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Mechanisms and Consequences of Particle Uptake
in Alveolar Macrophages





Inaugural-Dissertation



zur Erlangung des Doktorgrades
der Mathematisch-Naturwissenschaftlichen Fakultät
der Heinrich-Heine-Universität Düsseldorf








vorgelegt von

Agnes Martha Scherbart

aus Düren




Düsseldorf, Oktober 2010




aus dem Institut für Umweltmedizinische Forschung (IUF)
an der Heinrich-Heine Universität Düsseldorf gGmbH




























Gedruckt mit der Genehmigung der
Mathematisch-Naturwissenschaftlichen Fakultät der
Heinrich-Heine-Universität Düsseldorf



Referentin: Prof. Dr. Christine R. Rose

Koreferentin: Prof. Dr. Charlotte Esser


Tag der mündlichen Prüfung: 01. Dezember 2010




Die Neugier steht immer an erster Stelle eines Problems, das gelöst werden will.
Galileo Galilei
15.02.1564 - 08.01.1642
italienischer Physiker und Astronom















































































To my parents Renata and Diethard Scherbart and
To my sister Eva-Maria Scherbart













































TABLE OF CONTENT

Chapter I 1
1.1 Background - Where it all began 2

1.2 Nanoparticles - Benefits and Risks 4
1.2.1 The Particle Surface Properties - Reactive or Not 6
1.2.2 The Particle Size Distribution 8
1.2.3 The Ultrafine Hypothesis - A Question of Size 9
1.2.4 The Way of Exposure to Engineered Nanoparticles 9

1.3 The Lung - From Particle Inhalation to Pathogenesis 11
1.3.1 Particle Deposition in the Lung 12
1.3.2 The Clearance of Particles 13

1.4 Macrophages - Their Origin, Development, Differentiation & Function 15

1.5 Phagocytosis & Pinocytosis - Portals of Entry Into the Cell 16
1.5.1 Actin-Dependent Endocytosis 17
1.5.1.1 Phagocytosis 17
1.5.1.2 The Fc Receptor-Mediated Phagocytosis 17
1.5.1.3 Macropinocytosis 18
1.5.2 Actin-Independent Endocytosis 19
1.5.2.1 Clathrin-Mediated Endocytosis 19
1.5.2.2 Caveolae-Mediated Endocytosis 19
1.5.2.3 Clathrin- & Caveolin-Independent Endocytosis 19

1.6 Oxidative Stress - A Cell Fights Back 20
1.6.1 Cellular Generation of Reactive Oxygen / Nitrogen Species 20
1.6.2 Cellular Antioxidant Defence Mechanisms - Taking Care of Oneself 23

1.7 Inflammation & Oxidative Stress - Cellular Responses 25
1.7.1 Alveolar Macrophages - A Balance of Pro- & Anti-Inflammatory Actions 27

1.8 The Aim of the Thesis 29

1.9 References 31

I
?TABLE OF CONTENT

Chapter II 39

Contrasting Macrophage Activation by Fine and Ultrafine Titanium Dioxide Particles is
Associated with Different Uptake Mechanisms.

2.1. Introduction 42
2.2. Materials and Methods 45
2.3. Results 51
2.4. Discussion 64
2.5. References 69



Chapter I 75

Surface Iron Inhibits Quartz-Induced Cytotoxic and Inflammatory Responses in
Alveolar Macrophages.

3.1. Introduction 78
3.2. Materials and Methods 81
3.3. Results 88
3.4. Discussion 98
3.5. References 105



Chapter IV 113

Evaluation of Cytotoxic Effects and Oxidative Stress with Hydroxyapatite Dispersions
of Different Physicochemical Properties in Rat NR8383 Cells and Primary
Macrophages.




II TABLE OF CONTENT

Chapter V 127

5.1 Summary & General Discussion 129
5.2 References 135

5.3 Abstract 137
5.4 Zusammenfassung 138

5.5 List of Abbreviations 139

5.6 List of Publications 143

Danke an …

Eidesstattliche Erklärung














III TABLE OF CONTENT



IV

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