Elevated Circulatory Levels of Microparticles Are Associated to Lung Fibrosis and Vasculopathy During Systemic Sclerosis

Abstract

Background: Microparticles (MPs) are vesicular structures that derive from multiple cellular sources. MPs play important roles in intercellular communication, regulation of cell signaling or initiation of enzymatic processes. While MPs were characterized in Systemic Sclerosis (SSc) patients, their contribution to SSc pathogenesis remains unknown. Our aim was to investigate the potential role of MPs in SSc pathophysiology and their impact on tissue fibrosis. Methods: Ninety-six SSc patients and 37 sex-matched healthy donors (HD) were enrolled in this study in order to quantify and phenotype their plasmatic MPs by flow cytometry. The ability of MPs purified from SSc patients and HD controls to modulate fibroblast's extra-cellular matrix genes expression was evaluated in vitro by reverse transcriptase quantitative polymerase chain reaction. Results: SSc patients exhibited a higher concentration of circulatory MPs compared to HD. This difference was exacerbated when we only considered patients that were not treated with methotrexate or targeted disease-modifying antirheumatic drugs. Total circulatory MPs were associated to interstitial lung disease, lung fibrosis and diminished lung functional capacity, but also to vascular involvement such as active digital ulcers. Finally, contrary to HD MPs, MPs from SSc patients stimulated the production of extracellular matrix by fibroblast, demonstrating their profibrotic potential. Conclusions: In this study, we provide evidence for a direct profibrotic role of MPs from SSc patients, underpinned by strong clinical associations in a large cohort of patients.

Combined administration of inhaled DNase, baricitinib and tocilizumab as rescue treatment in COVID-19 patients with severe respiratory failure

“…Since immunothrombosis is crucially involved in the pathophysiology of COVID-19-related ARDS [ 23 ], mesenchymal cell/fibroblast accumulation in the lung is linked with the progression of COVID-19 severe respiratory failure [ 8 ] and fibroblasts under certain inflammatory conditions express TF [ 24 , 25 ], we examined whether COVID-19 environment could activate the TF/thrombin pathway in lung fibroblasts (LFs). We observed that plasma samples from treatment-naïve COVID-19 patients markedly induced TF expression in LFs, compared to untreated cells, as indicated by TF real-time quantitative PCR (qPCR), in-cell ELISA and immunofluorescence microscopy ( Fig.…”

Combined administration of inhaled DNase, baricitinib and tocilizumab as rescue treatment in COVID-19 patients with severe respiratory failure

“…Since immunothrombosis is crucially involved in pathology of COVID-19 ARDS [23], mesenchymal cell/fibroblast accumulation in lung is linked with the progression of COVID-19 severe respiratory failure [8] and fibroblasts under certain inflammatory conditions express TF [24,25], we examined whether COVID-19 environment could activate TF/thrombin pathway in LFs. We observed that plasma samples from treatment-naïve COVID-19 patients markedly induced TF expression in LFs, compared to untreated cells, as indicated by TF real-time quantitative PCR (qPCR), in-cell ELISA and immunofluorescence microscopy ( Figure 4A , B and D ).…”

Microparticles in Autoimmunity: Cause or Consequence of Disease?

“…Studies report different MP numbers in patients with SSc. Some studies show elevated numbers of MPs ( 70 , 158 , 165 , 166 ), whereas other studies report lower MP counts in patients with SSc ( 40 , 60 ). Nevertheless, MPs have been associated with certain clinical manifestations, such as interstitial pneumonia or perivascular inflammation ( 40 , 165 ), whereas MP numbers were inversely correlated with skin thickness scores ( 158 ).…”