Resolvin D1 enhances the resolution of lung inflammation caused by long-term Pseudomonas aeruginosa infection

Abstract

Pseudomonas aeruginosa lung infection is a main cause of disability and mortality worldwide. Acute inflammation and its timely resolution are crucial for ensuring bacterial clearance and limiting tissue damage. Here, we investigated protective actions of resolvin (Rv) D1 in lung infection induced by the RP73 clinical strain of P. aeruginosa. RvD1 significantly diminished bacterial growth and neutrophil infiltration during acute pneumonia caused by RP73. Inoculum of RP73, immobilized in agar beads, resulted in persistent lung infection up to 21 days, leading to a non resolving inflammation reminiscent of human pathology. RvD1 significantly reduced bacterial titer, leukocyte infiltration, and lung tissue damage. In murine lung macrophages sorted during P. aeruginosa chronic infection, RvD1 regulated the expression of Toll-like receptors, downstream genes, and microRNA (miR)-21 and 155, resulting in reduced inflammatory signaling. In vitro, RvD1 enhanced phagocytosis of P. aeruginosa by neutrophils and macrophages, recapitulating its in vivo actions. These results unveil protective functions and mechanisms of action of RvD1 in acute and chronic P. aeruginosa pneumonia, providing evidence for its potent pro-resolution and tissue protective properties on airway mucosal tissue during infection.

Inflammation in cystic fibrosis: An update

“…There was also a significant reduction in intracellular viable P aeruginosa in CF alveolar macrophages that were pre‐treated with RvD1 compared to those pre‐treated with vehicle, thereby demonstrating the importance of RvD1 in host defense. Codagnone et al evaluated the effect of exogenous RvD1 administration on the lung inflammatory response using the P aeruginosa agarose‐bead model . During the acute stage of infection, RvD1 decreased bacterial growth and neutrophil influx into the lungs, and during the chronic stage of infection, RvD1 decreased bacterial burden and leukocyte infiltration while limiting tissue destruction .…”

“…Codagnone et al evaluated the effect of exogenous RvD1 administration on the lung inflammatory response using the P aeruginosa agarose‐bead model . During the acute stage of infection, RvD1 decreased bacterial growth and neutrophil influx into the lungs, and during the chronic stage of infection, RvD1 decreased bacterial burden and leukocyte infiltration while limiting tissue destruction . The investigators also studied the impact of RvD1 on mouse alveolar macrophages obtained during chronic stages of infection ex vivo.…”

“…The investigators also studied the impact of RvD1 on mouse alveolar macrophages obtained during chronic stages of infection ex vivo. They demonstrated that RvD1 regulated the expression of Toll‐like receptors (TLRs), microRNA (miR)‐21, and miR‐155 and that RvD1 enhanced phagocytosis of neutrophils and macrophages in vitro . These studies support the notion that dysfunctional CFTR and the dysregulated inflammatory response in CF are closely associated and that RvD1 holds potential as a therapeutic in CF due to its beneficial effects on ion transport, host defense, and immunoregulation.…”

Surviving Deadly Lung Infections: Innate Host Tolerance Mechanisms in the Pulmonary System

“…On the other hand, there are some factors that play roles in boosting both tolerance and resistance, making them potentially more attractive for therapeutic use. Examples of these can be found in resolvins which have been shown to decrease inflammation in both long-term and acute bacterial infections as well as viral/bacterial coinfections (144)(145)(146)(147)(148)(149). In some cases, these lipid mediators can increase resistance to pathogens as well (147,149,150).…”

“…For instance, IAV has been observed to induce epithelial cell expression of TGF-β and processing of latent TGF-β precursor into active TGF-β to both suppress the host immune response and to enhance its own replication (136,170). Add-back therapeutic strategies introducing exogenous resolvins into the respiratory space have also been observed to augment tolerance in certain instances when they do not compromise pathogen clearance (144,146).…”