Predictive Biomarkers of Gastroesophageal Reflux Disease and Barrett’s Esophagus in World Trade Center Exposed Firefighters: a 15 Year Longitudinal Study

Abstract Gastroesophageal reflux disease (GERD) and Barrett’s Esophagus (BE), which are prevalent in the World Trade Center (WTC) exposed and general populations, negatively impact quality of life and cost of healthcare. GERD, a risk factor of BE, is linked to obstructive airways disease (OAD). We aim to identify serum biomarkers of GERD/BE, and assess the respiratory and clinical phenotype of a longitudinal cohort of never-smoking, male, WTC-exposed rescue workers presenting with pulmonary symptoms. Biomarkers collected soon after WTC-exposure were evaluated in optimized predictive models of GERD/BE. In the WTC-exposed cohort, the prevalence of BE is at least 6 times higher than in the general population. GERD/BE cases had similar lung function, D LCO , bronchodilator response and long-acting β-agonist use compared to controls. In confounder-adjusted regression models, TNF-α ≥ 6 pg/mL predicted both GERD and BE. GERD was also predicted by C-peptide ≥ 360 pg/mL, while BE was predicted by fractalkine ≥ 250 pg/mL and IP-10 ≥ 290 pg/mL. Finally, participants with GERD had significantly increased use of short-acting β-agonist compared to controls. Overall, biomarkers sampled prior to GERD/BE presentation showed strong predictive abilities of disease development. This study frames future investigations to further our understanding of aerodigestive pathology due to particulate matter exposure

(Table 1) Dissolved concentration of rare earth elements in rain waters from the eastern slopes of the Yunnan-Guizhou Plateau

World Trade Center-particulate matter(WTC-PM) exposure and metabolic-risk are associated with WTC-Lung Injury(WTC-LI). The receptor for advanced glycation end-products (RAGE) is most highly expressed in the lung, mediates metabolic risk, and single-nucleotide polymorphisms at the AGER-locus predict forced expiratory volume(FEV). Our objectives were to test the hypotheses that RAGE is a biomarker of WTC-LI in the FDNY-cohort and that loss of RAGE in a murine model would protect against acute PM-induced lung disease. We know from previous work that early intense exposure at the time of the WTC collapse was most predictive of WTC-LI therefore we utilized a murine model of intense acute PM-exposure to determine if loss of RAGE is protective and to identify signaling/cytokine intermediates. This study builds on a continuing effort to identify serum biomarkers that predict the development of WTC-LI. A case-cohort design was used to analyze a focused cohort of male never-smokers with normal pre-9/11 lung function. Odds of developing WTC-LI increased by 1.2, 1.8 and 1.0 in firefighters with soluble RAGE (sRAGE)≥97pg/mL, CRP≥2.4mg/L, and MMP-9≤397ng/mL, respectively, assessed in a multivariate logistic regression model (ROCAUC of 0.72). Wild type(WT) and RAGE-deficient(Ager-/-) mice were exposed to PM or PBS-control by oropharyngeal aspiration. Lung function, airway hyperreactivity, bronchoalveolar lavage, histology, transcription factors and plasma/BAL cytokines were quantified. WT-PM mice had decreased FEV and compliance, and increased airway resistance and methacholine reactivity after 24-hours. Decreased IFN-γ and increased LPA were observed in WT-PM mice; similar findings have been reported for firefighters who eventually develop WTC-LI. In the murine model, lack of RAGE was protective from loss of lung function and airway hyperreactivity and was associated with modulation of MAP kinases. We conclude that in a multivariate adjusted model increased sRAGE is associated with WTC-LI. In our murine model, absence of RAGE mitigated acute deleterious effects of PM and may be a biologically plausible mediator of PM-related lung disease

PM exposure affects small airways to a greater degree in WT compared to Ager^-/- mice.

<p>(A) WT-PM mice had significantly elevated tissue resistance at 1Hz p<0.001 (*). Ager^-/—PM had significantly decreased tissue resistance at 1Hz (†) compared the Ager^-/—PBS. (B) WT-PM, but not Ager^-/—PM mice had significantly (*) higher tissue damping compared to controls. N ≥5 mice per group. WT-PBS = 7, WT-PM = 15, Ager^-/—PBS = 8, and Ager^-/—PM = 7 mice were analyzed.</p

Age<i>r</i> ^-/- mice are protected from loss of lung function 24 hours after WTC-PM exposure.

<p><i>24 Hours after</i> a single exposure to WTC-PM, WT mice show significant differences in (A) FEV_0.2 (B) compliance and (C) resistance compared to PBS controls. These parameters did not differ between Ager^-/- mice exposed to PM and their PBS controls. (D) Airway Hyperreactivity (PC₂₀₀): WT-PM mice exhibited hyperreactivity, whereas Ager^-/—PM did not. A total of WT-PBS = 7, WT-PM = 15, Ager^-/—PBS = 8, and Ager ^-/—PM = 7 mice were analyzed. WT-PBS = 2, WT-PM = 3 and Ager^-/—PM = 2 were excluded from FEV_0.2 analyses as they did not meet standards outlined in the methods. Additionally, WT-PBS = 1 was excluded from methacholine analysis due to a dosing error.</p

Clinical measures, biomarker prevalence and model definition.

<p>Clinical measures, biomarker prevalence and model definition.</p

Case-cohort design.

<p>Of the 13,934-exposed rescue and recovery workers, 92% enrolled in the MMTP. A subset of n = 1720 experienced pulmonary symptoms and had a subspecialty pulmonary evaluation (SPE) before March 2008. Exclusion criteria were applied to form a baseline cohort of N = 801. Those with all biomarkers available were (n = 67) WTC-LI cases; and (n = 118) controls.</p

Quantifiable changes to lung histology after PM exposure.

<p>Light microscopic examination of representative hematoxylin and eosin stained sections of lung tissue 24 hours after exposure. (i) Images at 2X while, (ii, iii) are at 40X magnification. (A) WT-PBS exposed mice had normal lung architecture and no infiltrates, whereas (B) WT-PM exposure led to infiltrates, focal acute bronchoalveolar inflammation and interstitial thickening. (C) Ager^-/- mice that aspirated PBS and (D) WTC-PM showed no remarkable changes to normal lung architecture. (E) MLI was significantly (*) higher after PM exposure in WT mice but there was no change in Ager^-/- mice after PM exposure compared to their controls.</p