Rationale: Reopening the injured lung with deep inflation (DI) and positive end-expiratory pressure (PEEP) likely depends on the duration and severity of acute lung injury (ALI), key features of which include increased alveolar permeability and fibrin accumulation. We hypothesized that the response to DI and PEEP would worsen as ALI evolves, and that this would correspond with increasing accumulation of alveolar fibrin. Methods: C57BL/6 mice were anesthetized and aspirated 75µL of HCl (pH 1.8) or buffered normal saline. Subgroups were re-anesthetized 4, 14, 24, and 48 hours later. Following DI, tissue damping (G) and elastance (H) were measured periodically at PEEP of 1, 3, and 6 cmH₂O, and air within the lung (V_TG) was quantified by micro-computed tomography (CT). Results: Following DI, G and H increased with time during progressive lung derecruitment, the latter confirmed by micro-CT. The rise in H was greater in acid-injured mice than in controls (p<0.05), and also increased from 4 to 48 hours after acid aspiration, reflecting progressively worsening injury. The rise in H was reduced by PEEP, but this effect was significantly blunted by 48 hours (p<0.05), also confirmed by V_TG. Lung permeability and alveolar fibrin also increased over the 48 hour study period, accompanied by increasing levels and transcription of the fibrinolysis inhibitor plasminogen activator inhibitor-1. Conclusions: Lung injury worsens progressively in mice during the 48 hours following acid aspiration. This injury manifests as progressively increasing alveolar instability, likely due to surfactant dysfunction caused by increasing levels of alveolar protein and fibrin.