No abstract

The aim of this study was to examine the clinical characteristics, the histological features and the renal expression of vascular endothelial growth factor (VEGF) of five patients with sirolimus-associated thrombotic microangiopathy (TMA). Sirolimus-induced TMA occurs preferentially in kidneys with concomitant endothelial injury: it was observed in three patients with acute cellular rejection on calcineurin inhibitor-free regimen, in one patient with chronic graft rejection on a calcineurin inhibitor-free protocol and in one patient with chronic calcineurin inhibitor nephrotoxicity. We found that renal VEGF expression during sirolimusinduced TMA was significantly lower than VEGF expression in normal transplanted kidneys (p < 0.01). Decreased expression of VEGF seems to be a consequence of sirolimus treatment since (i) analysis of two biopsies performed after the switch of sirolimus to calcineurin inhibitor showed reappearance of VEGF expression, (ii) no decreased expression of VEGF was found in five kidneys with classical TMA and, (iii) an increased expression of VEGF was observed in seven kidneys with acute cellular rejection on a sirolimus-free immunosuppressive regimen (p < 0.01). The potential role of sirolimus-induced downregulation of VEGF as a predisposing factor to the development of TMA is discussed.

Cystic lung light chain deposition disease (CL-LCDD) is a recently described rare disorder characterised by numerous cysts and diffuse monoclonal nonamyloid light chain deposits surrounded by macrophagic giant cells. The mechanisms responsible for cyst development remain unknown.The objectives of the present study were to analyse the major components of the pulmonary extracellular matrix in CL-LCDD and to determine the influence of metalloproteinases (MMPs) by comparison with other cystic lung disorders.A virtually complete degradation of the elastic network was found in CL-LCDD. To a lesser degree, loss of fibrillar and basement membrane collagens was also observed. Macrophagic giant cells expressed MMP-1, MMP-2, MMP-9, MMP-12 and MMP-14 and in situ zymography highlighted a strong gelatinolytic activity. As in CL-LCDD, cystic lesions in Langerhans' cell histiocytosis (LCH) and lymphangioleiomyomatosis (LAM) were characterised by the lack of elastic fibres. Similarly, MMP were expressed in CL-LCDD and LCH but the labelled cells were different. In contrast, few MMPs were detected in LAM.In conclusion, elastolysis is common to cystic lung light chain deposition disease and other cystic lung disorders, suggesting its implication in cyst formation. Moreover, in cystic lung light chain deposition disease, a role of metalloproteinases in elastolysis is strongly indicated by the metalloproteinase expression and activity pattern.

Chronic obstructive pulmonary disease (COPD) is a major economic and social concern worldwide because of its impact on mortality and morbidity [1]. COPD is characterised by airway epithelium remodelling, a hallmark of dysregulated airway epithelium plasticity [2]. There are currently no available therapeutics to restore the integrity and functionality of the epithelium. Therefore, novel sources of investigation are becoming crucial to understand the alterations at the root of COPD initiation. Non-motile primary cilia are solitary sensor organelles playing a critical role in cell cycle control, proliferation, polarity and differentiation, particularly of ciliated cells possessing motile cilia [3, 4]. Primary cilia are assembled on different types of human cells depending on their state and activities in response to cellular quiescence where they relay extracellular signals and retract upon cell cycle re-entry [5]. Alterations of primary cilium structure and function are responsible for ciliopathies [6, 7]. Primary cilia may be crucial in determining outcomes during airway epithelial cell differentiation thus we hypothesised that primary cilia are present in adult epithelial cells and may play a key role in airway plasticity. First, we investigated the presence and localisation of primary cilia in the bronchial epithelium. Secondly, we analysed the relationships between primary cilia and clinical, functional and histological characteristics of non-COPD and COPD patients.