Phosphodiesterase 4 Inhibitor Roflumilast Ameliorates Polytrauma-Induced Acute Kidney Injury by Attenuating HMGB1 and Renal Inflammatory Pathways in Rats

Traumatic injury remains a critical global health challenge, with polytrauma frequently leading to multi-organ failure and mortality. A severe complication of polytrauma is acute kidney injury (AKI), which is driven by a massive systemic inflammatory response following the initial insult. This inflammation is exacerbated by the upregulation of phosphodiesterase 4 (PDE4) enzymes; therefore, PDE4 inhibition represents a rational therapeutic strategy. Roflumilast is an FDA-approved PDE4 inhibitor currently used for chronic obstructive pulmonary disease (COPD). This study evaluated the hypothesis that roflumilast can mitigate inflammation and prevent AKI in a polytrauma rat model. Anesthetized male Sprague-Dawley rats were randomly assigned to either a vehicle control group (n=9) or a roflumilast treatment group (0.2 mg/kg, n=10). All animals underwent a polytrauma protocol—including soft tissue injury, fibula fracture, and pressure-controlled hemorrhage—followed by whole blood resuscitation and a 72-hour observation period. Rats treated with roflumilast demonstrated higher survival rates compared to injury controls (70% vs. 33%). Furthermore, roflumilast treatment significantly lowered blood urea nitrogen (BUN, p< 0.05) and renal levels of Kidney Injury Molecule-1 (KIM-1, p< 0.05). Roflumilast also significantly reduced levels of circulating High Mobility Group Box 1 (HMGB1) (p< 0.05) and the proinflammatory cytokine Macrophage Inflammatory Protein-1 alpha (MIP-1α) (p< 0.05). These findings suggest that roflumilast is a promising therapeutic agent for mitigating trauma-induced AKI by attenuating systemic inflammatory response.