**7. SPMs' Role in Bacterial Clearance and Limiting Tissue Damage**

Resolution of acute inflammation has been shown to be crucial for ensuring bacterial clearance and limiting tissue damage. A few groups investigated the protective actions of LXA4 and RvD1 in lung infection induced by *Pseudomonas aeruginosa*. Patients with CF have a predisposition to chronic colonization and infection with *P. aeruginosa*, an organism whose presence in the CF lung is associated with progressive respiratory compromise. Antibiotics are insufficiently successful, because of resistance mechanisms developed by *P. aeruginosa* [68]. *P. aeruginosa* can escape killing by the immune system and establish chronic infections that do not resolve [69,70].

Karp et al. have shown that administration of a metabolically stable LXA4 analog in a mouse model of the chronic airway inflammation and infection associated with cystic fibrosis decreased pulmonary bacterial burden and attenuated disease severity [49]. In vitro, LXA4 has been reported to delay colonization of airway epithelium by *P. aeruginosa* by enhancing the airway transepithelial electrical resistance and the expression of the tight junction protein ZO-1 at the plasma membrane in human bronchial epithelial cells [64,71]. LXA4 also stimulates airway epithelial repair (migration and proliferation) via stimulation of ATP-sensitive potassium channel and mitogen-activated protein kinase pathway [72,73].

RvD1 decreased TNFα induced IL-8 secretion and enhanced the phagocytic and bacterial killing capacity of human CF alveolar macrophages [67]. RvD1 significantly diminished bacterial growth and neutrophil infiltration during acute pneumonia caused by a clinical strain of *P. aeruginosa*. Inoculum of *P. aeruginosa*, immobilized in agar beads, resulted in persistent lung infection and non-resolving inflammation. RvD1 significantly reduced bacterial load, 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 [74]. Finally, Eickmeier et al. have reported that RvD1 levels in plasma and sputum samples from patients with CF showed a positive correlation with sputum inflammatory markers. The plasma concentrations of RvD1 were ten times higher than sputum concentrations and sputum RvD1/IL-8 levels showed a positive correlation with FEV1 [51].

These data, seen in Figure 3, provide evidence for a role of SPM in acute and chronic *P. aeruginosa* pneumonia, and for its potent pro-resolution and tissue protective properties.

#### **8. Conclusions**

Cystic fibrosis, the most common lethal genetic disease in Western populations, is characterized by a chronic inflammation and sustained neutrophilic inflammation of the airways. The most recent reports suggest that the persistent inflammation in CF airways appeared to be due to an altered resolution phase and efficiency to contain infection rather than abnormalities in its triggering. Early studies suggested that the abnormal fatty acid metabolism in CF played a central role in the CF disease, and more recent studies demonstrated the sustained airway inflammation to be related to an abnormal eicosanoid class switching between SPM (lipoxin and resolvin) and leukotrienes. Although the precise role of CFTR mutation on SPM biosynthesis remains unclear, the role of SPM in resolving inflammation, in increasing the airway surface liquid layer, in enhancing bacterial clearance and tissue repair strongly suggest that the altered production of pro-resolving lipid mediators play a central in CF pathogenesis, as shown in Figure 3.

**Author Contributions:** Writing—Review & Editing, R.P. and V.U. Funding Acquisition, V.U.

**Funding:** This research was funded by Vaincre la Mucoviscidose grant number [RF20170502010].

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


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