Physiology, imaging and proteomics of non-ventilated vs. non-perfused lung injury: an experimental study

Background: The exclusion of one lung from ventilation or pulmonary artery perfusion triggers pathological mechanisms that can lead to lung injury. Although the final effect is similar for both insults, the underlying mechanisms may differ. Primary aim of this study was to compare severity of lung injury between non-ventilated (NVLI) and non-perfused (NPLI) lung injury. Secondary aims were to compare physiologic, imaging and proteomic signatures of NVLI vs NPLI. Methods: Sedated and paralyzed healthy female piglets (weight = 36 ± 5 kg) were mechanically ventilated for 24 h after left pulmonary artery ligation (NPLI group, n = 11) or exclusion from ventilation of the left lung (NVLI group, n = 10). Physiological data including electrical impedance tomography imaging of regional ventilation and perfusion were collected. Histological scoring was performed blindly as well as proteomic analysis of broncho-alveolar lavage (BAL) fluids and lung tissue samples at the end of the experiment. Results: The left lung of both groups received similarly low fraction (< 20%) of blood flow. The left side of the NPLI group was characterized by ventilation distributed only to the dead space and high ventilation/perfusion compartments, while the left lung of the NVLI group was characterized by perfusion only to the shunt compartment. The left lung of the NVLI group showed severe pulmonary vascular dysfunction (pulmonary vascular resistance > 2000 dyne/s/cm−5), while the left lung of the NPLI group was ventilated with raising inspiratory stress (driving pressure > 20 cmH2O at the end of the experiment and progressive decline in left lung compliance). The histologic lung injury score was higher for the left lung of the NVLI group compared to the left lung of the NPLI (left histological score: 10.3 ± 2.0 vs 6.4 ± 1.6, p < 0.0001), and pro-inflammatory alveolar cytokines were similarly more expressed in the left lung of the NVLI versus NPLI group (IL-1β: 418 ± 416 vs 53 ± 71, p < 0.001; IL-6: 406 ± 455 vs 99 ± 93, p = 0.036). Proteomic analysis showed signature specific for the two injuries, with two proteins, namely PRDX5 and DCTN1, being upregulated in NVLI left lung compared with the left NPLI lung. The right lung developed injury only in the NVLI group (right histological score: 5.5 ± 1.9 vs 3.0 ± 0.7, p < 0.001). Conclusions: Lung injury is more severe in terms of lung histological score in the collapsed lung of the NVLI group and involves also contralateral areas. At the mechanistic level, NVLI has specific physiologic mechanisms like vascular dysfunction and inflammation and presents unique proteomic profile in comparison to NPLI.