title: The renin inhibitor aliskiren protects rat lungs from the histopathologic effects of fat embolism.
abstract: 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.
  
  
  
  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.
  
  
  
  (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).
  
  
  
  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.
authors.affiliation: From the University of Kansas Medical Center, Department of Preventive Medicine and Public Health (A.N.F.); Department of Pathology (A.M., C.P.); Department of Internal Medicine (R.P., M.P.), University of Missouri; and Department of Pharmacology and Toxicology (A.M.P.), University of Kansas Medical Center, Kansas, MO.
authors.forename: Amanda N
authors.initials: AN
authors.lastname: Fletcher
authors.forename: Agostino
authors.initials: A
authors.lastname: Molteni
authors.forename: Rakesh
authors.initials: R
authors.lastname: Ponnapureddy
authors.forename: Chirag
authors.initials: C
authors.lastname: Patel
authors.forename: Mark
authors.initials: M
authors.lastname: Pluym
authors.forename: Alan M
authors.initials: AM
authors.lastname: Poisner
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004620:Embolism, Fat / Q000517:prevention & control*; D005650:Fumarates / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D014304:Triolein / Q000494:pharmacology
chemical_list: D000577:Amides; D005650:Fumarates; D014304:Triolein; C446481:aliskiren