Year of Award

2008

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Toxicology

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Andrij Holian

Commitee Members

David M. Shepherd, Fernando Cardozo-Pelaez, Kevan Roberts, Mark L. Grimes

Keywords

Crystalline silica, cytotoxicity, inflammation, lung, MARCO, titanium dioxide

Abstract

Alveolar macrophages (AM) form the first line of defense against chronic inflammation caused by occupational exposure to environmental particulates such as crystalline silica (CSiO2). The chronic inflammatory process triggered by CSiO2 is known to culminate into a fibrotic response called silicosis in the human lungs. Previous studies have indicated the role of membrane glycoproteins called scavenger receptors in binding of environmental particles. The scavenger receptors are classified into different classes (A-H) based on their structure and function. Class A scavenger receptors are critical in uptake of variety of ligands such as bacteria, acetylated lipoproteins and are typically found on macrophages, dendritic and epithelial cells. One of the members of this family is Macrophage receptor with collagenous structure (MARCO). Recent studies have focused on analyzing the interaction between MARCO and inorganic particles such as CSiO2 and titanium dioxide (TiO2). Both in vivo and in vitro binding studies have identified MARCO as a key receptor in CSiO2 uptake and subsequent cytotoxicity in AM from C57Bl/6 mice. Further in vitro studies using a transfected cell line revealed that the 100 amino acid residues long cysteine-rich (SRCR) domain at the C-terminal end of MARCO is required for binding of inorganic particles such as CSiO2, TiO2 and amorphous silica (ASiO2). Moreover, individual particles bind to SRCR domain of MARCO with unique differences and have varying requirements with respect to need for divalent cations. Our studies demonstrate that physiological absence of MARCO in C57Bl/6 mice leads to a more robust inflammatory response following CSiO2 exposure as compared to wild-type mice. The results suggest that diminished clearance of CSiO2 particles from the MARCO-/- lungs exacerbates the lung inflammation. These findings demonstrate that the involvement of different regions of SRCR domain may distinguish downstream events following particle binding. Taken together, these data establish the role of MARCO in uptake of various inorganic particles and elucidate the protective role of MARCO in CSiO2-induced lung inflammation.

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© Copyright 2008 Sheetal A. Thakur