THE PROTECTIVE EFFECTS OF ALISKIREN ON LUNG HISTOPATHOLOGY AFTER TRIOLEIN-INDUCED FAT EMBOLISM IN RATS

Abstract

Background: Fat embolization (FE) and the consequent fat embolism syndrome (FES) remain poorly understood complications of skeletal and other major trauma. While FE and FES can lead to major pulmonary damage including ARDS and death, current treatment of FES is limited to supportive therapy. The renin angiotensin system (RAS) plays a significant role in the pathophysiology of FE, and drugs interfering with the RAS, captopril and losartan, have reduced histopathologic pulmonary damage in a rat model of FE. In this study, we examine the potential therapeutic effects of aliskiren, a direct renin inhibitor, on lung histopathology following FE. Methods: A model of FE was created in unanesthetized rats using intravenous injection of the neutral fat triolein. Intraperitoneal injections of aliskiren at either 50 mg/kg or 100 mg/kg were performed one hour after FE induction via triolein. Rats were euthanized at 48 hours, and various pathology stains and methods were used to study and compare the lungs of these animals. Results: The lungs of the triolein only treated animals showed severe gross and histopathologic damage which was mitigated by aliskiren. (1) Fibrosis: Rats treated with triolein alone showed significant fibrotic changes with increased collagen and myofibroblast activation (p < 0.01). Aliskiren blocked this inflammatory and profibrotic process to a level indistinguishable from the controls (p < 0.01). (2) Fat: Rats treated with triolein alone showed a statistically significant increase in fat (p < 0.01) with subsequent aliskiren administration at both doses reducing the size, distribution, and amount of fat droplets (p<0.01). (3) Vasculitis: There was a trend in reduced lumen patency in the triolein only treated animals which improved after aliskiren treatment. Conclusions: Aliskiren protected the lungs of these rats from FE-induced pulmonary damage at 48 hours. Clinical implications include the use of aliskiren both prophylactically (before certain orthopedic procedures) and therapeutically (after severe trauma) to prevent the consequent severe pulmonary fibrosis of FE.