Antisense Intercellular Adhesion Molecule-1 (ICAM-1) Oligodeoxyribonucleotide Delivered During Organ Preservation Inhibits Posttransplant ICAM-1 Expression and Reduces Primary Lung Isograft Failure

Abstract

Abstract-Transiently increased expression of leukocyte adhesion receptors after lung preservation contributes to early graft demise by recruiting leukocytes, activating complement, and causing microcirculatory stasis. We hypothesized that inhibiting intercellular adhesion molecule-1 (ICAM-1) expression even briefly may significantly improve lung graft function and that the preservation period might provide a unique window to deliver a therapeutic pulse of antisense oligonucleotide ICAM-1 to inhibit ICAM-1 expression after transplantation. Interleukin-1␤-treated rat pulmonary endothelial cells given a 20-mer phosphorothioate oligonucleotide comprising an antisense span targeted to the 3Ј-untranslated region of rat ICAM-1 demonstrated an oligonucleotide dose-dependent reduction in ICAM-1 expression. Using a cationic liposomal carrier, this same antisense oligonucleotide (but not the sense control) instilled into the pulmonary vasculature at the time of preservation reduced subsequent graft ICAM-1 expression and graft leukostasis and markedly improved oxygenation, pulmonary blood flow, and graft survival. These experiments demonstrate that the preservation period presents a window during which to target an anti-ICAM-1 expression strategy to inhibit early adhesion receptor expression and improve functional outcome after lung transplantation. (Circ Res. 2000;86:166-174.)Key Words: intercellular adhesion molecule-1 Ⅲ lung transplantation Ⅲ isograft Ⅲ leukocyte adhesion receptor C linical lung transplantation at its best is a harrowing experience, because lung grafts can fail catastrophically shortly after reperfusion for reasons that are often not understood. 1,2 Clinical lung preservation strategies are directed toward maintaining proper electrolyte and osmotic homeostasis, but surprisingly little is done to protect the vast pulmonary vascular network on which the lung depends for both integrity and function. Because the early expression of the leukocyte adhesion receptor P-selectin can result in rapid sequestration of neutrophils (polymorphonuclear leukocytes [PMNs]) after lung transplantation, 3 promoting microcirculatory stasis and local tissue destruction, we hypothesized that a strategy that protects the lungs from early leukocyte recruitment could confer clinical benefit. Because P-selectin places neutrophils into a favorable steric relationship for intercellular adhesion molecule-1 (ICAM-1) binding to ␤ 2 -integrins, we hypothesized that early inhibition of inducible ICAM-1 expression might serve as a useful target for therapeutic intervention in lung transplantation to prevent acute graft injury. Toward this end, we have focused on the unique opportunity provided by the lung harvest procedure, during which it is possible to deliver agents (such as antisense oligodeoxynucleotides) ex vivo directly into the vasculature, which can block adhesion receptor expression during the first few critical hours after reperfusion. The current studies were designed to (1) elucidate the nature and functional relevance of endo...

Lung Transplantation: Opportunities for Research and Clinical Advancement

“…For example, glycoprotein adhesion receptors are strongly expressed on endothelium, and Weibel-Palade bodies undergo exocytosis (43). P-selectin is translocated to the endothelial surface, transcription of E-selectin increases, and expression of intracellular adhesion molecule 1 is upregulated (44). These events contribute to leukocyte diapedesis across the endothelial monolayer and tissue inflammation.…”

“…For example, transcriptional blockers, such as antisense Egr-1, administered during the preservation period prevent both coagulant and leukoadhesive events after lung transplantation (47). Other strategies to block leukoadhesion or coagulation have also been used successfully in the setting of experimental lung transplantation (44,52).…”

Interleukins in Atherosclerosis: Molecular Pathways and Therapeutic Potential

“…Antisense-mediated down-regulation of endothelial ICAM-1 expression on monocytes reduces endothelial adhesiveness for leukocytes, which may be advantageous in atherogenesis (Steidl et al, 2000). The applicability of ICAM-1 inhibition by means of antisense has been demonstrated in vivo, as it has been shown to be effective in the prevention of cardiac allograft or lung isograft failure in mice and rats, respectively (Stepkowski et al, 1994;Toda et al, 2000). In clinical studies, the phosphorothioate ICAM-1 antisense preparation ISIS 2302 has been found to be well tolerated and to significantly lower the need for steroid treatment in Crohn's disease (Yacyshyn et al, 1998).…”

Transcriptional Control of Cardiac Allograft Vasculopathy by Early Growth Response Gene-1 (Egr-1)

“…In the first, an antisense approach was used because of the recognized specificity and potency of the technique, particularly as applied to ex vivo preservation of an organ. [13][14][15] In the second approach, mice null for the Egr-1 gene, which exhibit reduced pulmonary vascular inflammatory and coagulant responses to oxygen deprivation or ischemia, 8 served as cardiac allograft donors. Theoretically, a multipronged approach to inhibit many inflammatory and coagulant cascades, by targeting a common transcription factor such as Egr-1 rather than the often-redundant mediators themselves, might be preferable to prevent parenchymal rejection and inhibit formation of CAV.…”