Hindawi Publishing Corporation PPAR Research Volume 2012, Article ID 617063, 12 pages doi:10.1155/2012/617063 Research Article The Nitrated Fatty Acid 10-Nitro-oleate Diminishes Severity of LPS-Induced Acute Lung Injury in Mice Aravind T. Reddy, Sowmya P. Lakshmi, and Raju C. Reddy Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University and Atlanta VA Medical Center, Atlanta, GA 30033, USA Correspondence should be addressed to Raju C. Reddy, raju.reddy@emory.edu Received 24 February 2012; Accepted 21 April 2012 Academic Editor: Jesse Roman Copyright © 2012 Aravind T. Reddy et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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. 1. Introduction 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. Regardless of the pre- cipitating cause, the earliest phases of ALI feature severe neutrophil-rich alveolar inflammation [2] and associated oxidant stress [3] that represent the proximate causes of much or all of the subsequent pulmonary injury. ALI morbidity and mortality remain high and there is no effective pharmacotherapy [4], underlining the urgent need for improved treatment modalities. Peroxisome proliferator-activated receptor γ (PPAR-γ) plays a central role in many of the feedback loops that normally limit inflammation and lead to its resolution [5–9] and is therefore a promising target for ALI pharmacotherapy. Among the many anti-inflammatory effects attributable to PPAR-γ activation are diminished increases in reactive oxy- gen species, cytokines, chemokines, and adhesion molecules [10]. A major mechanism underlying these actions is decreased activity of proinflammatory transcription factors such as NF-κB, AP-1, and STAT [5, 6]. Synthetic PPAR- γ agonists are widely used for treatment of diabetes but have been associated with adverse effects. A wide variety of endogenous molecules are known to activate PPAR- γ, but most either exhibit low potency or are present at low concentrations, leading to uncertainty regarding their physiological role. Nitrated fatty acids (NFAs) are activating ligands for all three PPARs, exhibiting their greatest potency as PPAR-γ agonists [11, 12]. They have also been shown to exhibit a number of PPAR-γ-dependent effects, including induction of adipogenesis [11] and of CD36 receptor expression by macrophages [12]. NFAs are produced endogenously by nonenzymatic reaction of NO or its inorganic reaction products with naturally present unsaturated fatty acids