Introduction
Sepsis and septic shock represent major causes of mortality in patients referred to intensive care units [
1]. Sepsis is defined by a Systemic Inflammatory Response Syndrome (SIRS) in the context of infection [
2]. This response is characterized by both pro-inflammatory and anti-inflammatory phases and involves the expression and secretion of distinct pro- and anti-inflammatory mediators such as cytokines and chemokines by different immune and parenchymal cells [
3]. Despite the rapid progresses of the “omics” research resulting in such sepsis-related panels of chemokines and cytokines, there is a high demand for new biomarkers that can help to better risk stratify patients and assist clinical decision-making in allocating resources of intensive care treatment [
4].
Osteopontin (OPN) represents a phosphorylated acidic glycoprotein that is involved in a broad variety of physiological and pathological processes such as cancer, fibrosis, inflammation and heart disease [
5‐
7]. Regarding inflammatory processes, OPN acts as a chemotactic factor for T cells, macrophages or neutrophils and modulates the function and differentiation of these inflammatory cells [
8]. Moreover, mediators of sepsis and inflammation, including tumour necrosis factor (TNF) and interleukin (IL)-1, stimulate the expression of OPN on a transcriptional level, which appears critical for the recruitment and activation of macrophages in inflammation and infection [
9]. Consequently, elevated serum and tissue levels of OPN were found in different diseases associated with systemic or focal inflammation, such as tuberculosis [
10], multiple sclerosis [
11], lupus erythematosus [
12] and Crohn’s disease [
13], thus suggesting that circulating OPN may hold potential as a biomarker for inflammatory and infectious diseases. Recently, OPN has been introduced as a novel biomarker in cardiac diseases, predicting the prevalence and prognosis of chronic and acute congestive heart failure and pulmonary hypertension [
14‐
17].
Despite the emerging roles of OPN in the regulation of inflammation and immunity, its functional involvement in systemic infections remains to be elucidated. Moreover, the diagnostic and prognostic value of OPN measurements in critically ill patients is currently unclear [
18]. We therefore conducted a large study with critically ill patients at a medical intensive care unit (ICU) and performed longitudinal measurements of OPN serum concentrations during the first days of ICU treatment. The aim of this study was to address the regulation and diagnostic value of OPN serum concentrations in critical illness, sepsis and/or multi-organ failure. Finally, we assessed whether OPN serum levels can serve as a prognostic predictor for ICU and long-term survival.
Discussion
In this study, we assessed OPN concentrations upon admission to the medical ICU before specific therapeutic interventions and at day 3 after ICU admission in a well-characterized cohort of critically ill patients [
23,
25,
33,
34]. In these patients, OPN serum concentrations were found to have a close association with the prognosis, especially if assessed at day 3 after admission to the ICU. OPN is a secreted phosphorylated protein that exists as a component of the extracellular matrix and as a soluble cytokine. Under basal conditions, OPN is biosynthesized by various tissue types including osteocytes, fibroblasts, osteoblasts, smooth muscle and endothelial cells [
35‐
38]. In the immune system, it is expressed by many cell types like macrophages, neutrophils, dendritic cells, natural killer (NK) cells and T and B lymphocytes [
39]. OPN’s capacity to interact with multiple surface receptors suggests that it is an active player in many physiological and pathological processes. It is upregulated due to many different stress stimuli, implying a functional role during stress response [
39]. Its functional relevance in immunity and during the inflammatory response to infection and cell damage are well documented [
39,
40]. For instance, OPN plays an important role in chemotaxis and recruitment of neutrophils and macrophages. Moreover, it modulates cell-mediated immune reactions by promoting the response of T helper (Th1)-type CD4
+ T cells and driving IL-17 expression [
41]. Importantly, OPN modulates immunity in different directions. Although it is widely designated as a pro-inflammatory factor, it can also mediate anti-inflammatory effects under certain conditions [
39].
Sepsis and the Systemic Inflammatory Response Syndrome (SIRS) represent states of profound dysbalance of the immune system in response to infection and/or organ damage, menacing the prognosis of many patients referred to the ICU [
23]. The exact pathomechanisms of sepsis/SIRS are not yet fully understood. The clinical picture is determined by an excessive inflammatory response of the immune system to the triggering stimulus, followed by a prolonged immunosuppressive state [
42]. Both stages of the disease process seem to comprise the prognosis. However, recent reports imply that especially the effects of the delayed immunosuppressive phase may have been underestimated [
42]. Both the initiation and progression of sepsis seems to be orchestrated by activated T cells, particularly CD4
+ T helper 1 (Th1) and Th2 cells [
43]. Moreover, Th17 cells that produce IL-17 have been demonstrated to play an important role in the regulation of pro- and anti-inflammatory factors during sepsis [
43]. OPN, that is also known as Eta-1 (early T lymphocyte activation gene 1), is highly expressed in activated T cells. It has been shown to regulate CD4+ T helper cell lineage commitment towards the specific Th subtypes [
9] and to drive IL-17 production [
41]. Thus, it seems obvious that OPN exerts important regulatory functions in the pathogenesis of sepsis. In this regard, Vaschetto and co-workers have demonstrated increased serum levels of OPN in patients suffering from sepsis and SIRS compared to healthy controls [
18]. On the one hand, our data confirm this report showing elevated OPN levels compared to healthy controls and lower levels of OPN in surviving versus non-surviving patients. Moreover, our work extends the results from Vaschetto et al., demonstrating that OPN correlated significantly better with the prognosis than “classical” prognostic markers like CRP, INR and creatinine and also than the sepsis marker PCT.
Of note, Vaschetto et al. even suggested that OPN serum levels may allow differentiating between sepsis and SIRS [
18]. In contrast, we could not recapitulate a strong specificity of OPN for the diagnosis of sepsis. In our study comprising a heterogeneous medical population of critically ill patients, there was no significant difference of OPN levels between patients with or without sepsis. Our results indeed indicate a fundamental role of OPN in the pathogenesis of inflammatory dysbalance of ICU patients, independent of the presence of an infection. Thus, our report might support the recently growing notion that the course and prognosis of disease patterns of ICU patients, like cardiogenic shock or liver failure, seem to be mainly determined by the patient’s inflammatory response that self-dynamically develops beyond the initial pathogenic stimulus [
44‐
46]. In line with this notion, OPN serum levels correlated both with markers of liver failure (alkaline phosphatase (AP); gamma glutamyl transpeptidase (GGT), bilirubin) heart failure (BNP), clinical scores like APACHE II and SAPS2 as well as novel prognostic markers like APRIL [
23] and circulating miR-133a [
25]. In this regard, it is not surprising that OPN is highly upregulated in conditions of critical illness upon admission to the ICU. The striking fact that patients with persistently elevated OPN levels (at day 3 of ICU treatment), in which OPN do not regress as usually seen in the cohort (Fig.
2), have a poor prognosis, is certainly very interesting to investigate on possible detrimental functions of persistently elevated OPN during systemic inflammation.
In spite of advances in diagnosis and treatment of critically ill patients throughout the recent decades, the triage, diagnostic and therapeutic management of these patients during the first week of ICU treatment still represents a major challenge. The promptness and accuracy of the initial decisions during the initial course of disease are of immense importance for the subsequent outcome of sepsis [
47] or cardiogenic shock [
48]. Inversely, failure of initiating the adequate therapy during the first phase of the disease may critically affect the mortality of these patients [
23]. In this respect, the use of novel biomarkers that allow rapid decision-making with sufficient accuracy may significantly improve the treatment and finally the outcome of ICU patients [
49,
50]. OPN serum levels seem to specifically unfold its power to predict the prognosis of patients in the early phase after ICU admission, thus offering a novel tool to guide treatment decisions at this critical time-point. Given that OPN at day 3 of ICU treatment is a strong predictor of mortality risk, one could speculate that its use might be implemented into established scoring systems together with markers that detect the initial cause of the critical illness leading to ICU admission (e.g. APRIL, which has recently been demonstrated to specifically detect sepsis [
23], or BNP as a marker of heart failure [
51]).
Taken together, our data provide evidence for a role of OPN as a diagnostic tool in the prognostic judgment of critically ill and septic patients during the early phase of their ICU stay. Certainly, these data need to be recapitulated in larger independent cohorts as well as in other ICU settings such as post-surgery care, before implementation into clinical algorithms can be considered. Moreover, although our data imply an important role of OPN in the molecular pathogenesis in critically ill patients, they do not provide a specific molecular mechanism of action. OPN may trigger either pro-inflammatory stimuli like TNF or IL-6 (Table
3) as well as anti-inflammatory stimuli [
9]. In this regard, a recent study by Fortis et al. demonstrated that OPN is required for enhanced glucocorticosteroid production in an animal model of sepsis [
52]. In line with the results from our report, the authors demonstrate that OPN is associated with a worsened outcome in sepsis in spite of enhanced glucocorticoid levels, which are thought to have a beneficial impact in severe sepsis [
52]. One might speculate that in the setting of sepsis, potentially beneficial targets of OPN are outbalanced by maladaptive effects. In our study, we assessed a more heterogeneous population of critically ill patients with different entities, including sepsis, but also cardiogenic shock or liver failure. The balance between pro- and anti-inflammatory effects of OPN might be specifically regulated in each of these entities. Nevertheless, the results from our study provide a clear rationale for future functional studies on the role of OPN in different disease models related to critical illness.
Acknowledgements
This work was supported by the German Research Foundation (DFG RO 4317/4-1). Moreover, the work was supported by a Starting Grant from the European Research Council within the FP 7 (ERC-2007-Stg/208237-Luedde-Med3-Aachen), the German Research Foundation (SFB-TRR57, P06 + P09) and the German Cancer Aid (Deutsche Krebshilfe Grant 110043).
The funding bodies had no role in the design, collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.
The authors would like to express their gratitude to members of the Luedde laboratory, Michaela Roderburg-Goor and Dr. Jane Beger, for helpful discussions.
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Competing interests
The authors declare that:
- In the past 5 years they have not received reimbursements, fees, funding, or salary from an organization that may in any way gain or lose financially from the publication of this manuscript, either now or in the future and that no such an organization is financing this manuscript.
- They do not hold any stocks or shares in an organization that may in any way gain or lose financially from the publication of this manuscript, either now or in the future.
- They do not hold or are not currently applying for any patents relating to the content of the manuscript. They have not received reimbursements, fees, funding, or salary from an organization that holds or has applied for patents relating to the content of the manuscript.
- They do not have any other financial competing interests.
Authors’ contributions
AK, CR, CT, DVC, FB, FT, HJH, MLu, MLue, NF, and TL designed the study, analyzed data and wrote the manuscript. CR, DVG and FB performed measurements. AK, CR, FB and FT performed statistical analyses. AK and FT collected data and organized patient recruitment. All authors read and approved the manuscript.