disclosed that typical mature elastic fibers and also elaunin fibers attach directly to the basal lamina, a feature that has not been reported previously in other tissues studied. This configuration is compatible with the idea that fibers of the elastic system restrict the mucosal folding during bronchoconstriction, and may also provide energy to restore airway configuration to its normal status after contraction.
Assuntos
Brônquios/citologia , Broncoconstrição/efeitos dos fármacos , Broncoconstritores/administração & dosagem , Tecido Elástico/citologia , Pulmão/citologia , Cloreto de Metacolina/administração & dosagem , Animais , Tecido Elástico/efeitos dos fármacos , Cobaias , Microscopia EletrônicaRESUMO
We assessed the effects of neurokinin (tachykinin) depletion by capsaicin (CAP) treatment on airway inflammation induced by repeated ovalbumin (OA) aerosol exposures (twice a week for 4 wk) in guinea pigs. The animals were then anesthetized, tracheostomized, mechanically ventilated and challenged with ovalbumin aerosol. Maximal values of respiratory system resistance and elastance after antigen challenge were significantly lower in capsaicin-treated guinea pigs than in intact animals (p < 0.001). Morphometric analysis of noncartilaginous airways revealed less intense bronchoconstriction (p < 0.001) and peribronchiolar edema (p < 0.001) in capsaicin-treated guinea pigs. Chronic antigen exposure resulted in a significant increase in lymphocytes and eosinophils both in bronchoalveolar lavage (BAL) fluid and airway wall. Immunohistochemistry with monoclonal antibodies revealed that most of the lymphocytes present in airway wall were CD4+ T cells. Capsaicin treatment resulted in values of CD4+ T cells in airway wall significantly lower than non-capsaicin-treated guinea pigs (p < 0.005). This difference was not observed in eosinophil recruitment. Our results suggest that neurokinin release by sensory nerve terminals results in an amplification of the pulmonary inflammatory changes induced by chronic antigen exposure. In addition, neurokinins play a role in T-cell recruitment induced by chronic allergen exposure.
Assuntos
Antígenos/administração & dosagem , Brônquios/patologia , Taquicininas/fisiologia , Administração por Inalação , Aerossóis , Resistência das Vias Respiratórias , Animais , Líquido da Lavagem Broncoalveolar/citologia , Broncoconstrição , Contagem de Linfócito CD4 , Capsaicina/farmacologia , Edema/patologia , Elasticidade , Cobaias , Inflamação , Pulmão/patologia , Complacência Pulmonar , Masculino , Ovalbumina/administração & dosagemRESUMO
The role of NK-1 and NK-2 receptors on the pulmonary response to capsaicin in guinea pigs was evaluated using intravenous infusion of selective nonpeptide antagonists of NK 1 (CP 96345, 300 nmol/kg, and SR 140333, 300 nmol/kg) and NK-2 (SR 48968, 100 nmol/kg) neurokinin receptors. Maximal values of pulmonary dynamic elastance (Edyn) and pulmonary resistance (RL) after capsaicin infusion were significantly lower in the presence of SR 48968 (p < .005). Morphometric analysis of lungs obtained by quick-freezing showed significant attenuation of airway contraction and peribronchiolar edema formation in the presence of NK-2 antagonist (p < .001). When compared to guinea pigs that received only capsaicin, animals that received SR 140333 or CP 96345 showed lower values of Edyn, RL, airway contraction, and peribronchiolar edema, but only the difference in Edyn values was significant. The combination of NK-1 and NK-2 antagonists was not more effective than NK-2 antagonist alone in attenuating capsaicin effects. The results suggest that airway effects of capsaicin are mainly mediated by activation of NK-2 receptors although NK-1 receptors may also play a role.
Assuntos
Capsaicina/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/ultraestrutura , Receptores da Neurocinina-1/fisiologia , Receptores da Neurocinina-2/fisiologia , Traqueia/efeitos dos fármacos , Traqueia/ultraestrutura , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Broncoconstrição/efeitos dos fármacos , Edema/induzido quimicamente , Cobaias , Masculino , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/farmacologia , Quinuclidinas/farmacologia , Receptores da Neurocinina-2/antagonistas & inibidoresRESUMO
Vasoactive intestinal peptide (VIP) is a potent bronchial smooth muscle relaxant. In the present study we measured the release of VIP-like immunoreactivity (VIP-LI) after tracheal infusion of capsaicin, histamine, and methacholine in isolated guinea pig lungs superfused through the trachea. We also studied if inhibition of VIP enzymatic cleavage using a combination of an inhibitor of neutral endopeptidase [thiorphan (Thio)] and an inhibitor of serine proteases [soybean trypsin inhibitor (STI)] influenced the airway effects of capsaicin. Infusion of capsaicin resulted in a significant increase in VIP-LI in the perfusate (12.32 +/- 4.80 to 33.52 +/- 8.46 fmol/5 min fraction; P < 0.001). There was no increase in VIP-LI after infusion of methacholine or histamine. Maximal changes in airway opening pressure (Pao) observed 0-10 min after tracheal infusion of capsaicin were significantly greater in the Thio group than the control group and the groups of lungs that received STI or STI + Thio (P < 0.005). In addition, recovery of VIP-LI in the superfusate after infusion of capsaicin was significantly greater in the group of lungs that was superfused with Thio + STI compared with STI, Thio, and control groups. Our results suggest that a bronchodilator peptide with the profile of enzymatic cleavage of VIP also modulates capsaicin effects, since the increase in Pao in the presence of Thio + STI was significantly lower than Thio alone.
Assuntos
Capsaicina/farmacologia , Fibras Nervosas/efeitos dos fármacos , Neurotoxinas/farmacologia , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Cobaias , Histamina/farmacologia , Masculino , Cloreto de Metacolina/farmacologia , Inibidores de Proteases/farmacologia , Tiorfano/farmacologia , Inibidores da Tripsina/farmacologiaRESUMO
The distribution and conformational changes of the fibers of the collagenous and elastic systems in guinea pig airways after a contractile agonist challenge are described. We observed a distinct pattern of behavior within the mucosal fibers during bronchoconstriction. Part of the fibers of the two systems tend to follow the epithelial invaginations towards the airway lumen, while the remaining ones seem to be attached to the internal smooth muscle. These layers of fibers in the mucosa are interconnected to one another and to the adventitial network by slender fibers. We suggest that the configuration and behavior of these fibers during bronchoconstriction may contribute to airway reopening after the contractile stimulus has ceased. The possible role of this mechanism in the pathophysiology of human asthma is discussed.
Assuntos
Cobaias , Animais , Broncoconstrição/fisiologia , Colágeno/fisiologia , Tecido Elástico/fisiologia , Elastina/metabolismo , Asma/fisiopatologia , Brônquios/ultraestruturaRESUMO
The role of neurokinins in the acute pulmonary response to antigen was studied in guinea pigs that received ovalbumin (50 mg/kg ip) on days 1 and 3 and capsaicin (50 mg/kg sc) on day 21 (OAC); ovalbumin on days 1 and 3 (OA1); capsaicin on day 1 and OA on days 8 and 10 (COA); and ovalbumin on days 8 and 10 (OA2). On day 28, guinea pigs were submitted to ovalbumin aerosol challenge. Maximal values of pulmonary dynamic elastance (Edyn) and pulmonary resistance (RL) were significantly lower in OAC and COA groups compared with OA1 and OA2 groups (P < 0.001). There was no difference between maximal Edyn and RL values obtained in OAC and COA groups. Morphometric analysis of lungs showed significantly (P < 0.05) lower values of contraction index of airways, peribronchial edema, and alveoli over inflation in guinea pigs that received capsaicin compared with intact guinea pigs. Capsaicin treatment did not influence the formation of specific IgG1 anaphylactic antibodies. We conclude that neurokinin depletion results in a decrease in the pulmonary mechanical and inflammatory responses to antigen challenge in sensitized guinea pigs. These effects are observed when capsaicin is given either before or after sensitization.