Injurious ventilation has an age-dependent affect on the pulmonary renin-angiotensin system in LPS-challenged rats

Introduction

The underlying molecular mechanisms for the association between aging and a higher susceptibility to develop ARDS are poorly understood. The pulmonary renin-angiotensin system (RAS), with a lung-protective (angiotensin-converting enzyme (ACE)2-angiotensin (Ang)-1,7-Mas receptor) axis and a lung-injurious (ACE-Ang II-Ang II receptor (AT1)) axis, has been implicated in the pathogenesis of ARDS and changes with age. We hypothesized that injurious ventilation has an age-dependent effect on the pulmonary RAS in LPS-challenged rats that is associated with increased lung injury.

Methods

Infant (~1/2 month), juvenile (~1 month), adult (~4 months) and older (~19 months) Wistar rats were challenged with intratracheal LPS and injurious ventilation using tidal volumes of15 ml/kg for 4 hours. Lung injury was assessed by wet-to-dry ratio and changes in P/F ratio. Levels of inflammatory mediators were measured in bronchoalveolar lavage fluid; mRNA expression of key genes of the pulmonary RAS was determined in lung homogenates.

Results

LPS-challenged and ventilated older rats showed higher mortality, larger change in wet-to-dry ratio and larger decline in P/F ratio, compared with other age groups. Increases in neutrophil influx and inflammatory mediators were age dependent, with higher levels with increasing age. Compared with controls, ventilated LPS- challenged rats showed a decrease in mRNA expression of ACE, ACE2, AT-1 and Mas receptor in all age groups, except for infants. The relative decrease in the mRNA expression of the Mas receptor was most extensive in older rats, thereby shifting the balance towards the lung injurious axis in this age group.

Conclusion

The effects of injurious ventilation on lung injury are age dependent in a model of LPS-challenged rats, which is associated with a more pronounced imbalance of the pulmonary RAS at the expense of the lung-protective axis with increasing age.