Importance of tumor necrosis factor-α cleavage process in post-transplantation lung injury in rats

Taichiro Goto, Akitoshi Ishizaka, Fujio Kobayashi, Mitsutomo Kohno, Makoto Sawafuji, Sadatomo Tasaka, Eiji Ikeda, Yasunori Okada, Ikuro Maruyama, Koichi Kobayashi

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32 Citations (Scopus)

Abstract

Tumor necrosis factor-α (TNF-α) has two forms with apparently different biological activities: a membrane-associated form and a soluble form. TNF-α-converting enzyme (TACE) mediates a cleavage of membrane-associated TNF-α to induce its bioactive soluble form. We hypothesized that inhibition of TACE might prevent TNF-α-induced tissue injury while preserving the benefits of TNF-α. In this study, we evaluated the role of TACE in acute inflammation using an inhibitor of the enzyme in a rat model of lung transplantation. Inbred Lewis rats underwent left lung isotransplantation, and the donor lungs were kept in Euro-Collins solution with or without the inhibitor. After 6 hours of ischemia, the left lung was transplanted into the recipient rat and reperfused for 4 hours. Inhibition of TACE significantly attenuated endothelial and alveolar septal damage, as assessed by radiolabeled albumin leakage after transplantation. The inhibition also attenuated neutrophil accumulation in the alveolar space and other histopathologic findings, including intercellular adhesion molecule-1 expression. In addition, significantly lower levels of monocyte chemotactic protein-1, cytokine-induced neutrophil chemoattractant-1, high mobility group box-1, and soluble epithelial cadherin and decreased neutrophil elastase activity were observed in bronchoalveolar lavage fluid from the rats treated with the inhibitor. We conclude that TACE mediates a critical step in the development of post-transplantation lung injury.

Original languageEnglish
Pages (from-to)1239-1246
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume170
Issue number11
DOIs
Publication statusPublished - 2004 Dec 1
Externally publishedYes

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Keywords

  • Acute inflammation
  • Epithelial cadherin
  • High mobility group box-1
  • Lung transplantation
  • TNF-α-converting enzyme

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Goto, T., Ishizaka, A., Kobayashi, F., Kohno, M., Sawafuji, M., Tasaka, S., Ikeda, E., Okada, Y., Maruyama, I., & Kobayashi, K. (2004). Importance of tumor necrosis factor-α cleavage process in post-transplantation lung injury in rats. American Journal of Respiratory and Critical Care Medicine, 170(11), 1239-1246. https://doi.org/10.1164/rccm.200402-146OC