Drug Discovery Opinion

Systemic inflammatory response syndrome (SIRS) is an exaggerated host inflammatory response to infection (sepsis) or to physical insults such as trauma. SIRS can lead to multiple organ dysfunction syndrome (MODS) and, amongst the under-35s, trauma is the leading cause of death in the United States. Although the pathways leading from infection to sepsis are relatively well understood, it has been much less clear why physical insults lead to SIRS. A study led by researchers at Beth Israel Deaconess Medical Center has now suggested a link between sepsis and SIRS that is caused by trauma. The team propose that mitochondria are released into the bloodstream after physical injury and, because mitochondria closely resemble the symbiotic bacteria from which they are believed to originate, they elicit a sepsis-like response.

Pathogen-associated molecular patterns (PAMPs) are molecules such as bacterial endotoxins which are recognised by pattern recognition receptors (PRRs) as non-self, and so trigger an innate immune response. Injured or necrotic tissue generates molecules known as damage-associated molecular pattern molecules (DAMPs) that can also initiate and perpetuate an immune response. Many DAMPs are molecules that are usually found exclusively within cells and, when released into the bloodstream, are not recognised as self and trigger an immune response. The team found blood samples from patients who had suffered multiple trauma contained high levels of mitochondrial DNA – often thousands-of-fold higher than normal levels – and that this DNA activates immune cells via toll-like receptor 9 which normally recognises bacterial or viral DNA. Mitochondrial peptides were also found to elicit an immune response via the formyl peptide receptor 1 (FPR1) which also plays a role in the immune response to bacterial infections. Mitochondrial DDA and peptides were found to act synergistically to activate neutrophils via downstream kinase pathways. In further experiments, injection of mitochondria into rats caused peritonitis and reproduced the pulmonary and hepatic inflammation typical of traumatic SIRS.

The study, which is published in the journal Nature, shows that trauma can initiate innate immune pathways identical to those activated in sepsis and may lead to new strategies for treating trauma patients as well as re-evaluation of patients believed to be suffering from sepsis.

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