Logo: to the web site of Uppsala University

Septic shock results from a dysregulated host response to infection, leading to life-threatening organ dysfunction. Limited treatment options and a heterogeneous, complex pathophysiology make septic shock a major challenge for clinicians and researchers. Hyaluronan is a versatile molecule that may influence several biological processes disrupted in septic shock, including macro- and microcirculation, endothelial and glycocalyx integrity, intravascular volume, and inflammation. This thesis aimed to deepen understanding of hyaluronan and its associated proteins in septic shock and to explore potential new treatments.

Study I analysed plasma hyaluronan, hyaluronidase activity, and endogenous hyaluronidase inhibition in experimental and clinical septic shock and in acute alcohol-related pancreatitis. Both the experimental control group and septic shock groups showed increased plasma hyaluronan and hyaluronidase inhibition with decreased hyaluronidase activity. This pattern was also observed in clinical septic shock, but in alcohol-related pancreatitis only plasma hyaluronidase activity was reduced.

Study II evaluated high-molecular-weight hyaluronan as an adjuvant to fluid resuscitation at the onset of septic shock in an experimental peritonitis model. A hyaluronan injection followed by infusion throughout the experiment did not reduce resuscitation requirements or alter the inflammatory response.

Study III investigated higher exposure to high-molecular-weight hyaluronan during the early phase of peritonitis-induced septic shock. Hyaluronan infusion, started immediately after induction of peritonitis, did not prevent vascular depletion after 6 hours, nor did it preserve glycocalyx integrity.

Study IV compared proteomic profiles of hyaluronan-related proteins between septic shock and acute alcohol-related pancreatitis. 663 proteins were identified of which 231 were up- or downregulated in septic shock and fifteen were identified as hyaluronan-related. Changes were more pronounced on day 1 than on day 4, and more marked in septic shock than in pancreatitis. Heavy chains of the inter-alpha-inhibitor family showed marked changes: ITIH1, ITIH2, and ITIH4 were decreased, whereas ITIH3 was increased.

In summary, plasma hyaluronan and endogenous hyaluronidase inhibition increased whereas hyaluronidase activity decreased in experimental and clinical septic shock. Supraphysiological hyaluronan concentrations did not prevent intravascular volume depletion, nor did they alter the inflammatory response or preserve glycocalyx integrity. Proteomic profiles of hyaluronan-related proteins differed markedly between septic shock and alcohol-induced pancreatitis.