In conclusion, during mechanical ventilation ACE, via Ang II, mediates the inflammatory response of both healthy and preinjured lungs. Acute respiratory stress 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 air flow (MV) can be Caerulomycin A life-saving for individuals 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 air flow of animals with lungs preinjured by intratracheal instillation of bacterial parts such as lipopolysaccharide (LPS) resulted in markedly higher inflammatory reactions compared with ventilated animals without preinjured lungs.5,6,7,8 Clinical and experimental studies found an association between the renin-angiotensin system (RAS) and ALI/ARDS.9,10 RAS also takes on a key part in the injurious effects of mechanical ventilation.11,12 In healthy rats, inhibition of the RAS component angiotensin-converting enzyme (ACE) attenuated swelling and lung injury during mechanical air flow with high tidal quantities.11 The effect of ACE within the inflammatory response may be explained by the fact that ACE generates the key factor of the RAS, angiotensin II (Ang II). II pathway was assessed by using its receptor antagonist Losartan. Mechanical air flow of LPS-exposed animals improved 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, improved ACE activity in BALF was accompanied by increased levels of Ang II and enhanced manifestation of its receptor on alveolar cells. Blocking the Ang II receptor attenuated the Caerulomycin A inflammatory mediator response to a larger degree than by obstructing ACE. In conclusion, during mechanical air flow 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 Caerulomycin A acute lung injury (ALI) and is characterized by severe hypoxemia, diffuse alveolar injury, pulmonary edema, and an excessive inflammatory response.1 Although mechanical air flow (MV) can be life-saving for individuals 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 air flow of animals with lungs preinjured by intratracheal instillation of bacterial parts such as lipopolysaccharide (LPS) resulted in markedly higher inflammatory reactions compared with ventilated animals without preinjured lungs.5,6,7,8 Clinical and experimental studies found an association between the renin-angiotensin system (RAS) and ALI/ARDS.9,10 RAS also takes on a key part in the injurious effects of mechanical ventilation.11,12 In healthy rats, inhibition of the RAS component angiotensin-converting enzyme (ACE) attenuated swelling and lung injury during mechanical air flow with high tidal quantities.11 The effect of ACE within 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 manifestation of proinflammatory mediators such as interleukin-8/Cytokine-induced Neutrophil Chemoattractant (CINC)-3 and interleukin-6 via the type 1 and type Rabbit polyclonal to ACOT1 2 Ang II receptors.13,14,15 Indeed, a similar attenuation of the inflammatory response was acquired during injurious mechanical ventilation by blocking the Ang II receptor or by treating with an ACE inhibitor.11,12 The present study investigates whether ACE mediates the exaggerated inflammatory response to mechanical air flow of LPS-exposed lungs as reflected by inflammatory mediator levels in bronchoalveolar lavage fluid (BALF), and whether ACE inhibition dampens this response. The part of Ang II in this process was also assessed by using its specific receptor antagonist. Materials and Methods Animal Preparation The study was authorized by the honest committee for animal experiments of the Erasmus Medical Center. The experiments were performed in a total of 81 male adult Sprague-Dawley rats, weighing 270 25 g (Harlan CPB, Zeist, The Netherlands). A tracheostomy was performed under inhalation anesthesia, and the carotid artery was catheterized. Anesthesia was managed by hourly intraperitoneal injections of pentobarbital sodium (60 mg kg?1, Nembutal; Algin BV, Maassluis, The Netherlands). Muscle relaxation was acquired with 2 mg kg?1 pancuronium bromide (Pavulon; Organon, Boxtel, The Netherlands) intramuscular hourly. Experimental Protocol From a group of 18 animals, nine were pretreated with 500 mg l?1 captopril (ACE inhibitor) in their drinking water for 5 days, and nine were not. After preparation, animals were connected to a Servo ventilator 300 (Siemens-Elema, Solar, Sweden) and ventilated for 4 hours inside a pressure controlled time-cycled mode with moderate pressure amplitudes: maximum inspiratory pressure (PIP) 26 cmH2O and positive end-expiratory pressure (PEEP) 5 cmH2O (tidal volume approximately 18 ml/kg). Respiratory rate was arranged at a rate of recurrence of 30 per min (inspiratory/expiratory percentage of 1 1:2) and, to keep up normocapnia, modified when necessary. Because oxygen requirements are usually improved in individuals with ALI/ARDS who are mechanically ventilated, we chose to study the effects of ACE inhibition on swelling in rats ventilated having a portion of inspired oxygen (FiO2) of 1 1.0. Blood gas analyses and blood pressure were recorded just before and hourly after randomization. Nonventilated animals (= 9) served as settings. To determine whether the effects of ACE inhibition on VILI were changed from the administration of an inflammatory stimulus, an additional group of 18 rats received 16 mg/kg?1 LPS (Abortus Equi S form; Metalon BmbH, Wusterhausen, Germany) intratracheally 24 hours before the air flow period. Of these LPS-exposed rats, nine were pretreated with captopril and nine were not (observe above) and all were consequently ventilated for 4 hours with the same moderate pressure amplitudes as above. Animals were sacrificed with an overdose of intra-arterial given pentobarbital sodium. Bronchial lavage was performed (= 6 per group) five instances with normal saline (30 ml/kg?1). The retrieved BALF was centrifuged.