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)

Permanent URL: https://etd.library.emory.edu/concern/etds/hq37vp80m?locale=zh
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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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