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ONO-5046, an elastase inhibitor, attenuates endotoxin-induced acute lung injury in rabbits.
Anesth Analg. 1997 May; 84(5):1097-103.A&A

Abstract

Endotoxin causes acute lung injury resembling acute respiratory distress syndrome. Elastase, as well as reactive oxygen species released from activated neutrophils, are thought to play pivotal roles in the pathogenesis of this lung injury. This study investigated whether ONO-5046, a specific elastase inhibitor, can attenuate acute lung injury induced by endotoxin in rabbits. Thirty-two male anesthetized rabbits were randomly assigned to receive one of four treatments (n = 8 for each group): infusion of saline without ONO-5046 treatment (Group S-S), infusion of saline with ONO-5046 (Group S-O), infusion of Escherichia coli endotoxin (100 micrograms/kg over 60 min) without ONO-5046 (Group E-S), and infusion of endotoxin with ONO-5046 (Group E-O). Fifteen minutes before the infusion of endotoxin (Groups E-O and E-S) or saline (Groups S-S and S-O), the animals received a bolus injection of ONO-5046 (10 mg/kg) followed by continuous infusion (10 mg.kg-1.h-1: Groups S-O and E-O) or saline (Groups S-S and E-S). The lungs of the rabbits were ventilated with 40% oxygen. Hemodynamics, peripheral leukocyte and platelet counts, and PaO2 were recorded during the ventilation period (6 h). Lung mechanics, cell fraction of the bronchoalveolar lavage fluid (BALF), activated complement, cytokines, and arachidonic acid metabolite concentrations in the BALF were measured at 6 h. The wet- to dry (W/D)-weight ratio of the lung and albumin concentrations in BALF were analyzed as indices of pulmonary edema. Endotoxin decreased lung compliance and PaO2, and increased the W/D weight ratio, neutrophil counts, and albumin concentration in the BALF. Concentrations of activated complement C5a, interleukin-6, interleukin-8, and thromboxane B2 in the BALF were increased by the infusion of endotoxin. ONO-5046 treatment attenuated these changes. Endotoxin caused extensive morphologic lung damage, which was lessened by ONO-5046. In conclusion, intravenous ONO-5046 pretreatment attenuated endotoxin-induced lung injury in rabbits. This beneficial effect of ONO-5046 may be due, in part, to a reduction in the levels of mediators that activate neutrophils, in addition to the direct inhibitory effect on elastase.

Authors+Show Affiliations

Department of Anaesthesiology and Intensive Care Unit, Kobe University School of Medicine, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9141938

Citation

Nishina, K, et al. "ONO-5046, an Elastase Inhibitor, Attenuates Endotoxin-induced Acute Lung Injury in Rabbits." Anesthesia and Analgesia, vol. 84, no. 5, 1997, pp. 1097-103.
Nishina K, Mikawa K, Takao Y, et al. ONO-5046, an elastase inhibitor, attenuates endotoxin-induced acute lung injury in rabbits. Anesth Analg. 1997;84(5):1097-103.
Nishina, K., Mikawa, K., Takao, Y., Maekawa, N., Shiga, M., & Obara, H. (1997). ONO-5046, an elastase inhibitor, attenuates endotoxin-induced acute lung injury in rabbits. Anesthesia and Analgesia, 84(5), 1097-103.
Nishina K, et al. ONO-5046, an Elastase Inhibitor, Attenuates Endotoxin-induced Acute Lung Injury in Rabbits. Anesth Analg. 1997;84(5):1097-103. PubMed PMID: 9141938.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ONO-5046, an elastase inhibitor, attenuates endotoxin-induced acute lung injury in rabbits. AU - Nishina,K, AU - Mikawa,K, AU - Takao,Y, AU - Maekawa,N, AU - Shiga,M, AU - Obara,H, PY - 1997/5/1/pubmed PY - 1997/5/1/medline PY - 1997/5/1/entrez SP - 1097 EP - 103 JF - Anesthesia and analgesia JO - Anesth Analg VL - 84 IS - 5 N2 - Endotoxin causes acute lung injury resembling acute respiratory distress syndrome. Elastase, as well as reactive oxygen species released from activated neutrophils, are thought to play pivotal roles in the pathogenesis of this lung injury. This study investigated whether ONO-5046, a specific elastase inhibitor, can attenuate acute lung injury induced by endotoxin in rabbits. Thirty-two male anesthetized rabbits were randomly assigned to receive one of four treatments (n = 8 for each group): infusion of saline without ONO-5046 treatment (Group S-S), infusion of saline with ONO-5046 (Group S-O), infusion of Escherichia coli endotoxin (100 micrograms/kg over 60 min) without ONO-5046 (Group E-S), and infusion of endotoxin with ONO-5046 (Group E-O). Fifteen minutes before the infusion of endotoxin (Groups E-O and E-S) or saline (Groups S-S and S-O), the animals received a bolus injection of ONO-5046 (10 mg/kg) followed by continuous infusion (10 mg.kg-1.h-1: Groups S-O and E-O) or saline (Groups S-S and E-S). The lungs of the rabbits were ventilated with 40% oxygen. Hemodynamics, peripheral leukocyte and platelet counts, and PaO2 were recorded during the ventilation period (6 h). Lung mechanics, cell fraction of the bronchoalveolar lavage fluid (BALF), activated complement, cytokines, and arachidonic acid metabolite concentrations in the BALF were measured at 6 h. The wet- to dry (W/D)-weight ratio of the lung and albumin concentrations in BALF were analyzed as indices of pulmonary edema. Endotoxin decreased lung compliance and PaO2, and increased the W/D weight ratio, neutrophil counts, and albumin concentration in the BALF. Concentrations of activated complement C5a, interleukin-6, interleukin-8, and thromboxane B2 in the BALF were increased by the infusion of endotoxin. ONO-5046 treatment attenuated these changes. Endotoxin caused extensive morphologic lung damage, which was lessened by ONO-5046. In conclusion, intravenous ONO-5046 pretreatment attenuated endotoxin-induced lung injury in rabbits. This beneficial effect of ONO-5046 may be due, in part, to a reduction in the levels of mediators that activate neutrophils, in addition to the direct inhibitory effect on elastase. SN - 0003-2999 UR - https://www.unboundmedicine.com/medline/citation/9141938/ONO_5046_an_elastase_inhibitor_attenuates_endotoxin_induced_acute_lung_injury_in_rabbits_ L2 - https://doi.org/10.1097/00000539-199705000-00026 DB - PRIME DP - Unbound Medicine ER -