Background: Lung cell activation and the subsequent inflammatory response play a major role in the pathophysiology of ventilator-induced lung injury (VILI), but the precise chain of events in terms of which cell types are activated and when remains unclear. We studied the detailed profile of cellular activation in the very early phase following the onset of high stretch ventilation in vivo . Methods: C57BL/6 mice were ventilated with low (8ml/kg) or high (38ml/kg) tidal volumes for 1-15 minutes. Lungs were immediately fixed and analysed by flow cytometry to measure MAP kinase pathway phosphorylation, specifically p38 and its downstream substrate MK2. Results: Endothelial cells (CD45- CD31+ CD41- CD105+) showed increased phospho-p38 and -MK2 after just 1 minute of high stretch ventilation (see table). In contrast, alveolar epithelial cells (AECs) (CD45- CD31- EpCAM+), both type 1 (T1α+ ICAM-1+) and type 2 (T1α- ICAM-1-), showed statistically significant increases only in phospho-p38 at this point. Alveolar macrophages (AMs) (CD45+ CD11b- F4/80+ CD11c+) only showed significant activation after 5 minutes of high stretch. Fluorescence intensity Phospho-p38 Phospho-MK2 Low High Low High Endothelium 5±1 9±1* 54±9 92±11* Type 1 AECs 7±2 13±1* 75±12 101±11 Type 2 AECs 9±1 16±2* 92±16 125±19 AMs 8±3 15±3 69±10 65±10 Mean±SE *p<0.05 vs Low n=7 Conclusion: Our data suggest that activation of the endothelium occurs prior to, or at least simultaneously to that of the epithelium, in response to high stretch. This almost instantaneous activation of the endothelium by stretch could directly trigger pulmonary intravascular inflammation during VILI, potentially contributing to systemic propagation of injury.
Woods et al. (Mon,) studied this question.