Attenuation of ventilator-induced acute lung injury in an animal model by inhibition of neutrophil adhesion by leumedins (NPC 15669)

Abstract

Objectives: Beta2-integrin (CD11b/CD18) expression, an indicator of neutrophil activation, has been associated with the development of acute respiratory distress syndrome. Leumedins act directly on leukocytes to inhibit the up-regulated expression of beta2-integrins involved in leukocyte adhesion. We examined the effect of such a new anti-inflammatory agent, NPC 15669 (N-[9H-(2,7-dimethylfluorenyl-9-methoxy)-carbonyl]-L-leucine), on neutrophil-mediated acute lung injury in an animal model.

Design: Prospective, randomized, blinded, controlled animal study.

Setting: An animal laboratory in a university setting.

Subjects: Adult New Zealand rabbits.

Interventions: After repeated lung lavages with normal saline to induce acute lung injury, anesthetized rabbits were randomly assigned to one of two groups (n = 6 per group): a) treatment group (pretreated with NPC 15669 [10 mg/kg i.v. bolus] 30 mins before lavage, followed by a continuous infusion [5 mg/kg/hr] for the duration [4 hrs] of the experiment); or b) control group (pretreatment and continuous infusion with placebo). All animals were mechanically ventilated with identical pressure settings over 4 hrs and were killed at the end of the experiment.

Measurements and main results: PaO2, PaCO2, and tidal volumes were repeatedly measured and airway pressure settings were noted every 30 mins. At the end of the experiment, lungs were taken out for measurements of the myeloperoxidase content, for conventional histology (hematoxylin and eosin staining), and for intracellular adhesion molecule-1 immunohistostaining. Pretreatment with NPC 15669 profoundly improved oxygenation from a PaO2 of 52 +/- 5 torr (6.9 +/- 0.7 kPa) to 250 +/- 161 torr (33.3 +/- 21.5 kPa) within 60 mins after lung lavage (p < .05). Oxygenation continued to improve throughout the study, reaching a maximal PaO2 value of 395 +/- 98 torr (52.7 +/- 13.1 kPa) at 4 hrs. In the control group, oxygenation remained poor throughout the observation period. PaO2 values differed significantly (51 +/- 20 torr [6.8 +/- 2.7 kPa] vs. 306 +/- 126 torr [40.8 +/- 16.8 kPa], p < .005) at 90 mins and at all subsequent measurements from those values in the NPC 15669 group. Dynamic lung compliance improved significantly 60 to 90 mins after repeated lung lavage. Histology demonstrated markedly less lung damage (hyaline membrane formation and leukocyte infiltration) in treated animals (p < .05) than in controls.

Conclusions: NPC 15669 seems to block inflammatory reactions by inhibiting the sequestration of neutrophils in acute, ventilator-associated lung injury. As a result, gas exchange and total lung compliance improve. Application of this and similar compounds affecting neutrophil adhesion warrants further investigation as a treatment modality for acute lung injury.