RESUMO
Mycobacterial diseases are prevalent in cancer and rheumatoid arthritis (RA) patients, especially those receiving tumor necrosis factor-α inhibitor (TNFi). However, the impact of cancer development on the risk of mycobacterial diseases among RA patients is unknown. Data from the Taiwan National Health Insurance Research Database were used to conduct a retrospective study to assess the occurrence of mycobacterial diseases in RA patients developing cancer (cancer-positive), those using TNFi (TNFi-exposure), those with cancer and using TNFi (cancer-TNFi-comb), and those without cancer and not using TNFi (cancer-TNFi-free). Cancer and TNFi exposure were time-dependent, and independent risk factors of mycobacterial diseases were assessed by Cox regression. Among 1344 RA patients diagnosed during 2000-2013, 68 (5·1%) developed cancer before their end points. The incidence rates of mycobacterial diseases in the cancer-positive (n = 56), TNFi-exposure (n = 290), cancer-TNFi-comb (n = 12), and cancer-TNFi-free (n = 986) subgroups were 6·7, 2·0, 7·6, and 1·3 per 1000 person-years, respectively. As compared with the cancer-TNFi-free group, the risk for mycobacterial diseases increased for the TNFi-exposure group (adjusted HR = 3·6, 95% confidence interval (95% CI) 1·1-11·5, P = 0·032) and remained high for cancer-positive (adjusted HR = 14·6, 95% CI 3·3-63·7, P < 0·001) after adjustment. This study suggested that cancer development increased the risk of mycobacterial diseases in RA patients, and risk assessment for this subgroup should be considered.
Assuntos
Artrite Reumatoide/epidemiologia , Infecções por Mycobacterium/epidemiologia , Neoplasias/epidemiologia , Adulto , Artrite Reumatoide/etiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium/microbiologia , Neoplasias/etiologia , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologiaRESUMO
AIMS: Erythropoietin (EPO), the key hormone involved in erythropoiesis, beneficially affects endothelial cells (ECs), but the detailed mechanisms are yet to be completely understood. In this study, we investigated the role of transient receptor potential vanilloid type 1 (TRPV1), a ligand-gated non-selective calcium (Ca2+ ) channel, in EPO-mediated endothelial nitric oxide synthase (eNOS) activation and angiogenesis. METHODS AND RESULTS: In ECs, EPO time dependently increased intracellular levels of calcium; this increase was abrogated by the Ca2+ chelators and pharmacological inhibitors of TRPV1 in bovine aortic ECs (BAECs) and TRPV1-transfected HEK293 cells. In addition, EPO-induced nitrite oxide (NO) production, phosphorylation of eNOS, Akt and AMP-activated protein kinase (AMPK) and the formation of TRPV1-Akt-AMPK-eNOS complex as well as tube formation were diminished by the pharmacological inhibition of TRPV1 in BAECs. Moreover, EPO time dependently induced the phosphorylation of phospholipase C-γ1 (PLC-γ1). Inhibition of PLC-γ1 activity blunted the EPO-induced Ca2+ influx, eNOS phosphorylation, TRPV1-eNOS complex formation and NO production. The phosphorylated level of eNOS increased in the aortas of EPO-treated wild-type (WT) mice or EPO-transgenic (Tg) mice but not in those of EPO-treated TRPV1-deficient (TRPV1-/- ) mice or EPO-Tg/TRPV1-/- mice. Matrigel plug assay showed that EPO-induced angiogenesis was abrogated in TRPV1 antagonist capsazepine-treated WT mice and TRPV1-/- mice. CONCLUSION: These findings indicate the EPO-induced Ca2+ influx via the activation of the PLC-γ1 signalling pathway, which leads to TRPV1 activation and consequently increases the association of the TRPV1-Akt-AMPK-eNOS complex, eNOS activation, NO production and angiogenesis.
Assuntos
Ativação Enzimática/fisiologia , Eritropoetina/metabolismo , Neovascularização Fisiológica/fisiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Bovinos , Células Endoteliais/metabolismo , Ativação Enzimática/efeitos dos fármacos , Eritropoetina/farmacologia , Células HEK293 , Humanos , Imunoprecipitação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
AIM: We investigated whether transient receptor potential vanilloid type 1 (TRPV1) was involved in the therapeutic effect of evodiamine, a main bioactive component in the fruit of Evodiae rutaecarpa, on the development of atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice and ApoE(-/-)TRPV1(-/-) mice. METHODS: Histopathology was examined by haematoxylin and eosin staining, levels of cytokines and mediators were evaluated by ELISA kits, and protein expression was determined by Western blotting. RESULTS: Chronic administration with evodiamine (10 mg kg(-1) body weight) reduced the size of atherosclerotic lesions and alleviated the hyperlipidaemia and systemic inflammation, as well as hepatic macrovesicular steatosis, in ApoE(-/-) mice. Treating ApoE(-/-) mice with evodiamine enhanced hepatic cholesterol clearance, as revealed by upregulation of hepatic low-density lipoprotein receptor and ATP-binding cassette (ABC) transporters ABCG5, ABCG8 and cholesterol 7α-hydrolase. Genetic deletion of TRPV1 in ApoE(-/-) mice promoted the progression of atherosclerosis; elevated the serum levels of cholesterol, cytokines and chemokines; and exacerbated hepatic macrovesicular steatosis. Moreover, genetic deletion of TRPV1 abrogated the evodiamine-evoked atheroprotection but not anti-obesity effect in ApoE(-/-) mice. CONCLUSION: Evodiamine may confer novel TRPV1-dependent atheroprotection and TRPV1-independent anti-obesity action.
Assuntos
Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Quinazolinas/farmacologia , Canais de Cátion TRPV/metabolismo , Animais , Apolipoproteínas E/deficiência , Western Blotting , Doença da Artéria Coronariana/genética , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Masculino , Camundongos , Camundongos Knockout , Canais de Cátion TRPV/genéticaRESUMO
AIM: Environmental cigarette smoke (CS) contains many compounds that are harmful to the respiratory system and lead to chronic lung inflammation and other lung diseases. Exercise training is known to confer protection against diseases with chronic inflammation by reducing inflammatory response in human or experimental animals. In this study, we investigated the preventive effect of exercise training against lung inflammation induced by environmental CS. METHODS AND RESULTS: In this study, two groups of mice received air exposure with (the exercise group) or without (the control group) exercise training for 8 weeks and another two groups received air exposure for the first 4 weeks and CS exposure for the following 4 weeks with (the exercise+CS group) or without (the CS group) exercise training for 8 weeks. As compared with lung tissues of control and exercise groups, those of the CS group showed significantly increased bronchoalveolar-capillary permeability, inflammatory cell infiltration, epithelial thickening, expression of proliferating cell nuclear antigen, mucin 2, cytokines, chemokines, adhesion molecules and activation of NF-κB. These CS-induced pathophysiologic consequences were largely prevented in the exercise + CS group. CONCLUSION: Collectively, prior exercise training may protect against lung inflammation induced by environmental CS in mice by attenuating the activation of NF-κB and the production of inflammatory mediators.
Assuntos
Pneumopatias/induzido quimicamente , Condicionamento Físico Animal , Fumar , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Inflamação/induzido quimicamente , Camundongos , Muco/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologiaRESUMO
OBJECTIVE: To compare, using two large nationwide population-based data sets, the risk of adverse pregnancy outcomes (low birthweight [LBW], preterm birth, small for gestational age [SGA] and congenital anomalies) among pregnant women with hyperthyroidism classified into three groups: receiving propylthiouracil (PTU) treatment during pregnancy, receiving methimazole/carbimazole (MMI) treatment, and no antithyroid treatment during pregnancy. DESIGN: A matched case-control study. SETTING: Taiwan. SAMPLE: A total of 2830 mothers with hyperthyroidism and 14,150 age-matched randomly selected mothers without hyperthyroidism were included. METHODS: Conditional logistic regression analyses were performed to examine the risk of adverse pregnancy outcomes (LBW, preterm birth, SGA and major congenital anomalies) among these three groups. MAIN OUTCOME MEASURES: LBW, preterm birth, SGA and major congenital anomalies. RESULTS: Women receiving PTU treatment during pregnancy had a higher risk of giving birth to LBW infants than those not receiving antithyroid treatment (odds ratio = 1.40; 95% CI 1.00-1.96), after adjusting for maternal education, anaemia, hyperlipidaemia, pregestational diabetes, pregestational hypertension, hyperemesis gravidarum and infant's gender and birth order. However, children of women receiving MMI treatment did not have increased risks of any adverse fetal outcome relative to mothers not receiving antithyroid treatment. CONCLUSIONS: Our study finds an increased risk of LBW among babies of mothers with hyperthyroidism receiving PTU treatment during pregnancy relative to untreated mothers with hyperthyroidism.
Assuntos
Antitireóideos/efeitos adversos , Anormalidades Congênitas/epidemiologia , Hipertireoidismo/tratamento farmacológico , Recém-Nascido de Baixo Peso , Recém-Nascido Pequeno para a Idade Gestacional , Complicações na Gravidez/tratamento farmacológico , Nascimento Prematuro/epidemiologia , Adulto , Antitireóideos/uso terapêutico , Carbimazol/efeitos adversos , Carbimazol/uso terapêutico , Estudos de Casos e Controles , Feminino , Humanos , Recém-Nascido , Modelos Logísticos , Masculino , Metimazol/efeitos adversos , Metimazol/uso terapêutico , Gravidez , Resultado da Gravidez/epidemiologia , Prevalência , Propiltiouracila/efeitos adversos , Propiltiouracila/uso terapêutico , Taiwan/epidemiologia , Adulto JovemRESUMO
In a series of studies carried out in different experimental models, we investigated the type(s) of lung afferents and mechanism(s) underlying the cigarette smoke-induced airway irritation and cough. In healthy non-smokers, the intensity of airway irritation and cough evoked by cigarette smoke was markedly reduced after premedication with hexamethonium. A similar pattern of responses was also triggered by inhalation of nicotine aerosol. These studies in human subjects suggested nicotine as the primary causative agent in cigarette smoke that evokes airway irritation. Indeed, single-fiber recording experiments performed in anesthetized dogs showed that both C-fibers and rapidly adapting receptors in the lungs and airways were stimulated by inhalation of one puff of cigarette smoke, and the intensity of this stimulatory effect was related to the nicotine content in the cigarette and abolished by hexamethonium. To further study the direct effect of nicotine on these sensory nerves, we measured the change in intracellular calcium concentration ([Ca(2+)](i)) of pulmonary sensory neurons isolated from the nodose and jugular ganglia of adult rats. Our results showed that nicotine evoked an abrupt and transient increase in [Ca(2+)](i) in approximately 34% of the 522 neurons tested, and 1,1-dimethyl-4-phenylpiperazinium, a selective agonist of the neuronal nicotinic acetylcholine receptors (NnAChRs), evoked a similar pattern of response as that of nicotine in these neurons. In conclusion, results of these studies show that nicotine exerts a direct stimulatory effect on vagal pulmonary sensory neurons. This stimulatory effect of nicotine is primarily responsible for the airway irritation and cough evoked by inhaled cigarette smoke, and is mediated through an activation of the NnAChRs.
Assuntos
Tosse/fisiopatologia , Estimulantes Ganglionares/efeitos adversos , Nicotina/efeitos adversos , Agonistas Nicotínicos/efeitos adversos , Receptores Nicotínicos/metabolismo , Fumaça/efeitos adversos , Adulto , Animais , Cães , Humanos , Exposição por Inalação , Irritantes/efeitos adversos , Pulmão/efeitos dos fármacos , Pulmão/inervação , Pulmão/fisiopatologia , Masculino , Neurônios , Neurônios Aferentes , Ratos , Receptores Nicotínicos/efeitos dos fármacos , Sistema Respiratório/fisiopatologia , Nicotiana/efeitos adversos , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiopatologiaRESUMO
We recently reported that wood smoke inhalation initially (within 5 min) causes airway injury and subsequently produces both airway and parenchymal injury after a delay (within 2 h). In this study, we investigated the mediator mechanisms of this delayed smoke-induced lung injury in 126 anesthetized and artificially ventilated guinea pigs who received challenges of either air or 40 tidal breaths of wood smoke. Two hours after inhalation, wood smoke produced various injurious responses, including increases in alveolar-capillary permeability, microvascular permeabilities, and histological injury scores, in airway and parenchymal tissues. Pre-treatment given before smoke challenge with CP-96,345 [a tachykinin NK1 receptor antagonist; (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-aza bicyclo(2.2.2.)-octan-3-amine], dimethylthiourea (a hydroxyl radical scavenger), or a combination of these two drugs largely alleviated both the airway and parenchymal responses, whereas pre-treatment with SR-48,968 [a tachykinin NK2 receptor antagonist; (S)-N-methyl-N(4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-butyl)benzamide] or a combination of CP-96,344 and SR-48,965 (inactive enantiomers) failed to do so. Post-treatment given at 5 min after smoke challenge with CP-96,345 or dimethylthiourea significantly alleviated the parenchymal responses, while having no effect on the airway responses. Pre-treatment with dimethylthiourea prevented the smoke-induced reduction in airway neutral endopeptidase activity (an enzyme for tachykinin degradation). We concluded that (1) tachykinins and hydroxyl radical play important roles in producing smoke-induced delayed lung injury in guinea pigs, and both may be involved in the spread of injury from the airways to the pulmonary parenchyma, and (2) the contribution of tachykinins is mediated via the activation of tachykinin NK1 receptors, and is associated with the hydroxyl radical-induced inactivation of airway neutral endopeptidase.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Sequestradores de Radicais Livres/uso terapêutico , Receptores de Taquicininas/metabolismo , Síndrome do Desconforto Respiratório/tratamento farmacológico , Taquicininas/metabolismo , Animais , Modelos Animais de Doenças , Cobaias , Radical Hidroxila/metabolismo , Masculino , Neprilisina/antagonistas & inibidores , Neprilisina/metabolismo , Receptores de Taquicininas/antagonistas & inibidores , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/enzimologia , Síndrome do Desconforto Respiratório/metabolismo , Tioureia/análogos & derivados , Tioureia/uso terapêutico , MadeiraRESUMO
Prior airway exposure to wood smoke induces an increase in airway responsiveness to subsequent smoke inhalation in guinea pigs (Life Sci. 63: 1513, 1998; 66: 971, 2000). To further characterize this airway hyperreactivity, we investigated and compared the airway responsiveness to bronchoconstrictor challenge before and 30 min after sham air exposure or wood smoke exposure in anesthetized and artificially ventilated guinea pigs. Various doses of substance P (0.8-6.4 microg/kg), capsaicin (0.2-3.2 microg/kg), prostaglandin F2alpha (30-3000 microg/kg), histamine (1-8 microg/kg), or acetylcholine (5-20 microg/kg) were intravenously injected at 2-min intervals in successively increasing doses to obtain the dose required to provoke a 200% increase in baseline total lung resistance (ED200). Wood smoke exposure significantly lowered the ED200 of substance P, capsaicin, and prostaglandin F2alpha whereas sham air exposure failed to do so. Furthermore, wood smoke exposure did not significantly alter the ED200 of histamine or acetylcholine. Pretreatment with phosphoramidon (2 mg/kg), an inhibitor of the neutral endopeptidase (the major degradation enzyme of substance P), before smoke exposure did not significantly affect the smoke-induced reduction in ED200 of substance P. Sectioning both cervical vagi before smoke exposure did not significantly alter the smoke-induced reduction in ED200 of capsaicin or prostaglandin F2alpha. These results suggest that airway exposure to wood smoke acutely produces airway hyperresponsiveness to substance P, capsaicin, and prostaglandin F2alpha, but not to histamine or acetylcholine. Since the combination of phosphoramidon and wood smoke exposure did not result in an additive potentiation of smoke-induced airway hyperresponsiveness to substance P, it is suggested that an inhibition of the degradation enzyme of substance P may contribute to this increase in airway reactivity. Furthermore, vagally-mediated bronchoconstriction does not play a vital role in enhanced airway responsiveness to capsaicin or prostaglandin F2alpha.
Assuntos
Hiper-Reatividade Brônquica/fisiopatologia , Broncoconstritores/farmacologia , Pulmão/efeitos dos fármacos , Fumaça/efeitos adversos , Substância P/farmacologia , Madeira , Acetilcolina/farmacologia , Resistência das Vias Respiratórias/efeitos dos fármacos , Resistência das Vias Respiratórias/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Hiper-Reatividade Brônquica/etiologia , Broncoconstritores/administração & dosagem , Capsaicina/farmacologia , Dinoprosta/farmacologia , Cobaias , Histamina/farmacologia , Injeções Intravenosas , Pulmão/fisiologia , Pulmão/fisiopatologia , Masculino , Mecânica Respiratória/efeitos dos fármacos , Mecânica Respiratória/fisiologiaRESUMO
Laryngeal exposure to wood smoke in rats evokes a reflex apnea which is mediated through superior laryngeal afferents (J. Appl. Physiol. 83: 723-730, 1997). To study the role of laryngeal C-fiber afferents in eliciting this response, capsaicin aerosol (0.05 - 0.2 microg/ml) and 5 ml of wood smoke were delivered separately into a functionally isolated larynx of anesthetized Sprague-Dawley rats at a constant flow rate of 1.4 ml/s, while animals breathed spontaneously. Studies were repeated after either an intravenous injection of ruthenium red (2 mg/kg; n = 8), a perineural capsaicin treatment (200 microg/ml for 5 min; n = 8) of the superior laryngeal nerves, or a perineural sham treatment (n = 8); Ruthenium red inhibits the stimulation of afferent C-fiber nerve endings by capsaicin, whereas perineural capsaicin treatment selective blocks the conduction of C-fiber afferents. Either ruthenium red or perineural capsaicin treatment abolished the apneic response to laryngeal capsaicin, but did not significantly affect the apneic response to laryngeal wood smoke. Furthermore, the apneic responses to both types of irritants were not significantly altered by perineural sham treatment, yet were completely eliminated by a subsequent denervation of superior laryngeal nerves. Our results suggest that superior laryngeal C-fiber afferents are not involved in eliciting the reflex apneic response to laryngeal wood smoke in anesthetized rats. It is speculated that this response may result mainly from the stimulation of myelinated afferents, possibly laryngeal irritant receptors.
Assuntos
Apneia/induzido quimicamente , Nervos Laríngeos/fisiopatologia , Laringe/fisiopatologia , Fibras Nervosas/fisiologia , Neurônios Aferentes/fisiologia , Fumaça/efeitos adversos , Aerossóis , Animais , Apneia/fisiopatologia , Capsaicina/administração & dosagem , Capsaicina/farmacologia , Feminino , Hemodinâmica/efeitos dos fármacos , Técnicas In Vitro , Nervos Laríngeos/citologia , Nervos Laríngeos/efeitos dos fármacos , Laringe/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Mecânica Respiratória/efeitos dos fármacos , Rutênio Vermelho/farmacologia , MadeiraRESUMO
We studied the mechanisms underlying the wood smoke-induced acute airway injury in 120 anaesthetized guinea pigs. Five minutes after airway exposure, various doses of wood smoke produced a dose-dependent increase in Evans blue dye contents at all airway levels measured. Additionally, inhaled wood smoke produced submucosal edema of the trachea and bronchus, and peribronchial edema. These acute airway responses were nearly abolished by pretreatment with CP-96,345 alone [a tachykinin NK(1) receptor antagonist; (2S, 3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-azabicyc lo( 2.2.2.)-octan-3-amine] or with a combination of CP-96,345 and dimethylthiourea (a hydroxyl radical scavenger), and were attenuated by pretreatment with dimethylthiourea alone, yet were not affected by pretreatment with SR-48,968 [a tachykinin NK(2) receptor antagonist; (S)-N-methyl-N(4-(4-acetylamino-4-phenylpiperidino)-2-(3, 4-dichlorophenyl)-butyl)benzamide], with a combination of CP-96,344 and SR-48,965 (inactive enantiomers), with MK-886 [a leukotriene biosynthesis inhibitor; L-663, 536(3-(1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl)-2, 2-dimethylpropanoic acid], with indomethacin (a cyclooxygenase inhibitor), or with N(G)-nitro-L-arginine methyl ester (a nitric oxide (NO) synthase inhibitor). The activity of airway neutral endopeptidase (an enzyme for tachykinin degradation) was not influenced by wood smoke at 5-min post-exposure. We conclude that both endogenous tachykinins and hydroxyl radical play an important role in producing smoke-induced acute airway plasma exudation and airway edema in guinea pigs. The contribution of tachykinins to these neurogenic responses is mediated via the activation of tachykinin NK(1) receptors and partly via a hydroxyl radical mechanism, and is not associated with inactivation of neutral endopeptidase.
Assuntos
Permeabilidade Capilar , Edema/etiologia , Radical Hidroxila/metabolismo , Doenças Respiratórias/etiologia , Lesão por Inalação de Fumaça/complicações , Taquicininas/fisiologia , Animais , Compostos de Bifenilo/farmacologia , Cobaias , Masculino , Neprilisina/metabolismo , Óxido Nítrico/fisiologia , Receptores da Neurocinina-1/fisiologia , Receptores da Neurocinina-2/fisiologia , MadeiraRESUMO
We investigated the vagal and mediator mechanisms underlying the tachypnea caused by pulmonary air embolism (PAE) in anesthetized and spontaneously breathing dogs. PAE was induced by infusion of air into the right atrium (0.2 ml. kg(-1). min(-1) for 10 min). The first PAE induction caused an increase in respiratory frequency accompanied by a decrease in tidal volume in each of the 30 animals studied. Subsequently, animals were evenly divided into five groups, and a second PAE induction was repeated after various experimental interventions. The tachypneic response to PAE was not significantly altered by pretreatment with a saline vehicle but was largely attenuated by either perivagal capsaicin treatment (a technique that selectively blocks the conduction of unmyelinated C fibers), pretreatment with ibuprofen (a cyclooxygenase inhibitor), or pretreatment with dimethylthiourea (a hydroxyl radical scavenger). Ultimately, the tachypneic response was nearly abolished by a bilateral cervical vagotomy. These results suggest that 1) lung vagal unmyelinated C-fiber afferents play a predominant role in evoking the reflex tachypneic response to PAE and 2) both cyclooxygenase products and hydroxyl radical are important in eliciting this vagally mediated response.
Assuntos
Capsaicina/farmacologia , Embolia Aérea/fisiopatologia , Embolia Pulmonar/fisiopatologia , Mecânica Respiratória/fisiologia , Nervo Vago/fisiopatologia , Animais , Cães , Feminino , Sequestradores de Radicais Livres/farmacologia , Ibuprofeno/farmacologia , Masculino , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/fisiologia , Mecânica Respiratória/efeitos dos fármacos , Tioureia/análogos & derivados , Tioureia/farmacologia , Volume de Ventilação Pulmonar , Fatores de Tempo , Nervo Vago/efeitos dos fármacosRESUMO
We investigated the airway responses evoked by nasal wood smoke in anesthetized Sprague-Dawley rats. Wood smoke (5 ml, 1.4 ml/s) was delivered into an isolated nasal cavity while animals breathed spontaneously. In study 1, nasal wood smoke triggered either an apneic response (n = 26) or a sniff-like response (n = 16) within 1 s after smoke exposure in 42 normal rats. Both airway responses were abolished by trigeminal nerve denervation and by nasal application of a local anesthetic or a hydroxyl radical scavenger, but they were not significantly affected by removal of smoke particulates or nasal application of a saline vehicle. In study 2, nasal wood smoke only triggered a mild apneic response in two rats neonatally treated with capsaicin and had no effect on breathing in the other six; the treatment is known to chronically ablate C fibers and some Adelta fibers. In contrast, nasal wood smoke evoked an apneic response in six rats neonatally treated with the vehicle of capsaicin and elicited a sniff-like response in the other two. These results suggest that the apneic and sniff-like responses evoked by nasal wood smoke result from the stimulation of trigeminal nasal C-fiber and Adelta-fiber afferents by the gas-phase smoke and that hydroxyl radical is the triggering chemical factor.
Assuntos
Sistema Respiratório/fisiopatologia , Fumaça/efeitos adversos , Animais , Apneia/etiologia , Apneia/fisiopatologia , Irritantes/toxicidade , Masculino , Cavidade Nasal , Ratos , Ratos Sprague-Dawley , Reflexo/fisiologia , MadeiraRESUMO
A prior airway exposure to wood smoke induces a tachykinin-dependent increase in airway responsiveness to the subsequent smoke inhalation in guinea pigs (Life Sci. 63: 1513, 1998). To further investigate the time course of, and the contribution of other chemical mediators to, this smoke-induced airway hyperresponsiveness (SIAHR), two smoke challenges (each 10 ml) separated by 30 min were delivered into the lungs of anesthetized guinea pigs by a respirator. In the control animals, the SIAHR was evidenced by the bronchoconstrictive response to the second smoke challenge (SM2) which was approximately 5.2-fold greater than that to the first challenge (SM1). This SIAHR was alleviated by shortening the elapsed time between SM1 and SM2 to 10 min or by extending it to 60 min, and was abolished by extending it to 120 min. This SIAHR was reduced by pretreatment with either MK-571 (a leukotriene D4-receptor antagonist) or dimethylthiourea (a hydroxyl radical scavenger), but was not affected by pretreatment with either pyrilamine (a histamine H1-receptor antagonist) or indomethacin (a cyclooxygenase inhibitor). The smoke-induced reduction in the neutral endopeptidase activity (a major enzyme for tachykinin degradation) measured in airway tissues excised 30 min post SM1 was largely prevented by pretreatment with dimethylthiourea. However, this reduction was not seen in airway tissues excised 120 min post SM1. These results suggest that 1) the SIAHR to inhaled wood smoke has a rapid onset time following smoke inhalation and lasts for less than two hours, 2) leukotrienes and hydroxyl radical may play contributory roles in the development of this SIAHR, and 3) hydroxyl radical is the major factor responsible for the smoke-induced inactivation of airway neutral endopeptidase, which may possibly participate in the development of this SIAHR.
Assuntos
Hiper-Reatividade Brônquica/induzido quimicamente , Radical Hidroxila/metabolismo , Leucotrienos/fisiologia , Fumaça/efeitos adversos , Madeira , Animais , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/enzimologia , Broncodilatadores/uso terapêutico , Cobaias , Antagonistas de Leucotrienos/uso terapêutico , Masculino , Neprilisina/metabolismo , Propionatos/uso terapêutico , Quinolinas/uso terapêutico , Tioureia/análogos & derivados , Tioureia/uso terapêuticoRESUMO
Previously, we showed that carotid bodies express neutral endopeptidase (NEP)-like enzyme activity and that phosphoramidon, a potent inhibitor of NEP, potentiates the chemosensory response of the carotid body to hypoxia in vivo. NEP has been shown to hydrolyze methionine enkephalin (Met-Enk) and substance P (SP) in neuronal tissues. The purpose of the present study is to determine whether NEP hydrolyzes Met-Enk and SP in the carotid body and if so whether these peptides contribute to phosphoramidon-induced potentiation of the sensory response to hypoxia. Experiments were performed on carotid bodies excised from anesthetized adult cats (n = 72 carotid bodies). The hydrolysis of Met-Enk and SP was analyzed by HPLC. The results showed that both SP and Met-Enk were hydrolyzed by the carotid body, but the rate of Met-Enk hydrolysis was approximately fourfold higher than that of SP. Phosphoramidon (400 microM) markedly inhibited SP hydrolysis ( approximately 90%) but had only a marginal effect on Met-Enk hydrolysis ( approximately 15% inhibition). Hypoxia (PO(2), 68 +/- 6 Torr) as well as exogenous administration of SP (10 and 20 nmol) increased the sensory discharge of the carotid body in vitro. Sensory responses to hypoxia and SP (10 nmol) were potentiated by approximately 80 and approximately 275%, respectively (P < 0.01), in the presence of phosphoramidon. SP-receptor antagonists Spantide (peptidyl) and CP-96345 (nonpeptidyl) either abolished or markedly attenuated the phosphoramidon-induced potentiation of the sensory response of the carotid body to hypoxia as well as to SP. These results demonstrate that SP is a preferred substrate for NEP in the carotid body and that SP is involved in the potentiation of the hypoxic response of the carotid body by phosphoramidon.
Assuntos
Corpo Carotídeo/enzimologia , Corpo Carotídeo/fisiologia , Neprilisina/metabolismo , Oxigênio/fisiologia , Substância P/metabolismo , Animais , Compostos de Bifenilo/farmacologia , Corpo Carotídeo/efeitos dos fármacos , Corpo Carotídeo/metabolismo , Gatos , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Encefalina Metionina/metabolismo , Feminino , Glicopeptídeos/antagonistas & inibidores , Glicopeptídeos/farmacologia , Hidrólise/efeitos dos fármacos , Hipóxia/fisiopatologia , Cinética , Masculino , Neprilisina/antagonistas & inibidores , Antagonistas dos Receptores de Neurocinina-1 , Receptores da Neurocinina-1/metabolismo , Substância P/análogos & derivados , Substância P/antagonistas & inibidores , Substância P/farmacologiaRESUMO
It is known that lung vagal C-fiber afferents play an important role in eliciting the tachypneic response to pulmonary air embolism (PAE), and can be subgrouped as those with low resistance (LRC) and those with high resistance (HRC) to perivagal capsaicin. In this study, we investigated the relative contributions of vagal LRC and HRC C-fiber afferents to the PAE-induced tachypneic response. Phrenic activity was recorded from 10 anesthetized, paralyzed, and artificially ventilated dogs. PAE was induced by infusion of air into the vein (2 ml/min, 1 ml/kg). During control conditions, induction of PAE produced a shortening in expiratory duration with no significant change in inspiratory duration, resulting in tachypnea. The PAE-induced tachypneic response was totally abolished by perivagal capsaicin treatment with a method (capsaicin concentration, 6 mg/ml; treatment duration, 25-30 min) that blocks the conduction of LRC C-fiber afferents, but not that of HRC C-fiber afferents. This tachypneic response was not affected by cooling of both vagi to a temperature (4.5 degrees C) that blocks the conduction of HRC C-fiber afferents, but not that of LRC C-fiber afferents. A bilateral cervical vagotomy virtually eliminated this tachypneic response. These results suggest that LRC C-fiber afferents are responsible for eliciting the reflex tachypneic response to PAE, whereas HRC C-fiber afferents play no vital role.
Assuntos
Embolia Aérea/fisiopatologia , Pulmão/inervação , Fibras Nervosas/fisiologia , Mecânica Respiratória/fisiologia , Nervo Vago/fisiologia , Anestesia , Animais , Capsaicina/farmacologia , Temperatura Baixa , Cães , Pulmão/fisiopatologia , Nervo Frênico/fisiologia , Nervo Vago/citologia , Nervo Vago/efeitos dos fármacosRESUMO
Neonatal capsaicin treatment chronically ablates unmyelinated C fibers, yet also destroys a small amount of myelinated fibers. Inhalation of wood smoke evokes respiratory reflexes resulting from stimulation of both lung C-fiber nerve endings (unmyelinated afferents) and irritant receptors (myelinated afferents). This study investigated the influences of neonatal capsaicin treatment on the immediate ventilatory responses to inhaled wood smoke in adult rats. Inhalation of wood smoke (approximately 6 ml) via a tracheostomy immediately triggered only an augmented inspiration in 16 rats neonatally treated with capsaicin (50 mg/kg, subcutaneous injection). In contrast, inhaled wood smoke evoked a slowing of respiration in 11 neonatal vehicle-treated rats and an augmented inspiration in another five. The inability to exhibit the slowing of respiration and the persistence of the augmented inspiration in capsaicin-treated rats are consistent with our hypothesis that these two reflex responses originate from stimulation of lung vagal C-fiber afferents and irritant receptors, respectively. Since all capsaicin-treated rats responded to smoke with an augmented inspiration, it is further suggested that neonatal capsaicin treatment selectively impairs the reflex functions of C-fiber afferents and well preserves the reflex functions of lung irritant receptors.
Assuntos
Animais Recém-Nascidos/fisiologia , Capsaicina/uso terapêutico , Mecânica Respiratória/fisiologia , Lesão por Inalação de Fumaça/tratamento farmacológico , Lesão por Inalação de Fumaça/fisiopatologia , Animais , Peso Corporal/fisiologia , Feminino , Irritantes/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Reflexo/efeitos dos fármacos , Vagotomia , MadeiraRESUMO
OBJECTIVE: To study the immediate effects of maximal voluntary (MV) breathing, with and without abdominal weight (AW) or inspiratory resistance (IR), on inspiratory muscle functions in chronic tetraplegic patients. DESIGN: A crossover trial design. SETTING: Rehabilitation department of a university hospital. PARTICIPANTS: Nine tetraplegic men injured at the C4 to T1 levels, with a mean duration of injury of 72.8 months. INTERVENTIONS: Each subject performed MV breathing without and with AW load (AWMV breathing) and IR load (IRMV breathing) separately. MAIN OUTCOME MEASURES: Electromyographic (EMG) activity of the inspiratory muscles, mouth pressure, inspiratory flow, and inspiratory volume. RESULTS: AWMV breathing evoked greater diaphragmatic EMG activity, inspiratory flow, and inspiratory volume than did IRMV breathing, although the increase of diaphragmatic EMG activity was not statistically significant. Conversely, IRMV breathing produced greater sternocleidomastoid EMG activity and negative mouth pressure than did AWMV breathing. Both AWMV and IRMV breathing evoked greater inspiratory muscle EMG activity than did MV breathing. CONCLUSION: AW and IR loads have differential immediate effects on the inspiratory muscle functions during MV breathing in patients with chronic tetraplegia, suggesting that these two breathing maneuvers may have dissimilar mechanisms of training in such patients. The muscle EMG activity evoked during MV breathing with AW or IR is greater than that without a mechanical load, implying that mechanically loaded training in tetraplegic patients results in load compensatory adjustments via their respiratory motor output to improve respiratory function.
Assuntos
Abdome/fisiopatologia , Resistência das Vias Respiratórias/fisiologia , Capacidade Inspiratória/fisiologia , Ventilação Voluntária Máxima/fisiologia , Quadriplegia/fisiopatologia , Músculos Respiratórios/fisiopatologia , Suporte de Carga/fisiologia , Adaptação Fisiológica/fisiologia , Adulto , Idoso , Doença Crônica , Estudos Cross-Over , Eletromiografia , Humanos , Masculino , Pessoa de Meia-Idade , Quadriplegia/classificação , Quadriplegia/etiologia , Traumatismos da Medula Espinal/complicações , Capacidade VitalRESUMO
Perivagal capsaicin treatment and vagal cooling are two techniques that have been widely used to study the respiratory reflexes mediated by lung vagal C-fibers because they can block the neural conduction of unmyelinated fibers. We hypothesized that there are two subgroups of lung vagal C-fibers which have different vulnerabilities to blockades by these two techniques. To test this hypothesis, afferent activity arising from lung vagal C-fibers was recorded in 29 anesthetized, paralyzed, and artificially ventilated dogs. Afferent C-fiber activity was recorded before and after various concentrations of perivagal capsaicin treatment or before and during various temperatures of vagal cooling. Of the 89 lung vagal C-fibers studied, 73 fibers were classified as the group of "low resistance" to capsaicin, while the other 16 were classified as the group of "high resistance". The former group differed from the latter due to their afferent activity being blocked at relatively low concentrations of perivagal capsaicin and at relatively low temperatures of vagal cooling. Our results suggest that lung vagal C-fibers can be categorized into two subgroups, based upon their different blocking thresholds for perivagal capsaicin and vagal cooling. Our data may provide information for researchers to further differentiate the respiratory reflexes originating from these two subgroups of lung vagal C-fibers.
Assuntos
Capsaicina/farmacologia , Pulmão/inervação , Fibras Nervosas/efeitos dos fármacos , Nervo Vago/citologia , Nervo Vago/fisiologia , Animais , Temperatura Corporal , Temperatura Baixa , Cães , Relação Dose-Resposta a Droga , Fibras Nervosas/fisiologia , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/fisiologia , Reflexo/fisiologia , Respiração Artificial , Limiar Sensorial , Nervo Vago/efeitos dos fármacosRESUMO
To study the mechanisms of wood smoke-induced bronchoconstriction, we measured total lung resistance (RL) and dynamic lung compliance (Cdyn) in anesthetized and mechanically ventilated guinea pigs. Airway exposure to various doses of wood smoke (lauan wood; 5, 10, and 15 breaths) resulted in a dose-dependent increase in RL and decrease in Cdyn. The smoke-induced changes in RL and Cdyn were significantly attenuated by pretreatment with atropine, CP-96,345 [(2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-aza bicyclo(2.2.2.)-octan-3-amine; a tachykinin NK1 receptor antagonist], and SR-48,968 [(S)-N-methyl-N(4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophen yl)-butyl)benzamide; a tachykinin NK2 receptor antagonist] in combination, atropine alone, and SR-48,968 alone, but were not significantly affected by pretreatment with the inactive enantiomers of CP-96,345 and SR-48,968, CP-96,345 alone, indomethacin (a cyclooxygenase inhibitor), and MK-571 [((3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl((3-dimethyl amino-3-oxo-propyl)thio)methyl)propanoic acid; a leukotriene D4 receptor antagonist]. The activity of airway neutral endopeptidase, a major enzyme for tachykinin degradation, was not significantly influenced by wood smoke during the development of bronchoconstriction. We conclude that: (1) both cholinergic mechanisms and endogenous tachykinins, but not cyclooxygenase products or leukotriene D4, play an important role in the acute bronchoconstriction induced by wood smoke, and (2) the contribution of tachykinins to this airway response is primarily mediated via the activation of tachykinin NK2 receptors, but is not associated with inactivation of the airway neutral endopeptidase.
Assuntos
Broncopatias/tratamento farmacológico , Broncoconstrição/efeitos dos fármacos , Antagonistas Colinérgicos/uso terapêutico , Receptores de Taquicininas/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Ácidos Araquidônicos/metabolismo , Atropina/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Broncopatias/induzido quimicamente , Broncopatias/enzimologia , Broncodilatadores/uso terapêutico , Relação Dose-Resposta a Droga , Cobaias , Masculino , Neprilisina/metabolismo , Fumaça/efeitos adversos , MadeiraRESUMO
The smoke-induced airway hyperresponsiveness (SIAHR) to inhaled wood smoke was investigated in anesthetized guinea pigs. Two smoke challenges (each 10 ml) separated by 30 min were delivered into the lungs by a respirator. In control animals, SIAHR was evidenced by an average bronchoconstrictive response (an increase in total lung resistance) to the second smoke challenge (SM2) that was approximately 4.3-fold greater than that to the first challenge (SM1). Pretreatment with CP-96,345 and SR-48,968 (neurokinin-1 and -2 receptor antagonists; each 1 mg/kg) in combination totally prevented this SIAHR, while pretreatment with CP-96,344 and SR48,965 (inactive enantiomers of CP-96,345 and SR-48,968, each 1 mg/kg) in combination failed to do so. Pretreatment with CP-96,345 (1 mg/kg), SR48,968 (1 mg/kg), or atropine (50 microg/kg) significantly alleviated this SIAHR. Pretreatment with phosphoramidon [an inhibitor of neutral endopeptidase (NEP); 2 mg/kg], which suppresses the degradation of tachykinins, induced an increase in airway reactivity that largely mimicked this SIAHR. The NEP activity measured in airway tissues excised 30 min after SM1 was significantly lower than that in air control value. These results suggest that 1) a prior wood smoke exposure induces an airway hyperresponsiveness to the subsequent wood smoke inhalation, 2) a tachykininergic mechanism involving both neurokinin-1 and -2 receptors is essential for, and a cholinergic mechanism is also involved in the development of this SIAHR, and 3) inactivation of airway NEP by wood smoke may contribute to this SIAHR.