Editors' ChoiceInfection

May the Resolvins Be with You…

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Science Translational Medicine  13 Jun 2012:
Vol. 4, Issue 138, pp. 138ec105
DOI: 10.1126/scitranslmed.3004426

Current antibiotics rely on only a few mechanisms to eradicate pathogens. Little innovation in the drug development pipeline and escalating drug resistance makes it increasingly challenging to contain bacterial infections—bad times to acquire an infection in the hospital. Now, Chiang and colleagues tap into a new line of research—involving compounds that resolve acute inflammation—that might extend therapeutic options.

Acute inflammation, which is a response to pathogens or injury, involves an influx of pathogen-attacking neutrophils; its resolution is an active process that includes the synthesis of specialized pro-resolving mediators (SPMs), such as resolvins and protectins, from fats. Using a mouse model of peritonitis (abdominal wall inflammation), the researchers established that a particular dose of Escherichia coli inoculated into the abdominal cavity elicited a confined inflammatory response. An immediate influx of neutrophils was replaced by a gradual increase in monocytes and macrophages, which remove neutrophils. Conversely, inoculation of 100-fold more E. coli prolonged neutrophil infiltration. This approach provided two forms of resolution of inflammation: A self-limited versus delayed form of peritonitis, which is ideal for differential analysis.

The researchers found a dynamic profile of SPM formation. For example, resolvin D5 (RvD5) and protectin D1 (PD1) reached much higher levels 12 hours after the low dose of E. coli as compared with after the high dose. Furthermore, administration of RvD1 and RvD5 to E. coli–infected mice increased phagocytosis of bacteria, alleviated the hypothermia that is commonly observed in these mice, and improved overall survival—underscoring the potential clinical relevance. Indeed, resolvins as well as PD1 fine-tune human macrophages and neutrophils in a way that activates antimicrobial mechanisms differentially whereas proinflammatory pathways stay dormant.

The authors also demonstrated that exogenous RvD1 and the antibiotic ciprofloxacin resolve E. coli–induced peritonitis similarly but are even more effective when coadministered. Additionally, subtherapeutic doses of a different antibiotic, vancomycine, resolved inflammation in a Staphylococcus aureus–induced skin infection in mice as fast as did RvD1, RvD5, and PD1; the combination was again more efficient than each single compound.

Such promising results encourage pursuing these SPMs as therapeutic options adjunctive to antibiotics. However, the relative wealth of data on the potential biological significance of SPMs in in vitro and animal models only emphasizes how few human studies have been conducted.

N. Chiang et al., Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature 484, 524–528 (2012). [Abstract]

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