Objective <p>This study aimed to investigate the impact of different mechanical ventilation strategies on pulmonary plasminogen activator inhibitor-1 (PAI-1) expression in a rat model.</p> Methods <p>Seventy-two specific pathogen-free (SPF) adult male Sprague-Dawley (SD) rats were randomly assigned to four groups (<i>n</i> = 18): Group C (spontaneous breathing), group S (low tidal volume, VT = 6 mL/kg), group R (regular tidal volume, VT = 10 mL/kg), and group L (high tidal volume, VT = 40 mL/kg). Each group was further divided into three subgroups based on mechanical ventilation duration (2, 4, or 6&#xa0;h). Following tracheotomy intubation, group C maintained spontaneous breathing, while the other groups underwent mechanical ventilation with a small animal ventilator. Lung wet-to-dry weight ratios, cell apoptosis rate, and lung injury score were recorded. PAI-1 and IL-8 levels were measured in bronchoalveolar lavage fluid (BALF), and PAI-1 mRNA expression in lung tissue was analyzed using real-time polymerase chain reaction (PCR).</p> Results <p>Progressive lung tissue injury was observed in Group L with increasing ventilation durations, accompanied by significant increases in PAI-1, IL-8, and PAI-1 mRNA expression, compared to group C (<i>P</i> &lt; 0.05). No significant differences were identified between Group S and group C, while group R exhibited mild lung injury and minimal increases in PAI-1 expression, observed only after 6&#xa0;h of ventilation. In group L, PAI-1, IL-8, and PAI-1 mRNA expression increased significantly with extended ventilation durations (<i>P</i> &lt; 0.05).</p> Conclusion <p>Mechanical ventilation strategies utilizing high tidal volumes were associated with substantial increases in PAI-1 expression in rat lung tissue and BALF, with these effects exacerbated by prolonged ventilation durations. These findings suggest that high tidal volume ventilation strategies may contribute to pulmonary injury by upregulating PAI-1 expression.</p>