A novel two-hit rodent model of postoperative acute lung injury: priming the immune system leads to an exaggerated injury after pneumonectomy.

objectivesPostoperative acute lung injury (PALI) is a rare, poorly understood, usually fatal condition, accounting for the majority of deaths following lung resection. Its low frequency and unpredictable development make the identification of the mechanisms of injury from clinical studies alone almost impossible. Multiple validated 'two-hit models' exist for ALI secondary to other causes. We describe a novel rodent 'two-hit' model of PALI: a low-grade immune stimulus, such as sepsis, greatly aggravates the injury in the remaining lung observed following pneumonectomy.

methodsUnder general anaesthesia, rats received either low-dose intratracheal lipopolysaccharide (IT-LPS) challenge (10 μg for 1 h) followed by left posterolateral thoracotomy, one-lung ventilation (OLV), pneumonectomy and 3 h of ventilation; 500 μl IT 0.9% saline followed by the same surgery or IT-LPS followed by sham surgery and ventilation. All other conditions were constant. Lung injury is heralded by neutrophil accumulation, which was determined by right lung bronchoalveolar lavage cell count. Data are presented as mean ± standard error of the mean. The T-test was used to compare normally distributed groups with correction for multiple comparisons.

resultsA dose-response curve identified the clinically relevant 'low dose' of LPS to be used in further studies. Ventilatory parameters were standardized to reflect clinical practice (volume-control, tidal volume of 6 ml/kg, positive end-expiratory pressure of 2 cmH2O, maximum airway pressure of <15 cmH2O). There was a degree of adaptation to obtain a consistent and robust model with retest validity. OLV and pneumonectomy alone produced a small lung injury (65.1 ± 5), as did 10 µg intratracheal LPS alone (50.7 ± 6.9). However, when OLV, pneumonectomy and 10 µg LPS were combined, an exaggerated injury occurred (161.4 ± 10.3), P = 0.007.

conclusionsEarly results show that a two-hit model of PALI is viable and that sepsis aggravates the response to pneumonectomy. The model is now being further characterized. Once established, this model will offer the chance to better understand PALI and to develop and test novel therapies and risk reduction strategies for the condition.