Die insuffiziente Kontrolle der posttraumatischen Entzündung als wichtiger pathogenetischer Faktor des Komplex-regionalen Schmerzsyndroms (CRPS)
Final Report Abstract
The complex regional pain syndrome (CRPS) is a clinically defined post-traumatic pain disorder, which affects 2-3% of all patients following e.g. fracture or surgery of the limbs. Diagnosis is challenging, treatment difficult and prevention still impossible. Therefore, aim 1 of the project was to answer the question, what are the most important inflammatory changes in the CRPS skin: The regulation of cytokines, of inflammatory peptides or of lipid mediators, which are involved in inflammation? We have been able to shown that it is the abundance of inflammatory mediators like cytokines, which is a main driver of the exaggerated inflammatory process of acute CRPS. The counter regulation by anti-inflammatory cytokines seems to be intact. Studies on peptides itself were not promising, but studies on peptidases like MMP-9 and ACE were, and they are ongoing. The data suggest that these peptidases hold an important role in CRPS pathophysiology. Clinically we could show that there are “peripheral inflammatory” and "central neuroplastic" clusters of CRPS patients. We therefore investigated the serum samples of these patients in more detail and looked for their effect on nociception. Investigations are ongoing but there seem to be serum proteins exclusively in “inflammatory” (but not "central") CRPS cases, which activate and sensitize nociceptors in mice. Thus, aim 2, the differentiation of patients, which are characterized by an "inflammatory" clinical CRPS phenotype, in contrast to patients characterized by a "central neuroplastic" clinical CRPS phenotype, has been partially fulfilled. In aim 3, the development of suitable analytical methods to reach aims 1 and 2, we have ambitiously attempted to (1) use as little patient material as technically possible (2) taking advantage of high-end sensitive instrumentation. This goal was achieved for small sample numbers. With larger sample sets the sensitive equipment needed more care than expedient for a screening method. We have thus developed a low-tech robust and highly promising bradykinin assay to monitor the protease activity requiring only a blood drop. The screening of more than 100 patient samples with this method confirmed the lowered ACE activity in CRPS. Furthermore, preliminary data indicated a potential wide use of the DP-PA assay, not only in the context of CRPS, using capillary blood, serum or plasma. The results are very exciting and culminated in more than 10 publications, 3 theses to Dr.med., and 1 M.sc. so far. Two graduation works to Dr.rer.nat are in progress. Grant applications to continue the work are in preparation.
Publications
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Activation of cutaneous immune responses in complex regional pain syndrome. The Journal of Pain, Vol. 15. 2014, Issue 5, pp. 485-495.
Birklein, F., Drummond, P. D., Li, W., Schlereth, T., Albrecht, N., Finch, P. M., Kingery, W. S., et al.
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Osteoprotegerin: a new biomarker for impaired bone metabolism in complex regional pain syndrome? Pain, Vol. 155. 2014, Issue 5, pp. 889–895.
Kramer, H. H., Hofbauer, L. C., Szalay, G., Breimhorst, M., Eberle, T., Zieschang, K., Birklein, F., et al.
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Complex regional pain syndrome: An optimistic perspective. Neurology, vol. 84, no. 1, pp. 89-96.
Birklein F., O'Neill, D., & Schlereth, T.
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Abundant cysteine side reactions in traditional buffers interfere with the analysis of posttranslational modifications and protein quantification: How to compromise. Rapid Communications in Mass Spectrometry. Vol. 30. 2016, Issue 15, pp. 1823–1828.
Bayer, M., König, S.
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Complex regional pain syndrome: evidence for warm and cold subtypes in a large prospective clinical sample. Pain, Vol. 157. 2016, Issue 8, pp. 1674–1681.
Bruehl, S., Maihöfner, C., Stanton-Hicks, M, Perez, R. S., Vatine, J. J., Brunner, F., Birklein, F., Schlereth, T., Mackey, S., Mailis-Gagnon, A., Livshitz, A., Harden, R. N.
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Interaction of calcitonin gene related peptide (CGRP) and substance P (SP) in human skin. Neuropeptides, Vol. 59. 2016, pp. 57-62.
Schlereth, T., Schukraft, J., Kramer-Best, H. H., Geber, C., Ackermann, T., & Birklein, F.
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A vote for robustness: Monitoring serum enzyme activity by thin-layer chromatography of dabsylated bradykinin products. Journal of Pharmaceutical and Biomedical Analysis, Vol. 143. 2017, pp. 199-203.
Bayer, M., König, S.
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Analyzing marker substances for Complex Regional Pain Syndrome (CRPS). Mercator Journal of Biomolecular Analysis, Vol. 1. 2017, Nr. 1, S. 1 - 23.
Schildt, A., Schlereth, T., Birklein, F., König, S.
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Bone Trauma Causes Massive but Reversible Changes in Spinal Circuitry. The Journal of Pain, Vol. 18. 2017, Issue 4, pp. 468-476.
Hirsch, S., Ibrahim, A., Kramer, L., Escolano-Lozano, F., Schlereth, T., & Birklein, F.
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Molecular signature for complex regional pain syndrome and its analysis. Expert Review of Proteomics, Vol. 14. 2017, Issue 10, pp. 857-867.
König, S., Schlereth, T., Birklein, F.
