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Role of the renin-angiotensin system in ventilator-induced lung injury: an in vivo study in a rat model

¹ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
² Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan
³ Department of Forensic Medicine, National Taiwan University Hospital, Taipei, Taiwan
⁴ Department of Internal Medicine, Far Eastern Memorial Hospital, Pan-Chiao, Taipei, Taiwan

Correspondence to:
Correspondence to:
Professor P C Yang
Department of Internal Medicine, National Taiwan University Hospital, No 7 Chung-Shan South Road, Taipei 100, Taiwan; pcyang{at}ha.mc.ntu.edu.tw

Background: Injurious mechanical ventilation can cause a pro-inflammatory reaction in the lungs. Recent evidence suggests an association of the renin-angiotensin system (RAS) with lung inflammation. A study was undertaken to investigate the pathogenic role of the RAS in ventilator-induced lung injury (VILI) and to determine whether VILI can be attenuated by angiotensin converting enzyme (ACE) inhibition.

Methods: Male Sprague-Dawley rats were mechanically ventilated for 4 h with low (7 ml/kg) or high (40 ml/kg) tidal volumes; non-ventilated rats were used as controls. Lung injury and inflammation were measured by the lung injury score, protein leakage, myeloperoxidase activity, pro-inflammatory cytokine levels and nuclear factor (NF)-B activity. Expression of the RAS components was also assessed. Some rats were pretreated with the ACE inhibitor captopril (10 mg/kg) for 3 days or received a concomitant infusion with losartan or PD123319 (type 1 or type 2 angiotensin II receptor antagonist) during mechanical ventilation to assess possible protective effects on VILI.

Results: In the high-volume group (n = 6) the lung injury score, bronchoalveolar lavage fluid protein concentration, pro-inflammatory cytokines and NF-B activities were significantly increased compared with controls (n = 6). Lung tissue angiotensin II levels and mRNA levels of angiotensinogen and type 1 and type 2 angiotensin II receptors were also significantly increased in the high-volume group. Pretreatment with captopril or concomitant infusion with losartan or PD123319 in the high-volume group attenuated the lung injury and inflammation (n = 6 for each group).

Conclusions: The RAS is involved in the pathogenesis of ventilator-induced lung injury. ACE inhibitor or angiotensin receptor antagonists can attenuate VILI in this rat model.

Abbreviations: ACE, angiotensin converting enzyme; ACE2, angiotensin converting enzyme 2; AT1, AT2, types 1 and 2 angiotensin II receptors; BAL, bronchoalveolar lavage; JNK1, c-Jun N-terminal kinase 1; MIP-2, macrophage inflammatory protein; MPO, myeloperoxidase; MV, mechanical ventilation; NF-B, nuclear factor-B; PCNA, proliferating cell nuclear antigen; PEEP, positive end-expiratory pressure; RAS, renin-angiotensin system; RT-PCR, reverse transcription and polymerase chain reaction; TNF, tumour necrosis factor ; VILI, ventilator-induced lung injury