Chapter 1. Introduction

Interstitial lung diseases comprise a heterogeneous group of disorders of the lower ­respiratory tract. This clinical entity includes numerous diseases, such as sarcoidosis, fibrosing alveolitis, hypersensitivity pneumonitis of various causes, pulmonary involvement related to autoimmune diseases, collagen vascular diseases, asbestosis and other pneumoconiosis. They are characterised by both acute and chronic inflammation and a generally irreversible process of fibrosis within the interstitium and the alveolar spaces. A typical feature of interstitial lung disease is intra-alveolar and interstitial accumulation of inflammatory cells, principally neutrophils and macrophages and, less frequently, immunologically active cells. The alveolar epithelium becomes damaged and denuded, ­progressing towards damage of the basement membrane (BM) in association with the activation of inflammatory and immune effector cells. Matrix proteins, such as ­hyaluronan, are released in a soluble form from the interstitium and accumulate in the alveolar spaces. These events lead to collapse and fusion of the alveolar units, and to a fibrotic response that results in increased collagen synthesis in interstitial and ­intra-alveolar fibroblasts. This finally causes a loss of function in the gas exchanging units and, ultimately, respiratory failure. (Chan et al. 1998).

Pulmonary fibrosis starts with the accumulation of type III collagen, which is later largely replaced by type I collagen and the formation of tight collagen fibres (Bateman et al. 1981, Kirk et al. 1984). Previous measurements of collagen metabolism have ­indicated that procollagen III aminoterminal propeptide (PIIINP) reflects the synthesis of type III collagen, although it can, to some extent, indicate degradation of collagen III fibres. Procollagen I carboxyterminal propeptide (PICP) reflects the synthesis but not the degradation of type I collagen fibres. (Risteli & Risteli 1995). Thus, measurement of procollagen propeptides as well as other markers of collagen metabolism (e.g. unique enzymes of collagen metabolism, such as prolyl hydroxylase and galactosyl hydroxylysyl glucosyltransferase) would offer theoretically methods for evaluating collagen metabolism and the development of fibrosis. Previous studies on procollagen III aminoterminal propeptide in fibrosing alveolitis and sarcoidosis have yielded divergent results. All but one of them have been carried out with antibodies against bovine PIIINP, which has been shown to be less specific to PIIINP than human antibodies with intra- and interassay ­variation of 10-25% (Risteli & Risteli 1990).

Fiberoptic bronchoscopy and bronchoalveolar lavage (BAL) offer an easy and non-invasive method to obtain cells and fluid from lung parenchyma (Davis 1994). Cell-differential counting in bronchoalveolar lavage fluid (BALF) may also help in the differential diagnosis for instance neutrophilia in BALF suggests fibrosing alveolitis, whereas an excessive amount of lymphocytes suggests sarcoidosis or allergic alveolitis (Taskinen et al. 1994).

Sarcoidosis causes granulomatous inflammation in various organs, although the lung is the organ most frequently affected (Stirling et al. 1998). The prognosis is good in most cases, and most patients recover completely even without any treatment. However, 10-20% of the sarcoidosis patients are at risk for developing progressive pulmonary fibrosis (Selroos 1969, Crystal et al. 1984). Several markers of disease activity have been ­suggested, but the results have been inconclusive. The only routine tests to stage the activity of sarcoidosis have been suggested to be clinical investigation, chest radiography and lung function testing. (Costabel et al. 1994). Fibrosing alveolitis can be idiopathic (King 1998) or associated with various connective tissue diseases (de Andrade & Kennedy 1999, Kelly 1999). The presentation of idiopathic fibrosing alveolitis is insidious in most patients, involving a progressive course of several years, but the onset can also be acute and fulminant. A favourable response to medication, most commonly corticosteroids or cytotoxic therapy, is only seen in one third of the patients. (Katzenstein & Myers 1998). There is no single reliable prognostic factor indicative of the activity of fibrosing alveolitis. The follow-up of these patients is based on spirometry and diffusion capacity values as well as changes in chest radiography and occasionally high-resolution computed tomography (HRCT) of the lungs (Johnston et al. 1999). Exposure to asbestos fibres may lead to hyaline plaques of parietal pleura, asbestos pleurisy, asbestosis and malignant diseases of the lower respiratory tract and the pleura. Pleural plaques do not cause impairment of respiratory capacity, whereas asbestosis leads to slowly progressive pulmonary fibrosis caused by asbestos fibres with a latency of 15-20 years from the first exposure to asbestos (Becklake 1987). It is not known, which individuals in an exposed population tend to develop fibrosis.

Interstitial lung diseases that lead to pulmonary fibrosis cause permanent impairment of pulmonary capacity, respiratory failure and ultimately death. So far, no reliable methods to predict the course of these diseases are available. The role of procollagen III propeptide has been widely studied, but the results have been conflicting, although there is some evidence that elevated levels of procollagen III aminoterminal propeptide in BALF and serum might correlate with active disease. The information available on procollagen I propeptides is limited.

The present study was undertaken to investigate the procollagen propeptide markers of type I and III collagen in sarcoidosis, fibrosing alveolitis and asbestos-related diseases and to assess their role in predicting the prognosis of these diseases.