Soluble RAGE, MMP-9 and CRP are predictive of particulate matter induced lung disease in WTC exposed firefighters.
Kwon-S; Echevarria-GC; Cho-S; Tsukiji-J; Rom-WN; Prezant-DJ; Schmidt-A; Weiden-MD; Nolan-A
Am J Respir Crit Care Med 2014 May; 189(Meeting Abstracts):A3168
RATIONALE: Development of ventilatory dysfunction following particulate exposure is a major health concern worldwide. The prevalence of metabolic syndrome is high in industrialized nations and is rapidly increasing in developing nations with high ambient particulates. The interaction of these two disorders is a topic of considerable importance. RAGE is the receptor for advanced glycation end products, which are products of the metabolism of proteins and lipids. RAGE mediates the inflammatory cascade produced by metabolic disorders. RAGE is associated with lung function in two large independent genome wide association studies, but the mechanism by which it alters FEV1 is unknown. In a recent study soluble (s)RAGE was a biomarker of emphysema severity. Our current study also focuses on Matrix metalloproteinase (MMP)-9 a known mediator of sRAGE and C-reactive protein (CRP) which similar to sRAGE has been implicated in the development of chronic vascular pathology. METHODS: Nested case-controls were derived from World Trade Center(WTC)-exposed firefighter cohort who presented for subspecialty pulmonary evaluation until 3/2008. For this pilot study cases (n=67) had FEV1 < lower limit of normal(LLN). Controls (n=118) were derived from the baseline cohort after stratification by BMI and FEV1 and had an FEV1>LLN. Demographics and pulmonary function testing were obtained from the FDNY Database. sRAGE, CRP and MMP-9 were measured in serum banked within 6 months of 9/11/01. We modeled the ability of sRAGE, CRP and MMP-9 to predict developing WTC-LI using logistic regression. adjusted for exposure intensity, pre-9/11 FEV1 and age at 9/11. Cutpoints used for this analysis were either previously published or optimized for the purposes of this analysis. RESULTS: sRAGE, CRP and MMPs levels were statistically no different in cases and controls but they were predictive of case status in unadjusted univariable regression. A serum sRAGE >= 97 pg/mL increased the odds by 2.11, a CRP >= 2400 ng/mL (2.4 mg/L) increased the odds to 3.01 and MMP-9 <= 397 ng/mL increased the odds to 1.99 of having WTC-LI respectively in a multivariable model adjusted for age on 9/11, BMI at the time of serum sampling and time of arrival (exposure). CONCLUSION: In this pilot study elevated sRAGE and CRP are predictive of a significantly increased risk of developing World Trade Center-LI. Low MMP-9 is associated with having WTC-LI. These data may lay the groundwork for mechanistic studies to understand the signaling intermediates of the RAGE axis in obstructive lung disease due to particulate matter exposure.
Particulates; Particulate-dust; Employee-exposure; Fire-fighters; Emergency-responders; Airborne-particles; Airborne-dusts; Respiratory-system-disorders; Pulmonary-system-disorders; Lung-disorders; Metabolic-disorders; Lipids; Proteins; Metabolism; Biomarkers; Metalloproteins; Spirometry; Pulmonary-function-tests; Risk-analysis; Statistical-analysis; Mathematical-models; Analytical-processes
A. Nolan, New York University, New York, NY
Cooperative-Agreement-Number-U10-OH-008243; Cooperative-Agreement-Number-U10-OH-008242; M062014
American Journal of Respiratory and Critical Care Medicine
New York City Fire Department