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Abstract
Lymphangioleiomyomatosis (LAM) is a rare and progressive cystic lung condition affecting approximately 3.4–7.5/million women, with an average lag time between symptom onset and diagnosis of upwards of 4 years. The aim of this work was to identify altered proteins in LAM serum which may be potential biomarkers of disease. Serum from LAM patient volunteers and healthy control volunteers were pooled and analysis carried out using quantitative 4-plex iTRAQ technology. Differentially expressed proteins were validated using ELISAs and pathway analysis was carried out using Ingenuity Pathway Analysis. Fourteen proteins were differentially expressed in LAM serum compared to control serum (p<0.05). Further screening validated the observed differences in extracellular matrix remodelling proteins including fibronectin (30% decrease in LAM, p = 0.03), von Willebrand Factor (40% reduction in LAM, p = 0.03) and Kallikrein III (25% increase in LAM, p = 0.03). Pathway networks elucidated the relationships between the ECM and cell trafficking in LAM. This study was the first to highlight an imbalance in networks important for remodelling in LAM, providing a set of novel potential biomarkers. These understandings may lead to a new effective treatment for LAM in the future.
Highlights
Lymphangioleiomyomatosis (LAM) is a progressive cystic lung condition that affects women of child bearing age, with the average age at diagnosis being 35 years [1]
Ethics Statement Serum was collected from LAM patients and healthy controls according to ethical guidelines approved by The University of Sydney Human Research Ethics Committee and participating hospitals
The experimental workflow for the isobaric tags for relative and absolute quantification (iTRAQ) experiments and subsequent validation is illustrated in Fig. 1, whereby two groups of LAM serum were each pooled (n = 3, n = 5) and complexed with two reporter iTRAQ labels (114 and 115, respectively) and the same was done with two groups of healthy control samples (n = 5, n = 5) which were labelled with the reporter ions 116 and 117, respectively
Summary
Lymphangioleiomyomatosis (LAM) is a progressive cystic lung condition that affects women of child bearing age, with the average age at diagnosis being 35 years [1]. There are a few known cases of LAM occurring sporadically in males [3], as well as some males with TSC but LAM [4] is generally a complex and multifactorial disease of females. The first official guidelines for diagnosis were published by the European Respiratory Society (ERS) LAM task force in 2010. These state that an individual with ‘definite’ LAM will have characteristic HRCT and a pathological biopsy or characteristic HRCT with angiomyolipoma, chylous effusion, lymphangiomyoma and definite or probable TSC [9]. The only potential indicative biomarker for LAM that exists is vascular endothelial growth factor-D (VEGF-D); it has been found that serum levels of VEGFD are elevated in some patients with LAM [10]. There have been no high-throughput proteomic studies of LAM serum content compared to age and gender matched healthy control serum previously
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