Receptor for Advanced Glycation End Products (RAGE) Contributes to World Trade Center Particulate Matter (WTC-PM)-Associated Lung Function Loss

Abstract

SESSION TITLE: Occupational and Environmental Lung Diseases SESSION TYPE: Original Investigation Poster PRESENTED ON: Saturday, April 16, 2016 at 11:45 AM - 12:45 PM PURPOSE: Urban environments have high ambient particulates and a coexisting high prevalence of metabolic syndrome. The contribution of these two conditions to pulmonary disease is a topic of considerable importance. RAGE is highly expressed in the lung and is a strong predictor of FEV in genome wide association studies. We established a murine model of high intensity PM exposure and quantified lung function after 24 hours and 28 days. We also investigated if loss of RAGE is protective against PM-induced lung injury. We also looked for histopathologic changes in lung architecture between wild-type mice and RAGE-/- that aspirated WTC-PM at both time points. METHODS: C57BL/6 wild-type mice and RAGE-/- were exposed to PBS or a single dose of 100μg of WTC-PM by oropharyngeal aspiration. After 24 hours and 28 days, mice were anesthetized, tracheotomized, and assessed for lung function and methacholine hyperreactivity on a Flexivent system. Bronchoalveolar lavage fluid (BAL) had cell differentials measured. Separate dedicated mice were used for histologic analysis to quanitfy area fraction of percent biovolume to airspace, and mean chord length. RESULTS: Lung Function: After 24 hours, WTC-PM aspiration in WT mice produces loss of FEV, decreased compliance, and increased resistance, tissue damping, and methacholine hyperreactivity. After 28 days, lung measures improve but hyperreactivity persists. RAGE-/- are protected from these WTC-PM effects at both time points. Impedance analysis shows that changes occur in the small airways of WT exposed to WTC-PM. Histopathology: Neutrophilia is seen at 24 hours in both WT and RAGE-/- BAL. At 24 hours, area fraction trended higher in those exposed to WTC-PM, and had significantly shorter mean chord lengths. After 28 days, WT mice showed acute on chronic changes in lung architecture, and had significantly higher area fraction and shorter chord lengths. RAGE-/- mice did not show a difference in measures of lung quantification after 24 hours or 28 days. CONCLUSIONS: This murine model of high intensity PM exposure shows that a single dose of WTC-PM can cause increased neutrophilia, resistance, and hyperreactivity, and decreased FEV 24 hours later. After 28 days, WTC-PM still shows persistent acute changes on chronic inflammation. RAGE-/- was associated with protection from the inflammatory effects of WTC-PM. CLINICAL IMPLICATIONS: Loss of RAGE protects against PM-induced lung injury and future airway hyperreactivity, and serve as a potential therapeutic target. DISCLOSURE: The following authors have nothing to disclose: Sophia Kwon, Erin Caraher, Hissam Haider, George Crowley, Audrey Lee, David Prezant, Anna Nolan No Product/Research Disclosure Information