Development of various forms of lung injury with increasing tidal volume in normal rats

Background: Mechanical ventilation (MV) with large tidal volumes (VT) causes lung edema, mechanical alterations, tissue lesions, and release of inflammatory markers. Objective: The aim of the present study is to explore the dependence of these events on tissue strain-stress. Methods: Sixty-three, normal, open-chest, normal rats were ventilated for 2-4 hours with VT from 7.5 (baseline ventilation) to 39.5mlkg-1 and PEEP ~2.5cmH2. Arterial blood gasses and mean pressure, and lung mechanics were measured during baseline ventilation before and after test ventilation, when cytokine, von Willebrand Factor (vWF), and albumin concentration in serum and broncho-alveolar lavage fluid (BALF), lung wet-to-dry ratio (W/D), and histologic injury scores were assessed. Main results: Elevation of W/D and serum vWF and cytokine concentration occurred with VT>25mlkg-1 and peak inflation pressure (Ppeak) >25cmH2O, whereas with VT>30mlkg-1 and Ppeak>30cmH2O, cytokine and albumin concentration increased also in BALF, arterial oxygen tension decreased, and lung mechanics and histology deteriorated, while W/D and serum vWF and cytokine concentration increased further. Conclusions: In normal rats, lung injury occurs once a definite volume and/or pressure threshold is overcome. Microvascular stress-strain failure leading to interstitial edema is the initial manifestation of injurious MV, as shown by elevated vWF and cytokine levels in serum only. Failure of the epithelial barrier with alveolar flooding occurs only at higher stress-strain levels, with inflammatory reaction, mechanical and histologic damage proportional to the concomitant edema formation.