Abstract
Because of the complexity and inherent variation in the critically ill patient populations, animal models are used extensively to study the underlying biological mechanisms, especially in the field of inflammation. However, every single one of the almost 150 clinical trials studying agents to block the inflammatory response in critically ill patients has failed. The main reason might be the completely different genomic response to acute inflammatory stress between humans and mice.
A recent study analyzed the genomic-wide expression in white cells obtained from patients with major blunt trauma, burns, and healthy humans administered with endotoxin and corresponding murine models (1). One of the main findings was that among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts. The percentage of genes changed in the same direction in human and mouse trauma was 60% with a rank correlation of 0.03. The respective changes in human and mouse endotoxemia were 48% and 0.01, respectively.
The good news, however, was that in humans the acute inflammatory stress from different etiologies results in highly similar genomic responses. For example, the percentage of genes changed in the same direction in human trauma and burns was 97% with a rank correlation of 0.86. The respective changes in human trauma and endotoxemia were 87% and 0.39, respectively. Most of the up-regulated pathways were related to innate immune response, and the down-regulated pathways were related to adaptive immunity.
This study seems to confirm the unproven hypothesis that molecular mechanisms involved in our response to acute inflammatory stress are similar regardless of the initiating etiology, be it tissue injury or microbial challenge. Microbial pathogen-associated molecular patterns (PAMPs) activate innate immunocytes through pattern recognition receptors, and similar responses are seen with cellular injury that can release “damage”-associated molecular patterns (DAMPs). Cellular disruption by trauma releases mitochondrial DAMPs with evolutionarily conserved similarities to bacterial PAMPs into the circulation, and these signals through the innate immune pathways are the key link between trauma, inflammation, and the systemic inflammatory response syndrome (SIRS) (2). The consistency of SIRS seen in all critically ill or injured patients reflects the same underlying biological response based on genomic changes of more than 5000 genes.
Another significant finding was that although the gene response time in all conditions occurred within the first 6–12 h, the recovery time of the genomic disturbances lasted for 1–6 months or more, long after we discharge our patients. Furthermore, genomic analysis of patients with complicated clinical outcomes exhibits persistent genomic expression changes consistent with defects in the adaptive immune response and increased inflammation. It seems that a new syndrome—persistent inflammation, immunosuppression, and catabolism syndrome (PICS)—has replaced late multiple organ failure as a predominant phenotype of chronic critical illness (3).
So, what are the clinical implications of these observations? First, do not blame the mouse if your new, highly specific (and expensive) anti-inflammatory drug does not work. Second, in view of the gene response time, early appropriate interventions (e.g. surgery, fluid administration, or vasoactive drugs) are important; sometimes “expectant” or “permissive” management (and the usual delay caused by the computed tomography (CT) scan) might not be what your patient needs right now. Third, do not be surprised if your patient feels lousy after “enhanced recovery after surgery,” as their genes might need more time to recover. Finally, this is another reason why same (emergency or acute care) surgeons should treat patients with trauma and nontrauma surgical emergencies, most commonly caused by inflammatory conditions and surgical sepsis.