Kinetics of adrenomedullin pathway activation in a porcine sepsis model and a human cohort of sepsis and septic shock

Sepsis is a life-threatening condition characterized by endothelial dysfunction. The peptide hormone adrenomedullin (ADM) plays a key role in sepsis owing to its potent vasodilatory effects, ability to maintain vascular integrity, and critical role in modulating immune responses and reducing inflammation. To gain its biological activity, the inactive ADM precursor (ADM-Gly) is converted into its active form (bio-ADM) by peptidylglycine α-amidating monooxygenase (PAM). Here, we present hourly resolved kinetics of ADM activation during early sepsis onset in a porcine model and analyze the AdrenOSS-1 human cohort data to assess biomarker changes in advanced sepsis progression. The porcine model data showed that both bio-ADM and ADM-Gly mean concentrations rose within the first two hours post-induction, preceding measurable sepsis onset, with a greater increase in ADM-Gly (260.8 ± 92.0 pg/mL) compared to bio-ADM (28.0 ± 12.9 pg/mL). PAM activity increased at 6 h (39.3 ± 10.5 Units), accompanied by a rise in the bio-ADM/ADM-Gly ratio. AdrenOSS-1 study revealed that ICU sepsis patients had higher ADM-Gly (121.5 pg/mL [IQR: 44.4-284.1]) and PAM activity (23.5 Units [IQR: 17.7-32.7]) than controls. Elevated ADM-Gly (> 730 pg/mL) and PAM activity (> 35.1 Units) were associated with increased 28-day mortality, with non-survivors exhibiting higher ADM-Gly (603.5 pg/mL [IQR: 131.1-1443]) and PAM activity (28.3 Units [IQR: 19.0-45.1]) than survivors. This study provides novel insights into the dynamics of adrenomedullin (ADM) homeostasis during sepsis progression, highlighting the critical interplay between its glycine-extended precursor (ADM-Gly), fully active form (bio-ADM), and the amidating enzyme PAM. The findings demonstrate that early and significant elevations in ADM-Gly, accompanied by delayed PAM activity, result in incomplete ADM amidation, compromising endothelial barrier function. Elevated ADM-Gly and PAM activity were associated with increased sepsis severity and 28-day mortality, while a higher bio-ADM/ADM-Gly ratio was linked to improved survival. These results underscore the potential of ADM-Gly, bio-ADM, and PAM as biomarkers for sepsis severity and prognosis, and support therapeutic strategies aimed at enhancing PAM activity to restore endothelial integrity and improve patient outcomes in sepsis.