Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury.

Abstract

The pathophysiology of ischemic acute renal failure is complex, and the role of leukocyte adhesion in this process is not well defined. A monoclonal antibody (mAb) against intracellular adhesion molecule 1 (anti-ICAM-1), administered at the time of bilateral renal ischemia in the rat, prevented both functional impairment and histologic changes of acute renal failure. Plasma creatinine measured (mg/dl) 24 hr after 30 min of ischemia was 0.61 ± 0.05 in the anti-ICAM-1-treated animals compared with 2.4 ± 0.14 (P < 0.0001) in the vehicle-treated ischemic group. Forty-eight hours after ischemia, creatinine values were 0.46 ± 0.05 and 2.03 ± 0.22 (P < 0.0001) in anti-ICAM-1 and vehicle-treated groups, respectively. A low dose of anti-ICAM-1 that was itself nonprotective, when given with partially protective doses of a mAb against lymphocyte function-associated antigen-i (anti-LFA-1), acted synergistically to prevent renal failure. Anti-ICAM-1 mAb also protected the kidney when administered 0.5 or 2 hr but not 8 hr after restoration of blood flow and when the ischemic period was extended to 40 min. Ischemia-induced increases in tissue myeloperoxidase, a marker of neutrophil infitration, were mitigated with anti-ICAM-1 treatment. Thus, anti-ICAM-1 mAb protected the kidney against ischemic renal failure, even when the antibody was administered after the ischemic period. These results suggest a critical role for leukocytes and adhesion molecules in the pathophysiology of ischemic inijury and may have important therapeutic implications.The pathophysiology of acute ischemic renal failure is poorly understood. Therapeutic interventions designed to inhibit cellular injury have frequently been either ineffective or equivocal in their effectiveness in both experimental animals and man, and rarely has an agent been effective when administered after the ischemic insult (1).We hypothesized that leukocyte adhesion plays a critical role in renal ischemia-reperfusion injury. Outer medullary vascular congestion that occurs in ischemic acute renal failure (2) may result from leukocyte-endothelial cell interactions with obstruction of the vasa recta or leukocyte-mediated increases in endothelial permeability leading to erythrocyte aggregation (3). This would sustain ischemia to the outer medulla, even if total renal blood flow were restored.Leukocyte adhesion to various cell types is mediated in large part by the three P2 integrins: CD11a/CD18 [lymphocyte function-associated antigen 1 (LFA-1)], CD11b/CD18 (Mac-i), and CD11c/CD18. The intercellular adhesion molecule 1 (ICAM-1, CD54) is a ligand for CD11a/CD18 and CD11b/CD18. The CD54-CD11/CD18 interactions are important determinants of leukocyte-endothelial cell adhesion (4). The purpose of our studies was to evaluate the effects of a monoclonal antibody (mAb) directed against ICAM-1 on ischemic acute renal failure in the rat.Ischemia results in increased tissue levels of proinflammatory mediators, including cytokines (5, 6) and products of arachidonic acid metabolism (7), which ...

Renal Ischemia/Reperfusion Injury

“…Although it is well demonstrated that leukocyte adhesion molecule blockade plays a tissue protective role in IRI in muscle and heart, it is still a matter of controversy in the kidney. CD11/CD18 and intercellular adhesion molecule-1 blockade are usually protective in experimental renal IRI (9,12). In contrast, induction of systemic neutropenia and selectin function blockade do not have a protective effect, suggesting a neutrophil-independent mechanism for renal protection (6).…”

“…Leukocyte adhesion molecules seem to facilitate polymorphonuclear neutrophils recruitment during reperfusion, being implicated as mediators of renal IRI (5,6). Complementary studies using mAb, antisense oligonucleotides, or gene "knockout" indicate that blockade of ␤2 integrins and/or intercellular adhesion molecule-1 attenuates IRI in some experimental models (7)(8)(9)(10)(11)(12)(13). Furthermore, it was proposed recently that T cells might also mediate IRI through the interaction with renal tubular epithelial cells (14).…”

Prevention and Treatment of Acute Renal Failure in Sepsis

“…Treatment of experimental animals with anti-ICAM-1 antibodies (89,92) or with antisense oligonucleotides for ICAM-1 (93) provided protection from ischemic ARF. ICAM-1 knockout mice appeared resistant to acute renal ischemic injury (89).…”

Vascular Endothelial Growth Factor (VEGF)-Induced Retinal Vascular Permeability Is Mediated by Intercellular Adhesion Molecule-1 (ICAM-1)

“…[12][13][14] The animals were randomly divided into five groups. The first group received no treatment.…”