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The combined pulmonary fibrosis and emphysema (CPFE) was reported first in 1990, but it has been comparatively underestimated until recently. Although the diagnostic findings of both emphysematous and fibrotic regions are detectable by high-resolution computed tomography (HRCT) of the chest, the degree of progressive fibrosis, which increases with emphysematous lesions, is difficult to evaluate. In this study, we hypothesized that the biomarkers for pulmonary fibrosis, surfactant protein D (SP-D), and KL-6 would serve as good indicators of fibrotic lesions in CPFE. We recruited 46 patients who had been diagnosed in our hospital with both emphysema and fibrosis by their CT scan image from April 2003 to March 2008. The correlation among their pulmonary function tests, composite physiologic index (CPI), and the serum levels of SP-D and KL-6 was evaluated. We found a correlation between KL-6 and %VC, %TLC, or CPI and between SP-D and %VC or CPI. Interestingly, the combined product of KL-6 and SP-D (KL-6xSP-D) was found to highly correlate with %VC and %TLC or CPI. These results show that both KL-6 and SP-D, and especially the product of SP-D and KL-6, are good indicators of the presence of fibrotic lesions in the lungs of CPFE patients.

Both SP-D and KL-6/MUC1 are established biomarkers of the interstitial pneumonias, including idiopathic pulmonary fibrosis (IPF), but the causes and clinical outcomes based on their independent effects are not known. Eleven asymptomatic patients, detected with honeycombing on high-resolution computed tomography (HRCT), were compared with 17 other IPF outpatients having slight respiratory symptoms and honeycombing as well. Although SP-D was increased in both groups, KL-6 was significantly higher in the symptomatic IPF group. When the patients (n=11) having both biomarkers elevated were compared with the other patients (n=6) with only SP-D elevated, the distribution of fibrotic lesions with honeycombing on HRCT was larger and the survival time was shorter in the patients having both biomarkers elevated. Immunohistochemical analysis also differentiated these biomarkers in the lung. These results suggest both a cause and the prognostic value of dissociation of these biomarkers.

The pathogenesis of acute exacerbation of idiopathic pulmonary fibrosis (IPF) remains to be elucidated. To evaluate the roles of inflammatory mediators in acute exacerbation, the concentrations of high mobility group protein B1 (HMGB1), a chief mediator of acute lung injury, and 18 inflammatory cytokines were measured in the bronchoalveolar lavage fluid, serially sampled from seven IPF patients after the onset of acute exacerbation. HMGB1 gradually increased in the alveolar fluid after the onset of acute exacerbation, in positive correlation with monocytes chemotactic protein-1 (MCP-1), a potent fibrogenic mediator. In the lung tissues of eight IPF patients autopsied after acute exacerbation, intense cytoplasmic staining for HMGB1 was observed in the alveolar epithelial cells in alveolar capillary augmented lesions, where the capillary endothelial cells remarkably reduced the expression of thrombomodulin, an intrinsic antagonist of HMGB1. These results suggest pathogenic roles for HMGB1 and MCP-1 in the late phase of acute exacerbation of IPF.