Quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by alveolar macrophages
Open accessAbstract
Background In the lung, macrophages attempt to engulf inhaled high aspect ratio pathogenic materials, secreting inflammatory molecules in the process. The inability of macrophages to remove these materials leads to chronic inflammation and disease. How the biophysical and biochemical mechanisms of these effects are influenced by fiber length remains undetermined. This study evaluates the role of fiber length on phagocytosis and molecular inflammatory responses to non-cytotoxic fibers, enabling development of quantitative length-based models.Methods Murine alveolar macrophages were exposed to short and long populations of JM-100 glass fibers, produced by successive sedimentation and repeated crushing, respectively. Interactions between fibers and macrophages were observed using time-lapse video microscopy, and quantified by flow cytometry. Inflammatory biomolecules (TNF-α, IL-1α, COX-2, PGE 2) were measured.Results Uptake of short fibers occurred more readily than for long, but long fibers were more potent stimulators of inflammatory molecules. Stimulation resulted in dose-dependent secretion of inflammatory biomolecules but no cytotoxicity or strong ROS production. Linear cytokine dose-response curves evaluated with length-dependent potency models, using measured fiber length distributions, resulted in identification of critical fiber lengths that cause frustrated phagocytosis and increased inflammatory biomolecule production.Conclusion Short fibers played a minor role in the inflammatory response compared to long fibers. The critical lengths at which frustrated phagocytosis occurs can be quantified by fitting dose-response curves to fiber distribution data.General significance The single physical parameter of length can be used to directly assess the contributions of length against other physicochemical fiber properties to disease endpoints.
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Strong correlations between fibre properties and adverse health effects have been reported for a wide variety of fibre materials.
“Observations of strong correlations between fibre properties and adverse health effects have been reported for a wide variety of fibre materials [14–16],”
From Macrophages bend long fibres with flexural rigidity lower than 3 mN·nm2 to avoid frustrated phagocytosis (2026) · cites this paper as [15]
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Cites
Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling
Ray, P. D., Huang, B.-W., & Tsuji, Y. (2012) · Cellular Signalling · doi:10.1016/j.cellsig.2012.01.008 · Cited by 4,373 · see citing works
Crosstalk of reactive oxygen species and NF-κB signaling
Morgan, M. J., & Liu, Z.-G. (2011) · Cell Research · doi:10.1038/cr.2010.178 · Cited by 3,505 · see citing works
Mechanisms of phagocytosis in macrophages
Aderem, A., & Underhill, D. M. (1999) · Annual Review of Immunology · doi:10.1146/annurev.immunol.17.1.593 · Cited by 2,854 · see citing works
Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica
Dostert, C., Pétrilli, V., Van Bruggen, R., Steele, C., Mossman, B. T., & Tschopp, J. (2008) · Science · doi:10.1126/science.1156995 · Cited by 2,658 · see citing works
H <sub>2</sub> O <sub>2</sub> , a Necessary Evil for Cell Signaling
Rhee, S. G. (2006) · Science · doi:10.1126/science.1130481 · Cited by 2,160 · see citing works
Role of target geometry in phagocytosis
Champion, J. A., & Mitragotri, S. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600997103 · Cited by 2,082 · see citing works
Self-citationMechanisms of Nanoparticle-Induced Oxidative Stress and Toxicity
Manke, A., Wang, L., & Rojanasakul, Y. (2013) · BioMed Research International · doi:10.1155/2013/942916 · Cited by 1,736 · see citing works
Inducible cyclooxygenase may have anti-inflammatory properties
Gilroy, D. W., Colville‐Nash, P., Willis, D., Chivers, J. E., Paul‐Clark, M. J., & Willoughby, D. A. (1999) · Nature Medicine · doi:10.1038/9550 · Cited by 1,243 · see citing works
Mechanisms in the Pathogenesis of Asbestosis and Silicosis
MOSSMAN, B. T., & CHURG, A. (1998) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm.157.5.9707141 · Cited by 971 · see citing works
Donaldson, K., Murphy, F. A., Duffin, R., & Poland, C. A. (2010) · Particle and Fibre Toxicology · doi:10.1186/1743-8977-7-5 · Cited by 916 · see citing works
Role of Particle Size in Phagocytosis of Polymeric Microspheres
Champion, J. A., Walker, A. H., & Mitragotri, S. (2008) · Pharmaceutical Research · doi:10.1007/s11095-008-9562-y · Cited by 887 · see citing works
Self-citationNanomaterial cytotoxicity is composition, size, and cell type dependent
Sohaebuddin, S. K., Thevenot, P., Baker, D. W., Eaton, J. W., & Tang, L. (2010) · Particle and Fibre Toxicology · doi:10.1186/1743-8977-7-22 · Cited by 676 · see citing works
Inflammation as a Tumor Promoter in Cancer Induction
Philip, M., Rowley, D. A., & Schreiber, H. (2004) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2004.06.006 · Cited by 640 · see citing works
Dinarello, C. A. (1997) · Cytokine & Growth Factor Reviews · doi:10.1016/s1359-6101(97)00023-3 · Cited by 581 · see citing works
Deposition, retention, and clearance of inhaled particles.
Lippmann, M., Yeates, D. B., & Albert, R. E. (1980) · Occupational and Environmental Medicine · doi:10.1136/oem.37.4.337 · Cited by 557 · see citing works
Role of iron in carcinogenesis: cancer as a ferrotoxic disease
Toyokuni, S. (2009) · Cancer Science · doi:10.1111/j.1349-7006.2008.01001.x · Cited by 552 · see citing works
Nagai, H., Okazaki, Y., Chew, S. H., Misawa, N., Yamashita, Y., Akatsuka, S., Ishihara, T., Yamashita, K., Yoshikawa, Y., Yasui, H., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1110013108 · Cited by 535 · see citing works
Yazdi, A. S., Guarda, G., Riteau, N., Drexler, S. K., Tardivel, A., Couillin, I., & Tschopp, J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008155107 · Cited by 525 · see citing works
Groß, O., Yazdi, A. S., Thomas, C. J., Masin, M., Heinz, L. X., Guarda, G., Quadroni, M., Drexler, S. K., & Tschopp, J. (2012) · Immunity · doi:10.1016/j.immuni.2012.01.018 · Cited by 460 · see citing works
Palomäki, J., Välimäki, E., Sund, J., Vippola, M., Clausen, P. A., Jensen, K. A., Savolainen, K., Matikainen, S., & Alenius, H. T. (2011) · ACS Nano · doi:10.1021/nn200595c · Cited by 408 · see citing works
The molecular basis of asbestos induced lung injury
Kamp, D. W., & Weitzman, S. A. (1999) · Thorax · doi:10.1136/thx.54.7.638 · Cited by 345 · cited 1× · see citing works
“In phagocytes oxidative stress responses at the plasma membrane in response to extracellular pathogenic material [44], and metal ions [2,45] can lead to the generation of extracellular ROS compounds.”
Yang, H., Bocchetta, M., Kroczynska, B., Elmishad, A. G., Chen, Y., Liu, Z., Bubici, C., Mossman, B. T., Pass, H. I., Testa, J. R., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604008103 · Cited by 322 · see citing works
Multiple roles of oxidants in the pathogenesis of asbestos-induced diseases
Shukla, A., Gulumian, M., Hei, T. K., Kamp, D., Rahman, Q., & Mossman, B. T. (2003) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(03)00060-1 · Cited by 288 · see citing works
Cell size of alveolar macrophages: an interspecies comparison.
Krombach, F., Münzing, S., Allmeling, A. M., Gerlach, J. T., Behr, J., & Dörger, M. (1997) · Environmental Health Perspectives · doi:10.1289/ehp.97105s51261 · Cited by 285 · see citing works
Brown, D. M., Kinloch, I. A., Bangert, U., Windle, A. H., Walter, D. M., Walker, G. S., Scotchford, C. A., Donaldson, K., & Stone, V. (2007) · Carbon · doi:10.1016/j.carbon.2007.05.011 · Cited by 271 · see citing works
Positive and Negative Regulation of NF-κB by COX-2
Poligone, B., & Baldwin, A. S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m106599200 · Cited by 263 · see citing works
Davis, J. M., Addison, J., Bolton, R., Donaldson, K., Jones, A. D., & Smith, T. A. (1986) · PubMed Central · Cited by 256 · see citing works
Murphy, F. A., Schinwald, A., Poland, C. A., & Donaldson, K. (2012) · Particle and Fibre Toxicology · doi:10.1186/1743-8977-9-8 · Cited by 252 · see citing works
Hansen, K., & Mossman, B. T. (1987) · PubMed · Cited by 227 · see citing works
Pulmonary Endpoints (Lung Carcinomas and Asbestosis) Following Inhalation Exposure to Asbestos
Mossman, B. T., Lippmann, M., Hesterberg, T. W., Kelsey, K. T., Barchowsky, A., & Bonner, J. C. (2011) · Journal of Toxicology and Environmental Health Part B · doi:10.1080/10937404.2011.556047 · Cited by 218 · see citing works
Müller, L. L., Riediker, M., Wick, P., Mohr, M., Gehr, P., & Rothen‐Rutishauser, B. (2009) · Journal of The Royal Society Interface · doi:10.1098/rsif.2009.0161.focus · Cited by 189 · see citing works
Schinwald, A., Murphy, F. A., Prina-Mello, A., Poland, C. A., Byrne, F., Movia, D., Glass, J. R., Dickerson, J. C., Schultz, D. A., Jeffree, C. E., et al. (2012) · Toxicological Sciences · doi:10.1093/toxsci/kfs171 · Cited by 181 · see citing works
Mbawuike, I. N., & Herscowitz, H. B. (1989) · Journal of Leukocyte Biology · doi:10.1002/jlb.46.2.119 · Cited by 177 · see citing works
Single-Walled Carbon Nanotubes Induces Oxidative Stress in Rat Lung Epithelial Cells
Sharma, C. S., Sarkar, S., Periyakaruppan, A., Barr, J. L., WISE, K. C., THOMAS, R. L., Wilson, B. L., & Ramesh, G. T. (2007) · Journal of Nanoscience and Nanotechnology · doi:10.1166/jnn.2007.431 · Cited by 175 · see citing works
Asbestos fiber length as related to potential pathogenicity: A critical review
Dodson, R. F., Atkinson, M. A., & Levin, J. L. (2003) · American Journal of Industrial Medicine · doi:10.1002/ajim.10263 · Cited by 170 · see citing works
Inflammasome activation and IL-1β target IL-1α for secretion as opposed to surface expression
Fettelschoss‐Gabriel, A., Kistowska, M., LeibundGut‐Landmann, S., Beer, H., Johansen, P., Senti, G., Contassot, E., Bachmann, M. F., French, L. E., Oxenius, A., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1109176108 · Cited by 169 · see citing works
Cytotoxicity of long and short crocidolite asbestos fibers in vitro and in vivo.
Goodglick, L., & Kane, A. B. (1990) · PubMed · Cited by 152 · see citing works
Inflammation generating potential of long and short fibre amosite asbestos samples.
Donaldson, K., Brown, G. M., Brown, D. M., Bolton, R., & Davis, J. M. (1989) · Occupational and Environmental Medicine · doi:10.1136/oem.46.4.271 · Cited by 124 · see citing works
Hillegass, J., Miller, J. M., MacPherson, M. B., Westbom, C. M., Sayan, M., Thompson, J. K., Macura, S. L., Perkins, T. N., Beuschel, S. L., Alexeeva, V., et al. (2013) · Particle and Fibre Toxicology · doi:10.1186/1743-8977-10-39 · Cited by 121 · see citing works
Schinwald, A., & Donaldson, K. (2012) · Particle and Fibre Toxicology · doi:10.1186/1743-8977-9-34 · Cited by 116 · see citing works
Huang, Z.-F., Massey, J. B., & Via, D. P. (2000) · Biochemical Pharmacology · doi:10.1016/s0006-2952(99)00312-3 · Cited by 110 · see citing works
Lee, J. K., Sayers, B. C., Chun, K., et al. (2012) · Particle and Fibre Toxicology · doi:10.1186/1743-8977-9-14 · Cited by 106 · see citing works
Nagai, H., & Toyokuni, S. (2010) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2010.06.015 · Cited by 103 · see citing works
Dong, J., Porter, D. W., Batteli, L. A., et al. (2014) · Archives of Toxicology · doi:10.1007/s00204-014-1428-y · Cited by 97 · see citing works
Behavior of crocidolite asbestos during mitosis in living vertebrate lung epithelial cells.
Ault, J. G., Cole, R. W., Jensen, C. G., Jensen, L. C. W., Bachert, L. A., & Rieder, C. L. (1995) · PubMed · Cited by 87 · see citing works
Xu, A., Zhou, H., Yu, D. Z., & Hei, T. K. (2002) · Environmental Health Perspectives · doi:10.1289/ehp.021101003 · Cited by 86 · see citing works
Miller, B. G. (1999) · The Annals of Occupational Hygiene · doi:10.1016/s0003-4878(99)00018-6 · Cited by 83 · see citing works
Biopersistence and durability of nine mineral fibre types in rat lungs over 12 months
Searl, A. (1999) · The Annals of Occupational Hygiene · doi:10.1016/s0003-4878(99)00017-4 · Cited by 80 · see citing works
Schinwald, A., Chernova, T., & Donaldson, K. (2012) · Particle and Fibre Toxicology · doi:10.1186/1743-8977-9-47 · Cited by 80 · see citing works
EFFECT OF FIBER LENGTH ON GLASS MICROFIBER CYTOTOXICITY
Dian, T. B. V. C. (1998) · Journal of Toxicology and Environmental Health · doi:10.1080/009841098158836 · Cited by 78 · see citing works
Ye, J., Shi, X., Jones, W. G., Rojanasakul, Y., Cheng, N., Schwegler‐Berry, D., Baron, P. A., Deye, G. J., Li, C., & Castranova, V. (1999) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.1999.276.3.l426 · Cited by 73 · see citing works
Wang, N. S., Jaurand, M., Magne, L., Kheuang, L., Pinchon, M. C., & Bignon, J. (1987) · PubMed Central · Cited by 71 · see citing works
CLEARANCE OF SIZED GLASS FIBRES FROM THE RAT LUNG AND THEIR SOLUBILITY IN VIVO
Morgan, A. E., Holmes, A. J., & Davison, W. (1982) · The Annals of Occupational Hygiene · doi:10.1093/annhyg/25.3.317 · Cited by 62 · see citing works
Case-referent survey of young adults with mesothelioma: I. lung fibre analyses
McDonald, J. (2001) · The Annals of Occupational Hygiene · doi:10.1016/s0003-4878(01)00046-1 · Cited by 57 · see citing works
Zeidler-Erdely, P. C., Calhoun, W. J., Ameredes, B. T., Clark, M. P., Deye, G. J., Baron, P. A., Jones, W. G., Blake, T. L., & Castranova, V. (2006) · Particle and Fibre Toxicology · doi:10.1186/1743-8977-3-5 · Cited by 41 · see citing works
Matsunaga, K., Klein, T., Friedman, H. P., & Yamamoto, Y. (2001) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb.24.3.4359 · Cited by 36 · see citing works
Case-referent survey of young adults with mesothelioma: II. occupational analyses
McDonald, J. C. (2001) · The Annals of Occupational Hygiene · doi:10.1016/s0003-4878(01)00047-3 · Cited by 35 · see citing works
Davis, J. M. (1994) · Environmental Health Perspectives · doi:10.1289/ehp.94102s5113 · Cited by 32 · see citing works
Biopersistence and durability of nine mineral fibre types in rat lungs over 12 months
Searl, A., Buchanan, D., Cullen, R. T., Jones, A. D., Miller, B. G., & Soutar, C. A. (1999) · The Annals of Occupational Hygiene · doi:10.1093/annhyg/43.3.143 · Cited by 32 · see citing works
Bignon, J., Saracci, R., & Touray, J. C. (1994) · Environmental Health Perspectives · doi:10.1289/ehp.94102s53 · Cited by 29 · see citing works
Donaldson, K., Miller, B. G., Sara, E., Slight, J., & Brown, R. C. (1993) · Europe PMC (PubMed Central) · Cited by 28 · see citing works
Characterization of a Vortex Shaking Method for Aerosolizing Fibers
Ku, B. K., Deye, G. J., & Turkevich, L. A. (2013) · Aerosol Science and Technology · doi:10.1080/02786826.2013.836588 · Cited by 22 · see citing works
Self-citationInvolvement of IL-1 genes in the cellular responses to carbon nanotube exposure
Arnoldussen, Y. J., Skogstad, A., Skaug, V., Kasem, M., Haugen, A., Benker, N., Weinbruch, S., Apte, R. N., & Zienolddiny, S. (2015) · Cytokine · doi:10.1016/j.cyto.2015.01.032 · Cited by 19 · see citing works
Epidemiological significance of mineral fiber persistence in human lung tissue.
McDonald, J. C. (1994) · Environmental Health Perspectives · doi:10.1289/ehp.94102s5221 · Cited by 16 · see citing works
Ku, B. K., Deye, G. J., & Turkevich, L. A. (2014) · Inhalation Toxicology · doi:10.3109/08958378.2013.854851 · Cited by 10 · see citing works
Self-citationCho, K. J., Turkevich, L. A., Miller, M. A., McKay, R. T., Grinshpun, S. A., Ha, K., & Reponen, T. A. (2012) · Journal of Occupational and Environmental Hygiene · doi:10.1080/15459624.2012.752321 · Cited by 7 · see citing works
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Mariani, E., Lisignoli, G., Borzì, R. M., & Pulsatelli, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20030636 · Cited by 706 · see citing works
Halappanavar, S., van den Brule, S., Nymark, P., Gaté, L., Seidel, C., Valentino, S., Zhernovkov, V., Høgh Danielsen, P., De Vizcaya, A., Wolff, H., et al. (2020) · Particle and Fibre Toxicology · doi:10.1186/s12989-020-00344-4 · Cited by 246 · see citing works
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Di Giuseppe, D., Zoboli, A., Vigliaturo, R., Gieré, R., Bonasoni, M. P., Sala, O., & Gualtieri, A. F. (2019) · Minerals · doi:10.3390/min9100618 · Cited by 26 · see citing works
“Time-lapse video microscopy of macrophage–asbestos fibrebinding events [62,63] showed that the macrophages try to internalise the long fibres by preferentially starting from their terminations.”
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- Authors
- Padmore, T., Stark, C., Turkevich, L. A., & Champion, J. A.
- Affiliations
- Georgia Institute of Technology (US)
- National Institute for Occupational Safety and Health (US)
- Corresponding author
- Champion, Julie A.
- Venue
- Biochimica et Biophysica Acta (BBA) - General Subjects
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 1861
- Issue
- 2
- Pages
- 58-67
- ISSN
- 0304-4165 (ISSN-L)
- PMC
- PMC5228597
- OpenAlex
- W2535627036
- Cited by
- 74
- References
- 66
- Citations by year
- 2026: 11 · 2025: 6 · 2024: 6 · 2023: 2 · 2022: 9 · 2021: 12 · 2020: 10 · 2019: 8 · 2018: 6 · 2017: 4
- FWCI
- 5.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochimica et Biophysica Acta (BBA) - General Subjects (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (CC999999)
- Laboratório Nacional de Luz Síncrotron
- National Institute for Occupational Safety and Health
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Occupational and environmental lung diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- fiber length, alveolar macrophages, phagocytosis, frustrated phagocytosis, inflammation, cytokine production, reactive oxygen species, dose-response curves, critical fiber length, chronic lung inflammation
- MeSH terms
- Animals, Cells, Cultured, Evaluation Studies as Topic, Glass, Inflammation, Macrophages, Phagocytosis, Tumor Necrosis Factor-alpha, Dinoprostone, Macrophages, Alveolar, Reactive Oxygen Species, Mice, Cyclooxygenase 2, Interleukin-1alpha
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