Faculty Bibliography

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.

Pulmonary disease after World Trade Center particulate matter(WTC-PM) exposure is associated with dyslipidemia and the receptor for advanced glycation end products (RAGE); however, the mechanisms are not well understood. We utilized a murine model and a multiOMIC assessment to understand the role of RAGE in the pulmonary long-term effects of a single high intensity exposure to WTC-PM. After 1-month(1-M), WTC-PM exposed wild-type(WT) mice had airway hyperreactivity(AHR) while RAGE-deficient(Ager-/-) were protected. PM-exposed WT mice also had histologic evidence of airspace disease while Ager-/- remained unchanged. Inflammatory mediators such as G-CSF, IP-10, and KC were differentially expressed after WTC-PM exposure. WTC-PM induced α-SMA, DIAPH1, RAGE and significant lung collagen deposition in WT compared to Ager-/-. Compared to WT with PM exposure, relative expression of phosphorylated to total CREB and JNK were significantly increased in the lung of PM-exposed Ager-/-, whereas Akt was decreased. Random forests of the refined lung metabolomic profile classified subjects with 92% accuracy; principal components analysis captured 86.7% of the variance in 3 components and demonstrated prominent sub-pathway involvement including known mediators of lung disease such as vitamin B6 metabolites, sphingolipids, fatty acids, and phosphatidylcholines. Treatment with a partial RAGE antagonist, pioglitazone, yielded similar fold-change expression of metabolites(N6-carboxymethyllysine, 1-methylnicotinamide, (N(1)+N(8))-acetylspermidine and Succinylcarnitine(C4-DC)) between WT and Ager-/- exposed to WTC-PM. RAGE can mediate WTC-PM-induced AHR, and warrants further investigation.

BACKGROUND:A reduced forced vital capacity without obstruction (low FVC) is the predominant spirometric abnormality reported in workers and volunteers exposed to dust, gases, and fumes at the World Trade Center (WTC) disaster site in 2001-2002. While low FVC has been associated with obesity and metabolic syndrome, its association with WTC occupational exposures has not been demonstrated. We estimated the prevalence of this abnormality and examined its association with WTC exposure level. METHODS:/FVC ratio) at any time in 10,284 workers with at least two spirometries between 2002 and 2018. Logistic regression and linear mixed models were used for the multivariable analyses. RESULTS: = 1.29, 95% CI 1.17, 1.43). Longitudinal FVC rate of decline did not differ by WTC site arrival time. CONCLUSIONS:Among WTC workers, the prevalence of low FVC increased over a 16-year period. Early arrival to the WTC disaster site was significantly associated with low FVC in males.

World Trade Center particulate matter (WTC-PM)-exposed firefighters with metabolic syndrome (MetSyn) have a higher risk of WTC lung injury (WTC-LI). Since macrophages are crucial innate pulmonary mediators, we investigated WTC-PM/lysophosphatidic acid (LPA) co-exposure in macrophages. LPA, a low-density lipoprotein metabolite, is a ligand of the advanced glycation end-products receptor (AGER or RAGE). LPA and RAGE are biomarkers of WTC-LI. Human and murine macrophages were exposed to WTC-PM, and/or LPA, and compared to controls. Supernatants were assessed for cytokines/chemokines; cell lysate immunoblots were assessed for signaling intermediates after 24 h. To explore the translatability of our in-vitro findings, we assessed serum cytokines/chemokines and metabolites of symptomatic, never-smoking WTC-exposed firefighters. Agglomerative hierarchical clustering identified phenotypes of WTC-PM-induced inflammation. WTC-PM induced GM-CSF, IL-8, IL-10, and MCP-1 in THP-1-derived macrophages and induced IL-1α, IL-10, TNF-α, and NF-κB in RAW264.7 murine macrophage-like cells. Co-exposure induced synergistic elaboration of IL-10 and MCP-1 in THP-1-derived macrophages. Similarly, co-exposure synergistically induced IL-10 in murine macrophages. Synergistic effects were seen in the context of a downregulation of NF-κB, p-Akt, -STAT3, and -STAT5b. RAGE expression after co-exposure increased in murine macrophages compared to controls. In our integrated analysis, the human cytokine/chemokine biomarker profile of WTC-LI was associated with discriminatory metabolites (fatty acids, sphingolipids, and amino acids). LPA synergistically elaborated WTC-PM's inflammatory effects in vitro and was partly RAGE-mediated. Further research will focus on the intersection of MetSyn/PM exposure.