Therapeutic time-window of a group IIA phospholipase A2 inhibitor in rabbit acute lung injury: Correlation with lung surfactant protection

Shingo Furue, Katsuya Mikawa, Kahoru Nishina, Makoto Shiga, Masahiko Ueno, Yasuhiko Tomita, Kenji Kuwabara, Isao Teshirogi, Takashi Ono, Yozo Hori, Akihiro Matsukawa, Masaru Yoshinaga, Hidefumi Obara

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Abstract

Objective: We attempted to determine whether group IIA secretory phospholipase A2 (sPLA2-IIA) blockade after the onset of lung injury exerted therapeutic efficacy in the treatment of oleic acid (0A)-induced acute lung injury by using S-5920/LY315920Na, a novel specific inhibitor of sPLA2-IIA, with special interest in the changes of lung surfactant. Design: Prospective animal study. Setting: University laboratory. Subjects: Forty Japanese white rabbits. Interventions: The rabbits, under anesthesia, were endotracheally intubated and mechanically ventilated and then were divided into the following groups: 0A + vehicle groups, intravenous infusion of 0A for the first 2 hrs (0.1 mL·kg-1·hr-1) with the addition of vehicle (1 or 2 hrs after 0A administration, each n = 9, total 18 rabbits); 0A + S-5920/LY315920Na groups, treated identically to the 0A control with the addition of S-5920/ LY315920Na (1 mg/kg bolus followed by infusion at 0.5 mg·kg-1·hr-1) after 0A (1 or 2 hrs after 0A administration, each n = 9, total 18 rabbits); saline control groups, treated with saline instead of OA with the addition of vehicle (1 hr after 0A administration, 4 rabbits). Arterial blood gas, lung mechanics, lung inflammation, lung surfactant phospholipids, and production of inflammatory mediators in the lung were measured. Measurements and Main Results: Treatment with S-5920/LY315920Na 1 hr after OA infusion, but not 2 hrs after infusion, significantly attenuated the lung injury, as estimated by hypoxemia, decreased lung compliance, pulmonary edema, and vascular permeability. The therapeutic efficacy was similar to that found in our previous pretreatment study. The treatment after 1 hr dramatically inhibited OA-induced surfactant degradation in the bronchoalveolar lavage fluid (BALF), without affecting the concentrations of thromboxane A2, leukotriene B4, and interleukin-8 in BALF. The degree of surfactant degradation in BALF paralleled well with the severity of the lung injury. Furthermore, recombinant human sPLA2-IIA reproduced the simillar hydrolysis pattern of isolated surfactant in vitro, which was inhibited by S-5920/LY315920Na. Conclusions: Our results indicate that therapeutic blockade of sPLA2-IIA ameliorated lung dysfunction via protection of surfactant degradation in an animal model of acute lung injury, and they suggest a new strategy in treating clinical acute lung injury.

Original languageEnglish
Pages (from-to)719-727
Number of pages9
JournalCritical care medicine
Volume29
Issue number4
DOIs
Publication statusPublished - Jan 1 2001
Externally publishedYes

Keywords

  • Acute lung injury
  • Acute respiratory distress syndrome
  • Interleukin-8
  • Leukotriene B
  • Lung surfactant degradation
  • Lyso-phosphatidylcholine
  • Neutrophil infiltration
  • Oleic acid
  • Phosphatidylglycerol
  • Phospholipase A
  • Thromboxane B

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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    Furue, S., Mikawa, K., Nishina, K., Shiga, M., Ueno, M., Tomita, Y., Kuwabara, K., Teshirogi, I., Ono, T., Hori, Y., Matsukawa, A., Yoshinaga, M., & Obara, H. (2001). Therapeutic time-window of a group IIA phospholipase A2 inhibitor in rabbit acute lung injury: Correlation with lung surfactant protection. Critical care medicine, 29(4), 719-727. https://doi.org/10.1097/00003246-200104000-00004