RESUMO
Neutrophil elastase (NE) has been recognized as a double-edge sword as it can be both host-defensive and pro-inflammatory depending on its tissue level and microenvironment. The present study was designed to examine whether inhibition of NE activity by sivelestat, a specific NE inhibitor with low cellular permeability, is beneficial for acute lung injury induced by Streptococcus pneumoniae in hamsters. Intratracheal inoculation of live S. pneumoniae (1.5 x 10(7) CFU/Lung) into hamsters caused acute lung injury characterized by an increase in lung alveolar permeability and leukocytes accumulation in the lungs. These pathophysiological changes, which were associated with elevation of NE activity in the bronchoalveolar lavage fluid (BALF), were transient but remained high 4-22 h post-bacterial inoculation. Intravenous infusion of sivelestat at 3mg/kg/h 0-22 h after bacterial inoculation reduced the increase in NE activity and lung alveolar permeability, as indicated by leakage of pre-injected human serum albumin into BALF, without affecting the number of leukocytes in BALF and lung interstitial tissue. Interestingly, the number of bacteria in BALF and lung interstitial tissue was also reduced by sivelestat to less than 10% of the control values. Furthermore, S. pneumoniae-induced decrease in the level of surfactant protein D (SP-D), a protein that protects against bacterial infection, was preserved by sivelestat treatment with a significant negative correlation between NE activity and SP-D content in BALF. These results suggest that sivelestat is beneficial in acute lung injury associated with lung bacterial infection and that this inhibitor rather decreases infection by preserving host defense system.
Assuntos
Glicina/análogos & derivados , Elastase de Leucócito/efeitos dos fármacos , Sulfonamidas/farmacologia , Lesão Pulmonar Aguda , Animais , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Colônia Microbiana , Cricetinae , Modelos Animais de Doenças , Glicina/antagonistas & inibidores , Glicina/farmacologia , Elastase de Leucócito/metabolismo , Mesocricetus , Pneumonia Pneumocócica/tratamento farmacológico , Pneumonia Pneumocócica/microbiologia , Proteínas Secretadas Inibidoras de Proteinases/farmacologia , Proteína D Associada a Surfactante Pulmonar/metabolismo , Streptococcus pneumoniae/efeitos dos fármacos , Sulfonamidas/antagonistas & inibidores , Fatores de TempoRESUMO
This study examined whether the specific inhibition of neutrophil elastase by sivelestat sodium hydrate (sivelestat) reduced deaths associated with severe acute lung injury after hydrochloric acid (HCl) aspiration in hamsters. Animals that received a single intratracheal instillation of HCl (0.2 N, 200 microL) time-dependently died by occlusion of their trachea with inflammatory exudate. In a time course study, these animals developed severe lung injury, peaking 12 to 24 h after HCl instillation, as indicated by hemorrhage and a massive increase in the protein concentration of bronchoalveolar lavage fluid. These changes were closely correlated with neutrophil elastase activity in bronchoalveolar lavage fluid. Sivelestat (0.01, 0.1 and 1 mg/kg/h), when intravenously infused during the first 48 h post-HCl instillation, dose-dependently reduced death in HCl-instilled hamsters. In a separate experiment, analysis of bronchoalveolar lavage fluid parameters and partial pressure of arterial oxygen (PaO(2)) 8 h post-HCl instillation showed that sivelestat at 1 mg/kg/h, i.v. significantly improved both bronchoalveolar lavage fluid parameters and PaO(2) levels with evidence of the inhibition of neutrophil elastase activity in bronchoalveolar lavage fluid. These results suggest that neutrophil elastase plays a significant role in this type of severe acute lung injury that leads to death by respiratory failure.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Glicina/análogos & derivados , Glicina/uso terapêutico , Elastase de Leucócito/antagonistas & inibidores , Pneumonia Aspirativa/tratamento farmacológico , Sulfonamidas/uso terapêutico , Animais , Líquido da Lavagem Broncoalveolar/química , Cricetinae , Relação Dose-Resposta a Droga , Hemorragia/patologia , Ácido Clorídrico , Técnicas In Vitro , Contagem de Leucócitos , Elastase de Leucócito/metabolismo , Pulmão/patologia , Masculino , Mesocricetus , Neutrófilos/patologia , Peroxidase/metabolismo , Pneumonia Aspirativa/mortalidade , Pneumonia Aspirativa/patologia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/prevenção & controle , Análise de SobrevidaRESUMO
Imbalance between neutrophil elastase (NE) and its endogenous protease inhibitors has been considered to be one of possible mechanisms by which NE causes lung tissue destruction. It has been shown that the amount and/or activity of NE is increased in blood and bronchoalveolar lavage fluid in patients with acute lung injury. Accordingly, animals undergoing acute lung injury have increased NE activity such as in blood and bronchoalveolar lavage fluid. Sivelestat sodium hydrate (Sivelestat) is a synthetic inhibitor of NE with highly specificity to NE. Many studies have indicated that Sivelestat treatment improves inflammatory and edematous changes of lungs and survival as well as increased NE activity in several animal models of acute lung injury. Clinical studies have demonstrated that Sivelestat improves this injury that is associated with systemic inflammatory response syndrome. As compared with endogenous protease inhibitors that have high molecular mass, Sivelestat, a synthetic and low molecular weight elastase inhibitor, may be delivered to the inflammatory sites more easily and effectively and is considred to improve typical symptoms of acute lung injury. Clinical use of Sivelestat would further clarify the usefulness of this compound in clinical acute lung injury.
Assuntos
Glicina/análogos & derivados , Glicina/farmacologia , Elastase de Leucócito/antagonistas & inibidores , Serpinas/farmacologia , Sulfonamidas/farmacologia , Animais , Ensaios Clínicos Fase III como Assunto , Modelos Animais de Doenças , Glicina/uso terapêutico , Humanos , Elastase de Leucócito/fisiologia , Elastase de Leucócito/toxicidade , Serpinas/uso terapêutico , Sulfonamidas/uso terapêutico , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Síndrome de Resposta Inflamatória Sistêmica/enzimologiaRESUMO
Beside its physiological function as a powerful host defense, neutrophil elastase is also known as one of the most destructive enzymes in the body. Current notion holds that neutrophil elastase is able to escape from regulation by multiple protease inhibitors at inflammatory sites. Once unregulated, this enzyme disturbs the function of the lung permeability barrier and induces the release of pro-inflammatory cytokines. These actions then cause symptoms that are typical in the pathophysiology of acute lung injury. In this article, we review recent progress in the understanding of the physiological activity of neutrophil elastase and its role in acute lung injury. Evidence in this review that supports the involvement of neutrophil elastase in the pathophysiology of acute lung injury includes: (1) neutrophil elastase levels are increased in both clinical and animal models of acute lung injury; (2) topical or systemic administration of neutrophil elastase produces typical symptoms of acute lung injury both in vitro and in vivo; and (3) inhibition of increased neutrophil elastase activity reduces symptoms of acute lung injury in animal models. A greater understanding of the role of this enzyme in the pathophysiology of acute lung injury will lead to better treatments for this complicated disease.