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RAGE mediates LPA induced pulmonary inflammation.

Authors
Cho-S; Kwon-S; Naveed-B; Schenck-E; Tsukiji-J; Schmidt-A; Prezant-DJ; Rom-WN; Weiden-M; Nolan-A
Source
Am J Respir Crit Care Med 2013 May; 187(Meeting Abstracts):A3787
NIOSHTIC No.
20044748
Abstract
RATIONAL: Mediators of metabolic syndrome, inflammation and vascular injury measured in serum collected within 6 months of WTC-PM exposure are predictive of abnormal forced expiratory volume in 1 second (FEV1). A key mediator of metabolic syndrome and vascular injury is lysophosphatidic acid (LPA), which binds to receptor for advanced glycation end products (RAGE). We hypothesized that elevated LPA levels predict pulmonary function decline, and that LPA combined with other risk factors for low FEV1, such as World Trade Center related particulate matter (WTC-PM), promotes inflammation through RAGE. METHODS: Our nested case-cohort study was derived from 801 WTC-exposed firefighters with normal pre-9/11 lung function who presented for subspecialty pulmonary evaluation (SPE) for respiratory symptoms after 9/11 and before Mar/2008. Susceptible cases were defined by FEV1 < LLN (Lower limit of normal) at SPE. Serum LPA levels were measured by ELISA. Alveolar Macrophages (AM[PHI]) and Monocyte Derived Macrophages (MDM[PHI]) were obtained from normal volunteers. MDM[PHI] were isolated by negative selection followed by differentiation with GM-CSF. Both AM[PHI] and MDM[PHI]were incubated in media alone, LPA (25microM), WTC-PM(10-53) (100microg/mL) and LPA with WTC-PM(10-53). Supernatants were collected after 24 hours and assayed for chemokines/cytokines by Luminex. RAGE expression in whole cell lysates of AM[PHI] was determined by Western Blot. RESULTS: LPA levels were significantly higher in susceptible cases than in controls. Elevated LPA level was a risk factor for developing abnormal FEV1. WTC-PM(10-53) induced IL-6, IL-1beta and G-CSF, in both MDM[PHI] and AM[PHI]. Addition of LPA to WTC-PM(10-53) in each of these cell lines led to further induction of above analytes as compared with PM(10-53) and LPA alone. AM[PHI] stimulated by LPA expressed less RAGE than unstimulated cells. However, when PM and LPA were combined, RAGE expression in AM[PHI] was maintained at a much higher level (data not shown). CONCLUSION: Elevated LPA is predictive of lung dysfunction as measured by FEV1 < LLN. Addition of LPA to cells exposed to PM further induces pro-inflammatory mediators and blocks the RAGE down-regulation produced by LPA alone. Modulation of RAGE expression in AM[PHI] could underlie the additive effects on inflammatory cytokine production when PM and LPA are combined. This data may lay the groundwork for mechanistic studies to understand the signaling intermediates of the LPA/RAGE axis in the lung.
Keywords
Particulates; Particulate-dust; Employee-exposure; Fire-fighters; Emergency-responders; Airborne-particles; Airborne-dusts; Respiratory-system-disorders; Pulmonary-system-disorders; Lung-disorders; Biomarkers; Pulmonary-function; Lung-function; Pulmonary-function-tests; Vital-capacity; Serology; Immune-reaction; Metabolic-disorders; Exposure-levels; Analytical-instruments; Analytical-processes; Acids; Chemical-binding; Lung-cells
Contact
S. Cho, New York University Division of Pulmonary and Critical Care, New York, NY
CODEN
AJCMED
Publication Date
20130501
Document Type
Abstract
Email Address
soojung.cho@nyumc.org
Funding Type
Cooperative Agreement; Grant
Fiscal Year
2013
NTIS Accession No.
NTIS Price
Identifying No.
Cooperative-Agreement-Number-U10-OH-008243; Cooperative-Agreement-Number-U10-OH-008242; Grant-Number-R01-OH-007350
ISSN
1073-449X
Source Name
American Journal of Respiratory and Critical Care Medicine
State
NY
Performing Organization
New York City Fire Department
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