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Endocytosis of Environmental and Engineered Micro‐ and Nanosized Particles

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Abstract

There are many studies with cells to find out how particles interact with them. In contrast to micronsized particles, which are actively taken up by phagocytosis or macropinocytosis, nanosized particles may be taken up by cells through different endocytic pathways or by another, yet to be defined mechanism. There is increasing evidence that it is the nanosized particles, which are a particular risk because of their high content of organic chemicals and their pro‐oxidative potential due to the high surface‐to‐volume ratio of the particles as compared to the bulk material. It is the goal of this article to create an understanding for the interaction of particles with biological systems, with particular consideration of the interaction of nanoparticles (NPs) with lung cells. One is attempting to understand, how NPs interact with cellular membranes, as it is hardly known, how they are taken up by cells, how they are trafficking in cells, and how they interact with subcellular compartments, such as with mitochondria or with the nucleus. Cells tend to defend themselves against any foreign material, which is taken up. In general, they try to eliminate particulate intruders and this is what they usually manage with micronsized particles. However, with NPs it is different. NPs may not be eliminated easily, and, hence may stimulate the cells to react in an unfavorable way. What we can learn is that NPs behave differently than microparticles. © 2011 American Physiological Society. Compr Physiol 1:1159‐1174, 2011.

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Figure 1. Figure 1.

Gas exchange structure of the human lung: the air blood tissue barrier. (A) Lung slice at low magnification (15×), showing gas exchange parenchyma (GP), blood vessels (BV), and airways (AW). Courtesy Institute of Anatomy, University of Bern, Bern, Switzerland. (B) Scanning electron micrograph of gas exchange parenchyma; alveoli (A) are clearly recognizable; magnification 60×. (C) Scanning electron micrograph of alveolar duct (AD) with adjacent alveoli (A); magnification 120×. Adapted from . (D) Scanning electron micrograph of interalveolar septum; the septum is broken up, showing erythrocytes (EC) in a capillary and the air‐blood tissue barrier (AT); A = alveoli; magnification 450×. Adapted from . (E) Transmission electron micrograph of interalveolar septa, showing capillaries with erythrocytes (black) meandering around connective tissue frame; A = alveolar air; magnification 400×. Adapted from . (F) Transmission electron micrograph of capillary (C) with erythrocytes (black) in an interalveolar septum; the three layers of the air‐blood tissue barrier (AT) can be seen; A = alveolar air; magnification 3200×. Figure adapted from .

Figure 2. Figure 2.

Air blood tissue barrier system of airways (A) and alveoli (B). Abbreviations: alveolar epithelium type I (AEPT I), alveolar epithelium type II (AEPT II), aqueous lining layer (ALL), airway/alveolar macrophage (AM), basal membrane (BM), capillary (C), connective tissue (CT), dendritic cell (DC), epithelial cell (EP), particle (P), surfactant (S), tight junction (TJ). Figure adapted from .

Figure 3. Figure 3.

Cellular uptake mechanisms of NPs and related intracellular trafficking. (A) Phagocytosis, an actin‐based mechanism occurring primarily in professional phagocytes, leading to phagosomes (AI) and phago‐lysosomes (PL). (B) Macropinocytosis, also an actin‐based pathway, engulfing NPs with poor selectivity, leading to macropinosomes (BI) that might be exocytosed or fuse with lysosomes to form phago‐lysosomes (PL). (C) Clathrin‐mediated endocytosis, associated with the formation of a clathrin lattice and depending on the GTPase dynamin, forming primary endosomes (CI) and late endosomes (CII) including multivesicular bodies (CIII). (D) Clathrin and caveolae independent endocytotic pathways. (E) Caveolae‐mediated endocytosis, with typical flask‐shaped invaginations made of caveolin dimers, also dynamin‐dependent and forming caveosomes (EI), which fuse with the ER (EII) or translocate through the cell (EIII). (F) Particle diffusion/transport through the apical plasma membrane, resulting in particles located freely in the cytosol. The figure and descriptions are adapted from and modified from .

Figure 4. Figure 4.

Macrophages exposed to polystyrene spheres in vitro in the presence of cytochalasin D. Laser‐scanning microscope images of monocyte‐derived macrophages are presented as 3D reconstruction. F‐actin is shown in light gray and made transparent, allowing a look inside the cell. The extent of taken up fluorescent polystyrene spheres by macrophages in the presence of cytochalasin D is shown in green, 1 μm (left) and 0.078 μm particles (right). Uptake inhibition of microsized particles (1 μm) was much more effective compared to NPs (0.078 μm; ).

Figure 5. Figure 5.

Visualization of engineered core‐shell NPs containing a fluorescence marker embedded in the shell in monocyte‐derived macrophage monocultures (gray), using laser‐scanning microscopy. The internalization of engineered polymer‐coated iron‐platinum NP, fluorescently labeled with the dye ATTO 590 embedded in the polymer shell (FePt‐PMA‐ATTO 2%, red) is shown in a 3D reconstruction (A). In (AD), localization and colocalization (turquoise) of the particles with lysosomes (yellow) are shown. By making the cell body channel (light gray) as well as the lysosome channel transparent the particles colocalized with the lysosomes become visible (C). The colocalization of particles in lysosomes is shown in D. Picture (E) shows mitochondria (blue) and particles (red) in a macrophage. Modified from .

Figure 6. Figure 6.

Distribution of plain gold NPs and PEG‐coated gold NPs in cellular compartments of various sizes. (A) Plain gold NPs and (B) PEG‐coated gold NPs were visualized intracellular by transmission electron microscopy. In (A), the particles (see arrows) are localized within vesicles of different size and in (B) within a lysosome (arrows I) and in the cytosol (arrow II). N = nucleus, M=mitochondria; scale bars: 500 nm. Figure adapted from .



Figure 1.

Gas exchange structure of the human lung: the air blood tissue barrier. (A) Lung slice at low magnification (15×), showing gas exchange parenchyma (GP), blood vessels (BV), and airways (AW). Courtesy Institute of Anatomy, University of Bern, Bern, Switzerland. (B) Scanning electron micrograph of gas exchange parenchyma; alveoli (A) are clearly recognizable; magnification 60×. (C) Scanning electron micrograph of alveolar duct (AD) with adjacent alveoli (A); magnification 120×. Adapted from . (D) Scanning electron micrograph of interalveolar septum; the septum is broken up, showing erythrocytes (EC) in a capillary and the air‐blood tissue barrier (AT); A = alveoli; magnification 450×. Adapted from . (E) Transmission electron micrograph of interalveolar septa, showing capillaries with erythrocytes (black) meandering around connective tissue frame; A = alveolar air; magnification 400×. Adapted from . (F) Transmission electron micrograph of capillary (C) with erythrocytes (black) in an interalveolar septum; the three layers of the air‐blood tissue barrier (AT) can be seen; A = alveolar air; magnification 3200×. Figure adapted from .



Figure 2.

Air blood tissue barrier system of airways (A) and alveoli (B). Abbreviations: alveolar epithelium type I (AEPT I), alveolar epithelium type II (AEPT II), aqueous lining layer (ALL), airway/alveolar macrophage (AM), basal membrane (BM), capillary (C), connective tissue (CT), dendritic cell (DC), epithelial cell (EP), particle (P), surfactant (S), tight junction (TJ). Figure adapted from .



Figure 3.

Cellular uptake mechanisms of NPs and related intracellular trafficking. (A) Phagocytosis, an actin‐based mechanism occurring primarily in professional phagocytes, leading to phagosomes (AI) and phago‐lysosomes (PL). (B) Macropinocytosis, also an actin‐based pathway, engulfing NPs with poor selectivity, leading to macropinosomes (BI) that might be exocytosed or fuse with lysosomes to form phago‐lysosomes (PL). (C) Clathrin‐mediated endocytosis, associated with the formation of a clathrin lattice and depending on the GTPase dynamin, forming primary endosomes (CI) and late endosomes (CII) including multivesicular bodies (CIII). (D) Clathrin and caveolae independent endocytotic pathways. (E) Caveolae‐mediated endocytosis, with typical flask‐shaped invaginations made of caveolin dimers, also dynamin‐dependent and forming caveosomes (EI), which fuse with the ER (EII) or translocate through the cell (EIII). (F) Particle diffusion/transport through the apical plasma membrane, resulting in particles located freely in the cytosol. The figure and descriptions are adapted from and modified from .



Figure 4.

Macrophages exposed to polystyrene spheres in vitro in the presence of cytochalasin D. Laser‐scanning microscope images of monocyte‐derived macrophages are presented as 3D reconstruction. F‐actin is shown in light gray and made transparent, allowing a look inside the cell. The extent of taken up fluorescent polystyrene spheres by macrophages in the presence of cytochalasin D is shown in green, 1 μm (left) and 0.078 μm particles (right). Uptake inhibition of microsized particles (1 μm) was much more effective compared to NPs (0.078 μm; ).



Figure 5.

Visualization of engineered core‐shell NPs containing a fluorescence marker embedded in the shell in monocyte‐derived macrophage monocultures (gray), using laser‐scanning microscopy. The internalization of engineered polymer‐coated iron‐platinum NP, fluorescently labeled with the dye ATTO 590 embedded in the polymer shell (FePt‐PMA‐ATTO 2%, red) is shown in a 3D reconstruction (A). In (AD), localization and colocalization (turquoise) of the particles with lysosomes (yellow) are shown. By making the cell body channel (light gray) as well as the lysosome channel transparent the particles colocalized with the lysosomes become visible (C). The colocalization of particles in lysosomes is shown in D. Picture (E) shows mitochondria (blue) and particles (red) in a macrophage. Modified from .



Figure 6.

Distribution of plain gold NPs and PEG‐coated gold NPs in cellular compartments of various sizes. (A) Plain gold NPs and (B) PEG‐coated gold NPs were visualized intracellular by transmission electron microscopy. In (A), the particles (see arrows) are localized within vesicles of different size and in (B) within a lysosome (arrows I) and in the cytosol (arrow II). N = nucleus, M=mitochondria; scale bars: 500 nm. Figure adapted from .

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Peter Gehr, Martin J.D Clift, Christina Brandenberger, Andrea Lehmann, Fabian Herzog, Barbara Rothen‐Rutishauser. Endocytosis of Environmental and Engineered Micro‐ and Nanosized Particles. Compr Physiol 2011, 1: 1159-1174. doi: 10.1002/cphy.c100035