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A2587 - Advanced Glycation End-Products Receptor: Mediator of Persistent Airway Reactivity After Particulate Matter Exposure
Author Block: S. Haider1, E. Caraher1, G. Crowley1, M. Sunseri2, R. Lam1, S. Kwon1, D. J. Prezant3, L. Chen4, A. Schmidt5, A. Nolan1; 1Departments of Medicine and Environmental Medicine, Division of Pulmonary Critical Care and Sleep, New York University School of Medicine, New York, NY, United States, 2Department of Medicine, New York University School of Medicine, New York, NY, United States, 3Bureau of Health Sciences, Fire Department of New York, Brooklyn, NY, United States, 4Department of Environmental Medicine, New York University School of Medicine, Tuxedo Park, NY, United States, 5Departments of Biochemistry and Molecular Pharmacology and Pathology, Division of Endocrinology, New York University School of Medicine, New York, NY, United States.
RATIONALE: World Trade Center-particulate matter(WTC-PM) exposed 1st-responders with higher soluble advanced glycation end-products receptor(sRAGE) and its lipid ligand lysophosphatidic acid(LPA) within the first 200 days were more likely to lose lung function. Lack of RAGE was not only protective of developing airway hyperreactivity within the first 24-hrs after an acute PM exposure but continued to be protective after 1-month(1-M), in our murine model. These findings highlight the possible importance of RAGE in PM associated lung injury. The adaptor proteins involved in RAGE signaling subsequent to PM exposure are not well understood. This is an effort to further define mediators of the persistence of PM associated lung injury. METHODS: Wild type(WT) and RAGE-deficient(Ager-/-) mice aspirated 200ug-PM(WTC-Aggregate,PM53) or PBS. Broncho-alveolar lavage(BAL), plasma and lung tissues collected at 24-hrs and 1-M. Mammalian Diaphenous-1(mDIAPH1) expression of the lung was quantified by immunofluorescence(IF),(Olympus-BX51/NikonD5100). Investigators blinded during selection and image assessment. Cytokines/chemokines were quantified in BAL and plasma, and analytes were assessed using magnetic bead based/ELISA. SPSS(23, IBM), Graphpad, Photoshop and ImageJ used for data analysis. RESULTS: PLASMA G-CSF fold change was significantly higher in WT mice 1-M after PM-exposure while no difference was seen at 24-hrs. BAL G-CSF and IL-6 were significantly higher in both PM-exposed WT and Ager-/- compared to PBS controls at 24-hrs and 1-M. IL-1α fold-change was higher in WT PM-exposed mice after 24-hrs compared to Ager-/- but not different at 1-M. While, IL-9 was only elevated in WTs exposed to PM after 1-M. IL-10 fold change was significantly higher in PM-exposed Ager-/- compared to PBS-controls at 1-M but was no different after 24-hrs. In contrast, RANTES, KC and MIP-2 fold-change were significantly decreased in PM exposed Ager-/- compared to WT after 1- month, but not at 24-hrs. BAL differentials were not significant at 1-M while at 24-hrs there was increased neutrophilia in WT PM-exposed. mDiaph1 IF was significantly lower after 1-M in PM-exposed WT but higher in Ager-/- when compared to PBS controls. RAGE expression was higher in PM exposed WT after 1-M compared to PBS controls. CONCLUSIONS: RAGE is not only important to the acute effects of PM exposure it also appears to be relevant to subacute PM effects. This is indicated by the differential expression of pro-(G-CSF, IL-6, IL-1α), anti-inflammatory(IL-10), and chemokines(RANTES, KC, MIP-2) in WT and Ager-/- mice. Expression of mDiaph1 is also attenuated after PM exposure. Further work needs to be done to understand the downstream mechanisms.