Abstract
Acute lung injury (ALI) is an inflammatory condition culminating in respiratory failure. There is currently no effective pharmacological treatment. Nitrated fatty acids (NFAs) have been shown to exert anti-inflammatory effects. We therefore hypothesized that delivery of NFAs directly to the site of inflammation would reduce the severity of ALI. Pulmonary delivery of 10-nitro-oleate following endotoxin-induced ALI in mice reduced markers of lung inflammation and injury, including capillary leakage, lung edema, infiltration of neutrophils into the lung, and oxidant stress, as well as plasma levels of proinflammatory cytokines. Nitro-oleate delivery likewise downregulated expression of proinflammatory genes by alveolar macrophages, key cells in regulation of lung inflammation. These effects may be accounted for by the observed increases in the activity of PPAR-γ and the PPAR-γ-induced antioxidant transcription factor Nrf2, together with the decreased activity of NF-κB. Our results demonstrate that pulmonary delivery of NFAs reduces severity of acute lung injury and suggest potential utility of these molecules in other inflammatory lung diseases.
Highlights
A variety of pulmonary and extrapulmonary insults can result in acute lung injury (ALI), which is characterized by capillary leakage and resulting pulmonary edema and hypoxemia [1]
The crystal structure of LNO2 bound to the Peroxisome proliferator-activated receptor γ (PPAR-γ) ligand binding site has been reported [19], no similar information is available for OA-NO2
To demonstrate activation of endogenous PPAR-γ, A549 cells were transfected with the luciferase gene under control of a PPAR response element
Summary
A variety of pulmonary and extrapulmonary insults can result in acute lung injury (ALI), which is characterized by capillary leakage and resulting pulmonary edema and hypoxemia [1]. These multiple origins of ALI are reflected in different animal models of the disease, of which pulmonary administration of bacterial endotoxin (lipopolysaccharide; LPS) is among the most common. A wide variety of endogenous molecules are known to activate PPARγ, but most either exhibit low potency or are present at low concentrations, leading to uncertainty regarding their physiological role
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