Association between age-dependent changes in the pulmonary renin angiotensin system and severity of lung injury

Abstract

Background: A growing body of evidence indicates that age plays a critical role in the development and outcome of ARDS. However, the molecular mechanisms linking aging with ARDS have not been elucidated. An age-dependent imbalance in the pulmonary renin-angiotensin system (RAS) might form an explanation. Objectives: We investigated whether there are age-related changes in the pulmonary RAS in an animal model of acute lung injury (ALI). We hypothesized that during ALI, aging is associated with a shift from the lung protective pathway [Angiotensin converting enzyme (ACE) 2] to the lung injurious pathway [ACE], thereby increasing the inflammatory mediator response and lung injury. Methods: Lung injury was induced in rats of four different age groups (infants, juveniles, adults, and elderly) by intratracheal administration of LPS and mechanical ventilation. Results: With increasing age, ACE activity in bronchoalveolar lavage fluid increased (from 0.05 RFU/min in infants to 0.16 RFU/min in elderly; p for trend = 0.02). In contrast, membrane-bound ACE activity in lung-homogenate declined, indicating shedding. No changes in ACE2 activity were found, thereby shifting the balance in the alveolar compartment towards the injurious pathway. This age-dependent imbalance was associated with increased inflammatory mediator response and lung injury (wet-to-dry ratio and histology). Conclusions: Our data shows that increasing age is associated with higher ACE activity in the alveolar compartment which correlates with aggravated inflammation and lung injury. These changes should be taken into account in terms of dosing and effectiveness of RAS modulating agents for treatment of ARDS.