Nitrated fatty acid, 10-nitrooleate protects against hyperoxia-induced acute lung injury in mice.

The antioxidant and anti-inflammatory effects of electrophilic nitrated fatty acid (NFA); 10-nitrooleate, have been reported. The present study investigated whether 10-nitrooleate has a protective role against hyperoxic-induced acute lung injury (HALI). Using a C57BL/6 mice model of HALI, we investigated the protective effect of 10-nitrooleate. C57BL/6 mice were administered with NFA intratracheally, exposed to hyperoxia for 48 h to induce HALI, and kept at room air for 24 h. Bronchoalveolar lavage (BAL) fluid and lung samples were collected after 24 h of post hyperoxia to analyze markers associated with HALI. Intratracheal (IT) and intraperitoneal (IP) administration of NFA notably attenuated hyperoxia-induced infiltration of inflammatory cells, alveolar-capillary leakage, upregulation of proinflammatory cytokine levels (IL-6 and TNFα) into the BAL fluid, and resolution of inflammation in the lung. Western blot analyses showed that 10-nitrooleate reduced the expression of the inflammatory transcription factor NFκB p65 subunit and increased antioxidant proteins HO-1 and NQO1 expression in the lung tissues compared to vehicle-treated animals. Moreover, 10-nitrooleate reversed the hyperoxia-induced expression of mitophagy-associated markers (PINK1 and p62/SQSTM1), thereby protecting the HALI/ acute respiratory distress syndrome (ARDS). IT and IP delivery of 10-nitrooleate reduces hyperoxia-induced ALI/ARDS by regulating the antioxidant pathways and restoring the mitochondrial homeostasis by regulating mitophagy. It is suggested that NFAs can be further evaluated as supplementary therapy for critically ill patients like COVID-19/ARDS.

Electrophilic nitrated fatty acids are potential therapeutic candidates for inflammatory and fibrotic lung diseases.

Several types of exposures can cause acute or chronic inflammatory reactions in the lungs often leading to asthma, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute lung injury, lung cancer, and other deleterious health outcomes. Current therapy, with inhaled or oral glucocorticoids, successfully targets inflammation but also produces adverse effects that limit their enthusiastic use. Accordingly, the need remains for interventions that are safer and more effective. Nitrated fatty acids (NFAs) are highly electrophilic and are produced endogenously by non-enzymatic reactions of nitric oxide with conjugated unsaturated fatty acids. The literature indicates that NFAs are detected in humans at the nanomolar range and are produced more robustly under inflammatory conditions. Recent studies on novel NFAs report antiinflammatory, antioxidant, and antifibrotic effects, while also acting as partial agonists of peroxisome proliferator-activated receptor-gamma (PPAR-γ). Furthermore, these functions of NFAs occur via reversible electrophilic alkylation of cysteine residues and regulation of antiinflammatory, antioxidant signaling through modulation of transcription factors, including nuclear factor E2-related factor 2 (Nrf2), PPAR-γ, and NF-κB. Here, we review and update the role of NFA signaling mechanisms and their therapeutic potential in various lung diseases. As NFAs display strong electrophilic interaction with multimechanistic pathways, they can be considered promising drug candidates for challenging lung diseases.