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Quantification of the Tissue Changes in the Human Lung with Chronic Lung Disease Using a Combination of Computed Tomography and Stereology

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Quantification of the Tissue Changes in the Human Lung with Chronic Lung Disease Using a Combination of Computed Tomography and Stereology QUANTIFICATION OF THE TISSUE CHANGES IN THE HUMAN LUNG WITH CHRONIC LUNG DISEASE USING A COMBINATION OF COMPUTED TOMOGRAPHY AND STEREOLOGY by HARVEY OWEN COXSON B.Sc, The University of British Columbia, 1986 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIRMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Experimental Medicine) We a^ept this thesis as>GOTTfl7rfning ;te>fhe required standard THE UNIVERSITY OF BRITISH COLUMBIA April 1998 © Harvey Owen Coxson, 1998 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of The University of British Columbia Vancouver, Canada DE-6 (2/88) ABSTRACT Idiopathic pulmonary fibrosis (IPF) and pulmonary emphysema are chronic lung diseases exhibiting progressive deterioration in pulmonary function as the lung architecture is remodeled. This thesis quantifies these tissue changes using a novel combination of computed tomography (CT) and quantitative histology. Pre-operative CT scans were obtained from patients with IPF, patients receiving lung volume reduction surgery for diffuse emphysema and from patients with minimal to mild emphysema undergoing lobectomy for a small peripheral • •• • • • j. tumour. Total lung volume was calculated using the pixel dimensions on the CT scan while airspace and tissue volume as well as the regional lung expansion were estimated using the X- ray attenuation values. Tissue samples were obtained at either open lung biopsy (IPF) or surgical resection (control and emphysema) and prepared for quantitative histology. A method for correcting the histology specimens to an in vivo level of inflation was developed so that the tissue composition and surface area could be estimated using stereologic techniques. The data shows that there is a reorganization of lung parenchyma in IPF with a disproportionate loss of airspace and surface area without increasing the total amount of tissue. The patients with emphysema show evidence of a progressive proteolytic destruction of tissue volume and surface area. There is a negative correlation between regional lung expansion and surface area in emphysema and a positive correlation between surface area and the diffusing capacity of the lung in both diseases. This technique should prove useful in the longitudinal assessment of chronic lung diseases and the monitoring of response to treatment. TABLE OF CONTENTS ABSTRACT ii TABLE OF CONTENTS iii LIST OF TABLES vi LIST OF FIGURES vii ACKNOWLEDGEMENTS viii PREFACE ix CHAPTER 1: INTRODUCTION TO QUANTITATIVE ANALYSIS OF THE LUNG 1 1.1 Quantitative Histology Of The Lung 1 1.1.1 Sampling 1 1.1.2B\as 2 1.1.3 Variance 3 1.2 Stereological Methods 4 1.2.1 Stereological Probes 4 1.2.2 Cavalieri's Volume Estimator 6 7.2.3 Volume Fraction 7 1.2.4 Surface Area 7 1.2.5 Multi-Level Sampling Design 11 1.3 Quantitative Gross Analysis Using Computed Tomography 12 CHAPTER 2: WORKING HYPOTHESIS. SPECIFIC AIMS AND STRATEGY 16 2.1 Working Hypothesis 16 2.2 Specific Aims 17 2.3 Strategy 17 2.4 Summary 17 CHAPTER 3: THE NORMAL HUMAN LUNG 18 3.1 Descriptions of the Lung 18 3.1.1 Gross Lung Structure 20 3.1.2 Cellular Lung Structure 21 3.1.3 Extra-cellular Matrix 23 3.2 The Clinical Measurement of Lung Function 25 iii 3.3 The Pleural Pressure Gradient 27 3.4 Experiment #1 28 3.5 Material and Methods 28 3.5.1 Pulmonary Function Studies 29 3.5.2 CT Studies 29 3.5.3 Quantitative Histology 33 3.5.4 Statistical Analysis 35 3.6 Results 35 3.7 Discussion 45 CHAPTER 4: INTERSTITIAL LUNG DISEASE 48 4.1 Introduction to Interstitial Pulmonary Fibrosis (IPF) 48 4.1.1 Clinical Description of IPF 49 4.1.2 Radiological Description of IPF 50 4.1.3 Histological Description of IPF 50 4.2 Fibrotic Mechanisms 51 4.2.1 Cellular Mechanisms of IPF 51 4.2.2 Molecular Mechanisms of IPF 52 4.3 Quantitative Studies of IPF 53 4.4 Experiment #2 55 4.5 Material and Methods 55 4.5.1 Pulmonary Function Studies 56 4.5.2 CT Studies 57 4.5.3 Quantitative Histology 58 4.5.4 Statistical Analysis 62 4.6 Results 62 4.7 Discussion 72 CHAPTER 5: PULMONARY EMPHYSEMA 76 5.1 Introduction to Pulmonary Emphysema 76 5.1.1 Functional Description of Emphysema 11 5.1.2 Radiological Description of Emphysema 78 5.1.3 Histological Description of Emphysema 78 5.2 Pathogenesis of Emphysema 80 5.2.1 Protease/Antiprotease Theory 80 5.2.2 Inflammatory-Repair Mechanism 81 iv 5.3 Quantitative Studies in Emphysema 82 5.3.1 Gross Analysis 82 5.3.2 Histologic Analysis 83 5.3.3 Radiological Analysis 84 5.4 Experiment #3 85 5.5 Materials and Methods 86 5.5.1 Pulmonary Function Studies 87 5.5.2 CT Studies 87 5.5.3 Quantitative Histology 88 5.5.4 Statistical Analysis 92 5.6 Results 93 5.7 Discussion 104 CHAPTER 6: SUMMARY AND DISCUSSION 108 6.1 Summary 108 6.2 Future Directions 112 6.3 Conclusion 113 REFERENCES 115 v LIST OF TABLES Table 1. Stereologic rules for the selection of a sampling probe. 5 Table 2. Cellular composition of the lung. 21 Table 3. Pulmonary Function Data. 37 Table 4. Individual lobar volumes measured by CT in 9 patients. 38 Table 5. Lobar weight and volume. 39 Table 6. Lung volume and Gas per Gram of Tissue. 40 Table 7. Stereology. 41 Table 8. Patient Demographics. 65 Table 9. Lung Volumes and Weights. 66 Table 10. CT Estimated Regional Lung Inflation. 67 Table 11. Light Microscopy Volume Fractions (%). 68 Table 12. Patient Demographics. 96 Table 13. Lung Volumes and Weights. 97 Table 14. CT Estimated Regional Lung Inflation. 98 Table 15. Quantitative Histology. 99 Table 16. Percent Emphysema of Resected Lobe. 100 vi LIST OF FIGURES Figure 1. Representation of variance and bias in a sample. 4 Figure 2 Sample point counting grid on an object. ,6 Figure 3. Sample point counting grid on light microscopic section of human lung. 8 Figure 4. Sample intercept counting grid on light microscopic section of human lung. 9 Figure 5. Multi-level sampling design. 10 Figure 6. CT scan of human lung showing segmentation of the different lobes. 31 Figure 7. A representative CT analysis slice. 32 Figure 8. Graph of the CT density of the lung. 42 Figure 9. Graph of the pressure volume curves. 43 Figure 10. Graph of the pleural pressure gradient. 44 Figure 11. Classification of interstitial lung diseases based on pathogenesis. 48 Figure 12. Representative electron micrograph from IPF patient biopsy. 61 Figure 13. CT density of the lung. 69 Figure 14. Volume fraction of the tissue in the biopsied regions of lung. 70 Figure 15. Weight of the interstitial components. 71 Figure 16. CT scan of human lung with emphysema using the density mask. 89 Figure 17. Gross lung slice and CT scan. 90 Figure 18. CT density of the lung. 101 Figure 19. Mixed effects regression line for surface area per volume and lung inflation. 102 Figure 20. Mixed effects regression line for surface area and diffusing capacity of the lung for carbon monoxide. 103 Figure 21. Mixed effects regression line for surface area and diffusing capacity of the lung for carbon monoxide for all patients. 111 Figure 22. Three dimensional reconstruction of a human lung with emphysema. 114 vii ACKNOWLEGMENTS No scientific work can be completed without the assistance and support of many people. As such, I wish to thank my supervisor and mentor Dr. James C. Hogg for getting me started in. this field and tortus guidance and support through all of the aspects of my career in science. I also wish to thank my supervisory committee, Drs. Peter D. Pare, Clive R. Roberts, and John R. Mayo for their constructive input and instruction. This project would not have been possible without collaborations from the University of Iowa under the direction of Gary W. Hunninghake and Dr. Robert R. Rogers at the University of Pittsburgh. I also wish to thank Ms. Hayedeh Bezad and Dr. Benard Meshi for their technical assistance with the stereology; the Histology Laboratory St. Paul's Hospital for processing the histological material; the computed tomography/magnetic resonance imaging staff at St. Paul's Hospital for gathering and transferring the CT images; Dr. Kenneth P. Whittall and Mr. Don Kirkby for their wizardry with the computers; Ms. Barbara Moore for collecting the pulmonary function data; Messrs Joe Comeau and Stuart Greene for their computer and photographic expertise; and Ms. Lorri Verburgt and Ms. Yulia D'Yachkova for their statistical advice. Special appreciation is also extended to my good friends (Paul and Mary Lacey and Gary and Heidi Rae) who introduced me to fly fishing and provided me with so much moral support through this time. Thank you also to my parents and family who always believed in me. Finally, I wish to thank my wife Maureen for her patience, faith and unwavering love. Thank you all and God bless you. viii PREFACE Chapters 3 and 4 are modifications of published papers. The introduction has been re• written to match thesis requirements, and the methods have been modified to reduce redundancies.
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