title: Age-Dependent Changes in the Pulmonary Renin-Angiotensin System Are Associated With Severity of Lung Injury in a Model of Acute Lung Injury in Rats.
abstract: OBJECTIVE
  A growing body of evidence suggests that age affects the main pathophysiologic mechanisms of the acute respiratory distress syndrome. This may imply the need for developing age-tailored therapies for acute respiratory distress syndrome. However, underlying molecular mechanisms governing age-related susceptibility first need to be unraveled. In a rat model of acute lung injury, we investigated whether age affects the balance between the two key enzymes of the pulmonary renin-angiotensin system, angiotensin-converting enzyme, and angiotensin-converting enzyme 2. We hypothesized that aging shifts the balance toward the lung injury-promoting angiotensin-converting enzyme, which may form an explanation for the differences in severity of lung injury between different age groups.
  
  
  METHODS
  Prospective, randomized controlled animal study.
  
  
  METHODS
  University medical research laboratory.
  
  
  METHODS
  Infant (15 ± 2 d), juvenile (37 ± 2 d), adult (4 ± 0.2 mo), and elderly (19.5 ± 0.5 mo) male RCCHan Wistar rats.
  
  
  METHODS
  Lung injury was induced by intratracheal administration of lipopolysaccharide (5 mg/kg) and 4 hours of mechanical ventilation (15 mL/kg).
  
  
  RESULTS
  In lipopolysaccharide-exposed and mechanical ventilated rats, angiotensin-converting enzyme activity in bronchoalveolar lavage fluid increased 3.2-fold in elderly when compared with infants. No changes in bronchoalveolar lavage fluid angiotensin-converting enzyme 2 activity were found. In addition, membrane-bound angiotensin-converting enzyme activity decreased. Together with the presence of angiotensin-converting enzyme-sheddase ADAM9 (a disintegrin and metalloproteinase domain-containing protein 9) and an age-dependent increase in tumor necrosis factor-α, an activator of ADAM9, these results indicate increased shedding of angiotensin-converting enzyme in the alveolar compartment, thereby shifting the balance toward the injurious pathway. This imbalance was associated with an increased inflammatory mediator response and more lung injury (wet-to-dry ratio and histology) in elderly rats.
  
  
  CONCLUSIONS
  Increasing age is associated with an imbalance of the pulmonary renin-angiotensin system, which correlates with aggravated inflammation and more lung injury. These changes might form the ground for new therapeutic strategies in terms of dosing and effectiveness of renin-angiotensin system-modulating agents for treatment of acute respiratory distress syndrome.
authors: 1Department of Pediatric Intensive Care, Academic Medical Center, Amsterdam, the Netherlands.2Department of Intensive Care, Academic Medical Center, Amsterdam, the Netherlands.3Laboratory of Experimental Intensive Care and Anesthesiology (LEICA), Academic Medical Center, Amsterdam, the Netherlands.4Department of Intensive Care, University Medical Center Leiden, Leiden, the Netherlands.5Department of Pediatrics, Laboratory of Neonatology, University Medical Center Leiden, Leiden, the Netherlands.6Division of Women and Child Health, Departments of Pediatric Surgery and Obstetrics, Center for Fetal Medicine, University of Leipzig, Leipzig, Germany.7Departments of Respiratory Medicine and Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.8Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands.9Department of Neonatology, Academic Medical Center, Amsterdam, the Netherlands.10Department of Pharmacology and Therapeutics, School of Medicine and School of Pharmacy, University College Cork, Cork, Ireland.
authors: Laura R A
authors: LR
authors: Schouten
authors: Hendrik J F
authors: HJ
authors: Helmerhorst
authors: Gerry T M
authors: GT
authors: Wagenaar
authors: Tom
authors: T
authors: Haltenhof
authors: René
authors: R
authors: Lutter
authors: Joris J T H
authors: JJ
authors: Roelofs
authors: Job B M
authors: JB
authors: van Woensel
authors: Anton H L C
authors: AH
authors: van Kaam
authors: Albert P
authors: AP
authors: Bos
authors: Marcus J
authors: MJ
authors: Schultz
authors: Thomas
authors: T
authors: Walther
authors: Roelie M
authors: RM
authors: Wösten-van Asperen
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000503:physiopathology*; D000367:Age Factors; D000818:Animals; D008168:Lung / Q000503:physiopathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000502:physiology*; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000503:physiopathology