A, The peripheral blood cell index SII was suppressed in HD-caffeine at baseline compared to placebo, and at 8h after UCO compared to LD-caffeine group. SIRI was elevated in the LD-caffeine group compared to the placebo on day 1. The SII and SIRI scores were evaluated by Mixed effect analysis with Tukey’s correction for multiple comparisons. The summary column graphs are showing means ± SEM. HD-caffeine: n=3–8, LD-caffeine: n=3–19, Placebo: n=10–21;B, At 6 days after the UCO, we measured changes in IP-10 in the LD-caffeine group compared to the placebo, as well as age-matched control and in IL-36 that was higher in the LD-caffeine group compared to control. No changes were observed in IL-4,IL-6, IFγ, IP-10, or VEGF-α. We used Mann-Whitney test. LD-caffeine: n=11–12, Placebo: n=26–32. The box graphs show mean as plus sign “+” and median with IQR. WBC- white blood cells, ALC- absolute lymphocyte count, ANC- absolute neutrophil count, Mono- monocytes, Eos- eosinophils, PLT- platelets, SIRI- systemic inflammation response index (SIRI=ANC*Mono/ALC), SII- systemic immune-inflammation index (SII=ANC*PLT/ALC), *p<0.05, ****p<0.0001. LD-caffeine-treated group, green, Control- yellow, Placebo- black.