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OBJECTIVES/GOALS: Particulate matter (PM) and metabolic syndrome (MetSyn) increase risk of World Trade Center-Lung Injury (WTC-LI). Mediterranean-type diets have also been found to improve lung function. Fire Department of New York 1st-responders with a high PM exposure at WTC and MetSyn may have improved lung function after a Mediterranean dietary intervention. METHODS/STUDY POPULATION: Food Intake REstriction for Health OUtcome Support and Education (FIREHOUSE) randomized clinical trial (RCT) assessed our hypothesis that a low-calorie Mediterranean (LoCalMed) intervention targeting clinically relevant disease modifiers will improve metabolic risk, subclinical indicators of cardiopulmonary disease, quality of life, and lung function in firefighters with WTC-LI. Primary-outcome targeted a LoCalMed loss of BMI(≥1kg/m2). Secondary-outcomes included lung function, quality of life, and cardiovascular health. Male firefighters with WTC-LI and a BMI>27kg/m2 were randomized to: 1. LoCalMed (n=46); or 2. Usual Care (UC; n=43). Clinicaltrials.gov:NCT03581006. RESULTS/ANTICIPATED RESULTS: LoCalMed’s estimated efficacy on BMI reduction crossed the pre-specified significance boundary on interim analysis compared to UC. In addition, improvements were observed in secondary-outcomes of lung health (FEV1 and FVC), inflammation (WBC), vascular disease (DBP), quality of life (SF-36, health perception) and dietary habits (less cholesterol, carbohydrates, fats, and sweets and increased protein) in the LoCalMed arm. DISCUSSION/SIGNIFICANCE: LoCalMed significantly decreased BMI and alleviated adverse health outcomes in our WTC-exposed first responders. A fully powered RCT is required to determine if this approach is efficacious for the treatment of WTC-associated pulmonary disease, as well as LoCalMed’s generalizability to PM associated disease.

OBJECTIVES/GOALS: Metabolic syndrome (MetSyn) is a risk for World Trade Center-Lung Injury (WTC-LI; defined as developing FEV11 LLN (N = 5,746). Data assessed from last pre-9/11 till August 1, 2017. Longitudinal MetSyn characteristics were assessed using 3 models: i. A linear mixed effect model to assess the effect size of longitudinal MetSyn and its components on longitudinal FEV1% predicted as an outcome; ii. a time-dependent Cox regression to assess the associations of MetSyn to time of onset of WTC-LI; iii. a novel, partially linear single index regression model with repeatedly measured MetSyn to assess their joint effects and delineate their relative contribution on the longitudinal lung function in the WTC-FDNY cohort. RESULTS/ANTICIPATED RESULTS: In Model I, BMI 30 kg/m2 had the largest effect size compared to ever-smoking, with −2.524 (95%CI: −2.708,−2.340) compared to −1.681(−2.325,−1.038) respectively. Having MetSyn, defined as 3/5 risk factors, had an effect size of −2.319(−2.526,−2.112). In Model II, hazards of triglycerides 150mg/dL were highest at 1.497(1.336, 1.677), followed by BMI 30 kg/m2 at 1.406(1.256, 1.575), and HDLModel III The proposed methods will be applied to our cohort study. DISCUSSION/SIGNIFICANCE OF IMPACT: MetSyn is both a predictor and concurrent marker of WTC-LI. The single index model can not only reduce dimensionality of the covariates, but also provides efficient estimates of the joint MetSyn effects, allowing linear or nonlinear effects. Future studies will investigate dietary intervention as a potential disease-modifying factor. CONFLICT OF INTEREST DESCRIPTION: NA, nothing to disclose.

OBJECTIVES/SPECIFIC AIMS: Obstructive lung disease following particulate matter (PM) exposure is a major health concern. Coexisting metabolic syndrome (MetSyn) often occurs. Receptor for advanced glycation end products (RAGE) is highly expressed in the lung, is a strong predictor of FEV1, and is a key mediator of MetSyn. To determine if the loss of RAGE protects from the persistence of effects of particulate associated lung injury in a murine model. METHODS/STUDY POPULATION: Wild type (WT) and RAGE knockout (RKO) mice were exposed to 100 μg of PM (WTC-Aggregate, PM53) or PBS control by oropharyngeal aspiration. Lung function, methacholine challenge, and bronchoalveolar lavage (BAL) were quantified 28 days after PM exposure using flexiVent (Scireq Montreal, QC). BAL was obtained and cell differentials, cytokines and transcription factors were assayed. Bio-volume to airspace ratio and mean chord length were measured (Image J and Adobe Photoshop). RESULTS/ANTICIPATED RESULTS: WT mice were hyper-reactive to methacholine compared with their PBS controls 28 days after a single exposure to PM. They recovered from increased neutrophilia, loss of FEV, decreased compliance, and increased resistance, which were previously observed 24-hours after exposure. RKO were not hyper-reactive when compared with their own PBS controls. Lung histology shows persistence of loss of alveolar space in WT mice exposed to PM after 28 days. Area fraction was significantly higher in PM exposed WT mice after 28 days which was not significant after 24 hours. Mean chord length was significantly shorter for PM exposed at both time points for WT mice. The relative expression of phosphorylated to total CREB and ERK1/2 proteins was lower in RKO PM exposed mice compared with WT PM while STAT3 expression was lower in WT PM compared with WT PBS. PM induced a lower fold change of total proteins from the PBS controls in RKO for CREB, p38, ERK1/2, STAT3, and STAT5. JNK and p70S6k total proteins expressed a decreased fold change in WT PM exposed mice compared with WT PBS controls. DISCUSSION/SIGNIFICANCE OF IMPACT: A single dose of PM can produce persistent airway hyper-reactivity after 28 days of exposure. This PM induced injury is alleviated in the absence of RAGE, similar to what was seen at 24 hours. Inhibiting RAGE may be key to limiting the persistent inflammatory effects of high intensity PM exposure.

OBJECTIVES/SPECIFIC AIMS: In this pilot case-control study, the metabolome was quantified in subjects with previously measured serum and clinical biomarkers. The serum metabolome was then integrated with existing serum and clinical biomarkers of WTC-exposed firefighters to identify pathways significant to loss of lung function following acute PM-exposure. This robust subset of metabolite and serum biomarkers may be clinically relevant to predicting progression to lung disease in a larger cohort. METHODS/STUDY POPULATION: Serum drawn within 6 months of 9/11 was analyzed in this pilot. Clinical measures were obtained from electronic medical records. Never-smoking, male, WTC-exposed firefighters with normal pre-9/11 lung function were segregated based on FEV1 percent predicted (FEV1 %Pred) at symptomatic presentation. Cases of WTC-LI (FEV1 %Pred