A Novel Swine Model of the Acute Respiratory Distress Syndrome Using Clinically-Relevant Injury Exposures

Abstract

To date, existing animal models of the acute respiratory distress syndrome (ARDS) have failed to translate preclinical discoveries into effective pharmacotherapy or diagnostic biomarkers. To address this translational gap, we developed a high-fidelity swine model of ARDS utilizing clinically-relevant lung injury exposures. Fourteen male swine were anesthetized, mechanically ventilated, and surgically instrumented for hemodynamic monitoring, blood, and tissue sampling. Animals were allocated to one of three groups: 1) Indirect lung injury only: animals were inoculated by direct injection of E. coli into the kidney parenchyma, provoking systemic inflammation and distributive shock physiology; 2) Direct lung injury only: animals received volutrauma, hyperoxia, and bronchoscope-delivered gastric particles; 3) Combined indirect and direct lung injury: animals were administered both above-described indirect and direct lung injury exposures. Animals were monitored for up to 12 hours, with serial collection of physiologic data, blood samples, and radiographic imaging. Lung tissue was acquired post-mortem for pathological examination. In contrast to indirect lung injury only and direct lung injury only groups, animals in the combined indirect and direct lung injury group exhibited all of the physiological, radiographic, and histopathologic hallmarks of human ARDS: impaired gas exchange (mean PaO2/FiO2 ratio 124.8 ± 63.8), diffuse bilateral opacities on chest radiographs, and extensive pathologic evidence of diffuse alveolar damage. Our novel porcine model of ARDS, built on clinically-relevant lung injury exposures, faithfully recapitulates the physiologic, radiographic, and histopathologic features of human ARDS, and fills a crucial gap in the translational study of human lung injury.

Breath analysis for detection and trajectory monitoring of acute respiratory distress syndrome in swine

“…We used a recently-described swine model of ARDS that uses clinically-relevant exposures (sepsis, hyperoxia, volutrauma, and aspiration) and faithfully recapitulates the physiologic, radiographic, and histopathologic features of ARDS [15]. As reported recently, this model fulfills both clinical criteria (Berlin Definition) [9] and experimental criteria for animal models of ARDS [21].…”

“…All procedures were carried out in compliance with the university's institutional standards for care and use of laboratory animals in accordance with NIH guidelines [22]. Detailed physiologic data regarding these animals has previously been published [15]. Animals were fasted overnight with libitum access to water and on the day of the experiment, anesthesia was induced.…”

“…The anesthesia level was monitored for the experiment's duration by assessing corneal reflex, jaw tension, and hemodynamics, including blood pressure, heart rate, and respiratory rate. More details for animal preparation can be found in [15,23].…”

“…Animals were subjected to systemic infection via an injection of E. Coli into the kidney parenchyma (3.5 x 10 11 CFU Strain CFT073 E. Coli in a total of approximately 5 mL at a rate of 0.333 mL/min) as previously described [15,23]. Lung injury was induced utilizing a combination of volume-trauma (tidal volumes of 15 mL/kg), hyperoxia (100% FiO2), and the instillation of gastric particles (1-2 mL/kg) into the airways via bronchoscope [24].…”

“…In our present work, we overcame the aforementioned limitations by using a newly developed and optimized the swine model of ARDS that accurately recapitulates the human conditions [15].…”