Macrophage Polarization and Endothelial Dysfunction in Response to Cigarette Smoke and Ketone Body Administration

Cigarette smoking promotes endothelial dysfunction through inflammation and macrophage polarization toward a pro-inflammatory M1 phenotype. Ketone bodies have been reported to have vascular benefits and may represent a therapeutic approach by modulating macrophage responses. This study investigated the impact of cigarette smoke on macrophage polarization and whether ketone body administration could alter these effects in an animal model.

A randomized post-test-only control group design was conducted in 20 male Wistar rats assigned to four groups: control, smoke-exposed without intervention, and smoke-exposed treated with ketone bodies at low (1.5 g/kg/day) or high (6 g/kg/day) doses. Wistar rats were exposed to cigarette smoke (40 cigarettes/day) for 4 weeks, followed by ketone body administration. Macrophage polarization was assessed by calculating the M1/M2 ratio.

Cigarette smoke exposure increased M1 macrophage expression and produced an M1- dominant phenotype compared with controls (K⁷ 14.11 ± 10.15 vs. K- 7.00 ± 9.93, p = 0.109). Ketone body administration showed a trend toward reduced M1 and M2 macrophage counts and lowered the M1/M2 ratio, with the lowest ratio observed at the highest ketone dose (K⁷ 6.96 ± 8.55 vs P2 2.88 ± 2.86, p = 0.348).

Cigarette smoke promoted M1-dominant polarization, supporting its proinflammatory role in endothelial dysfunction. Ketone body administration could shift the balance toward a more anti-inflammatory profile, with higher doses favoring M2 activity.

These findings provide initial evidence that ketone bodies may affect macrophage polarization under cigarette smoke exposure, supporting their potential as modulators of vascular inflammation.