Altered fatty acid metabolism and reduced stearoyl-coenzyme a desaturase activity in asthma.

BACKGROUND: Fatty acids and lipid mediator signaling play an important role in the pathogenesis of asthma, yet this area remains largely underexplored. The aims of this study were (i) to examine fatty acid levels and their metabolism in obese and nonobese asthma patients and (ii) to determine the functional effects of altered fatty acid metabolism in experimental models. METHODS: Medium- and long-chain fatty acid levels were quantified in serum from 161 human volunteers by LC/MS. Changes in stearoyl-coenzyme A desaturase (SCD) expression and activity were evaluated in the ovalbumin (OVA) and house dust mite (HDM) murine models. Primary human bronchial epithelial cells from asthma patients and controls were evaluated for SCD expression and activity. RESULTS: The serum desaturation index (an indirect measure of SCD) was significantly reduced in nonobese asthma patients and in the OVA murine model. SCD1 gene expression was significantly reduced within the lungs following OVA or HDM challenge. Inhibition of SCD in mice promoted airway hyper-responsiveness. SCD1 expression was suppressed in bronchial epithelial cells from asthma patients. IL-4 and IL-13 reduced epithelial cell SCD1 expression. Inhibition of SCD reduced surfactant protein C expression and suppressed rhinovirus-induced IP-10 secretion, which was associated with increased viral titers. CONCLUSIONS: This is the first study to demonstrate decreased fatty acid desaturase activity in humans with asthma. Experimental models in mice and human epithelial cells suggest that inhibition of desaturase activity leads to airway hyper-responsiveness and reduced antiviral defense. SCD may represent a new target for therapeutic intervention in asthma patients.

Brain and blood indole metabolites after peripheral administration of(14)C-5-HT in rat.

Radioactive techniques were used to reexamine the reports that pharmacological quantities of peripheral serotonin (5-hydroxytryptamine or 5-HT) gain access to brain parenchyma. Intravenous injection of 0.108-4.19 mg/kg of(14)C-5-HT (3.55 µCi/100 g weight) produced significant metabolic differences in brain but not blood as a function of dose at up to 10 min after injection. Neither of the metabolites, 5-hydroxyindoleacetic acid nor 5-hydroxytryptophol, were detectable in brain following their intravenous injection, suggesting that when such metabolites are found in brain they represent central metabolism. It has also been shown that peripheral compartments in general, and specifically blood in the cerebral vasculature and the adrenergic nerve endings in the cerebral blood vessels, contribute to the uptake and metabolism of 5-HT. We conclude that doses up to 0.435 mg/kg 5-HT do not cross the blood-brain barrier in the rat but are being totally metabolized in nonneuronal tissues that are invariably removed and assayed along with brain parenchyma. The level at which 5-HT actually passes the blood-brain barrier was found to be at least 0.863 mg/kg. This value is one-third lower than that previously reported.