Faculty Bibliography

RATIONALE/BACKGROUND:Impaired sphingolipid synthesis is linked genetically to childhood asthma and functionally to airway hyperreactivity. OBJECTIVES/OBJECTIVE:To investigate if sphingolipid synthesis could be a target for asthma therapeutics. METHODS:The effects of GlyH-101 and fenretinide via modulation of de novo sphingolipid synthesis on airway hyperreactivity was evaluated in mice deficient in serine palmitoyl-CoA transferase, the rate limiting enzyme of sphingolipid synthesis. The drugs were also used directly in human airway smooth muscle and epithelial cells to evaluate changes in de novo sphingolipid metabolites and calcium release. RESULTS:GlyH-101 and fenretinide increased sphinganine and dihydroceramides (de novo sphingolipid metabolites) in lung epithelial and airway smooth muscle cells, decrease intracellular calcium concentration in airway smooth muscle cells, and decrease agonist-induced contraction in proximal and peripheral airways. GlyH-101 also decreased airway hyperreactivity in SPT-deficient mice in vivo. CONCLUSIONS:This study identifies the manipulation of sphingolipid synthesis as a novel metabolic therapeutic strategy to alleviate airway hyperreactivity.

Fire Department of New York (FDNY) rescue and recovery workers exposed to World Trade Center (WTC) particulates suffered loss of forced expiratory volume in 1 s (FEV₁). Metabolic Syndrome increased the risk of developing WTC-lung injury (WTC-LI)_. We aim to attenuate the deleterious effects of WTC exposure through a dietary intervention targeting these clinically relevant disease modifiers. We hypothesize that a calorie-restricted Mediterranean dietary intervention will improve metabolic risk, subclinical indicators of cardiopulmonary disease, quality of life, and lung function in firefighters with WTC-LI. To assess our hypothesis, we developed the Food Intake REstriction for Health OUtcome Support and Education (FIREHOUSE), a randomized controlled clinical trial (RCT). Male firefighters with WTC-LI and a BMI > 27 kg/m² will be included. We will randomize subjects (1:1) to either: (1) Low Calorie Mediterranean (LoCalMed)-an integrative multifactorial, technology-supported approach focused on behavioral modification, nutritional education that will include a self-monitored diet with feedback, physical activity recommendations, and social cognitive theory-based group counseling sessions; or (2) Usual Care. Outcomes include reduction in body mass index (BMI) (primary), improvement in FEV₁, fractional exhaled nitric oxide, pulse wave velocity, lipid profiles, targeted metabolic/clinical biomarkers, and quality of life measures (secondary). By implementing a technology-supported LoCalMed diet our FIREHOUSE RCT may help further the treatment of WTC associated pulmonary disease.