Plasma hyaluronan, hyaluronidase activity and endogenous hyaluronidase inhibition in sepsis: an experimental and clinical cohort study

Jaap van der Heijden; Constantinos Kolliopoulos; Paul Skorup; Marko Sallisalmi; Paraskevi Heldin; Michael Hultström; Jyrki Tenhunen

doi:10.1186/s40635-021-00418-3

Plasma hyaluronan, hyaluronidase activity and endogenous hyaluronidase inhibition in sepsis: an experimental and clinical cohort study

Intensive Care Med Exp. 2021 Oct 11;9(1):53. doi: 10.1186/s40635-021-00418-3.

Authors

Jaap van der Heijden¹, Constantinos Kolliopoulos², Paul Skorup³, Marko Sallisalmi⁴, Paraskevi Heldin², Michael Hultström^{5

6}, Jyrki Tenhunen⁵

Affiliations

¹ Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, 75185, Uppsala, Sweden. jaap.vanderheijden@surgsci.uu.se.
² Department Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
³ Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden.
⁴ Division of Anaesthesia and Intensive Care Medicine, Intensive Care Units, Department of Surgery, Helsinki University Hospital, Helsinki, Finland.
⁵ Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, 75185, Uppsala, Sweden.
⁶ Department of Medical Cell Biology, Integrative Physiology, Uppsala University, Uppsala, Sweden.

Abstract

Background: Plasma hyaluronan concentrations are increased during sepsis but underlying mechanisms leading to high plasma hyaluronan concentration are poorly understood. In this study we evaluate the roles of plasma hyaluronan, effective plasma hyaluronidase (HYAL) activity and its endogenous plasma inhibition in clinical and experimental sepsis. We specifically hypothesized that plasma HYAL acts as endothelial glycocalyx shedding enzyme, sheddase.

Methods: Plasma hyaluronan, effective HYAL activity and HYAL inhibition were measured in healthy volunteers (n = 20), in patients with septic shock (n = 17, day 1 and day 4), in patients with acute pancreatitis (n = 7, day 1 and day 4) and in anesthetized and mechanically ventilated pigs (n = 16). Sixteen pigs were allocated (unblinded, open label) into three groups: Sepsis-1 with infusion of live Escherichia coli (E. coli) 1 × 10⁸ CFU/h of 12 h (n = 5), Sepsis-2 with infusion of E. coli 1 × 10⁸ CFU/h of 6 h followed by 1 × 10⁹ CFU/h of the remaining 6 h (n = 5) or Control with no E. coli infusion (n = 6).

Results: In experimental E. coli porcine sepsis and in time controls, plasma hyaluronan increases with concomitant decrease in effective plasma HYAL activity and increase of endogenous HYAL inhibition. Plasma hyaluronan increased in patients with septic shock but not in acute pancreatitis. Effective plasma HYAL was lower in septic shock and acute pancreatitis as compared to healthy volunteers, while plasma HYAL inhibition was only increased in septic shock.

Conclusion: Elevated plasma hyaluronan levels coincided with a concomitant decrease in effective plasma HYAL activity and increase of endogenous plasma HYAL inhibition both in experimental and clinical sepsis. In acute pancreatitis, effective plasma HYAL activity was decreased which was not associated with increased plasma hyaluronan concentrations or endogenous HYAL inhibition. The results suggest that plasma HYAL does not act as sheddase in sepsis or pancreatitis.

Keywords: Glycocalyx; Hyaluronan; Hyaluronidase; Hyaluronidase inhibitor; Pancreatitis; Sepsis; Sheddase.