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.
Histones are essential for packaging DNA into the cell nucleus and also play a role in regulating gene expression but scientists at the Oklahoma Medical Research Foundation, the Howard Hughes Medical Institute, and the Temple University School of Medicine have shown that histones released into the blood stream at the onset of sepsis can have devastating effects.
Sepsis – a life-threatening condition caused by the immune system going into overdrive in its fight against infection – can lead to small blood clots blocking blood flow to vital organs resulting in organ failure. Histones are part of the body’s rapid response to infections, but the new study shows that, when released into the bloodstream, they contribute to endothelial damage, organ failure and death. Histones are also released in response to severe physical trauma such as traffic accident injuries, gunshot wounds or battlefield injuries.
Earlier research by members of the team had shown that histone levels increased in the circulation of baboons challenged with a lethal dose of Escherichia coli and accompanied the onset of renal dysfunction. Co-administration of activated protein C (APC) protected the animals from the effects of sepsis and in vitro experiments revealed that macrophages rescued from a sepsis-like response by APC contained fragments of cleaved histones. When the team examined blood samples taken in the baboon studies, they found that cleavage of histones by APC reduced their toxicity and prevented a lethal reaction to infection. In cultures of human endothelial cells, and in mice, histones alone – in the absence of injury or infection – were shown to produce a sepsis-like response. The team then showed that the effects of sepsis could be reduced in both cell culture experiments and in several mouse models of sepsis by treatment with an anti-histone antibody.
The study, which was published online on 25th October in the journal Nature Medicine, suggests that blocking the action of histones, either by increasing enzymatic cleavage or by using antibodies, could provide a new way of managing sepsis and controlling internal bleeding following severe trauma.
The team also plan to explore the contribution of histones to autoimmune diseases such as lupus or diabetes as well as diseases associated with cardiovascular or other tissue injury.