Targeting the ACE/Ang II Axis with Captopril Attenuates Neuroinflammation and Cerebral Injury Following Fat Embolism.

Background

Fat embolism (FE) is a severe complication following long-bone fractures. While the initial mechanical insult primarily affects the pulmonary vasculature, the subsequent systemic hypoxia and inflammatory cascades frequently lead to cerebral fat embolism (CFE). This progression highlights a critical, yet under-explored, pathogenic crosstalk within the lung-brain axis. The Renin-Angiotensin System (RAS), particularly the Angiotensin-Converting Enzyme (ACE)/Angiotensin II (Ang II) pathway, is a potent driver of inflammation and is highly expressed in both pulmonary and cerebral tissues. This study aimed to investigate whether modulating this axis with captopril, a specific ACE inhibitor, could attenuate the lung-brain inflammatory crosstalk and protect against CFE-induced neuroinflammation.

Methods

FE was induced in rats via intravenous injection of fat micelles. Captopril (1, 5, 10, or 20 mg/kg) was administered immediately post-induction. Brain injury was assessed using Oil Red O and H&E staining, brain water content, and malondialdehyde (MDA) assays. ACE expression and localization were evaluated via Western blot and immunofluorescence. The RAS balance was assessed by quantifying Ang II and Ang-(1-7) levels using ELISA. Inflammatory and hypoxic markers, including iNOS, HIF-1α, and phosphorylated ERK (p-ERK), were analyzed by Western blot.

Results

In this study, we observed rapid microvascular occlusion, brain edema, and neuronal damage within 2 h. FE triggered a significant upregulation of ACE, predominantly localized in cortical astrocytes, alongside elevated oxidative stress (MDA) and Ang II levels. Systemic administration of captopril (5 mg/kg) significantly mitigated these cerebral injuries. Captopril not only suppressed local astrocytic ACE expression and Ang II release but also restored the neuroprotective Angiotensin-(1-7) levels. Furthermore, captopril effectively blunted the hypoxia-driven inflammatory cascades, significantly downregulating iNOS expression and the HIF-1α/VEGF/ERK signaling pathway.

Conclusions

Our findings suggest that CFE is a consequence of dysregulated lung-brain axis communication, driven by hypoxia and RAS overactivation. By inhibiting ACE, captopril effectively modulates this axis, reducing oxidative stress and neuroinflammation. Targeting the ACE/Ang II pathway represents a promising therapeutic strategy for managing the neurological complications of FE syndrome.