Qi Shi,1,* Tingting Hu,2,* Lixia Xu,2,* Jiayuanyuan Fu,1 Yehong Fang,1 Yu Lan,1 Weijia Fan,2 Qiaoli Wu,2 Xiaoguang Tong,1– 3 Hua Yan1– 3 

1Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, 300070, People’s Republic of China; 2Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin, 300350, People’s Republic of China; 3Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, 300350, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Hua Yan, Clinical College of Neurology, Neurosurgery and Neurorehabilitation, Tianjin Medical University, Tianjin, 300070, People’s Republic of China, Email yanh2023@tmu.edu.cn

Background: Acute lung injury (ALI) is a serious yet common complication in patients with traumatic brain injury (TBI), often associated with poor prognosis. The development of TBI-induced ALI is closely associated with excessive oxidative stress and NLRP3 inflammasome activation. Fingolimod, an immunomodulatory agent, has been reported to attenuate inflammatory responses, restore blood-brain barrier integrity, reduce cerebral edema, and mitigate associated neurological deficits.
Objective: This study aimed to investigate the mechanistic role of NLRP3 inflammasome activation in TBI-induced ALI and to evaluate the therapeutic potential of fingolimod in targeting this inflammatory pathway.
Results: A rat TBI model was established using the classical free-fall method, and animals were treated with fingolimod (0.5 or 1 mg/kg) daily for three days. The TBI model rats presented with clear signs of histopathological pulmonary damage, an increase in the permeability of capillaries in the lung, and pulmonary edema that coincided with significantly increased NLRP3, caspase-1, and ASC expression in lung tissue samples. This overexpression of NLRP3 inflammasome machinery resulted in the release of IL-1β. Fingolimod treatment, however, reversed all of these effects such that it suppressed NLRP3 activity and normalized levels of IL-1β, leading to the alleviation of inflammation. In line with these results, LPS and nigericin (NLRP3 agonist)-treated NR8383 cells treated using fingolimod exhibited reductions in reactive oxygen species production and NLRP3 inflammasome activation.
Conclusion: These findings suggest that NLRP3 inflammasome activation and oxidative stress are key mediators of TBI-induced ALI. Fingolimod exerts protective effects against this condition by inhibiting NLRP3 inflammasome activation, highlighting its potential as a therapeutic agent for TBI-associated pulmonary complications.

Keywords: traumatic brain injury, acute lung injury, fingolimod, NLRP3 inflammasomes, reactive oxygen species