Type I and III procollagen propeptides in sarcoidosis, fibrosing alveolitis and asbestos-related lung diseases

Lauri Lammi

Vaasa Central Hospital, Department of Pulmonary Medicine, FIN 65130 Vaasa and Department of Internal Medicine, University of Oulu, P.O. Box 5000, FIN 90401 Oulu

Abstract

The most threatening outcome of interstitial lung diseases is death caused by progressive pulmonary fibrosis characterised by increased collagen deposition, although the clinical course is highly ­variable. The aim of this study was to evaluate the role of procollagen I and III propeptides in estimating collagen metabolism and its relationship to disease activity and prognosis in patients with sarcoidosis, fibrosing alveolitis and asbestos-related lung diseases.

The study included 160 patients. The levels of procollagen I carboxyterminal propeptide (PICP) and procollagen III aminoterminal propeptide (PIIINP) in serum, bronchoalveolar lavage fluid (BALF) and epithelial lining fluid (ELF) were assessed from 137 patients employing human antigens. There were 60 patients with sarcoidosis, 18 with fibrosing alveolitis and 5 with asbestosis and 17 controls. Thirty-seven patients had been exposed to asbestos, but did not show parenchymal involvement. Twenty-five of them had pleural plaques, while 12 had normal chest radiographs. Immunohistochemical stainings for procollagen I aminoterminal (PINP) and III aminoterminal propeptide were carried out on open lung biopsies of the remaining 23 of the 160 patients, of whom 13 had sarcoidosis and 10 fibrosing alveolitis. Antibodies to these procollagen peptides react with the aminoterminal domains of the corresponding propeptides intracellularly and with the respective pN-collagen in collagen fibres in the extracellular space.

Procollagen III aminoterminal propeptide was elevated in the sera of the patients with sarcoidosis and fibrosing alveolitis, but not in the asbestosis or asbestos-exposed patients as compared to the controls. The level of PIIINP in BALF was highest in sarcoidosis and second highest in fibrosing alveolitis, but hardly detectable in the other groups. BALF-PICP was higher in the patients with fibrosing alveolitis, sarcoidosis and asbestosis than in the controls. PIIINP in BALF correlated with BALF-PICP, serum angiotensin-converting enzyme (S-ACE), interleukin 2-receptor, BALF-albumin and BALF-lymphocytes and BALF-PICP had a significant correlation with BALF-albumin and BALF-lymphocytes in sarcoidosis. BALF/ELF-PICP had an inverse correlation with the specific diffusion coefficient (DLCO/VA) in fibrosing alveolitis. Both PIIINP and PICP were higher in ELF than in serum in sarcoidosis and fibrosing alveolitis and PICP was higher in ELF compared to serum in asbestosis, suggesting active local synthesis in the lower respiratory tract. The levels of PIIINP in BALF were significantly elevated in sarcoidosis patients with parenchymal involvement compared to those without. Detectable PIIINP in BALF also predicted a poor outcome in fibrosing alveolitis. BALF-PIIINP reflected the disease activity based on chest radiographs in sarcoidosis and a poor prognosis in fibrosing alveolitis, whereas BALF-PICP marked the development of fibrosis.

In lung biopsy specimens, type I and III pN-collagens were increased in fibrosing alveolitis and sarcoidosis. Type I pN-collagen was expressed in areas with damaged or deficient alveolar epithelium. Type III pN-collagen was present underneath regenerative, metaplastic alveolar and bronchiolar type epithelium and was accumulated both in the loose, newly formed fibrosis and in the denser old fibrosis. Type I procollagen was present in intracellular spots in newly formed fibrosis. In sarcoidosis, type I procollagen was present intracellularly in granulomas, whereas type III pN-collagen was expressed extracellularly around granulomas.

Dedication

To my family

Table of Contents
Acknowledgements
Abbreviations
List of original communications
1. Introduction
2. Review of the literature
2.1. Sarcoidosis
2.2. Fibrosing alveolitis
2.3. Asbestos-related lung diseases
2.4. Procollagen and collagen synthesis
2.5. Use of collagen markers in diseases
2.6. Bronchoalveolar lavage
2.6.1. Cell findings in bronchoalveolar lavage fluid
2.6.2. Soluble constituents in bronchoalveolar lavage fluid
2.7. Collagens and procollagens in immunohistochemical lung specimens
2.7.1. Normal lung
2.7.2. Sarcoidosis
2.7.3. Fibrosing alveolitis
2.8. Procollagen propeptides in bronchoalveolar lavage fluid and serum in diffuse parenchymal lung diseases
2.8.1. Sarcoidosis
2.8.2. Fibrosing alveolitis
2.8.3. Asbestos-related pulmonary disorders and other pneumoconiosis
2.8.4. Other parenchymal disorders
3. Purpose of the present study
4. Materials and methods
4.1. Study population
4.2. Methods
4.2.1. Bronchoalveolar lavage and serum (I-III)
4.2.2. Immunohistochemical methods (IV)
4.3. Statistical analysis
5. Results
5.1. Procollagen I carboxyterminal propeptide and procollagen III aminoterminal propeptide in bronchoalveolar lavage fluid and serum of sarcoidosis and fibrosing alveolitis patients (I,II)
5.2. Procollagen propeptide markers and other disease activity markers in sarcoidosis and fibrosing alveolitis (I, II)
5.3. Lung collagens in open lung biopsies in lung sarcoidosis and fibrosing alveolitis (IV)
5.3.1. Normal lung
5.3.2. Sarcoidosis
5.3.3. Fibrosing alveolitis
5.4. Procollagen I carboxyterminal propeptide and procollagen III aminoterminal propeptide in bronchoalveolar lavage fluid and serum in asbestos-related lung diseases (III)
6. Discussion
6.1. Study population
6.2. Detection of procollagens in serum, BALF and ELF
6.3. Accumulation and distribution of type I procollagen and pN-collagen in sarcoidosis and fibrosing alveolitis as detected in immunohistochemical evaluation of open lung biopsy specimens (IV)
6.4. PIIINP and PICP in serum, BALF and ELF in patients with sarcoidosis, fibrosing alveolitis and asbestos-related lung diseases (I-III)
6.5. PIIINP and PICP as possible markers of disease activity and prognosis in sarcoidosis, fibrosing alveolitis and asbestos-related lung diseases (I-III)
7. Conclusions
References
List of Tables
1. Comparison of methods for determining BALF-PIIINP in previous studies.
2. Clinical characteristics of the patients with sarcoidosis and fibrosing alveolitis and the controls (I-II).
3. Clinical characteristics of the patients exposed to asbestos fibres (III).
4. Characteristics of the patients with sarcoidosis in the immunohistochemical study (IV).
5. Characteristics of the patients with fibrosing alveolitis in the immunohistochemical study (IV).
6. The concentrations of PIIINP and PICP in serum, BALF and ELF in the patients with sarcoidosis and fibrosing alveolitis and the controls (I-II).
7. Levels of S-IL-2R, S-ACE, S-PIIINP, S-PICP, BALF-albumin, BALF-lymphocytes, BALF-PIIINP and BALF-PICP in non-parenchymal and parenchymal sarcoidosis (I).
8. Prognostic significance of BALF procollagen markers in fibrosing alveolitis (all causes of death) (II).
9. Prognostic significance of BALF procollagen markers in fibrosing alveolitis (patients who died of fibrosing alveolitis) (II).
10. Concentrations of PIIINP and PICP in serum, BALF, and ELF in the patients with asbestosis and those without parenchymal involvement (III).
List of Figures
1. Schematic presentation of the extracellular processes of collagen synthesis. Modified from Prockop & Kivirikko (1984).
2. Individual values of PICP in ELF and BALF in subjects with asbestosis, pleural plaque disease and individuals with no changes in chest radiographs. ELF-PICP was not available for one patient in pleural plaque disease group because of missing BALF-urea.
3. Individual values of PICP and PIIINP in BALF in subjects exposed to asbestos fibres without parenchymal involvement in relation to the number of asbestos bodies/ml (AB) in BALF.
  Next
  Acknowledgements

Homepage of this publication

Library Units | Collections | Databases | Library News | Library Services | Electronic Collection | Links elsewhere | Alphabetical Index

© 2000 Oulu University Library