Review Article
Silica binding and toxicity in alveolar macrophages

https://doi.org/10.1016/j.freeradbiomed.2007.12.027Get rights and content

Abstract

Inhalation of the crystalline form of silica is associated with a variety of pathologies, from acute lung inflammation to silicosis, in addition to autoimmune disorders and cancer. Basic science investigators looking at the mechanisms involved with the earliest initiators of disease are focused on how the alveolar macrophage interacts with the inhaled silica particle and the consequences of silica-induced toxicity on the cellular level. Based on experimental results, several rationales have been developed for exactly how crystalline silica particles are toxic to the macrophage cell that is functionally responsible for clearance of the foreign particle. For example, silica is capable of producing reactive oxygen species (ROS) either directly (on the particle surface) or indirectly (produced by the cell as a response to silica), triggering cell-signaling pathways initiating cytokine release and apoptosis. With murine macrophages, reactive nitrogen species are produced in the initial respiratory burst in addition to ROS. An alternative explanation for silica toxicity includes lysosomal permeability, by which silica disrupts the normal internalization process leading to cytokine release and cell death. Still other research has focused on the cell surface receptors (collectively known as scavenger receptors) involved in silica binding and internalization. The silica-induced cytokine release and apoptosis are described as the function of receptor-mediated signaling rather than free radical damage. Current research ideas on silica toxicity and binding in the alveolar macrophage are reviewed and discussed.

Introduction

Silicon (Si) is the second most abundant element on earth next to carbon. A Si atom combined with two oxygen (O) atoms creates silicon oxide or silica (SiO2), naturally occurring as quartz or sand. There are multiple crystalline forms and one amorphous form of silica. Inhalation of the crystalline form of silica has been historically associated with the development of a severe respiratory disease, silicosis, which is a lung pneumoconiosis characterized by alveolar proteinosis and diffuse fibrosis resulting in progressively restrictive lung function [1]. Silicosis has been primarily associated with long occupational exposures to crystalline silica that typically occur in sandblasting, silica milling, rock drilling, and tunneling [2], [3]. There is evidence that silica exposure can also be linked to the development of autoimmune diseases such as scleroderma (systemic sclerosis), rheumatoid arthritis, chronic renal disease, and lupus [4]. Additionally, silica inhalation is believed to be the cause of some rare lung cancers [5], although significant relative risk (RR) of lung cancer is associated only with individuals who already have silicosis from silica exposure [6]. Based on the relative dose–response or exposure–response relationships in experimental animal studies, silica seems to be a uniquely hazardous particle type [7].

Given the diversity of pathologies associated with silica exposure, it is unlikely that one common mechanism is responsible for all of the possible diseases. Although the exact sequence of events (from silica inhalation to disease) is not known, it is generally accepted that the alveolar macrophage (AM) is a relevant cell type to study [1]. Because the role of the AM is to clear the lung of inhaled debris, it is reasonable to assume that the macrophage is the first cell of the body that will have significant contact with the inhaled silica particle. Upon contact, the AM will bind to the silica and begin to engulf the particle. If the AM survives the silica encounter, it will likely migrate out of the lungs to either the proximal lymph nodes or through the mucosal–ciliary escalator and eventually out of the respiratory tract [8]. If the AM stays in the lung it will migrate to the interstitial space and become an activated interstitial macrophage (IM) that could contribute directly to pathogenesis [9]. Some research indicates that the IM may play an important role in the progression of silica-induced lung disease [10], [11].

Investigators studying the AM/silica particle interaction have developed several hypotheses to describe how silica is toxic to AM. Some explanations of toxicity focus on the surface qualities of the silica such as free radicals and surface charge. Others suggest that silica can cause the AM to self-destruct by apoptosis or lysosomal disruption, which could lead to the development of autoantigens. The purpose of this review article is to present all of the current research regarding silica toxicity of the AM, because most researchers in this area would agree that the initial toxicity of the AM is an important first step in the development of disease.

Section snippets

Surface modifications of inhaled silica by lung surfactant

Before the inhaled silica particles are encountered by AM, lung surfactant composed of phospholipids (PL) and surfactant proteins (SP) could potentially coat the outer surface of the silica particles, modifying the surface chemistry and ultimately influencing the toxicity. This interaction can be further complicated by free radical modifications of the phospholipids and proteins occurring on surface contact with the silica. Some research has focused on this aspect of silica toxicity by using

The receptor-mediated hypothesis of silica binding and toxicity

As inhaled silica particles are encountered by AM in the lung, the physical contact at the cell/particle interface is the first critical step in particle recognition and internalization. The important factors in silica particle recognition and binding are the physical surface characteristics of the particle and the pattern recognition receptors that act as an adhesive [35], [36], binding the silica for further processing by the AM. Some researchers believe that the specific receptors involved

The free radical hypothesis of silica toxicity

When researchers refer to free radical damage initiated by silica inhalation, they are usually describing more than one possible process. There are several possible sources of free radicals resulting from silica internalization, including particle-derived reactive oxygen species (ROS), cell-derived ROS and reactive nitrogen species (RNS), and the interaction of particle- and cell-derived free radicals producing peroxynitrite (ONOOO2radical dot) from nitric oxide (NOradical dot) and superoxide anion (O2radical dot) [66]. In

The lysosomal permeability hypothesis of silica toxicity

When AM encounter inhaled crystalline silica particles, a process to engulf the particles is initiated immediately. The internalized silica particle is entrapped in a lysosomal compartment where low pH conditions activate strong digestive enzymes that attempt to degrade the particle, as would occur if bacteria were being internalized. The silica particle cannot be broken down in the lysosomal compartment, and the resulting failure can lead to a loss of membrane integrity in the process. Some

The role of silica exposure in macrophage immune dysfunction

The development of autoimmune disease is obviously a complex process that involves more than one cell type. Silica exposure has long been associated with a variety of autoimmune problems, including rheumatoid arthritis, lupus, scleroderma, and glomerulonephritis with significant RR of greater than 3.0 [4]. The cause of silica-induced autoimmunity is undetermined at this time, but experimental evidence does exist suggesting silica can alter normal AM immune function. Coupled with the fact that

Conclusions

Several biological rationales describing the binding and toxicity of silica with the AM have been presented in this review article. A summary describing the relative strengths and weaknesses of each theory of silica toxicity can be found in Table 1. It should be noted that none of the hypotheses presented here are mutually exclusive of one another. It is possible that all of the research in this area is the correct interpretation of the toxicological reality silica inhalation presents. Several

Acknowledgments

This publication was made possible by Grant P20-RR-017670 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR or NIH. Additional funding for this research was provided by Grant ES 015294 from the NIEHS.

References (120)

  • N. Gao et al.

    Effects of phospholipid surfactant on apoptosis induction by respirable quartz and kaolin in NR8383 rat pulmonary macrophages

    Toxicol. Appl. Pharmacol.

    (2001)
  • X. Liu et al.

    Phospholipid surfactant adsorption by respirable quartz and in vitro expression of cytotoxicity and DNA damage

    Toxicol. Lett.

    (1998)
  • P.J. Gough et al.

    The role of scavenger receptors in the innate immune system

    Microbes Infect.

    (2000)
  • L. Peiser et al.

    The function of scavenger receptors expressed by macrophages and their role in the regulation of inflammation

    Microbes Infect.

    (2001)
  • J.E. Murphy et al.

    Biochemistry and cell biology of mammalian scavenger receptors

    Atherosclerosis

    (2005)
  • K. Nakamura et al.

    Molecular cloning of a mouse scavenger receptor with C-type lectin (SRCL). 1. A novel member of the scavenger receptor family

    Biochim. Biophys. Acta

    (2001)
  • Y. Jiang et al.

    Identification and characterization of murine SCARA5, a novel class A scavenger receptor that is expressed by populations of epithelial cells

    J. Biol. Chem.

    (2006)
  • R.F. Hamilton et al.

    Class A type II scavenger receptor mediates silica-induced apoptosis in Chinese hamster ovary cell line

    Toxicol. Appl. Pharmacol.

    (2000)
  • S. Acton et al.

    The collagenous domains of macrophage scavenger receptors and complement component C1q mediate their similar, but not identical, binding specificities for polyanionic ligands

    J. Biol. Chem.

    (1993)
  • L. Andersson et al.

    Functional changes in scavenger receptor binding conformation are induced by charge mutants spanning the entire collagen domain

    J. Biol. Chem.

    (1998)
  • S.K. Chao et al.

    Cell surface regulation of silica-induced apoptosis by the SR-A scavenger receptor in a murine lung macrophage cell line (MH-S)

    Toxicol. Appl. Pharmacol.

    (2001)
  • J.R. Ojala et al.

    Crystal structure of the cysteine-rich domain of scavenger receptor MARCO reveals the presence of a basic and an acidic cluster that both contribute to ligand recognition

    J. Biol. Chem.

    (2007)
  • R. Iyer et al.

    Silica-induced apoptosis mediated via scavenger receptor in human alveolar macrophages

    Toxicol. Appl. Pharmacol.

    (1996)
  • R.F. Hamilton et al.

    MARCO mediates silica uptake and toxicity in alveolar macrophages from C57BL/6 mice

    J. Biol. Chem.

    (2006)
  • T. Nakamura et al.

    HSP90, HSP70, and GAPDH directly interact with the cytoplasmic domain of macrophage scavenger receptors

    Biochem. Biophys. Res. Commun.

    (2002)
  • H.Y. Hsu et al.

    Ligand binding to macrophage scavenger receptor-A induces urokinase-type plasminogen activator expression by a protein kinase-dependent signaling pathway

    J. Biol. Chem.

    (1998)
  • L.G. Fong et al.

    The processing of ligands by the class A scavenger receptor is dependent on signal information located in the cytoplasmic domain

    J. Biol. Chem.

    (1999)
  • H.Y. Hsu et al.

    Ligands of macrophage scavenger receptor induce cytokine expression via differential modulation of protein kinase signaling pathways

    J. Biol. Chem.

    (2001)
  • S. Gordon

    Pattern recognition receptors: doubling up for the innate immune response

    Cell

    (2002)
  • B. Fubini et al.

    Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis

    Free Radic. Biol. Med.

    (2003)
  • M. Valko et al.

    Free radicals and antioxidants in normal physiological functions and human disease

    Int. J. Biochem. Cell. Biol.

    (2007)
  • B. Fubini et al.

    The surface chemistry of crushed quartz dusts in relation to its pathogenicity

    Inorg. Chim. Acta Bioinorg. Chem.

    (1987)
  • HochstrasserG. et al.
  • L.N. Daniel et al.

    Oxidative DNA damage by crystalline silica

    Free Radic. Biol. Med.

    (1993)
  • Z. Elias et al.

    Cytotoxic and transforming effects of silica particles with different surface properties in Syrian hamster embryo (SHE) cells

    Toxicol. In Vitro

    (2000)
  • Y.M. Janssen et al.

    Expression of antioxidant enzymes in rat lungs after inhalation of asbestos or silica

    J. Biol. Chem.

    (1992)
  • Y.J. Cho et al.

    Silica-induced generation of reactive oxygen species in Rat2 fibroblast: role in activation of mitogen-activated protein kinase

    Biochem. Biophys. Res. Commun.

    (1999)
  • F. Chen et al.

    Dependence and reversal of nitric oxide production on NF-κB in silica and lipopolysaccharide-induced macrophages

    Biochem. Biophys. Res. Commun.

    (1995)
  • F. Chen et al.

    Essential role of NF-κB activation in silica-induced inflammatory mediator production in macrophages

    Biochem. Biophys. Res. Commun.

    (1995)
  • M. Ding et al.

    Freshly fractured crystalline silica induces activator protein-1 activation through ERKs and p38 MAPK

    J. Biol. Chem.

    (1999)
  • V. Castranova et al.

    Silica and silica induced lung diseases

    (1996)
  • W.R. Parks

    Occupational lung disorders

    (1982)
  • A. Peretz et al.

    Silica, silicosis, and lung cancer

    Isr. Med. Assoc. J.

    (2006)
  • G. Oberdorster

    Significance of particle parameters in the evaluation of exposure-dose-response relationships of inhaled particles

    Inhal. Toxicol.

    (1996)
  • N.L. Lapp et al.

    How silicosis and coal workers' pneumoconiosis develop—a cellular assessment

    Occup. Med.

    (1993)
  • I.Y. Adamson et al.

    Comparison of alveolar and interstitial macrophages in fibroblast stimulation after silica and long or short asbestos

    Lab. Invest.

    (1991)
  • D.H. Bowden et al.

    Silica-induced pulmonary fibrosis involves the reaction of particles with interstitial rather than alveolar macrophages

    J. Pathol.

    (1989)
  • T.D. Tetley et al.

    Changes in pulmonary surfactant and phosphatidylcholine metabolism in rats exposed to chrysotile asbestos dust

    Biochem. J.

    (1977)
  • B. Muller et al.

    Effect of air pollutants on the pulmonary surfactant system

    Eur. J. Clin. Invest.

    (1998)
  • R.W. Spech et al.

    Surfactant protein A prevents silica-mediated toxicity to rat alveolar macrophages

    Am. J. Physiol., Lung Cell. Mol. Physiol.

    (2000)
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