Motivation: Every lecture on sepsis starts with a Venn diagram showing an overlap between SIRS (systemic inflammatory response syndrome) and general infection with the intersection defined as sepsis. I get the sepsis part, but I have always wondered about other non-infectious causes of SIRS like pancreatitis or trauma. Since the injured tissue is our own and subject to constant immunologic surveillance, what exactly is so inflammatory about it when injured? Recently, a group in Boston examined this issue and proposed a remarkable hypothesis to explain the phenomenon.
Paper: Circulating Mitochondrial DAMPs Cause Inflammatory Responses to Injury. Zhang, Q. et. al. Nature (2010) 464: 104-107. http://www.nature.com/nature/journal/v464/n7285/full/nature08780.html
Hypothesis: The authors observed that when innate immunity responds to infection, specific signals expressed on invading micro-organisms called pathogen-associated molecular patterns (PAMPs) are recognized. Some of these specific signals like N-formylated peptides are also expressed by mitochondria, which are thought to have a bacterial origin. The authors postulated that when human tissue is injured, release of the mitochondrial products is inflammatory.
Method (clinical): Plasma was collected from 15 patients presenting with acute accidental trauma. The age range was 17-71. Patients did not either have significant medical co-morbidities or have major open or intestinal injuries. For controls, plasma was collected from healthy volunteers aged 26-61. Most did not have chronic illnesses except two controls with Type II diabetes.
Results: I will just highlight some of the key results from the paper.
When trauma patients were compared to healthy controls, the concentration of mitochondrial DNA (mtDNA) in trauma plasma was 2.7 ug/mL (sem 0.94) compared to barely detectable in control plasma. Bacterial products (tested by measuring ribosomal subunit 16S RNA) was absent from all samples. To demonstrate the inflammatory and activating nature of mitochondrial products, human neutrophils exposed to mitochondrial products showed signs of activation by producing cytokines like IL-8 and expressing proteases such as matrix-metalloprotease 8 (MMP-8). Other downstream activation cascade markers were also increased. In culture, human neutrophils became activated and migrated towards regions with mitochondrial products. In the paper, the authors also identify specific receptors in neutrophils that are likely involved in sensing mitochondrial products.
To test biological significance, rats were intravenously given mitochondrial degradation products equivalent to a 5% liver injury. Remarkably, as in sepsis ARDS, rats showed marked oxidative lung injury, increased pulmonary permeability, accumulation of IL-6, and PMN infiltration into airways. Rat livers also demonstrated increased PMN accumulation.
Discussion: The paper has clinical relevance because it showed (1) that after trauma, the concentration of mitochondrial products is increased in plasma and (2) that mitochondrial products are inflammatory and can lead to injury at least in animal models. While tissue injury may release a number of products that are inflammatory, this paper pins down a novel pathway that at the very least contributes to the process and provides concrete mechanistic basis of why tissue injury is inflammatory. A direct consequence of describing these interactions could be development of inhibitors that could pharmacologically decrease the PMN activation process and decrease the severe damage that tissue injury like pancreatitis produces.
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