Abstract
BackgroundThe renin-angiotensin system (RAS) plays a role in the pathogenesis of ARDS, Angiotensin II (Ang-II) contributing to the pathogenesis of inflammation and fibrogenesis. Angiotensin-(1-7) (Ang-(1-7)) may antagonize the effects of Ang-II. This study was aimed at evaluating the potential for Ang-(1-7) to reduce injury, inflammation and fibrosis in an experimental model of ARDS in the acute and late phases.MethodsMale Sprague Dawley rats underwent an instillation of 0.1 M hydrochloric acid (HCl, 2.5 ml/kg) into the right bronchus. In an acute ARDS study, acid-injured rats were subjected to high stretch mechanical ventilation (18 ml/kg) for 5 h and randomized to receive an intravenous infusion of either vehicle (saline), Ang-(1-7) at low dose(0.27 μg/kg/h) (ALD), or high dose (60 μg/kg/h) (AHD) starting simultaneously with injury or 2 h afterwards. Arterial blood gas analysis and bronchoalveolar lavage (BAL) were performed to assess the injury. For the late ARDS study, after HCl instillation rats were randomized to either vehicle or high dose Ang-(1-7) (300 μg/kg/day) infused by mini osmotic pumps for two weeks, and lung hydroxyproline content measured.ResultsIn the acute ARDS study, Ang-(1-7) led to a significant improvement in oxygenation (PaO2/FiO2 : vehicle 359 ± 86; ALD 436 ± 72; AHD 44 442 ± 56; ANOVA p = 0.007) and reduced white blood cells counts (vehicle 4,519 ± 2,234; ALD 2,496 ± 621; AHD 2,744 ± 119/mm3; ANOVA p = 0.004). Only treatment with high dose Ang-(1-7) reduced inflammatory cell numbers in BAL (vehicle 127 ± 34; AHD 96 ± 34/ μl; p = 0.033). Interestingly also delayed administration of Ang-(1-7) was effective in reducing injury. In later ARDS, Ang-(1-7) decreased hydroxyproline content (649 ± 202 and 1,117 ± 297 μg/lung; p < 0.05).ConclusionsAngiotensin-(1-7), decreased the severity of acute lung injury and inflammation induced by combined acid aspiration and high stretch ventilation. Furthermore, continuous infusion of Ang-(1-7) reduced lung fibrosis 2 weeks following acid aspiration injury. These results call for further research on Ang-(1-7) as possible therapy for ARDS.
Highlights
The renin-angiotensin system (RAS) plays a role in the pathogenesis of Acute Respiratory Distress Syndrome (ARDS), Angiotensin II (Ang-II) contributing to the pathogenesis of inflammation and fibrogenesis
The pathogenesis of ARDS can be influenced by the activation of the reninangiotensin system (RAS), a well-known hormonal system involved in the regulation of blood pressure homeostasis and fluid and salt balance
Acute ARDS study: two-hit model Animals were anesthetized with Ketamine 100 mg/kg and Xylazine 4 mg/kg (Ketavet 100, Intervet Productions, Aprilia, Latina, Italy; Rompun 2%, Bayer, Milano, Italy), orotracheally intubated and subjected to high stretch ventilation (Inspira ASV, Harvard Apparatus, Holliston, MA, USA) with the following parameters: tidal volume 18 ml/kg; respiratory rate 35/min; PEEP 2 to 2.5 cmH2O; inspiration to expiration ratio (I/E) 35%; fraction of inspired oxygen (FiO2) 0.5
Summary
The renin-angiotensin system (RAS) plays a role in the pathogenesis of ARDS, Angiotensin II (Ang-II) contributing to the pathogenesis of inflammation and fibrogenesis. Angiotensin-(1-7) (Ang-(1-7)) may antagonize the effects of Ang-II. This study was aimed at evaluating the potential for Ang-(1-7) to reduce injury, inflammation and fibrosis in an experimental model of ARDS in the acute and late phases. The pathogenesis of ARDS can be influenced by the activation of the reninangiotensin system (RAS), a well-known hormonal system involved in the regulation of blood pressure homeostasis and fluid and salt balance. The activation of Ang-II and its receptor angiotensin II receptor type 1 (AT1R) plays a role in the pathophysiology of several diseases, including atherosclerosis, myocardial infarction, stroke, diabetes, nephrosclerosis, and tumorigenesis [5]. An association has been demonstrated between ACE polymorphism and the susceptibility, progression and outcome in ARDS [6,7,8,9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
