The Nitrated Fatty Acid 10-Nitro-Oleate Attenuates Allergic Airway Disease

Abstract

Asthma is a serious, growing problem worldwide. Inhaled steroids, the current standard therapy, are not always effective in this chronic inflammatory disease and can cause adverse effects. We tested the hypothesis that nitrated fatty acids (NFAs) may provide an effective alternative treatment. NFAs are endogenously produced by nonenzymatic reaction of NO with unsaturated fatty acids and exert anti-inflammatory actions both by activating the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)γ and via PPAR-independent mechanisms, but whether they might ameliorate allergic airway disease was previously untested. We found that pulmonary delivery of the NFA 10-nitro-oleic acid (OA-NO2) reduced the severity of murine allergic airway disease, as assessed by various pathological and molecular markers. Fluticasone, an inhaled steroid commonly used to treat asthma, produced similar effects on most end points, but only OA-NO2 induced robust apoptosis of neutrophils and their phagocytosis by alveolar macrophages. This suggests that OA-NO2 may be particularly effective in neutrophil-rich, steroid-resistant severe asthma. In primary human bronchial epithelial cells, OA-NO2 blocked phosphorylation and degradation of IκB and enhanced inhibitory binding of PPARγ to NF-κB. Our results indicate that the NFA OA-NO2 is efficacious in preclinical models of allergic airway disease and may have potential for treating asthma patients.

A computational model of unresolved allergic inflammation in chronic asthma

“…7). This finding is consistent with the well-documented existence of abnormally long-lived neutrophils and eosinophils in chronic allergic inflammatory diseases such as asthma (9,11,13,19). The effect received a further substantial boost if both anti-inflammatory cells and mast cells were able to encounter a fourfold increase in the number of particles before becoming desensitized.…”

“…8). These results suggest that therapies aimed at increasing apoptosis in neotrophils and/or eosinophils might be efficacious in treating chronic allergic asthma (11,13,20).…”

Sweat lipid mediator profiling: a noninvasive approach for cutaneous research

“…The role of 8-HETE in cutaneous disease remains unclear, but it is believed that as a potent neutrophil chemoattractant, 8-HETE may promote cutaneous inflammation (41). On the other hand, 10-nitrooleate has been demonstrated to be a signaling molecule in cultured murine keratinocytes (42), and to reduce the severity of murine allergic airway disease, an atopic disorder similar to asthma, by suppressing inflammation and hypersensitivity (43). Therefore, it is possible that 8-HETE and 10-nitrooleate influence cutaneous inflammation and systemic atopy, and further testing of lesional AD skin may be necessary to establish an association between these lipid mediators and AD.…”

Nitro-Oleic Acid Attenuates OGD/R-Triggered Apoptosis in Renal Tubular Cells via Inhibition of Bax Mitochondrial Translocation in a PPAR-γ-Dependent Manner

“…They mediate a broad range of anti-inflammatory, anti-oxidative and vascular-protective actions. NO 2 -FA suppress pro-inflammatory gene expression and neutrophil infiltration by either direct nitroalkylation of the nuclear factor κB (NF κB) p65 subunit or inhibition of pro-inflammatory STAT signaling [11,12,13]. They exert vascular protection by up-regulating HO-1 and endothelial nitric oxide synthase (eNOS) expression in pulmonary epithelium and aortic endothelial cells [14,15,16].…”

“…Notably, NO 2 -FA have been found to be robust endogenous activating ligands for all three PPARs, exhibiting the greatest potency as PPAR-γ agonists [18,19,20]. They possess a number of PPAR-γ-dependent effects, including promoting adipogenesis in 3T3-L1 pre-adipocytes, inducing CD36 receptor expression in macrophages [18,19] and inhibiting NF-κB activation in inflammatory disease [12,21,22]. …”