Proteome analysis of bronchoalveolar lavage in pulmonary langerhans cell histiocytosis

Abstract

BackgroundPulmonary Langerhans-cell histiocytosis (PLCH) is a rare interstitial lung disease characterized by clusters of Langerhans cells, organized in granulomas, in the walls of distal bronchioles. It is a diffuse lung disease related to tobacco smoking but otherwise of unknown etiopathogenesis.MethodsIn this study we used a proteomic approach to analyze BAL protein composition of patients with PLCH and of healthy smoker and non-smoker controls to obtain insights into the pathogenetic mechanisms of the disease, to study the effect of cigarette smoking on susceptibility to PLCH and to identify potential new biomarkers.ResultsTwo-dimensional electrophoresis and image analysis revealed proteins that were differently expressed (quantitatively and qualitatively) in the three groups of subjects. The proteins were identified by mass spectrometry and have various functions (antioxidant, proinflammatory, antiprotease) and origins (plasma, locally produced, etc.). Many, such as protease inhibitors (human serpin B3) and antioxidant proteins (glutathione peroxidase and thioredoxin) are already linked to PLCH pathogenesis, whereas other proteins have never been associated with the disease. Interestingly, numerous proteolytic fragments of plasma proteins (including kininogen-1 N fragments and haptoglobin) were also identified and suggest increased proteolytic activity in this inflammatory lung disease. Differences in protein expression were found between the three groups and confirmed by Principal Component Analysis (PCA).ConclusionAnalysis of BAL proteomes of PLCH patients and of smoker and non-smoker controls also proved to be useful for researching the pathogenetic mechanisms and for identifying biomarkers of this rare diffuse lung disease.

Intriguing bronchoalveolar lavage proteome in a case of pulmonary langerhans cell histiocytosis

“…A previous study of the BALF proteome in PLCH [19] reported much more discrete alterations than in our case. The reason for this is unclear, but it might well be that our patient was more seriously ill at the time of investigation.…”

“…This notion is supported by the great number of inflammatory cells found in the BALF. Moreover, the proteolytic activity due to inflammation has been reported to be increased in the PLCH lung [19], which might explain the great loss of anti-inflammatory and protective proteins and the low concentration of protein found in the BALF of the present PLCH case. Thus, the intriguing BALF proteome as shown in the present case opens up new lines of research into the pathophysiology of PLCH and how its pathogenesis differs from that in COPD.…”

Susceptibility to COPD: Differential Proteomic Profiling after Acute Smoking

“…The differential SerpinB3 and Uteroglobin response on smoking between the two young groups suggests that these proteins might be crucial for the very first steps towards COPD, given its modulatory function in inflammation and fibrosis [27] and release of lysosomal proteinases from damaged epithelial cells [34]. SerpinB3 concentrations have been shown to be higher in bronchoalveolar lavage fluid of smokers than non-smokers [35]. It was therefore an unanticipated observation that the expression of this protective protein was not restored to baseline 24 hours after acute smoke exposure in non-susceptible individuals, in contrast to the susceptible individuals.…”

Cystic lung disease

“…Other mediators such as metalloproteinases have been implicated in tissue remodelling, cyst formation and fibrosis, and osteopontin, a glycoprotein with cytokine properties and pro-chemotactic activity for macrophages, monocytes, Langerhans cells and dendritic cells, has been shown to be upregulated in patients with PLCH 6. Proteome analysis of bronchoalveolar lavage7 promises to provide valuable information about pathogenetic mechanisms and biomarkers in PLCH. A recent study found BRAF V600E mutations in concurrent nodules from two of five patients,8 supporting the hypothesis that PLCH is a clonal proliferation, and that targeted therapies may be indicated in some patients.…”