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Progranulin is a growth and survival factor implicated in tumorigenesis and drug resistance. Several studies showed that progranulin is expressed in breast cancer tissue and inversely correlates with survival. B lymphocyte chemoattractant, also known as B cell-attracting chemokine 1 (BCA-1), is a member of the CXC subtype of the chemokine superfamily. BCA-1 is critical for secondary lymphoid tissue development and navigation of lymphocytes within the microcompartments of the tissue. There are no data on the content of progranulin and BCA-1 in bronchoalveolar lavage fluid (BALF) of non-small cell lung cancer (NSCLC) patients. To study this issue, we measured BALF content of progranulin and BCA-1 in 46 NSCLC patients before chemotherapy and 15 healthy subjects. Both markers were elevated in cancer patients compared to healthy subjects (progranulin: 61.4 (1.6-384.0) vs. 6.5 (0.6-12.9) ng/ml, p = 0.001 and BCA-1: 30.8 (24.3-70.8) vs. 15.4 (13.3-19.5) pg/ml, p = 0.0001). The cut-off BALF level concerning NSCLC vs. controls, investigated using the receiver-operating characteristic (ROC) curve, yielded 6.5 ng/ml for progranulin and 15.4 pg/ml for BCA-1. We failed to find any association between the BALF content of progranulin or BCA-1 and the stage of tumor or prospectively assessed treatment response. However, BALF progranulin associated with time to tumor progression (r = 0.61; p = 0.04). In addition, a higher BALF content of BCA-1 in NSCLC patients associated with shorter overall survival. We conclude that progranulin and BCA-1 in BALF of NSCLC patients before chemotherapy may be prognostic factors of cancer progression.

Osteoprotegerin (OPG) is a soluble decoy receptor for receptor activator of nuclear factor-kappa B ligand (sRANKL). OPG promotes endothelial cell survival and neoangiogenesis. Dysregulation of the OPG/RANKL system has been detected in several tumors. In the present study, we evaluated the clinical usefulness of OPG and sRANKL assessment in bronchoalveolar lavage fluid (BALF) of patients with advanced non-small cell lung cancer (NSCLC). We measured the concentration of OPG and sRANKL in BALF of 44 NSCLC patients and 15 healthy volunteers taken as control subjects. The OPG content was higher in the NSCLC group than that in controls [0.48 (0.12-1.45) vs. 0.23 (0.14-0.75) pmol/l; p = 0.0001]. There were no significant differences in sRANKL content between the NSCLC and control groups [1.22 (0.74-23.00) vs. 1.12 (0.79-4.39) pmol/l; p = 0.67]. However, we found that the greater the level of sRANKL in NSCLC patients, the shorter the overall survival. We found a correlation between the content of sRANKL and the percentage of lymphocytes in BALF of NSCLC patients (r = 0.52; p = 0.041). We conclude that NSCLC patients have a higher content of OPG in BALF than healthy people. A high level of sRANKL in BALF of NSCLC patients may predict worse survival.

Osteoprotegerin (OPG), a soluble tumor necrosis factor receptor family molecule, protects endothelial cells from apoptosis in vitro and promotes neovascularization in vivo. Angiogenesis may be crucial for the course and outcome of sarcoidosis. In this study, we evaluated the clinical usefulness of OPG and its ligand, a soluble receptor activator of nuclear factor-kappaB (sRANKL), in bronchoalveolar lavage fluid (BALF) in patients with sarcoidosis (BBS, Besniera-Boeck-Schaumann disease). We studied 22 BBS patients and 15 healthy volunteers as a control group. The levels of OPG, sRANKL, and interleukin-18 (IL-18) were measured by the Elisa method. The BALF levels of sRANKL and IL-18 were higher in the BBS patients compared with controls [sRANKL: 2.12 (0.82-10.23) vs. 1.12 (0.79-4.39) pmol/l, p = 0.03; IL-18: 34.29 (12.50-133.70) vs. 13.05 (12.43-25.88) pg/ml, p = 0.001]. There were no significant differences between the concentration of OPG in the BBS patients and healthy controls [0.22 (0.14-0.81) vs. 0.23 (0.14-0.75) pmol/l]. In the BBS patients we found correlations between sRANKL and IL-18 in BALF (r = 0.742, p = 0.0001) and between OPG and lung diffusing capacity for carbon monoxide (DLCO) (r = -0.528, p = 0.029). Receiver-operating characteristic (ROC) curve was applied to find the cut-off for the BALF level of sRANKL (BBS vs. healthy: 1.32 pmol/l). We conclude that OPG and sRANKL may have usefulness in clinical evaluation of BBS patients.

Hepatocyte growth factor (HGF) is involved in tumorigenesis, interleukin-20 (IL-20) is an inhibitor of angiogenesis, and interleukin-22 (IL-22) stimulates tumor growth. The aim of this study was to determine the level of HGF, IL-20, and IL-22 in both serum and bronchoalveolar lavage fluid (BALF) of non-small cell lung cancer (NSCLC) patients before onset of chemotherapy, the nature of the interrelationships between these markers, and their prognostic significance regarding post-chemotherapy survival time. We studied 46 NSCLC patients and 15 healthy subjects as a control group. We found significantly higher serum levels of HGF and IL-22 in the NSCLC patients than those in controls [pg/ml: HGF - 1911 (693-6510) vs. 1333 (838-3667), p = 0.0004; IL-22 - 10.66 (1.44-70.34) vs. 4.69 (0.35-12.29), p = 0.0007]. In contrast, concentrations of HGF and IL-22 in BALF were lower in NSCLC patients than those in controls [pg/ml: HGF - 72 (6-561) vs. 488 (14-2003), p = 0.0002; IL-22 - 2.28 (0.70-6.52) vs. 3.72 (2.76-5.64), p = 0.002]. In the NSCLC patients, there was a negative correlation between the serum level of IL-20 and time to tumor progression (r = -0.405, p = 0.04) and between the serum level of HGF and survival time (r = -0.41, p = 0.005). In addition, a higher serum level of HGF and a higher BALF level of IL-22 in patients were linked with a shorter overall survival. We conclude that HGF, IL-20, and IL-22 in the serum and BALF of NSCLC patients before chemotherapy may be a prognostic of cancer progression.

Thrombospondin-2 (TSP-2) is an endogenous negative regulator of vascularization in human cancer. TSP-2 regulates angiogenesis through binding and sequestration of the proangiogenic fibroblast growth factor-2 (FGF-2). However, it is unclear whether TSP-2 and FGF-2 are related to prognosis in non-small cell lung cancer (NSCLC). To study this issue, we measured serum (Elisa) levels of TSP-2 and FGF-2 in 40 NSCLC patients (before chemotherapy) and 22 healthy subjects. Both TSP-2 and FGF-2 concentrations were elevated in the NSCLC group compared with control (TSP-2: 26.72±8.00 vs. 18.64±5.50 ng/ml, p=0.002; FGF-2: 11.90±5.80 vs. 7.26±3.90 pg/ml, p=0.01). Receiver-operating characteristic (ROC) curves were applied to find the cut-off serum levels of TSP-2 and FGF-2 (NSCLC vs. healthy: TSP-2=15.09 ng/ml, FGF-2=2.23 pg/ml). Patients before treatment with the TSP-2 level<24.15 ng/ml had a median survival of 23.7 months, but those with TSP-2>24.15 ng/ml had only 9 months' median survival (p=0.007). Patients with FGF-2 level>11.21 pg/ml had significantly shorter survival than patients with FGF-2<11.21 pg/ml (7.5 months vs. 16 months, p=0.034). We conclude that NSCLC patients have higher serum concentrations of TSP-2 and FGF-2 than healthy people. High levels of TSP-2 and FGF-2 may predict worse survival.

Recently, it has been reported that lack of cathepsins prevent the development of lung granulomas in a mouse model of Besnier-Boeck-Schaumann (BBS) disease, sarcoidosis. There is no data about cathepsin V (Cath V) in bronchoalveolar lavage fluid (BALF) in humans. Endostatin is a novel inhibitor of lung epithelial cells. The role of this protein in BBS is not determined. The aim of this study was to evaluate the concentration of endostatin, Cath V, and IL-18 in BALF of BBS patients. We studied 22 BBS patients (Stage 2). The control group consisted of 20 healthy subjects. Cath V concentration was lower in BBS than in healthy group (16.03±8.60 vs. 32.25±21.90 pg/ml, p=0.004). Both endostatin and IL-18 levels were higher in BBS than in the control group (0.88±0.30 vs. 0.29±0.04 ng/ml, p=0.028; 40.37±31.60 vs. 14.61±1.30 pg/ml, p=0.007, respectively). In BBS there were correlations between the levels of endostatin and IL-18 (r=0.74, p=0.001) as well as endostatin and DLCO (diffusing capacity for carbon monoxide) (r=-0.6, p=0.013). Receiver-operating characteristic (ROC) curves were applied to find the cut-off for the BALF levels of Cath V, endostatin, and IL-18. We conclude that Cath V and endostatin may represent an index of pulmonary sarcoidosis activity.

Lung cancer is associated with poor prognosis. The aim of this study was to evaluate the clinical usefulness of HMGB-1 (high-mobility group protein B1) and TGF-β (transforming growth factor beta) in patients with advanced non-small cell lung cancer (NSCLC). We studied 45 patients with NSCLC prior to chemotherapy, 23 patients with Besnier-Boeck-Schaumann (BBS) disease (sarcoidosis), and 15 healthy volunteers. HMGB-1 and TGF-β levels were measured in serum and BALF samples using ELISA method. A higher serum HMGB-1 and TGF-β levels were in NSCLC patients compared with the other groups. TGF-β concentration in BALF was significantly higher in NSCLC than in healthy controls (p=0.047) but lower than in BBS (p=0.016). Serum HMGB-1 in NSCLC correlated with age and gender while its level in BALF was associated with distant metastasis. A higher levels of HMGB-1 in the serum of NSCLC patients with progressive disease was linked with shorter overall survival and disease-free survival. We found a positive correlation between HMGB-1 and TGF-β in BALF of IIIB NSCLC group and overall survival (p=0.04; p=0.003). Our findings confirmed that the measurement of HMGB-1 and TGF-β levels in serum and BALF of patients with NSCLC prior to treatment may have clinical usefulness and predict poor prognosis.

The mechanisms of sarcoidosis (Besniera-Boeck-Schaumann disease, BBS) remain incompletely understood, although recent observations suggested an important contribution of interleukin-33 (IL-33). So far, there are no data about bronchoalveolar lavage fluid (BALF) concentration of IL-33 in patients with BBS. In the present study we attempted to relate the concentration of IL-33 to IL-18, a well-known marker of BBS activity, in BALF of BBS patients. We examined 24 BBS patients (stage II). The age-matched control group consisted of 24 healthy subjects. The levels of IL-33 and IL-18 in BALF were higher in BBS patients than in the control group [IL-33: 4.8 (0.1-12.5) vs. 3.4 (0.6-56.9) pg/ml, p=0.024; IL-18: 33.2 (5.7-122.0) vs. 10.8 (1.9-45.8) pg/ml, p=0.002]. In the BBS group, the correlations between IL-33 and IL-18 (r=0.606, p=0.002), and between IL-33 and diffusion lung capacity for carbon monoxide (DLCO) (r=-0.500, p=0.035) were found. The receiver-operating characteristic curves were applied to find the cut-off serum levels of IL-33 and IL-18 in BALF (BBS vs. healthy: IL-33 2.7 pg/ml and IL-18 16.4 pg/ml). We conclude that IL-33 appears an important factor of pulmonary BBS activity.

Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), ligands for the Tie-2 receptor expressed on endothelial cells, play a critical role in angiogenesis, in concert with vascular endothelial growth factor (VEGF). Angiogenesis is important for tumor growth and development and also is implicated in the pathogenesis of interstitial lung diseases. The aim of this study was to evaluate the concentration of Ang-1, Ang-2, Tie-2, interleukin-18 (IL-18), transforming growth factor beta-1 (TGF β1), and VEGF domain in both serum and bronchoalveolar lavage fluid (BALF) of lung cancer patients before chemotherapy. We studied 45 non-small cell lung cancer (NSCLC) patients (M/F; 38/7; mean age 62 ± 4 years). The age-matched control groups consisted of 15 sarcoidosis (BBS), 15 hypersensivity pneumonitis (HP), and 15 healthy subjects. The patients with NSCLC had a significantly higher level of Ang-1 compared with the BBS and healthy subjects, and a higher level of Ang-2 compared with the healthy subjects in both serum and BALF. BALF level of IL-18 was lower in the NSCLC than that in the HP group, but higher than that in the BBS patients. Serum level of IL-18 was higher in the NSCLC than in the healthy subjects. The NSCLC group had lower VEGF in BALF than that in healthy subjects. Receiver-operating characteristics (ROC) curves were applied to find the cut-off the serum levels of Ang-1 and Ang-2 levels in BALF. We did not find any correlation between the levels of Ang-1, Ang-2, Tie-2, and the stage of tumor or treatment response (prospectively). We conclude that the angiogenic axis Ang-1 and Ang-2/Tie-2 may play an important role in lung cancer development and their concentrations may be a useful marker at the time of initial diagnosis of lung cancer.