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.
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.
Kumasaka
T
T
Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University, Indianapolis 46202, USA.
Quinlan
W M
WM
Doyle
N A
NA
Condon
T P
TP
Sligh
J
J
Takei
F
F
Beaudet
A l
Al
Bennett
C F
CF
Doerschuk
C M
CM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001483:Base Sequence; D018845:CD11 Antigens / Q000502:physiology; D004487:Edema / Q000209:etiology; D004731:Endotoxins / Q000633:toxicity*; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009154:Mutation; D009504:Neutrophils / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D018410:Pneumonia, Bacterial / Q000209:etiology*
D000911:Antibodies, Monoclonal; D018845:CD11 Antigens; D004731:Endotoxins; D016376:Oligonucleotides, Antisense; D018799:Intercellular Adhesion Molecule-1