TY - JOUR
T1 - 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
AU - Schouten, Laura R A
AU - Helmerhorst, Hendrik J F
AU - Wagenaar, Gerry T M
AU - Haltenhof, Tom
AU - Lutter, René
AU - Roelofs, Joris J T H
AU - van Woensel, Job B M
AU - van Kaam, Anton H L C
AU - Bos, Albert P
AU - Schultz, Marcus J
AU - Walther, Thomas
AU - Wösten-van Asperen, Roelie M
PY - 2016/12
Y1 - 2016/12
N2 - OBJECTIVES: 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.DESIGN: Prospective, randomized controlled animal study.SETTING: University medical research laboratory.SUBJECTS: Infant (15 ± 2 d), juvenile (37 ± 2 d), adult (4 ± 0.2 mo), and elderly (19.5 ± 0.5 mo) male RCCHan Wistar rats.INTERVENTIONS: Lung injury was induced by intratracheal administration of lipopolysaccharide (5 mg/kg) and 4 hours of mechanical ventilation (15 mL/kg).MEASUREMENTS AND MAIN 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.
AB - OBJECTIVES: 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.DESIGN: Prospective, randomized controlled animal study.SETTING: University medical research laboratory.SUBJECTS: Infant (15 ± 2 d), juvenile (37 ± 2 d), adult (4 ± 0.2 mo), and elderly (19.5 ± 0.5 mo) male RCCHan Wistar rats.INTERVENTIONS: Lung injury was induced by intratracheal administration of lipopolysaccharide (5 mg/kg) and 4 hours of mechanical ventilation (15 mL/kg).MEASUREMENTS AND MAIN 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.
KW - acute respiratory distress syndrome
KW - aging
KW - angiotensin-converting enzyme
KW - lipopolysaccharide
KW - lung injury
KW - mechanical ventilation
U2 - 10.1097/CCM.0000000000002008
DO - 10.1097/CCM.0000000000002008
M3 - Article
C2 - 27513359
SN - 0090-3493
VL - 44
SP - e1226-e1235
JO - Critical Care Medicine
JF - Critical Care Medicine
IS - 12
ER -