Effects of tnf-α-converting enzyme inhibition on acute lung injury induced by endotoxin in the rat

Mie Shimizu, Naoki Hasegawa, Tomoyasu Nishimura, Yoshihiko Endo, Yoshiki Shiraishi, Wakako Yamasawa, Hidefumi Koh, Sadatomo Tasaka, Hisato Shimada, Yasushi Nakano, Seitaro Fujishima, Kazuhiro Yamaguchi, Akitoshi Ishizaka

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22 Citations (Scopus)

Abstract

We studied the effects of TNF-converting enzyme inhibition with Y-41654, which down-regulates the production of soluble TNF-α (sTNF-α), on acute lung injury induced by intratracheal administration of LPS. We first verified in vitro that pretreatment of isolated alveolar macrophages from Sprague-Dawley male rats with 20 μL of 0.1-mM Y-41654, decreased significantly (P < 0.05) the concentration of sTNF-α in cell supernatants induced by 10 μg/mL of LPS. We then studied four groups of rats (each n = 10) including 1) a control group, 2) an LPS group (300 μg /kg, instilled intratracheally), 3) a Y-41654 group, and 4) a treatment group treated with Y-41654 after LPS instillation. Y-41654, 10 mg/kg in 0.7 mL of phosphate-buffered saline, was administered (i.v.), 15 min before and 0.5, 1.5, 2.5, and 3.5 h after saline or LPS instillation. The animals were observed for 4 h. In the animals treated with Y-41654, the concentrations of sTNF-α and protein in bronchoalveolar lavage fluid, and the number of neutrophils in lung tissue and bronchoalveolar lavage fluid were significantly lower at 4 h than in the LPS group (P < 0.05). In conclusion, sTNF-α plays an important role in the development of acute lung injury induced by intratracheal administration of LPS, in part modulating neutrophil kinetics.

Original languageEnglish
Pages (from-to)535-540
Number of pages6
JournalShock
Volume32
Issue number5
DOIs
Publication statusPublished - 2009 Nov 1

Keywords

  • Bronchoalveolar lavage
  • Cytokine
  • LPS
  • Lung inflammation
  • Membrane-bound TNF
  • Neutrophil
  • Soluble TNF

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

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  • Cite this

    Shimizu, M., Hasegawa, N., Nishimura, T., Endo, Y., Shiraishi, Y., Yamasawa, W., Koh, H., Tasaka, S., Shimada, H., Nakano, Y., Fujishima, S., Yamaguchi, K., & Ishizaka, A. (2009). Effects of tnf-α-converting enzyme inhibition on acute lung injury induced by endotoxin in the rat. Shock, 32(5), 535-540. https://doi.org/10.1097/SHK.0b013e3181a2adb7