title: Angiotensin-(1-7) improves oxygenation, while reducing cellular infiltrate and fibrosis in experimental Acute Respiratory Distress Syndrome.
abstract: BACKGROUND
  The renin-angiotensin system (RAS) plays a role in the pathogenesis of ARDS, Angiotensin II (Ang-II) contributing to the pathogenesis of inflammation and fibrogenesis. Angiotensin-(1-7) (Ang-(1-7)) may antagonize the effects of Ang-II. This study was aimed at evaluating the potential for Ang-(1-7) to reduce injury, inflammation and fibrosis in an experimental model of ARDS in the acute and late phases.
  
  
  METHODS
  Male Sprague Dawley rats underwent an instillation of 0.1 M hydrochloric acid (HCl, 2.5 ml/kg) into the right bronchus. In an acute ARDS study, acid-injured rats were subjected to high stretch mechanical ventilation (18 ml/kg) for 5 h and randomized to receive an intravenous infusion of either vehicle (saline), Ang-(1-7) at low dose(0.27 μg/kg/h) (ALD), or high dose (60 μg/kg/h) (AHD) starting simultaneously with injury or 2 h afterwards. Arterial blood gas analysis and bronchoalveolar lavage (BAL) were performed to assess the injury. For the late ARDS study, after HCl instillation rats were randomized to either vehicle or high dose Ang-(1-7) (300 μg/kg/day) infused by mini osmotic pumps for two weeks, and lung hydroxyproline content measured.
  
  
  RESULTS
  In the acute ARDS study, Ang-(1-7) led to a significant improvement in oxygenation (PaO2/FiO2 : vehicle 359 ± 86; ALD 436 ± 72; AHD 44 442 ± 56; ANOVA p = 0.007) and reduced white blood cells counts (vehicle 4,519 ± 2,234; ALD 2,496 ± 621; AHD 2,744 ± 119/mm(3); ANOVA p = 0.004). Only treatment with high dose Ang-(1-7) reduced inflammatory cell numbers in BAL (vehicle 127 ± 34; AHD 96 ± 34/ μl; p = 0.033). Interestingly also delayed administration of Ang-(1-7) was effective in reducing injury. In later ARDS, Ang-(1-7) decreased hydroxyproline content (649 ± 202 and 1,117 ± 297 μg/lung; p < 0.05).
  
  
  CONCLUSIONS
  Angiotensin-(1-7), decreased the severity of acute lung injury and inflammation induced by combined acid aspiration and high stretch ventilation. Furthermore, continuous infusion of Ang-(1-7) reduced lung fibrosis 2 weeks following acid aspiration injury. These results call for further research on Ang-(1-7) as possible therapy for ARDS.
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy, vanessa.zambelli@unimib.it.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Zambelli
authors.forename: Giacomo
authors.initials: G
authors.lastname: Bellani
authors.forename: Roberto
authors.initials: R
authors.lastname: Borsa
authors.forename: Federico
authors.initials: F
authors.lastname: Pozzi
authors.forename: Alice
authors.initials: A
authors.lastname: Grassi
authors.forename: Margherita
authors.initials: M
authors.lastname: Scanziani
authors.forename: Vittoria
authors.initials: V
authors.lastname: Castiglioni
authors.forename: Serge
authors.initials: S
authors.lastname: Masson
authors.forename: Alessandra
authors.initials: A
authors.lastname: Decio
authors.forename: John G
authors.initials: JG
authors.lastname: Laffey
authors.forename: Roberto
authors.initials: R
authors.lastname: Latini
authors.forename: Antonio
authors.initials: A
authors.lastname: Pesenti