Prognostic significance of surfactant protein A, surfactant protein D, Clara cell protein 16, S100 protein, trefoil factor 3, and prostatic secretory protein 94 in idiopathic pulmonary fibrosis, sarcoidosis, and chronic pulmonary obstructive disease.
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Identification of serum and bronchoalveolar lavage fluid (BALF) biomarkers may facilitate diagnosis and prognostication in various lung disorders.Serum and BALF levels of surfactant protein A (SP-A), surfactant protein D (SP-D), Clara cell protein 16 (CC16), S100 protein, trefoil factor 3 (TFF3), and prostatic secretory protein 94 (PSP94) were evaluated in 94 consecutive patients (idiopathic pulmonary fibrosis (IPF; n=18), sarcoidosis (n=25), chronic obstructive pulmonary disease (COPD; n=51)), and in 155 healthy controls.Biomarkers were measured at diagnosis and compared with disease characteristics. Both uniparametric and multiparametric analyses were used.Seven significant correlations were found: 1) BALF PSP94 level correlated with prognosis of sarcoidosis (P=0.035); 2) BALF SP-D level with pulmonary functions in IPF (P=0.032); 3) BALF SP-D and TFF3 with IPF mortality (P=0.049 and 0.017, respectively); 4) serum TFF3 level with COPD mortality (P=0.006,); 5) serum SP-A with pulmonary functions impairment in IPF (P=0.011); 6) serum SP-D level was associated with HRCT interstitial score in IPF (P=0.0346); and 7) serum SP-A was associated with staging of COPD according to spirometry (P<0.001). Moreover, our analysis showed that some biomarker levels differed significantly among the diseases: 1) BALF SP-D level differed between sarcoidosis and IPF; 2) serum SP-A level differed among IPF, sarcoidosis, COPD and was also different from healthy controls; 3) serum S100A6, S100A11 levels differed among IPF, sarcoidosis, COPD from healthy controls 4) serum SP-D, CC16, TFF-3 levels distinguished IPF patients from healthy controls; and 5) serum CC16, TFF3, PSP94 distinguished COPD patients from healthy controls. Our study shows that some of selected biomarkers should have prognostic value in the analysed lung disorders. On the other hand, these biomarkers do not appear to be unequivocally suitable for differential diagnosis of these disorders.Keywords:
Surfactant protein D
Surfactant protein A
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Abstract The lung is continuously exposed to inhaled pollutants, microbes and allergens. Therefore, the pulmonary immune system has to defend against harmful pathogens, while an inappropriate inflammatory response to harmless particles must be avoided. In the bronchoalveolar space this critical balance is maintained by innate immune proteins, termed surfactant proteins. Among these, surfactant protein D (SP‐D) plays a central role in the pulmonary host defence and the modulation of allergic responses. Several human lung diseases are characterized by decreased levels of bronchoalveolar SP‐D. Thus, recombinant SP‐D has been proposed as a therapeutical option for cystic fibrosis, neonatal lung disease and smoking‐induced emphysema. Furthermore, SP‐D serum levels can be used as disease activity markers for interstitial lung diseases. This review illustrates the emerging role of SP‐D translated from in vitro studies to human lung diseases.
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Surfactant protein A
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In interstitial pulmonary diseases investigations are conducted to find markers of the activity of the interstitial processes so that noninvasive monitoring of the disease might be possible. In 188 patients divided into 9 groups: 42 with active sarcoidosis, 24 with inactive sarcoidosis, 16 with active sarcoidosis treated with steroids and 22 with inactive sarcoidosis after corticotherapy, 17 with avian fanciers' lung exposed to the antigen, 16 with avian fanciers' lung after a year interval in exposure to the antigen, 20 with advanced and 13 with moderate idiopathic pulmonary fibrosis, and 18 healthy persons the BAL was performed. In the BALF concentrations of protein and phospholipids were assayed by colorimetric method. The results indicate usefulness of the studied biochemical parameters in BALF in evaluation of the activity of interstitial pulmonary diseases. Significant differences were found between the results in the active group of patients compared to the control group and to the inactive forms of interstitial pulmonary diseases. Particularly valuable is phospholipids to protein concentration ratio in BALF.
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Bronchoalveolar lavage (BAL) is a diagnostic tool often used during the management of interstitial lung diseases (ILD). However, its diagnostic value in discrimination between entities comprising the very heterogenous group of ILD, is still a controversial issue. The objective of our study is to assess the diagnostic value of BAL in the management of ILD, by comparing the cytological findings in BAL fluid among the different diseases of this group.It was a retrospective, observational study of 151 patients between January 2012 and December 2015. BAL fluid cytology was performed to analyse the distribution of leucocytes population subsets in patients with ILD.The mean age was 52.78 years; 74.83% were women. The analysis of the following main groups of diseases was performed : sarcoïdosis (n = 30), idiopathic pulmonary fibrosis (IPF; n = 22), other idiopathic interstitial pneumonia (non specific interstitial pneumonia, cryptogenic organising pneumonia and respiratory bronchiolitis interstitial lung disease; n = 20) and connective tissue disease (n = 14). Overall, out of 141 patients, 22% had sarcoïdosis, 15.6% had idiopathic pulmonary fibrosis (IPF), 14.18% had other idiopathic interstitial pneumonia (IIP) and 9.9% had connective tissue disease (CTD). Mixed alveolitis was common in the 4 groups, sarcoïdosis had higher proportion of lymphocytes and IPF had higher neutrophils count. However, there was no significant statistical difference of BAL cellular count among these diseases (p > 0.05). Also, the prevalence of studied diseases did not change with variation of BAL cellular count (p > 0.05).Alone, the BAL cytological analysis has a limited value to provide substantial information that could lead to discriminate between diseases that form ILD. Thus, it must be always associated with other diagnostic methods.
Idiopathic interstitial pneumonia
Usual interstitial pneumonia
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Microarray studies have shown that matrilysin or matrix metalloproteinase (MMP)‐7 is highly upregulated in the lungs of patients with idiopathic pulmonary fibrosis (IPF), but MMP‐7 protein expression has not been systematically compared between IPF and other interstitial lung diseases. MMP‐7 levels in bronchoalveolar lavage fluid (BALF) were compared to corresponding samples from nonspecific interstitial pneumonia (NSIP), sarcoidosis, and healthy controls. MMP‐7 levels in the BALF were determined by ELISA and localization of MMP‐7 in the lung tissue by immunohistochemistry. MMP‐7 was similarly elevated in the BALF of all these disorders compared to healthy controls (p=0.007). Even control subjects with prolonged cough displayed a tendency towards elevated MMP‐7 expression. There was a negative correlation between BALF MMP‐7 levels and forced expiratory vital capacity (r=−0.348, p=0.02, n=42). In IPF lung, MMP‐7 immunoreactivity appeared predominantly in the fibrotic parenchyma and arterial wall. In sarcoidosis and NSIP, prominent MMP‐7 immunoreactivity was found in areas of inflammation. These results demonstrate that elevated BALF MMP‐7 is not restricted to IPF alone but is also observed in other interstitial lung diseases and cannot be used as a differential diagnostic marker for IPF.
Matrilysin
Idiopathic interstitial pneumonia
Usual interstitial pneumonia
Parenchyma
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DLCO
Pulmonary Diffusing Capacity
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Recently, we published an analytical two-dimensional electrophoresis (2-DE) protein map of human bronchoalveolar lavage fluid (BALF) using a pool of BALFs from various patients. In this report, the effect of lung disorders on the protein composition of the lung epithelial lining fluid was investigated by 2-DE of BALFs from individual patients with well-defined interstitial lung diseases: sarcoidosis, idiopathic pulmonary fibrosis (IPF) and hypersensitivity pneumonitis (HP), using improved experimental conditions. On these gels, about 600-1000 stained protein spots could be identified in a BALF sample containing 25 microg of protein, and our original human BALF protein database has, therefore, been considerably extended. Altogether, 429 protein spots corresponding to 66 different proteins (including isoforms, protein subunits and fragments) were identified by microsequence analysis and by matching with a human blood plasma 2-DE protein map available in the SWISS-2DPAGE database. A human 2-DE BALF database was established and is available on the World Wide Web (http://www.umh.ac.be/-biochim/proteomic.htm+ ++). The significance of the modifications observed between the different lung pathologies is discussed with the aim of understanding the mechanistic bases of lung disease pathogenesis and finding new potential lung markers of disorders.
Hypersensitivity pneumonitis
Human lung
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Identification of serum and bronchoalveolar lavage fluid (BALF) biomarkers may facilitate diagnosis and prognostication in various lung disorders.Serum and BALF levels of surfactant protein A (SP-A), surfactant protein D (SP-D), Clara cell protein 16 (CC16), S100 protein, trefoil factor 3 (TFF3), and prostatic secretory protein 94 (PSP94) were evaluated in 94 consecutive patients (idiopathic pulmonary fibrosis (IPF; n=18), sarcoidosis (n=25), chronic obstructive pulmonary disease (COPD; n=51)), and in 155 healthy controls.Biomarkers were measured at diagnosis and compared with disease characteristics. Both uniparametric and multiparametric analyses were used.Seven significant correlations were found: 1) BALF PSP94 level correlated with prognosis of sarcoidosis (P=0.035); 2) BALF SP-D level with pulmonary functions in IPF (P=0.032); 3) BALF SP-D and TFF3 with IPF mortality (P=0.049 and 0.017, respectively); 4) serum TFF3 level with COPD mortality (P=0.006,); 5) serum SP-A with pulmonary functions impairment in IPF (P=0.011); 6) serum SP-D level was associated with HRCT interstitial score in IPF (P=0.0346); and 7) serum SP-A was associated with staging of COPD according to spirometry (P<0.001). Moreover, our analysis showed that some biomarker levels differed significantly among the diseases: 1) BALF SP-D level differed between sarcoidosis and IPF; 2) serum SP-A level differed among IPF, sarcoidosis, COPD and was also different from healthy controls; 3) serum S100A6, S100A11 levels differed among IPF, sarcoidosis, COPD from healthy controls 4) serum SP-D, CC16, TFF-3 levels distinguished IPF patients from healthy controls; and 5) serum CC16, TFF3, PSP94 distinguished COPD patients from healthy controls. Our study shows that some of selected biomarkers should have prognostic value in the analysed lung disorders. On the other hand, these biomarkers do not appear to be unequivocally suitable for differential diagnosis of these disorders.
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Surfactant protein A
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Background: Surfactant protein (SP)-A and SP-D are useful biomarkers for the diagnosis and evaluation of activity of interstitial lung diseases. SP-A and SP-D, which are lung specific proteins, belong to a subgroup of the C-type lectin superfamily. It has been reported that those proteins play important roles in fibrotic lung. Although they are mainly produced by type II pneumocytes and clara cells, it is not clarified these production and clearance in fibrotic lung. Methods: To elucidate those issues, we measured levels of SP-A, SP-D and KL-6 by enzyme-linked immunosorbent assay in BAL fluid (BALF) and serum of 24 IPF patients, 36 NSIP patients (8 patients diagnosed by surgical biopsy, 28 patients clinically diagnosed) and 17 sarcoidosis patients. The levels of SP-A and SP-D in BALF were compared with those from 20 healthy controls. We investigated also the relationship of protein levels between serum and BALF. Results: In IPF and NSIP patients, SP-D levels in BALF were significantly lower than those from healthy controls (p=0.006 and p=0.003) and sarcoidosis patients (p=0.02 and p=0.01). SP-A levels in BALF were no significant difference among these patients and controls. The significant positive correlation of SP-D levels between serum and BALF was found in IPF patients (r=0.529, p=0.008). In NSIP patients, the correlation of SP-D levels between them was not significant. No correlation of SP-A levels between serum and BALF was observed in any patients groups. Conclusion: In IPF patients, SP-D levels in BALF were lower than those in healthy controls and had significant positive correlation with those in serum.
Surfactant protein D
Surfactant protein A
Lung biopsy
Idiopathic interstitial pneumonia
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Bronchoalveolar lavage (BAL) is a useful diagnostic tool in interstitial lunge diseases (ILD). However, differential cell counts are often non specific and immunocytochemistry is time consuming. Staining of glyoproteins by periodic acid Schiff (PAS) reaction may help in discriminating different forms of ILD. In addition, PAS staining is easy to perform. BAL cells from patients with idiopathic pulmonary fibrosis (IPF) (n = 8), sarcoidosis (n = 9), and extrinsic allergic alveolitis (EAA) (n = 2) were investigated. Cytospins from BAL cells were made and cells were stained using Hemacolor quick stain and PAS staining. Lymphocytic alveolitis was found in sarcoidosis and EAA whereas in IPF both lymphocytes and neutrophils were increased. PAS positive cells were significantly decreased in EAA compared to IPF and sarcoidosis (25.5% ± 0.7% vs 59.8% ± 25.1% and 64.0% ± 19.7%, respectively) (P < 0.05). No significant correlation between PAS positive cells and inflammatory cells was observed. These results suggest that PAS staining of BAL cells may provide additional information in the differential diagnosis of ILD. Further studies ware warranted to evaluate PAS staining in larger numbers of BAL from patients with ILD.
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Extrinsic Allergic Alveolitis
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In interstitial lung disease, the number of alveolar macrophages (AMs) can be increased. This may be caused by recruitment of precursor cells from peripheral blood and/or local proliferation in the lung. We therefore analysed proliferation, by studying both the expression of the nuclear proliferation antigen, Ki67, and the deoxyribonucleic acid (DNA) content, using the Feulgen reaction followed by cytometry. The patients had interstitial lung disease, i.e. sarcoidosis (n = 20), extrinsic allergic alveolitis (n = 20), idiopathic lung fibrosis or lung involvement in collagen-vascular disease (n = 19). In all patient groups there was a significant increase in proliferating AMs compared to healthy controls (4.2 versus 1.4% Feulgen, 2.1 versus 0.5% Ki67), with a significant correlation between these two parameters. A positive correlation was also found in bronchoalveolar lavage (BAL) between numbers of lymphocytes and proliferating cells in sarcoidosis and in fibrosis. In fibrosis, numbers of eosinophils and proliferating cells were also positively correlated. Our main finding was, however, a positive correlation between numbers of proliferating cells (Feulgen) and lung function parameters, especially vital capacity and oxygen tension (PO2) at rest, in patients with sarcoidosis and lung fibrosis. By contrast, in extrinsic allergic alveolitis, no correlation could be observed between proliferating cells and cell population or lung function. Our results suggest that local proliferation of macrophages is an important element in interstitial lung disease.
Extrinsic Allergic Alveolitis
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