Translational studies of neutrophils, macrophages, and T cells in the human lung: implications for cystic fibrosis and other chronic respiratory pathologies 公开
Giacalone, Vincent (Fall 2022)
Published
Abstract
Neutrophils comprise the largest subset of circulating leukocytes in humans, and maintain a significant presence in the lungs. In-depth investigation of their effector and regulatory functions has revealed new relationships with other leukocyte subsets such as macrophages and T cells. In cystic fibrosis (CF), sterile neutrophilic inflammation begins in the airways at a young age and drastically impacts the functions of other cell types while contributing to bronchiectasis. Clinical studies have traditionally relied on samples collected by invasive techniques such as bronchoalveolar lavage, but these samples are increasingly difficult to obtain.
The research presented in this dissertation focuses on four main areas of CF research with the common element of neutrophilic inflammation. First, we investigated the role of the PD-1 pathway in exhaustion of airway macrophages and how this coincides with the early stages of neutrophil recruitment. Second, we identified signatures of T-cell activation during acute pulmonary exacerbations in young children, which contrasts with the functional impairment of T cells later in CF lung disease. However, concomitant increases in neutrophil frequency in circulation and cytokine concentrations in the airways and plasma are suggestive of future waves of neutrophil recruitment to the airways. Third, we demonstrated that minimally invasive collection of induced sputum from young children with CF, already employed in routine care, can yield data on cellular and soluble markers of inflammation that are comparable to those from more invasive bronchoalveolar lavage. Finally, we used an in vitro transmigration model to generate new insights into neutrophil and monocyte function after their recruitment to the lung which would be difficult or impossible to obtain with primary samples, such as the dynamics of acid sphingomyelinase, IL-29, and nitric oxide production. By adapting this model to study pulmonary Yersinia pestis infection, we obtained data suggesting that Y. pestis virulence factors block calcium flux in neutrophils.
This dissertation advances the knowledge of CF lung disease by providing novel insights about coordinated immune responses in the lung, with implications for other acute and chronic pulmonary diseases.
Table of Contents
Chapter 1 1
1.1: Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease 2
1.1.1. Introduction 2
Table 1.1.1.1. 3
Figure 1.1.1.1. 5
1.1.2 Stress responses 6
Figure 1.1.2.1. 11
Figure 1.1.2.2. 15
1.1.3 Neutrophils in chronic respiratory pathologies 17
1.1.4 Conclusion 22
1.2: Immunomodulation in cystic fibrosis: why and how? 23
1.2.1 Introduction 23
1.2.2 Targeting immune cells in the CF lung 25
Figure 1.2.2.1. 33
Figure 1.2.2.2. 37
1.2.3 Protein-directed therapies 39
1.2.4 Conclusion 46
1.3 References 48
Chapter 2 98
2.1 At-a-glance commentary 99
2.2 Abstract 100
2.3 Introduction 101
2.4 Methods 103
Table 2.4.1. 105
Table 2.4.2. 107
Figure 2.4.1. 109
Table 2.4.3. 111
2.5 Results 113
Figure 2.5.1. 114
Figure 2.5.2. 116
Figure 2.5.3. 117
Table 2.5.1. 119
Figure 2.5.4. 120
Figure 2.5.5. 122
Figure 2.5.6. 123
Figure 2.5.7. 125
Figure 2.5.8. 128
Figure 2.5.9. 130
Figure 2.5.10. 131
2.6 Discussion 132
2.7 References 135
Chapter 3 147
3.1 At-a-glance commentary 148
3.2 Abstract 149
3.3 Introduction 150
3.4 Methods 152
Table 3.4.1. 153
Table 3.4.2. 155
Table 3.4.3. 156
3.5 Results 160
Table 3.5.1. 161
Figure 3.5.1. 162
Figure 3.5.2. 163
Figure 3.5.3. 164
Figure 3.5.4. 165
Figure 3.5.5. 166
Figure 3.5.6. 167
Figure 3.5.7. 168
Figure 3.5.8. 170
Figure 3.5.9. 171
3.6 Discussion 172
3.7 References 178
Chapter 4 185
4.1 At-a-glance commentary 186
4.2 Abstract 187
4.3 Introduction 188
4.4 Methods 191
Table 4.4.1. 192
Figure 4.4.1. 193
Table 4.4.2. 194
Table 4.4.3. 196
Table 4.4.4. 198
Table 4.4.5. 199
Table 4.4.6. 200
Table 4.4.7. 203
Figure 4.4.2. 208
4.5 Results 210
Figure 4.5.1. 212
Figure 4.5.2. 213
Figure 4.5.3. 215
Figure 4.5.4. 216
Figure 4.5.5. 218
Figure 4.5.6. 220
Figure 4.5.7. 222
Table 4.5.1. 224
4.6 Discussion 225
4.7 References 230
Chapter 5 238
5.1 At-a-glance commentary 239
5.2 Abstract 240
5.3 Introduction 241
5.4 Methods 243
Figure 5.4.1. 244
5.5 Results 247
Figure 5.5.1. 248
Figure 5.5.2. 250
Figure 5.5.3. 252
Figure 5.5.4. 253
Figure 5.5.5. 255
5.6 Discussion 256
5.7 References 261
Chapter 6 269
6.1 Summary of findings 270
6.2 Implications for CF lung disease pathogenesis 271
6.3 Expanding therapeutic options for CF lung disease 273
6.4 Future directions in CF lung disease research 274
6.5 Conclusion 276
Figure 6.5.1. 277
6.6 References 278
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