Protectin DX Exhibits Protective Effects in Mouse Model of Lipopolysaccharide-Induced Acute Lung Injury

Abstract

Background:Acute lung injury (ALI) is a severe disease with high mortality and poor prognosis. Protectin DX (PDX), a pro-resolving lipid mediator, exhibits protective effects in ALI. Our experiment aimed to explore the effects and related mechanisms of PDX in mice with ALI induced by lipopolysaccharide (LPS).Methods:BALB/c mice were randomly divided into five groups: sham, LPS, LPS plus 1 ng of PDX (LPS + PDX-1 ng), LPS plus 10 ng of PDX (LPS + PDX-10 ng), and LPS plus 100 ng of PDX (LPS + PDX-100 ng). Bronchoalveolar lavage fluids (BALFs) were collected after 24 h, and total cells, polymorphonuclear leukocytes, monocyte-macrophages, and lymphocytes in BALF were enumerated. The concentration of interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor-alpha (TNF-α), macrophage inflammatory protein (MIP)-1α, and MIP-2 in BALF was determined, and histopathological changes of the lung were observed. The concentration of protein in BALF and lung wet/dry weight ratios were detected to evaluate pulmonary edema. After determining the optimal dose of PDX, neutrophil–platelet interactions in whole blood were evaluated by flow cytometry.Results:The highest dose of PDX (100 ng/mouse) failed to provide pulmonary protective effects, whereas lower doses of PDX (1 ng/mouse and 10 ng/mouse), especially 1 ng PDX, alleviated pulmonary histopathological changes, mitigated LPS-induced ALI and pulmonary edema, inhibited neutrophil infiltration, and reduced pro-inflammatory mediator (IL-1β, IL-6, TNF-α, and MIP-1α) levels. Meanwhile, 1 ng PDX exhibited pro-resolving functions in ALI including upregulation of monocyte-macrophage numbers and anti-inflammatory mediator IL-10 levels. The flow cytometry results showed that PDX could inhibit neutrophil–platelet interactions in ALI.Conclusion:PDX exerts protective effects in LPS-induced ALI by mitigating pulmonary inflammation and abrogating neutrophil–platelet interactions.

PDX regulates inflammatory cell infiltration via resident macrophage in LPS‐induced lung injury

“…TNF‐α is a central mediator of inflammation and plays an important role in the host response to injury, but overexpression of TNF‐a can result in severe tissue damage and underlies a number of disease states, such as rheumatoid arthritis, ARDS and malignancy 28,29 . In the present study, we found that PDX could inhibit TNF‐α expression to protect lung tissues, which was consistent with a previous study showing that PDX abolished zymosan‐A‐induced TNF‐α production 30 . We also found that TNF‐α was mainly expressed on recruited macrophages and worked by binding with TNFR, which was expressed on resident macrophages.…”

Specialized proresolving mediators in infection and lung injury

“…The treated mice also had reduced TNF‐α and neutrophil infiltration into the lungs 83 . Additionally, PDX improved lung histopathology, reduced lung inflammation, and mitigated pulmonary edema in a mouse model of acute lung injury 84 …”

“…83 Additionally, PDX improved lung histopathology, reduced lung inflammation, and mitigated pulmonary edema in a mouse model of acute lung injury. 84 While further studies, and particularly clinical studies, are necessary, the preclinical data suggest that SPMs could offer a new therapeutic strategy to decrease the severity and duration of ARDS by improving alveolar fluid clearance and decreasing excessive inflammation.…”

N-3 PUFAs and their specialized pro-resolving lipid mediators on airway inflammatory response: beneficial effects in the prevention and treatment of respiratory diseases

“…92 Only 1 ng per animal of PDX, an isomer of PD1, can alleviate lipopolysaccharide-induced acute lung injury, inhibiting neutrophil infiltration and reducing pro-inflammatory mediators such as IL-1β, IL-6, TNF-α, and MIP-1α. 93 In acute lung injury, PDX improved the alveolar fluid clearance and decreased edema by upregulating the sodium channel and Na, K-ATPase levels. 94 With respect to acute lung injury, Xia et al 95 described that PDX ameliorates cecal ligation-induced sepsis through the decrease of IL-1β, IL-6, TNF-α, and MCP-1 in BALF, with the consequent decline of neutrophil influx.…”