Damage-Associated Molecular Patterns in Human Diseases by Walter Gottlieb Land

Author:Walter Gottlieb Land
Language: eng
Format: epub
ISBN: 9783030538682
Publisher: Springer International Publishing

8.4.5 Résumé: The Use of the “Homeostatic Window” of DAMP and SAMP Concentrations in Exploiting DAMPs and SAMPs as Therapeutic Targets

According to the reports quoted in this chapter, one can conceivably assume that DAMPs and fewer SAMPs (?) will soon find their way into clinical routine as diagnostic, prognostic, and predictive biomarkers in traumatic diseases.

Much more different, that is, more difficult to assess is their future routine use as therapeutic targets and therapeutics, respectively. Undoubtedly, treatment modalities based on inhibitors/antagonists, specifically targeting DAMPs, have provided encouraging results in many preclinical models of infectious and sterile injury-induced inflammatory responses. And one does not need to be a prophet to predict that clinical trials will be designed and conducted soon to explore whether blocking DAMPs and SAMPs in SIRS and CARS will benefit patients.

However, before starting such trials, the possible risks of future therapeutic exploitation of DAMPs and SAMPs have to be clearly defined and solidly assessed. First of all, and to repeat possible safety guidelines outlined in Sect. 7.​3.​3, the DAMP/SAMP ratio in plasma (and body fluids if applicable) is proposed to be determined by choosing, for example, measurement of key DAMPs such as HMGB1 and mtDNA as well as key SAMPs such as SPMs. For such studies, and also to select and recruit patients that might benefit from such interventions, there is a need to develop assays for plasma DAMP and SAMP assessments providing rapid information about the continuously monitored DAMP/SAMP ratio. Further, in adherence to this ratio, the “homeostatic windows” for DAMP and SAMP concentrations that are required to establish a restitutio ad integrum following injury have to be taken into account, in particular, when the course of the disease prompts the clinician to decide at what point to start the treatment (compare Fig. 8.3). Regarding severe traumatic injuries, laboratory values of DAMPs above the “homeostatic window” may signal an increased risk of hyperinflammation and organ dysfunction, and laboratory values below the window pose the risk of compromised defensive repairing, that is, healing processes. On the other hand, values of SAMPs above the “homeostatic window” may carry an increased risk of hyperresolution and immunosuppression, whereas values below the window may signal an increased risk of hyperinflammation and organ dysfunction.

Fig. 8.3This figure is the same as Fig. 7.​1 in Sect. 7.​3.​3 but this time ideally designed to help the intensive care clinician decide to exploit DAMPs and SAMPs as therapeutic targets in the post-polytrauma period. According to this conceptual model, and guided by continuous monitoring of DAMP and SAMP levels, excessive DAMP levels should be decreased to homeostatic levels in the initial hyperinflammatory phase to prevent MOF; in the hyperresolving phase, excessive SAMPs levels should be decreased to homeostatic levels to prevent immunosuppression-promoted susceptibility to infection. The timely weaning and application of the inhibiting agents depend on the continuously measured DAMP and SAMP levels, which should be in the “homeostatic window,” that is, adjusted to levels that were previously determined in controlled inflammatory and resolving responses as explored in clinical trials.

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