protectin-d1 and Acute-Lung-Injury

Inflammation is an essential host defence against infection, but can be damaging when excessive. Resolution of inflammation is an active process, and the pro-resolution effects of lipoxins, resolvins and protectins have received significant interest. Here, we review emerging data on the role of these lipid mediators in infectious disease. Lipoxins influence host control of Mycobacterium tuberculosis, Toxoplasma gondii, Trypanosoma cruzi and Plasmodium berghei cerebral malaria in mice. Their effects are protective in toxoplasmosis, T. cruzi infection and cerebral malaria but detrimental in tuberculosis; related to the balance between pathogen-control and excessive immune response. Topical lipoxin abrogates the tissue damage seen in a rabbit model of Porphyromonas gingivalis periodontitis. The increased virulence of H5N1 influenza A virus in mice correlates with reduced expression of SOCS2, required to mediate the effects of lipoxin. Mice unable to synthesize lipoxin suffer increased lung pathology during respiratory syncytial virus infection. Protectin suppresses influenza A virus replication in vitro and increases survival in a mouse model of severe influenza infection. Resolvins were investigated in a number of animal models of systemic bacterial infection, and were found to enhance phagocytic clearance of bacteria, reduce inflammation severity, promote neutrophil apoptosis, modulate neutrophil chemotaxis and importantly, reduce mortality. Interestingly, resolvin also enhances the antibacterial effect of ciprofloxacin and vancomycin. Topical resolvin application reduces the severity of herpes simplex virus ocular infection in mice. If the effects of these mediators translate from pre-clinical studies into successful clinical trials, they represent promising new strategies in managing infectious disease.

Topics: Acute Lung Injury; Animals; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Infections; Lipoxins; Sepsis

Protectin D1 (PD1), derived from docosahexaenoic acid, has been shown to control and resolve inflammation in some experimental models of inflammatory disorders. We investigated the protective roles of protectin D1 in pulmonary inflammation and lung injury induced by lipopolysaccharide (LPS).. Mice were randomly assigned to six groups (n = 6 per group): sham-vehicle group, sham-PD1 group, sham-zVAD-fmk group, LPS-vehicle group, LPS-PD1 group, and LPS-PD1-zVAD-fmk group. Mice were injected intratracheally with 3 mg/kg LPS or saline, followed 24 hours later by intravenous injection of 200 µg/mouse PD1 or vehicle. At the same time, some mice were also injected intraperitoneally with the pan-caspase inhibitor zVAD-fmk. Seventy-two hours after LPS challenge, samples of pulmonary tissue and bronchoalveolar lavage fluid were collected. Optical microscopy was used to examine pathological changes in lungs. Cellularity and protein concentration in bronchoalveolar lavage fluid were analyzed. Lung wet/dry ratios and myeloperoxidase activity were measured. Apoptosis of neutrophils in bronchoalveolar lavage fluid (BALF) was also evaluated by flow cytometry.. Intratracheal instillation of LPS increased neutrophil counts, protein concentration in bronchoalveolar lavage fluid and myeloperoxidase activity, it induced lung histological injury and edema, and also suppressed apoptosis of neutrophils in BALF. Posttreatment with PD1 inhibited LPS-evoked changes in BALF neutrophil counts and protein concentration and lung myeloperoxidase activity, with the outcome of decreased pulmonary edema and histological injury. In addition, PD1 promoted apoptosis of neutrophils in BALF. The beneficial effects of PD1 were blocked by zVAD-fmk.. Posttreatment with PD1 enhances resolution of lung inflammation during LPS-induced acute lung injury by enhancing apoptosis in emigrated neutrophils, which is, at least in part, caspase-dependent.

Topics: Acute Lung Injury; Animals; Apoptosis; Docosahexaenoic Acids; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Neutrophils; Peroxidase