Hyaluronan serum concentrations are elevated in critically ill patients and associated with disease severity
Highlights
► Hyaluronan (HA) is a biomarker in chronic liver disease by reflecting matrix proteins. ► HA is significantly elevated in critically ill patients compared to healthy controls. ► Highest HA levels found in ICU patients with liver cirrhosis or patients with sepsis. ► HA levels correlate with biomarkers of organ dysfunction and systemic inflammation. ► HA levels reflect severity of critical illness.
Introduction
Hyaluronic acid (HA), also termed hyaluronan, is a high molecular weight glycosaminoglycan with linear polysaccharide structure and synthesized by many cell types, including fibroblasts or other matrix-producing cells [1]. In healthy individuals, HA is abundantly found in heart valves, skin, skeletal tissues, the vitreous of the eye, and synovial fluid, thus representing a matrix component that exerts lubricant-like functions by binding large amounts of water [2]. More recently, it has been unraveled that HA, besides its properties as a matrix protein, additionally exerts functions in the regulation of inflammatory processes [3]. Interestingly, inflammatory cytokines like tumor necrosis factor (TNF), lymphotoxin and interferons stimulate HA production, for instance after lung injury [4]. The accumulation of HA in inflamed tissue is subsequently involved in attracting neutrophils and T-cells and by modulating their effector functions [5], [6].
HA is normally found at low concentrations in the circulation, because it is rapidly cleared from the bloodstream by the endothelial cells in the liver sinusoids [7]. HA serum concentrations have been evaluated as a biomarker for fibrotic liver diseases. Serum HA levels appear to be closely associated with the degree of fibrosis in patients with chronic liver diseases, due to the increased extracellular matrix deposition in hepatic fibrosis and reduced clearance by sinusoidal endothelial cells [8], [9], [10]. Moreover, serum HA levels have been described to be elevated in patients with sepsis, potentially caused by impaired endothelial clearance in the liver sinusoids, but the exact regulation of HA levels remained elusive [11], [12]. More recently, experimental animal models suggested that high-molecular weight HA might be a promising new treatment option for sepsis-induced lung injury by ameliorating pulmonary capillary leakage and by limiting inflammatory cascades [13], [14].
However, there are no sufficient data at present concerning the mechanisms of HA regulation in critically ill patients from large cohorts. Before testing the possible therapeutic effects of HA in humans, clinical studies on profiles of endogenous HA regulation in the critically ill are needed. Therefore, we conducted the present study on a large cohort of well characterized critically ill patients to provide information about HA serum concentrations in different circumstances of critical disease such as sepsis or decompensated liver cirrhosis, to identify possible pathogenic functions of HA by correlations with a wide number of markers of inflammation, organ dysfunction and metabolism, and to examine potential protective effects of HA for the outcome of critically ill patients.
Section snippets
Patients and control collective
The study population consisted of 164 critically ill patients (100 males/64 females, median age 64 years; range 21–90 years) who were admitted to the Medical ICU at the RWTH-University Hospital Aachen, Germany. Patients who were expected to have a short-term (< 72 h) intensive care treatment due to post-interventional observation or acute intoxications were not included into this study [15]. 101 patients who met the criteria proposed by the American College of Chest Physicians and the Society of
Hyaluronan serum concentrations are elevated in critically ill patients with highest values in cirrhosis and sepsis
To unravel the potential pathogenic role or diagnostic value of serum hyaluronic acid (HA) in critically ill patients, we measured HA serum concentrations in 164 patients upon admission to the medical ICU prior to therapeutic interventions. Critically ill patients displayed significantly higher HA serum concentrations as compared with healthy controls (median 270.5 μg/L, range 0–2842, in ICU patients versus 11 μg/L, range 0–195, in controls, P < 0.001; Fig. 1A). Hyaluronan serum levels were also
Discussion
Hyaluronic acid (HA) has long been investigated as a potentially central molecule in critical care medicine, due to its association with liver diseases [8] and sepsis [11], [12]. More recently, direct immunological functions of HA by regulating inflammatory cell recruitment, release of inflammatory cytokines, and cell migration have been proposed [3]. This prompted us to revisit the role of HA in a large, well characterized cohort of critically ill patients at a medical ICU in a prospective
Acknowledgments
This work was supported by the German Research Foundation (DFG Ta434/2-1 and SFB/TRR57).
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These authors contributed equally to this work.