Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 May 15;97(10):2362–2369. doi: 10.1172/JCI118679

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.

T Kumasaka 1, W M Quinlan 1, N A Doyle 1, T P Condon 1, J Sligh 1, F Takei 1, A l Beaudet 1, C F Bennett 1, C M Doerschuk 1
PMCID: PMC507317  PMID: 8636417

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.

Full Text

The Full Text of this article is available as a PDF (382.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agrawal S., Temsamani J., Tang J. Y. Pharmacokinetics, biodistribution, and stability of oligodeoxynucleotide phosphorothioates in mice. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7595–7599. doi: 10.1073/pnas.88.17.7595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Albelda S. M., Smith C. W., Ward P. A. Adhesion molecules and inflammatory injury. FASEB J. 1994 May;8(8):504–512. [PubMed] [Google Scholar]
  3. Anazodo M. I., Wainberg M. A., Friesen A. D., Wright J. A. Sequence-specific inhibition of gene expression by a novel antisense oligodeoxynucleotide phosphorothioate directed against a nonregulatory region of the human immunodeficiency virus type 1 genome. J Virol. 1995 Mar;69(3):1794–1801. doi: 10.1128/jvi.69.3.1794-1801.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Andres D. W., Kutkoski G. J., Quinlan W. M., Doyle N. A., Doerschuk C. M. Effect of pentoxifylline on changes in neutrophil sequestration and emigration in the lungs. Am J Physiol. 1995 Jan;268(1 Pt 1):L27–L32. doi: 10.1152/ajplung.1995.268.1.L27. [DOI] [PubMed] [Google Scholar]
  5. Bennett C. F., Condon T. P., Grimm S., Chan H., Chiang M. Y. Inhibition of endothelial cell adhesion molecule expression with antisense oligonucleotides. J Immunol. 1994 Apr 1;152(7):3530–3540. [PubMed] [Google Scholar]
  6. Bennett C. F., Crooke S. T. Regulation of endothelial cell adhesion molecule expression with antisense oligonucleotides. Adv Pharmacol. 1994;28:1–43. doi: 10.1016/s1054-3589(08)60492-5. [DOI] [PubMed] [Google Scholar]
  7. Bullard D. C., Qin L., Lorenzo I., Quinlin W. M., Doyle N. A., Bosse R., Vestweber D., Doerschuk C. M., Beaudet A. L. P-selectin/ICAM-1 double mutant mice: acute emigration of neutrophils into the peritoneum is completely absent but is normal into pulmonary alveoli. J Clin Invest. 1995 Apr;95(4):1782–1788. doi: 10.1172/JCI117856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Burch R. M., Mahan L. C. Oligonucleotides antisense to the interleukin 1 receptor mRNA block the effects of interleukin 1 in cultured murine and human fibroblasts and in mice. J Clin Invest. 1991 Oct;88(4):1190–1196. doi: 10.1172/JCI115421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Burns A. R., Doerschuk C. M. Quantitation of L-selectin and CD18 expression on rabbit neutrophils during CD18-independent and CD18-dependent emigration in the lung. J Immunol. 1994 Oct 1;153(7):3177–3188. [PubMed] [Google Scholar]
  10. Burns A. R., Takei F., Doerschuk C. M. Quantitation of ICAM-1 expression in mouse lung during pneumonia. J Immunol. 1994 Oct 1;153(7):3189–3198. [PubMed] [Google Scholar]
  11. Chiang M. Y., Chan H., Zounes M. A., Freier S. M., Lima W. F., Bennett C. F. Antisense oligonucleotides inhibit intercellular adhesion molecule 1 expression by two distinct mechanisms. J Biol Chem. 1991 Sep 25;266(27):18162–18171. [PubMed] [Google Scholar]
  12. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  13. Cossum P. A., Sasmor H., Dellinger D., Truong L., Cummins L., Owens S. R., Markham P. M., Shea J. P., Crooke S. Disposition of the 14C-labeled phosphorothioate oligonucleotide ISIS 2105 after intravenous administration to rats. J Pharmacol Exp Ther. 1993 Dec;267(3):1181–1190. [PubMed] [Google Scholar]
  14. Crooke S. T. Progress toward oligonucleotide therapeutics: pharmacodynamic properties. FASEB J. 1993 Apr 1;7(6):533–539. doi: 10.1096/fasebj.7.6.7682523. [DOI] [PubMed] [Google Scholar]
  15. Cybulsky M. I., Chan M. K., Movat H. Z. Acute inflammation and microthrombosis induced by endotoxin, interleukin-1, and tumor necrosis factor and their implication in gram-negative infection. Lab Invest. 1988 Apr;58(4):365–378. [PubMed] [Google Scholar]
  16. Dean N. M., McKay R., Condon T. P., Bennett C. F. Inhibition of protein kinase C-alpha expression in human A549 cells by antisense oligonucleotides inhibits induction of intercellular adhesion molecule 1 (ICAM-1) mRNA by phorbol esters. J Biol Chem. 1994 Jun 10;269(23):16416–16424. [PubMed] [Google Scholar]
  17. Dean N. M., McKay R. Inhibition of protein kinase C-alpha expression in mice after systemic administration of phosphorothioate antisense oligodeoxynucleotides. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11762–11766. doi: 10.1073/pnas.91.24.11762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Doerschuk C. M., Markos J., Coxson H. O., English D., Hogg J. C. Quantitation of neutrophil migration in acute bacterial pneumonia in rabbits. J Appl Physiol (1985) 1994 Dec;77(6):2593–2599. doi: 10.1152/jappl.1994.77.6.2593. [DOI] [PubMed] [Google Scholar]
  19. Doerschuk C. M., Winn R. K., Coxson H. O., Harlan J. M. CD18-dependent and -independent mechanisms of neutrophil emigration in the pulmonary and systemic microcirculation of rabbits. J Immunol. 1990 Mar 15;144(6):2327–2333. [PubMed] [Google Scholar]
  20. Galbraith W. M., Hobson W. C., Giclas P. C., Schechter P. J., Agrawal S. Complement activation and hemodynamic changes following intravenous administration of phosphorothioate oligonucleotides in the monkey. Antisense Res Dev. 1994 Fall;4(3):201–206. doi: 10.1089/ard.1994.4.201. [DOI] [PubMed] [Google Scholar]
  21. Gao W. Y., Jaroszewski J. W., Cohen J. S., Cheng Y. C. Mechanisms of inhibition of herpes simplex virus type 2 growth by 28-mer phosphorothioate oligodeoxycytidine. J Biol Chem. 1990 Nov 25;265(33):20172–20178. [PubMed] [Google Scholar]
  22. Hellewell P. G., Young S. K., Henson P. M., Worthen G. S. Disparate role of the beta 2-integrin CD18 in the local accumulation of neutrophils in pulmonary and cutaneous inflammation in the rabbit. Am J Respir Cell Mol Biol. 1994 Apr;10(4):391–398. doi: 10.1165/ajrcmb.10.4.7510985. [DOI] [PubMed] [Google Scholar]
  23. Hendrix C. W., Margolick J. B., Petty B. G., Markham R. B., Nerhood L., Farzadegan H., Ts'o P. O., Lietman P. S. Biologic effects after a single dose of poly(I):poly(C12U) in healthy volunteers. Antimicrob Agents Chemother. 1993 Mar;37(3):429–435. doi: 10.1128/aac.37.3.429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hoke G. D., Draper K., Freier S. M., Gonzalez C., Driver V. B., Zounes M. C., Ecker D. J. Effects of phosphorothioate capping on antisense oligonucleotide stability, hybridization and antiviral efficacy versus herpes simplex virus infection. Nucleic Acids Res. 1991 Oct 25;19(20):5743–5748. doi: 10.1093/nar/19.20.5743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Horley K. J., Carpenito C., Baker B., Takei F. Molecular cloning of murine intercellular adhesion molecule (ICAM-1). EMBO J. 1989 Oct;8(10):2889–2896. doi: 10.1002/j.1460-2075.1989.tb08437.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Narayanan R., Higgins K. A., Perez J. R., Coleman T. A., Rosen C. A. Evidence for differential functions of the p50 and p65 subunits of NF-kappa B with a cell adhesion model. Mol Cell Biol. 1993 Jun;13(6):3802–3810. doi: 10.1128/mcb.13.6.3802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sands H., Gorey-Feret L. J., Cocuzza A. J., Hobbs F. W., Chidester D., Trainor G. L. Biodistribution and metabolism of internally 3H-labeled oligonucleotides. I. Comparison of a phosphodiester and a phosphorothioate. Mol Pharmacol. 1994 May;45(5):932–943. [PubMed] [Google Scholar]
  28. Scheynius A., Camp R. L., Puré E. Reduced contact sensitivity reactions in mice treated with monoclonal antibodies to leukocyte function-associated molecule-1 and intercellular adhesion molecule-1. J Immunol. 1993 Jan 15;150(2):655–663. [PubMed] [Google Scholar]
  29. Segal G. M., Smith T. D., Heinrich M. C., Ey F. S., Bagby G. C., Jr Specific repression of granulocyte-macrophage and granulocyte colony-stimulating factor gene expression in interleukin-1-stimulated endothelial cells with antisense oligodeoxynucleotides. Blood. 1992 Aug 1;80(3):609–616. [PubMed] [Google Scholar]
  30. Sligh J. E., Jr, Ballantyne C. M., Rich S. S., Hawkins H. K., Smith C. W., Bradley A., Beaudet A. L. Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8529–8533. doi: 10.1073/pnas.90.18.8529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Sokoloski J. A., Sartorelli A. C., Rosen C. A., Narayanan R. Antisense oligonucleotides to the p65 subunit of NF-kappa B block CD11b expression and alter adhesion properties of differentiated HL-60 granulocytes. Blood. 1993 Jul 15;82(2):625–632. [PubMed] [Google Scholar]
  32. Stepkowski S. M., Tu Y., Condon T. P., Bennett C. F. Induction of transplantation tolerance by treatment with ICAM-1 antisense oligonucleotides and anti-LFA-1 monoclonal antibodies. Transplant Proc. 1995 Feb;27(1):113–113. [PubMed] [Google Scholar]
  33. Takei F. Inhibition of mixed lymphocyte response by a rat monoclonal antibody to a novel murine lymphocyte activation antigen (MALA-2). J Immunol. 1985 Mar;134(3):1403–1407. [PubMed] [Google Scholar]
  34. Ulich T. R., Watson L. R., Yin S. M., Guo K. Z., Wang P., Thang H., del Castillo J. The intratracheal administration of endotoxin and cytokines. I. Characterization of LPS-induced IL-1 and TNF mRNA expression and the LPS-, IL-1-, and TNF-induced inflammatory infiltrate. Am J Pathol. 1991 Jun;138(6):1485–1496. [PMC free article] [PubMed] [Google Scholar]
  35. Watson R. W., Redmond H. P., Bouchier-Hayes D. Role of endotoxin in mononuclear phagocyte-mediated inflammatory responses. J Leukoc Biol. 1994 Jul;56(1):95–103. doi: 10.1002/jlb.56.1.95. [DOI] [PubMed] [Google Scholar]
  36. Wickstrom E. Oligodeoxynucleotide stability in subcellular extracts and culture media. J Biochem Biophys Methods. 1986 Sep;13(2):97–102. doi: 10.1016/0165-022x(86)90021-7. [DOI] [PubMed] [Google Scholar]
  37. Winn R. K., Harlan J. M. CD18-independent neutrophil and mononuclear leukocyte emigration into the peritoneum of rabbits. J Clin Invest. 1993 Sep;92(3):1168–1173. doi: 10.1172/JCI116686. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES