title: Therapeutic time window for angiotensin-(1-7) in acute lung injury.
abstract: There is presently no proven pharmacological therapy for the acute respiratory distress syndrome. Recently, we and others discovered that the heptapeptide angiotensin-(1-7) [Ang-(1-7)] shows significant beneficial effects in preclinical models of acute lung injury (ALI). Here, we aimed to identify the best time window for Ang-(1-7) administration to protect rats from oleic acid (OA) induced ALI.
  
  
  
  The effects of i.v. infused Ang-(1-7) were examined over four different time windows before or after induction of ALI in male Sprague-Dawley rats. Haemodynamic effects were continuously monitored, and loss of barrier function, inflammation and lung peptidase activities were measured as experimental endpoints.
  
  
  
  Ang-(1-7) infusion provided the best protection against experimental ALI when administered by continuous infusion starting immediately after 30 min OA infusion till the end of the experiment (30-240 min). Both pretreatment (-60 to 0 min before OA) and short-term therapy (30-90 min) also had beneficial effects although less pronounced than the effects achieved with the optimal therapy window. Starting infusion of Ang-(1-7) 60 min after the end of OA treatment (90-240 min) did not protect barrier function or haemodynamics but still reduced myeloperoxidase activity and increased ACE2/ACE activity ratio respectively.
  
  
  
  Our findings indicate that early initiation of therapy after ALI and continuous drug delivery are most beneficial for optimal therapeutic efficiency of Ang-(1-7) treatment in experimental ALI and, presumably accordingly, in clinical acute respiratory distress syndrome.
authors.affiliation: Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Supé
authors.affiliation: Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Center for Perinatal Medicine, Clinic of Paediatric Surgery, University of Leipzig, Leipzig, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Kohse
authors.affiliation: Department of Cardiac Pathobiology, Excellence Cluster Cardiopulmonary System, Gießen, Germany.|Department of Nephrology-MK3, University Hospital Dresden, Dresden, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Gembardt
authors.affiliation: Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, ON, Canada.|Departments of Physiology and Surgery, University of Toronto, Ontario, Canada.|German Heart Institute, Berlin, Germany.
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
authors.affiliation: Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.|Center for Perinatal Medicine, Department of Obstetrics, University of Leipzig, Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy*; D000803:Angiotensin I / Q000008:administration & dosage* / Q000627:therapeutic use*; D000818:Animals; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D019301:Oleic Acid; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D010446:Peptide Fragments; D019301:Oleic Acid; D000803:Angiotensin I; C118790:angiotensin I (1-7)