Fenretinide Prevents Inflammation and Airway Hyperresponsiveness in a Mouse Model of Allergic Asthma

Abstract

Arachidonic acid (AA) and docosahexaenoic acid (DHA) play important roles in inflammation and disease progression, where AA is viewed as proinflammatory and DHA as antiinflammatory. We observe in our model of allergic asthma that the AA/DHA ratio is significantly skewed in a proinflammatory direction. Fenretinide, a vitamin A derivative, has been shown to correct fatty acid imbalances in other diseases. Therefore, we explored if fenretinide can have a protective effect in allergic asthma. To accomplish this, we measured the levels of AA and DHA in the lungs of nonallergic, ovalbumin-induced allergic, and fenretinide-treated allergic mice. We also investigated the effect of allergic asthma and fenretinide treatment on markers of oxidative stress, levels of metabolites, IgE production, airway hyperresponsiveness, and histological changes. Our data demonstrate that treatment of allergen-sensitized mice with fenretinide before allergen challenge prevents ovalbumin-induced changes in the AA/DHA ratio. The levels of several metabolites, such as serotonin, and markers of cellular stress, which are increased after ovalbumin challenge, are also controlled by fenretinide treatment. We observed the protective effect of fenretinide against ovalbumin-induced airway hyperresponsiveness and inflammation in the lungs, illustrated by a complete block in the infiltration of inflammatory cells to the airways and dramatically diminished goblet cell proliferation, even though IgE remained high. Our results demonstrate that fenretinide is an effective agent targeting inflammation, oxidation, and lung pathology observed in allergic asthma.

Epithelial Anion Transport as Modulator of Chemokine Signaling

“…Changes in substrate availability (arachidonic acid (AA) versus docosahexaenoic acid (DHA)) can skew the inflammatory response, with allergic individual showing lower levels of DHA [ 146 ]. In a murine model of asthma, the proinflammatory balance was reversed using the vitamin A-derivative fenretinide to favor DHA over AA [ 147 ].…”

Four amino acids as serum biomarkers for anti-asthma effects in the ovalbumin-induced asthma mouse model treated with extract of Asparagus cochinchinensis

“…Of these, only 11 metabolites (choline, cholic acid, cortol, cholesterol, phosphatidylcholines, triglycerisdes, 5methoxy-tryptophan, creatine, mannose, galactose and arabinose) were dramatically recovered after Dex treatment [8]. Also, a significant alteration on 19 metabolite concentrations were detected in the serum of OVAchallenged BALB/c mice, although only 5 metabolites of these 14 metabolites (arginine, C3DC1C4OH, carnitine, serotonin, and tyrosine) recovered in OVA+Fenretinide (FEN) treated mice [9]. Furthermore, 6 metabolites related with sphingolipid, bile acid, purine and fatty acid metabolism were altered in the serum of OVA-induced asthma model: dodecanoic acid (P1), myristic acid (P2), phytosphingosine (P3), sphinganine (P4), inosine (P13) and taurocholic acid (P15) [7].…”

“…Metabolomics is a highly sensitive analytical tool with capability to simultaneously detect numerous metabolic markers in a single sample [14]. This approach has been applied in several studies to analyze the BALF or serum of OVA-induced asthma model, as well as asthma model treated with therapeutic drugs [7][8][9][10]. However, to date, there are no metabolomic studies that have investigated these metabolic changes in the serum of OVA-induced asthma mice treated with BAW.…”

“…Various metabolites in energy metabolism (mannose, arabinose and galactose), amino acid metabolism (5-methoxy-tryptophan and N-acetyltyrosine) and lipid metabolism (diglycerides and triglycerides) were significantly altered in the BALF from OVA-challenged BALB/c mice treated with Vehicle or dexamethasone (Dex) [8]. Also, the several plasma metabolites, such as serotonin, C3DC + C4OH, camitine, tyrosine and arginine, increased after OVA challenge but were controlled by fenretinide treatment in A/J mice [9]. Moreover, 12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE) was identified as one of the major biosynthesized molecule which was amplified by omega-3 fatty acid eicosapentaenoic acid (EPA) administration in OVA-challenged C57BL/6 mice [10].…”

Diet and asthma

“…Moreover, treatment of sensitized mice with fenretinide (60mg/kg/day) prevents ovalbumin (OVA)-induced changes in arachidonic acid metabolism, oxidative stress, AHR and inflammation in the lungs(10). Consistent with potential anti-inflammatory effects of vitamin A or vitamin A sources, increased levels of carotenoids (11) or β-carotene (12) in serum have been associated with reduced levels of markers of systemic inflammation (such as C-reactive protein (CRP) and IL-6) in humans.…”