SPMs and infection
Current strategies in treating infection aim to reduce inflammation by using proinflammatory molecule inhibitors and/or by inhibiting bacterial proliferation using antibiotics. Such approaches approach is applicable for certain infections, but inhibiting the immune response is associated with an increase in mortality, especially in patients with sepsis. On many occasions, sepsis survivors succumb to subsequent and persistent, recurring, hospital-acquired and secondary infections. This fact, combined with the increasing resistance to many antibiotics, makes seeking an alternative treatment for infections more important.
Recent studies have identified a new group of mediators in infection resolution processes, specialist pro-resolving mediators (SPMs). These molecules are produced by innate immune system cells through enzymatic conversion of essential fatty acids (lipoxins derived from arachidonic acid and resolvins, protectins and maresins from eicosapentaenoic and docosahexaenoic acids). They are actively involved in reprogramming the immune response by promoting elimination of invading pathogens, contraregulating the production of proinflammatory molecules (citokines and chemokines) and pro-inflammatory eicosanoids (prostaglandins and leukotrienes) and favouring tissue regeneration and repair (essential to re-establishing the protective barrier and, therefore, preventing re-infection). They do this by regulating leukocyte traffic and stimulating phagocytosis of apoptotic cells, bacteria and cellular waste by macrophages.
SPMs have potential as possible therapeutic agents against a variety of pathogens. As well as their ability to reprogramme the immune response, they show additive effects when administered with currently used drugs, including antibiotics, permitting an experimental reduction in the dose. All this suggests that new resolution-based treatments for infections could be developed.
In humans, production of D-series resolvins is up-regulated and circulating levels of A4 lipoxins raised in patients with active tuberculosis infections, compared to patients with latent infections; in patients with sepsis, the lipid mediator profile correlates with the results, and a relationship has also been observed between SPM levels and results in patients with cystic fibrosis (in which Pseudomonas aeruginosa infections are a major cause of death).
In in vitro experiments and studies with animal models, a relationship has been observed between the degree of infection, or the results, and the presence of different SPMs. Their use as a therapeutic agent has also been studied in some cases, with promising results: peritoneal infections due to Escherichia coli, infections of the airways caused by bacteria (E. coli, P. aeruginosa, Streptococcus pneumoniae, nontypeableHaemophilus influenzae, Cryptococcus neoformans) and viruses (respiratory syncytial virus, influenza virus), skin and eye infections due to bacteria (Staphylococcus aureus, P. aeruginosa) and viruses (herpes simplex type 1 virus), parasitic infections of the gastrointestinal tract (Toxoplasma gondii, Schistosoma japonicum) and parasitic infections of the central nervous system (cerebral malaria initiated by Plasmodium infection).
SPMs also have major potential as biomarkers for infection status: assessing their levels could provide information on how effective a given treatment is.
Therefore, SPMs represent a key element in a new paradigm for treating infection-inflammation which could be used to strengthen host immune response and favour the end of the infection.
Dalli J. Does promoting resolution instead of inhibiting inflammation represent the new paradigm in treating infections? Mol Aspects Med. 2017 Apr 5. [Epub ahead of print]