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.

Nitrated fatty acids (NFAs) are endogenous agonists of peroxisome proliferator‐activated receptor γ (PPAR‐γ) that have been shown to exhibit anti‐inflammatory and antioxidant activity. We investigated NFA effects in the OVA model of allergic airway disease. The glucocorticoid fluticasone (Flut) was used as a positive control. Pulmonary administration of the NFA 10‐nitro‐oleic acid (OA‐NO2) or Flut produced significant and essentially indistinguishable reductions in airway hyperresponsiveness, lung and BAL fluid cytokine concentrations, OVA‐specific IgE concentrations, and mucus production. Both likewise produced similar and significant reductions in eosinophil infiltration and oxidative stress, reflecting reduced adhesion molecule expression. In vitro studies using both immortalized and human bronchial epithelial cells cultured at an air‐liquid interface demonstrated that OA‐NO2 increased expression and activity of PPAR‐γ and decreased activity of the pro‐inflammatory transcription factor NF‐κB. Increased expression of the glucocorticoid receptor and activity of the antioxidant transcription factor Nrf2 were also observed. Our results thus demonstrate beneficial NFA effects that suggest potential therapeutic utility in asthma. This work was supported by National Institutes of Health grant HL093196.

Hyperbaric oxygen (HBO) therapy is proven to be very successful for diabetic foot ulcer (DFU) treatment and has been demonstrated to have antimicrobial effect, increased angiogenesis and enhanced collagen synthesis. In the present study, we investigated the molecular mechanism underlying HBO therapy particularly the role of Nrf2 in wound healing process. In addition, we have studied the levels of angiogenic markers in ulcer tissues and their correlation with Nrf2 during HBO therapy compared with a standard therapy (Non-HBO) for DFU. A total of 32 patients (16 males and 16 females) were recruited and randomized to standard wound care alone (n=17) or HBO therapy in combination with standard wound care (n=15). Our results showed that the tissue levels of Nrf2 along with the downstream targets showed significant increase in patients who underwent HBO therapy. It induces angiogenesis with significantly increasing the levels of angiogenesis markers such as EGF, VEGF, PDGF, FGF-2 and CXCL10 in the tissue samples. The HIF-1α expression showed a 4.9-fold and eNOS with a 4.5-fold among HBO therapy when compared to Day 0 subjects. HBO therapy sensitize macrophages to release FGF-2 and EGF thereby promotes angiogenesis. Further it increased the levels of CXCL-8, which is a potent neutrophil attractant thereby promote the release chemokine CCL2, a well-known mediator of neovascularization. The Spearman’s correlation showed that Nrf2 have a positive correlation with EGF, VEGF, PDGF and HIF-1α. In conclusion, the findings of the present study suggest that HBO therapy promote wound healing by increasing oxygen dispersion to damaged tissues, stimulating angiogenesis, alleviating inflammation, and increasing the levels of NO. It is evidenced that elevated Nrf2 transiently regulates angiogenic gene expression in wound biopsies, which may enhance chronic wound healing. Disclosure D. Umapathy: None. P. Vikraman: None. V. Alladi: None. S. Arumugam: None. S. Dornadula: None. K. Amin: None. R. Kesavan: None. R. Kunka Mohanran: None.