gms | German Medical Science

Objectives: Trauma and tissue damage trigger an inflammatory response required for postinjury regeneration and tissue repair. In severe trauma, overwhelming systemic inflammation (SIRS) can result in additional damage to host cells and the development of multi-organ failure and sepsis. In the present study, we hypothesized based on transcriptomic screening analyses that activation of the heme degradation pathway is closely linked to the inflammatory response and contributes to adverse events during trauma-induced SIRS.

Methods: In a prospective, single-center study, blood samples were collected from patients with multiple injury (injury severity score > 16 points) over a period of 21 days after trauma (at day 0, 1 ,2, 3, 5, 7, 10, 14, and 21). Isolated RNA samples were analyzed for dynamic gene expression changes. In a first step, a subset of the patient cohort (n=10) was screened by microarray technology. Based on explorative gene set analyses, components of the heme degradation pathway were identified as the pathway, in which the strongest changes occurred. In a second step, samples from patients with complete clinical and experimental data sets (n=67) were selectively analyzed for transcription of haptoglobin (HP), cluster of differentiation (CD) 163, heme oxygenase-1 (HMOX1), and biliverdin reductase (BLVR) by quantitative RT-PCR and correlated with clinical outcome parameters. Samples were examined as separate cohorts for discovery and validation data in different laboratories to assess potential batch-effects for PCR measurements.

Results and Conclusion: Transcription rates of the components of the heme degradation pathway HP, CD163, HMOX1 and BLVR collectively showed robust changes following trauma, with considerable interindividual differences. Patients who received large volume blood transfusions showed more severe levels of SIRS than patients without hemorrhagic shock, which was associated with an increased length of stay on the ICU. On the transcriptional level, the severity of SIRS was reflected by the expression of HP. Moreover, upregulation of the anti-inflammatory heme degradation pathway was associated with increased incidence of infectious complications, including sepsis. Among all parameters analyzed, HP and HMOX1 were identified as the most promising biomarkers for assessment of the activation level of the heme degradation pathway in trauma-induced SIRS.

The results of the present study indicate that activation of the heme degradation pathway, which may be triggered by release of free heme after massive blood transfusion in particular, affects the inflammatory response after severe trauma and thereby contributes to increased susceptibility to infectious complications. These findings are likely to have direct implications for the treatment strategy of severely injured patients since the underlying pathophysiology needs to be taken into account in order to minimize the risk for second hit damage and secondary complications.