Background Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), often the outcome of pneumonia and/or sepsis, are serious conditions that can lead to acute respiratory failure. ARDS is characterised by severe tissue inflammation and pulmonary oedema leading to arterial hypoxaemia. While there has been some advance in understanding the pathophysiology of ARDS, treatment options are limited. This work details a novel large animal model of ALI/ARDS intended for therapeutic efficacy studies.
Methods ALI/ARDS was induced in several sheep by pulmonary inoculation of up to 1010 CFU Streptococcus pneumoniae (log-phase culture), delivered as a bolus instillation or via nebulisation. Prior to bacterial inoculation, cannulas were surgically placed for the collection of venous and arterial blood samples to assess inflammation and monitor changes in arterial blood gases over time. In some experiments, ventilation under general anaesthesia was included to provide tighter control of breathing parameters. Bronchoalveolar lavage (BAL) was performed at the beginning and end of the experiment (48/72h post-bacterial inoculation), with post-mortem lung tissue samples collected for histopathological analyses.
Results There was a decline in PaO2 levels, indicative of mild-moderate ARDS, within 4-6h following S. pneumoniae inoculation. Due to respiratory compensation, more severe ARDS (PaO2/FiO2 <150) could only be maintained under controlled ventilation, but could be recovered with increased O2 delivery. Neutrophils were elevated in blood and BAL post-inoculation, together with cytokines IL-6, IL-8 and TNF. At post-mortem, tissue sections taken from S. pneumoniae infected lungs showed marked infiltration of neutrophils into the alveolar and interstitial spaces, and changes suggesting widespread tissue damage (increased hyaline membrane deposits, proteinaceous debris and alveolar septal thickening). Injury scores were significantly elevated in infected sheep compared to controls.
Conclusions ALI/ARDS induced in sheep by pulmonary S. pneumoniae inoculation resulted in extensive acute lung inflammation, lung injury and bronchopneumonia that was maintained through the period of experimentation (up to 72h). This included a marked decline in blood gases reflecting a state of moderate to severe ARDS, which could be sustained under controlled ventilation. This model provides unique opportunities for non-clinical investigations into emerging therapies for ARDS.