The renin inhibitor aliskiren protects rat lungs from the histopathologic effects of fat embolism.

BACKGROUND: Fat embolism (FE) and the consequent FE syndrome occurring after trauma or surgery can lead to serious pulmonary injury, including ARDS and death. Current treatment of FE syndrome is limited to supportive therapy. We have shown in a rat model that the renin angiotensin system plays a significant role in the pathophysiology of FE because drugs interfering with the renin angiotensin system, captopril and losartan reduce the histopathologic pulmonary damage. The purpose of the current study was to determine if inhibition of renin by aliskiren, an FDA-approved drug for treating hypertension, would produce effective protection in the same model. METHODS: The FE model used intravenous injection of the neutral fat triolein in unanesthetized rats. Intraperitoneal injections of saline or aliskiren at either 50 or 100 mg/kg were performed 1 hour after FE induction via triolein. Rats were euthanized at 48 hours, and various histologic stains were used to examine the lungs. RESULTS: (1) Fibrosis: rats treated with triolein showed significant fibrotic changes with increased collagen and myofibroblast activation (p < 0.0001 for both trichrome and α-smooth muscle actin staining). Aliskiren blocked this inflammatory and profibrotic process to a level indistinguishable from the controls (p < 0.0001 for both trichrome and α-smooth muscle actin staining). (2) Fat: rats treated with triolein showed a statistically significant increase in fat (p = 0.0006). Subsequent aliskiren administration at both doses reduced the size, distribution, and amount of fat droplets (low dose, p = 0.0095; high dose, p = 0.0028). (3) Vessel patency: the low dose of aliskiren blocked the reduction of lumen patency observed after triolein administration (p = 0.0058). CONCLUSIONS: Aliskiren protected the lungs of rats from gross and histopathologic 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 pathologic sequelae.

Persistent and progressive pulmonary fibrotic changes in a model of fat embolism.

BACKGROUND: Fat embolism (FE) after trauma and some orthopedic procedures is known to cause acute lung injury, including acute respiratory distress syndrome. However, its potential long-term effects on the lung are unknown. A previous study using a rat model of FE found significant histopathologic changes in the lungs after intravenous injection of triolein for up to 11 days. This study detailed the persistence of the lung damage and investigated the input of the renin-angiotensin system in its pathology. METHODS: Unanesthetized rats were injected via the tail vein with 0.2 mL saline or triolein. After euthanasia, at 3 weeks or 6 weeks, lung sections were stained to highlight cellular structure, presence of collagen and fat, or immunolabeled for smooth muscle actin or angiotensin peptides. RESULTS: At 3 weeks or 6 weeks after triolein injection, there was no dilatation of the heart or inferior vena cava, no congestion of the liver or spleen, no adventitial edema, nor was fluid present in alveoli or pleural cavity as reported in animals at earlier time points. Persisting pathology included reduced lumen patency, thickening of the media of small arteries and arterioles, and vascular and septal inflammation. Although the fat content of the lung decreased from week 3 to week 6, there was a progressive increase in collagen, smooth muscle actin, and angiotensin peptides. CONCLUSIONS: This model extends the effect of FE on pulmonary pathology to 6 weeks, revealing persistent vasculitis, septal inflammation, and progressive fibrotic changes which are associated with increased presence of angiotensin peptides.

Mitigating effects of captopril and losartan on lung histopathology in a rat model of fat embolism.

BACKGROUND: Fat embolization (FE) is an often overlooked and poorly understood complication of skeletal trauma and some orthopedic procedures. Fat embolism can lead to major pulmonary damage associated with fat embolism syndrome (FES). METHODS: A model of FE in unanesthetized rats, using intravenous injection of the neutral fat triolein, was used to study the potential therapeutic effect on lung histopathology of altering the production of, or response to, endogenous angiotensin (Ang) II. Either captopril, an Ang I converting enzyme inhibitor, or losartan, an Ang II type 1 receptor blocker, was injected 1 hour after FE by triolein injection. After euthanasia at 48 hours, histopathologic evaluation was used to compare the drug-treated animals with control animals that received only triolein. RESULTS: Histology of the lungs of rats treated only with triolein revealed severe, diffuse pathology. Alveolar septa showed severe, diffuse inflammation. Bronchial lumina showed severe mucosal epithelial loss. The media of the pulmonary small arteries and arterioles was thicker, and the lumen patency was reduced 60% to 70%. Trichrome staining confirmed the abundant presence of collagen in the media and adventitia, as well as collagen infiltrating the bronchial musculature. Both captopril and losartan treatments reduced the inflammatory, vasoconstrictor, and profibrotic effects present at 48 hours (p<0.001). With treatment, the vascular lumen remained patent, and the fat droplets were reduced in size and number. There was a reduction in the number of infiltrating leukocytes, macrophages, myofibroblasts, and eosinophils, along with a significant decrease in hemorrhage and collagen deposition (p<0.001). Pathologic changes in bronchial epithelium were also diminished. CONCLUSIONS: The results suggest that the use of drugs that act on the renin-Ang system might provide an effective and targeted therapy for fat embolism syndrome.

Fat embolism: evolution of histopathological changes in the rat lung.

The pathophysiology of Fat Embolism Syndrome (FES) is poorly understood and subject to some controversy. Evaluation of the evolution of histological changes in the lungs of patients with FES is impractical. The current theories of FES were established through acute clinical observations and acute animal experiments, but sequential changes in the histology of lungs over a prolonged period have not been made. The progressive effects of fat embolization of the lungs were examined in a rat model over a period of 11 days. Triolein, a major bone marrow fat, was administered to conscious Sprague-Dawley rats via the caudal vein. Rats were euthanized at 24, 48, 96 h, and 11 days, but some died within a few hours. Histomorphometric evaluations of lung tissue were made, including stains for fat, collagen, and smooth muscle actin. Arterial and arteriolar patency decreased progressively up to 96 h, but returned toward normal after 11 days. A striking finding was the very early presence of inflammation and fibrosis after only several hours, persisting up to 11 days. The results of this study provide evidence of both very early and prolonged changes due to fat embolization.