Pneumoproteins in interstitial lung diseases

The interstitial lung diseases (ILD)s are a diverse group of pulmonary disorders that are classified together because of similar clinical, roentgenographic, physiologic, or pathologic manifestations, compromising over 100 different members that have been broadly classified into several categories. The major abnormality in ILDs is disruption of the lung parenchyma. Sarcoidosis is the commonest ILD in the western world. In our own experience, hypersensitivity pneumonitis is also quite common in the Utrecht region. The lung epithelial cells produce surfactant, mucus and several lung-epithelium-specific proteins. These lung-epithelium-specific proteins can be classified in three separate groups: the mucins, CC10, and the surfactant proteins. Some proteins that are secreted by pulmonary cells are not only present at the surface of the respiratory tract, but are also detectable in the blood. Hermans and Bernard introduced the term pneumoproteins for these markers. Because these proteins are produced in the lungs, their presence in serum can only be explained by leakage through the alveolar-capillary membrane into the vascular compartment. Biomarkers can be used to diagnose a disease, to monitor disease activity, to assess disease severity, and to predict the course of a disease. We studied these four qualities of pneumoproteins in the two most prevalent ILDs at our department (sarcoidosis and hypersensitivity pneumonitis). Although KL-6 and SP-D can help to differentiate bacterial pneumonia from ILD, pneumoproteins have little diagnostic value since these proteins are elevated in various ILDs, and, therefore, lack specificity. Pneumoproteins are for example unable to differentiate sarcoidosis from hypersensitivity pneumonitis. However, as demonstrated in this thesis, pneumoproteins can be useful to monitor ILD activity and assess disease severity. Although CC10, KL-6 and SP-D had been studied separately in sarcoidosis, we were the first to perform a comparative analysis. In sarcoidosis, CC10 and KL-6 reflected disease severity, since they both correlated with radiologic stage and pulmonary function impairment. SP-D did not seem to be useful as serum marker in sarcoidosis. In bird fanciers' lung (hypersensitivity pneumonitis), KL-6 and SP-D correlated with disease activity. Some genetic polymorphisms influence regulatory mechanisms and cause interindividual differences in protein production. A correlation between serum CC10 and SP-D, and their encoding genes had already been described. We confirmed the CC10 gene-protein association in a Dutch Caucasian population of healthy controls and sarcoidosis patients. Previous studies found a similar association for CC10 in Japanese sarcoidosis patients, and Australian asthmatic children. Furthermore, we were the first to demonstrate that serum KL-6 levels are influenced by a mucin 1 gene polymorphism, and we calculated genotype-specific reference intervals. We conclude that serum pneumoproteins are useful biomarkers for the monitoring of ILD patients. Using genotype-specific reference intervals might improve their clinical value