Role of the intercellular adhesion molecule-1 (ICAM-1) in endotoxin-induced pneumonia evaluated using ICAM-1 antisense oligonucleotides, anti-ICAM-1 monoclonal antibodies, and ICAM-1 mutant mice

Toshio Kumasaka, William M. Quinlan, Nicholas A. Doyle, Thomas P. Condon, James Sligh, Fumio Takei, Arthur L. Beaudet, C. Frank Bennett, Claire M. Doerschuk

Research output: Contribution to journalArticlepeer-review

186 Scopus citations

Abstract

This study examined the effectiveness of antisense oligonucleotides targeted to intercellular adhesion molecule-1 (ICAM-1) to inhibit endotoxin-induced upregulation of ICAM-1 and neutrophil emigration and compared the apparent role of ICAM-1 when examined using antisense oligonucleotides, anti-ICAM-1 antibodies, and ICAM-1 mutant mice. Antisense oligonucleotides inhibited upregulation of ICAM-1 mRNA at 4 and 24 h after instillation of endotoxin in a dose-dependent manner. Neutrophil emigration into the alveolar spaces at 24 h was inhibited by 59%, similar to inhibition using the anti-ICAM-1 antibodies 3E2 (58%) and YN1/ 1 (75%). No inhibition was observed in the ICAM-1 mutant compared to wild-type mice. These data show that antisense oligonucleotides targeted to ICAM-1 inhibit the endotoxin-induced upregulation of ICAM-1 in the lung and are as effective as anti-ICAM-1 antibodies in preventing neutrophil emigration. The incomplete inhibition by either antisense oligonucleotides or antibodies suggests that alternative adhesion pathways that do not require ICAM-1 are important in neutrophil emigration in the lungs. The disparity in the role of ICAM-1 when evaluated using antisense or antibodies compared to mutant mice suggests that either these inhibitors are exerting additional effects on endothelial cells other than blockade of ICAM-1 or mutant mice have upregulated the ICAM-1 - independent pathways to compensate for the long-term loss of ICAM-1.

Original languageEnglish (US)
Pages (from-to)2362-2369
Number of pages8
JournalJournal of Clinical Investigation
Volume97
Issue number10
DOIs
StatePublished - May 15 1996
Externally publishedYes

Keywords

  • Adhesion molecules
  • Endothelial cells
  • Lung injury
  • Neutrophils
  • Pneumonia

ASJC Scopus subject areas

  • Medicine(all)

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