KL-6, surfactant protein (SP)-A, SP-D, and monocyte chemoattractant protein-1 (MCP-1) are reported to be sensitive markers for interstitial lung diseases (ILD). However, each marker has been studied independently. The aim of this study was a comparative analysis of the diagnostic values of these markers. Subjects consisted of 33 patients with ILD (21 cases of idiopathic pulmonary fibrosis and 12 associated with collagen vascular diseases) and 82 control subjects (12 cases of bacterial pneumonia and 70 healthy volunteers). Receiver operating characteristic curves revealed that KL-6 was superior to the other markers. The cut-off levels for these markers that resulted in the highest diagnostic accuracy were determined to be 465 U/ml for KL-6, 48.2 ng/ml for SP-A, 116 ng/ml for SP-D, and 1080 pg/ml for MCP-1. The sensitivity, specificity, and diagnostic accuracy were 93.9%, 96.3%, and 95.7% for KL-6; 81.8%, 86.6%, and 85.2% for SP-A; 69.7%, 95.1%, and 87.8% for SP-D; and 51.5%, 92.7%, and 80.9% for MCP-1; respectively. The serum levels of SP-A and SP-D, but not of KL-6, were significantly higher in patients with bacterial pneumonia than in healthy volunteers. These results suggest that of the markers studied, KL-6 is the best serum marker for ILD.

No abstract

KL-6, a mucin-like high-molecular-weight glycoprotein, is a serum marker indicating the disease activity of pneumonitis, such as idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis, and sarcoidosis. Immunohistochemical studies have shown that KL-6 is strongly expressed on Type 2 pneumocytes and also exists on epithelial cells in other organs. It has not been clarified whether the increased levels of KL-6 in sera from patients with pneumonitis are derived from the lower respiratory tract. In this study, KL-6 levels were evaluated in bronchoalveolar lavage fluid (BALF) samples from 9 healthy control subjects and 32 patients with interstitial pneumonitis. An abnormally high level of KL-6 in BALF was observed in 70% (7 of 10) of patients with IPF, 64% (9 of 14) of patients with sarcoidosis, and 100% (8 of 8) of patients with hypersensitivity pneumonitis but in none of the healthy control subjects. KL-6 levels in BALF were significantly correlated with numbers of total cells (p < 0.001), lymphocytes (p < 0.001), and neutrophils (p < 0.05) and with concentrations of albumin (p < 0.001) and total protein (p < 0.001) in BALF and, further, with serum KL-6 levels (p < 0.01). These results indicate that increased levels of serum KL-6 in patients with pneumonitis reflect the production levels of KL-6 derived from damaged or regenerating Type 2 pneumocytes in the lower respiratory tract.

Circulating interleukin-6 (IL-6) levels were determined using a sensitive enzyme immunoassay in adults with asthma in stable condition during naturally occurring attacks and before and after allergen inhalation tests. IL-6 was significantly elevated even in asymptomatic asthmatic subjects (n = 17) compared with normal control subjects (n = 17). During naturally occurring asthmatic attacks, serum IL-6 levels were significantly elevated in comparison with those in a symptom-free condition (4 wk interval; n = 8, p < 0.01). No significant difference was observed in serum IL-6 levels obtained from control asymptomatic asthmatic subjects during the period (n = 10). There was a significant elevation in circulating IL-6 levels in eight asthmatic patients following inhalation of allergen but not methacholine. These results suggest that IL-6 is involved in the pathophysiology of bronchial asthma.

Searching for early predictive markers of the therapeutic effects of high-dose corticosteroids ("pulse therapy") on patients with rapidly progressing idiopathic pulmonary fibrosis (IPF), we evaluated 14 such patients, who had received weekly pulse therapy for at least 3 wk. Eight patients responded to the treatment and survived. However, six patients failed to respond, and all of them died within 3 mo after treatment. Serum levels of KL-6 (MUC1 mucin), neutrophil elastase (NE), and lactate dehydrogenase (LDH) were measured before, and at 1 wk and 3 wk after treatment. Levels of KL-6 decreased significantly in patients who lived, whereas KL-6 levels tended to increase in patients who died. The values of NE did not change significantly. LDH levels decreased significantly at 1 wk, and tended to decrease at 3 wk in patients who lived. However, in patients who died, they did not significantly change. At the first cycle of treatment when clinical effects may not be evident, the decrease in KL-6 but not LDH levels was significantly related to a favorable outcome, whereas their increase was related to a poor outcome. Results suggest that monitoring with KL-6 may contribute to early clinical decisions for alternative therapy in the management of rapidly progressing IPF.

KL-6 in serum and bronchoalveolar lavage fluid has been reported to be a sensitive marker indicating the activity of fibrosing lung diseases. The molecule is clustered in MUC1 mucin according to the findings of immunohistochemical and cytometric studies. To elucidate the pathogenic role of KL-6 in fibrosing lung disease, we characterized its biochemical properties and examined whether purified KL-6 is chemotactic for human fibroblasts in vitro using modified Boyden chambers. Biochemical properties of purified KL-6 were similar to those of other MUC1 mucins previously reported. KL-6 promoted the migration of 5 of 5 human lung fibroblasts and 3 of 4 human skin fibroblasts. Checkerboard analysis revealed that KL-6 was chemotactic as well as chemokinetic. Though platelet-derived growth factor, fibroblast growth factor, or fibronectin were also chemotactic for fibroblasts in the experimental system, only fibronectin augmented KL-6-induced chemotaxis. These observations indicate that KL-6 is one of the chemotactic factors for most fibroblasts and that the increased KL-6 in the epithelial lining fluid in small airways may cause the intra-alveolar fibrosis in fibrosing lung diseases.

Our findings indicate that beta-blockers have an important immunoregulatory role in modifying the dysregulated cytokine network in DCM. This effect of beta-blockers may be partly responsible for the efficacy of therapeutic drugs for heart failure.

1. This study was conducted to assess the role of artrial and brain natriuretic peptides during acute myocardial ischaemia associated with dynamic exercise. 2. Study subjects consisted of 35 angiographically proven patients with angina pectoris and 35 angiographically normal control subjects. All subjects underwent 201Tl dynamic exercise testing. The presence and localization of the exercise-induced acute myocardial perfusion defect were assessed by 201Tl single-photon emission computed tomography. The severity score was calculated using the early image for quantitative assessment of the acute myocardial perfusion defect. 3. Plasma levels of atrial natriuretic peptide increased from 21.3 +/- 3.8 to 72.2 +/- 26.7 pg/ml (P < 0.01) in the angina pectoris group, and increased from 19.4 +/- 2.4 to 36.4 +/- 17.4 pg/ml (P < 0.01) in the control group during dynamic exercise. Plasma levels of brain natriuretic peptide increased from 2.8 +/- 0.8 to 6.9 +/- 2.6 pg/ml (P < 0.01) in the angina pectoris group, but did not change significantly in the control group (from 2.7 +/- 0.7 to 2.9 +/- 1.0 pg/ml) during dynamic exercise. At peak exercise, plasma levels of these natriuretic peptides in the angina pectoris group were significantly higher than those in the control group (P < 0.01). 4. At peak exercise, there were correlations between the plasma level of atrial natriuretic peptide and heart rate in both the angina pectoris and control groups (P < 0.01, r = 0.46; P < 0.01, r = 0.51, respectively), but no significant correlations between the plasma level of brain natriuretic peptide and heart rate in either group. The plasma levels of these peptides at peak exercise correlated well with the severity score in the angina pectoris group (atrial natriuretic peptide, r = 0.71, P < 0.01; brain natriuretic peptide, r = 0.69, P < 0.01).