Does promoting resolution instead of inhibiting inflammation represent the new paradigm in treating infections?

Abstract

Infections arise when the host response is overwhelmed by pathogens leading to organ dysfunction. In some instances patients progress to more severe conditions, including septic shock, that are associated with increased mortality. Current strategies in treating infections aim at either blocking inflammation using inhibitors to pro-inflammatory molecules and/or inhibiting bacterial growth using antibiotics. These approaches find their origins in studies conducted by Joseph Lister who demonstrated that applying carbolic acid to wounds promoted wound healing without suppuration, reducing both the necessity of amputation and mortality. While this approach is still applicable to certain infections, inhibition of the immune response is also associated with increased mortality, especially in septic patients. In many instances sepsis survivors succumb later to persistent, recurrent, nosocomial and secondary infections. This, together with a rise in resistance to many frontline antibiotics, has prompted a search for alternative ways to treat infections. Recent studies investigating processes engaged by the host response during self-resolving infections identified a novel group of mediators, termed as specialized pro-resolving mediators (SPM). These molecules, produced via the enzymatic conversion of essential fatty acids, actively reprogram the immune response to promote clearance of invading pathogens, and counter-regulate the production of inflammation-initiating molecules. Furthermore, recent studies also demonstrate that these mediators promote tissue repair and regeneration, essential processes in the re-establishment of barrier and prevention of re-infection. The scope of the present review is to discuss the evidence underpinning the endogenous protective roles of these novel mediators, as well as the evidence demonstrating that dysregulation in their production and actions contribute to disease pathogenesis in infections. This review will also discuss the potential of resolution pharmacology-based approaches in developing new therapeutics for combatting infections that do not interfere with the immune response.