Ventilator-Induced Inflammatory Response in Lipopolysaccharide-Exposed Rat Lung Is Mediated by Angiotensin-Converting Enzyme

Angiotensin-converting enzyme (ACE) mediates the ventilator-induced inflammatory response in healthy lungs via angiotensin II (Ang II). A rat model was used to examine the role of ACE and Ang II in the inflammatory response during mechanical ventilation of preinjured (ie, lipopolysaccharide [LPS]-exposed) lungs. When indicated, rats were pretreated with the ACE inhibitor captopril and/or intratracheal administration of LPS. The animals were ventilated for 4 hours with moderate pressure amplitudes. Nonventilated animals served as controls. ACE activity and levels of Ang II and inflammatory mediators (interleukin-6, Cytokine-induced Neutrophil Chemoattractant (CINC)-3, interleukin-1β, and interleukin-10) were determined in bronchoalveolar lavage fluid (BALF). The localization of ACE and Ang II type 1 receptor in lung tissue was determined by immunohistochemistry. The role of the Ang II pathway was assessed by using its receptor antagonist Losartan. Mechanical ventilation of LPS-exposed animals increased ACE activity and levels of inflammatory mediators in BALF compared with ventilated nonexposed and LPS-exposed nonventilated animals. Blocking ACE by captopril attenuated the lung inflammatory response. Furthermore, increased ACE activity in BALF was accompanied by increased levels of Ang II and enhanced expression of its receptor on alveolar cells. Blocking the Ang II receptor attenuated the inflammatory mediator response to a larger extent than by blocking ACE. In conclusion, during mechanical ventilation ACE, via Ang II, mediates the inflammatory response of both healthy and preinjured lungs.Acute respiratory distress syndrome (ARDS) is the most severe form of acute lung injury (ALI) and is characterized by severe hypoxemia, diffuse alveolar injury, pulmonary edema, and an excessive inflammatory response.¹ Although mechanical ventilation (MV) can be life-saving for patients with ALI/ARDS, it may induce lung injury, known as ventilator-induced lung injury (VILI), with characteristics similar to that caused by ARDS.^2,3,4 Mechanical ventilation of animals with lungs preinjured by intratracheal instillation of bacterial components such as lipopolysaccharide (LPS) resulted in markedly higher inflammatory responses compared with ventilated animals without preinjured lungs.^5,6,7,8Clinical and experimental studies found an association between the renin-angiotensin system (RAS) and ALI/ARDS.^9,10 RAS also plays a key role in the injurious effects of mechanical ventilation.^11,12 In healthy rats, inhibition of the RAS component angiotensin-converting enzyme (ACE) attenuated inflammation and lung injury during mechanical ventilation with high tidal volumes.¹¹ The effect of ACE on the inflammatory response may be explained by the fact that ACE generates the key factor of the RAS, angiotensin II (Ang II). Ang II stimulates expression of proinflammatory mediators such as interleukin-8/Cytokine-induced Neutrophil Chemoattractant (CINC)-3 and interleukin-6 via the type 1 and type 2 Ang II receptors.^13,14,15 Indeed, a similar attenuation of the inflammatory response was obtained during injurious mechanical ventilation by blocking the Ang II receptor or by treating with an ACE inhibitor.^11,12The present study investigates whether ACE mediates the exaggerated inflammatory response to mechanical ventilation of LPS-exposed lungs as reflected by inflammatory mediator levels in bronchoalveolar lavage fluid (BALF), and whether ACE inhibition dampens this response. The role of Ang II in this process was also assessed by using its specific receptor antagonist.