gms | German Medical Science

Objectives: Respiratory failure can be a severe complication of multiple trauma (MT). Apart from MT itself, extensive systemic inflammation due to surgical intervention influences the occurrence and progression of respiratory failure. Two key innate immune systems responding to trauma are complement and the Toll-like receptors (TLRs). Targeting these systems may thus aid in ensuring a rapid immunological balance after MT. Cellular communication is key in regulating the immunological balance and tissue regeneration after MT and it occurs in part through microRNAs (miRNAs), important post-transcriptional gene regulators.

The aim of this study was therefore to determine miRNA expression in lung tissue of a porcine MT model to better understand the cellular mechanisms that underlie respiratory failure after MT upon surgical treatment (early total care, ETC) and immunomodulatory medication (IM).

Methods: The current study is a branch of the main study previously published [1]. Briefly, we used a porcine MT model consisting of blunt chest trauma, liver laceration, bilateral femur fracture, and controlled haemorrhagic shock. Animals were operatively and medically stabilized. They were monitored under ICU standards for 72 hours. Two treatment groups were studied, ETC (n=7), and ETC+IM (n=4). The IM consisted of a 2-kDa peptide blocking C5 cleavage, thus preventing C5a and C5b-9 formation; and an inhibitory mAb against CD14, an important co-factor for several TLRs (e.g. TLR4 and -2).A control group (n=6) was only ICU treated without trauma. Lung tissue was sampled, microRNAs were isolated, transcribed, analyzed by qPCR array, and validated. Lastly, in silico messenger RNA target prediction was performed to identify them and the possible pathways involved.

Results and conclusion: Over 90 miRNAs associated with lung function, fibrosis, and inflammation were evaluated. Six miRNAs were significantly deregulated among the treatment groups ETC and ETC+IM, compared to the control group. Of these, miR-122 and miR-129 were significantly upregulated in the ETC group. In the ETC+IM group, miR-503 was significantly downregulated while miR-122, miR-192, miR-382, and miR-194a were significantly upregulated. In silico target analysis revealed miRNA-mRNA interactions related to pulmonary fibrosis, Systemic Inflammatory Response Syndrome, inflammation, and tissue regeneration.

This study revealed surgical and MI treatment-specific miRNA expression profiles in lung tissue from a porcine MT model. These miRNAs played regulatory roles in pulmonary inflammation and tissue regeneration. The six validated miRNAs showed involvement in processes such as hypoxia-ischemia, oxidative stress, chronic pulmonary inflammation, and pneumocyte apoptosis. Collectively, these data broaden our view of the cellular mechanisms underlying respiratory failure after MT. Finally, inhibition of C5 and CD14 may aid in balancing the immune response after trauma.