Recombinant Human Erythropoietin and Acetazolamide Does Not Attenuate the Altitude-Induced Inflammatory Response

Inflammation increases in unacclimatized individuals sojourning to high altitude (HA). Recombinant human erythropoietin (rEPO) and acetazolamide (AZ) act as anti-inflammatories and may mitigate the HA induced pro-inflammatory response. However, the effect of pre-ascent rEPO and prophylactic AZ on inflammation has not been studied during HA exposure. Study Objective:To determine inflammatory response to 14-day HA exposure in individuals receiving rEPO and AZ (rEPO+AZ) versus placebo and AZ (PL+AZ). We hypothesize that rEPO+AZ will reduce the inflammatory response to HA acclimatization as compared to PL+AZ. Methods: Volunteers received rEPO (n=8; 6M/2F;) or PL (n=10; 8M/2F) subcutaneously 3x/weekly (50IU/kg body mass) for 4 weeks at sea level (SL; Natick, MA; 50m) prior to HA exposure. All volunteers received 250 mg b.i.d. of AZ for 2.5 days prior to ascent and on day 1 of HA. Venous blood was collected at SL pre-(SL1) and post- (SL2) receiving rEPO or PL, and on HA days 1 (HA1), 2 (HA2), 7 (HA7), and 14 (HA14; Pike’s Peak, CO; 4300m, 460 mmHg). Serum concentrations of IL-1β, IL-1ra, IL-6, IL-10, TNF-α, and VEGF were measured. All data were analyzed by fitting a linear mixed model with treatment (rEPO+AZ vs. PL+AZ), time, and treatment x time interaction as fixed factors with SL1 concentrations set as covariates. Non-normally distributed variables were log transformed. Results: Serum TNF-α and VEGF significantly increased over time (p<0.001). Pairwise comparisons showed increased concentrations at HA1 (+14.1%, p<0.001; +7.6%, p=0.020, respectively), HA2 (+13.6%, p<0.001; +8.0%, p=0.012), HA7 (+11.6%, p=0.006, +8.4%, p=0.007), and HA14 (+16.4%, p<0.001; +13.1%, p<0.001) as compared to SL2, but there were no differences between HA days (p>0.05). Additionally, there were no treatment x time interaction for serum TNF-α or VEGF (p > 0.05). Serum TNF-α was 13.1% higher in rEPO+AZ compared to PL+AZ, albeit not significant (main effect of treatment; p=0.057). There was no treatment x time interaction effect for IL-1β, IL-1ra, IL-6, IL-10, TNF-α or VEGF, (p > 0.05 for all). A significant main effect of time was found for IL-1β concentrations (p=0.033), however post hoc analysis revealed no significant difference between days. Conclusion: Inflammation increased at HA exposure when compared to SL. However, there was no difference in inflammatory responses between rEPO+AZ and PL+AZ. Our novel findings indicate combined use of rEPO+AZ does not attenuate the altitude-induced inflammatory response when compared to AZ only. Funded by USMRDC; authors’ views not representative of the US Army or DoD policy. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.