© 2003 Robert A. Freitas Jr. All Rights Reserved.

Robert A. Freitas Jr., Nanomedicine, Volume IIA: Biocompatibility, Landes Bioscience, Georgetown, TX, 2003

15.6.3.4 Phagocyte Ingesta

Phagocytes are specialized cells optimized for ingestion of foreign particles (Section 15.4.3.1). The capacity of a phagocyte for ingestion of chemically inert nanorobots (e.g., Section 15.1.2, Chapter 15.3, Section 15.4.3) or their detritus (Section 15.4.4), without causing its destruction and subsequent re-release of the particulate matter, has already been addressed. Some particles are highly toxic to phagocytes. For instance, just 0.05 µg of silica per 10⁶ macrophages [4561], or 0.002% of cell volume assuming 1166 micron³ per rat alveolar macrophage [4562], was cytotoxic.* Asbestos particles are more tolerable. An environment of 6.6-900 µg per 10⁶ mouse peritoneal macrophages are required to induce fibrosis [4561], a volume of ~2.1-280 micron³ per macrophage, though not all of this material was ingested by the cells. Ultrafine carbon particles were safely administered to rat alveolar macrophages in the amount of 1 µg per 10⁶ macrophages or ~1 micron³/cell [768], or 0.1% of cell volume.

* Extensive in vitro and in vivo research has been conducted to evaluate the effects of crystalline silica on mammalian cells, but the precise molecular mechanism responsible for the cellular injury that precedes the lung disease is unknown [5982]. Four basic mechanisms have been proposed [5983] to explain the cause of the cellular damage:

(1) direct cytotoxicity of crystalline silica, resulting in lung cell damage, release of lipases and proteases, and eventual lung scarring;

(2) activation of oxidant production by pulmonary phagocytes, which overwhelms the antioxidant defenses and leads to lipid peroxidation, protein nitrosylation, cell injury, and lung scarring;

(3) stimulation of the alveolar macrophages and epithelial cells to release inflammatory mediators (e.g., interleukin-8, leukotriene B4, platelet-activating factor, tumor necrosis factor, platelet-derived growth factor) that recruit polymorphonuclear leukocytes and macrophages, resulting in the production of proinflammatory cytokines and reactive species and further lung injury and scarring; and

(4) stimulation of the alveolar macrophages and epithelial cells to secrete growth factors (e.g., interleukin-1, tumor necrosis factor, platelet-derived growth factor, fibronectin, and alveolar macrophage-derived growth factor) that initiate fibroblast proliferation and collagen synthesis, with eventual scarring.

Latex or polystyrene beads are among the most popular particles for ingestion burden experiments [778]. Guinea pig neutrophils can ingest up to 3.8% of cell volume in 3-micron polystyrene beads, but only 3.0% of cell volume of 0.3-micron beads (Table 15.1). Peritoneal phagocytes from striped bass each ingested an average of four 3.12-micron latex beads during a 30-minute incubation time [3002], giving a phagocytic capacity of ~64 micron³/phagocyte or ~4% of cell volume. Rabbit alveolar macrophages cultured in suspensions or on monolayers of latex particles internalized a maximum of 45 1-micron particles (45 micron³/cell or ~3% of cell volume) and 10 2-micron particles (~80 micron³/cell or ~5% of cell volume) at saturation [4563]. A study of rat alveolar macrophages confirmed particle burdens exceeding 15 2-micron microspheres (~63 micron³ or ~4% of cell volume) [4564]. Interestingly, murine bone-marrow macrophages that are only 13.8 microns in diameter can ingest IgG-opsonized beads up to 20 microns in diameter [2876], representing an amazing ~200% of cell volume. Of course, phagocytes that eat too many latex microspheres develop an impaired mobility [778, 4565, 4566].

What about inorganic particles? Rat alveolar macrophages can ingest at least ~1 micron³/cell of iron oxide particles (~0.1% of cell volume) without ill effect [4567], and another experiment [4568] found up to 72 spherical 2.6-micron iron oxide particles (~663 micron³) had been nonfatally ingested by human alveolar macrophages each of mean volume 4990 micron³ [4562], a much larger cell burden of ~13% foreign particles by volume. Murine macrophages suffer only ~10% mortality after ingesting up to 2500 alumina ceramic 0.6-micron particles, or ~10% of cell volume, although mortality rises to ~30% after ingesting a similar volume concentration of 2-micron particles [1074]. Micrographs of live mouse peritoneal macrophages [652] and human monocytes [641] that have been induced to ingest diamond dust particles up to 5 microns in diameter appear to have internalized particles amounting to 10-20% of their cell volume. A particle burden “overload criterion” (i.e., producing complete macrophage immobilization) of ~600 micron³ per rat alveolar macrophage (a ~50% cellular volumetric burden for 1166-micron³ cells [4562]) has been proposed by Oberdorster et al [4566].

Last updated on 30 April 2004