Abstract
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.
Highlights
During the events of September 11, 2001, Fire Department of New York City (FDNY) firefighters were exposed to World Trade Center-particulate matter (WTC-PM), a known cause of lung function loss. [4,5,6,7,8,9] In WTC-PM exposed firefighters, metabolically active biomarkers have been associated with the development of Obstructive airway disease (OAD).[10,11,12,13,14,15]
Mediators of metabolism have been associated with WTC-LI in previous studies of the FDNY cohort. [10, 51, 52] receptor for advanced glycation end-products (RAGE), a biologically plausible mediator of PM-induced lung disease, was the focus of this investigation
The inverse relationship between soluble RAGE (sRAGE) and MMP-9 seen in the WTC-exposed FDNY cohort maintains plausibility because MMP-9 levels may decrease as it is consumed to cleave RAGE
Summary
[4,5,6,7,8,9] In WTC-PM exposed firefighters, metabolically active biomarkers have been associated with the development of OAD.[10,11,12,13,14,15] Increasing evidence supports the importance of the receptor for advanced glycation end-products (RAGE), known as the advanced glycation end-product receptor (AGER), in OAD. RAGE is a member of the immunoglobulin super family, exists in many isoforms and binds diverse ligands including products of metabolic stress such as AGEs, High Mobility Group Box-1(HMGB1), S100 and amyloid-β peptides. The membrane bound form, generally referred to as RAGE or AGER, has been shown to be a key mediator in many chronic conditions including inflammation, vascular injury and metabolic syndrome. The membrane bound form, generally referred to as RAGE or AGER, has been shown to be a key mediator in many chronic conditions including inflammation, vascular injury and metabolic syndrome. [16,17,18] Soluble forms of RAGE can be formed by variations in splicing or cleavage by metalloproteinases, including ADAM10 and MMP-9; total soluble RAGE includes all soluble isoforms and is traditionally denoted by sRAGE and may act as a decoy receptor for RAGE ligands. [19,20,21] the utility of sRAGE as a diagnostic biomarker in emphysema and chronic inflammatory diseases is currently being explored. [22, 23]
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