Increased Soluble VCAM-1 and Normal P-Selectin in Cystic Fibrosis: a Cross-Sectional Study

Nowak, Jan Krzysztof; Wojsyk‐Banaszak, Irena; Mądry, Edyta; Wykrętowicz, Andrzej; Krzyżanowska, Patrycja; Drzymała-Czyż, Sławomira; Nowicka, Agata; Pogorzelski, Andrzej; Sapiejka, Ewa; Skorupa, Wojciech; Szczepanik, Mariusz; Lisowska, Aleksandra; Walkowiak, Jarosław

doi:10.1007/s00408-017-0029-y

Cited by 11 publications

(11 citation statements)

References 84 publications

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“…Accordingly, the combination treatment of VX-770 + VX-809 (Orkambi®) was able to partially rescue the pro-inflammatory phenotype of CF patient-derived ECs as measured by inflammatory marker gene expression and leukocyte adhesion. Also, our results are in accordance with earlier findings in CF patients where increased soluble EC activation molecules were detected in the plasma and serum, and correlating in some cases, with impaired lung function [55][56][57][58][59][60] .…”

Section: Discussionsupporting

confidence: 93%

Transcriptomic analysis of CFTR-impaired endothelial cells reveals a pro-inflammatory phenotype

et al. 2020

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Cystic fibrosis (CF) is a life-threatening disorder characterised by decreased pulmonary mucociliary and pathogen clearance, and an exaggerated inflammatory response leading to progressive lung damage. CF is caused by bi-allelic pathogenic variants of the cystic fibrosis transmembrane conductance regulator (CFTR) gene which encodes a chloride channel. CFTR is expressed in endothelial cells (ECs) and EC dysfunction has been reported in CF patients, but a role for this ion channel in CF disease progression is poorly described.We used an unbiased RNA sequencing approach in complementary models of CFTR silencing and blockade (by the CFTR inhibitor CFTRinh-(172)) in human ECs to characterise the changes upon CFTR impairment. Key findings were further validated in vitro, in vivo in CFTR knock-out mice and ex vivo in CF patient-derived ECs.Both models of CFTR impairment revealed that EC proliferation, migration and autophagy were downregulated. Remarkably though, defective CFTR function led to EC activation and a persisting pro-inflammatory state of the endothelium with increased leukocyte adhesion. Further validation in CFTR knock-out mice revealed enhanced leukocyte extravasation in lung and liver parenchyma associated with increased levels of EC activation markers. In addition, CF patient-derived ECs displayed increased EC activation markers and leukocyte adhesion, which was partially rescued by using CFTR modulators VX770-VX809.Our integrated analysis thus suggests that ECs are no innocent bystanders in CF pathology, but rather may contribute to the exaggerated inflammatory phenotype, raising the question whether normalisation of vascular inflammation might be a novel therapeutic strategy to ameliorate the disease severity of CF.

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Section: Discussionsupporting

confidence: 93%

Transcriptomic analysis of CFTR-impaired endothelial cells reveals a pro-inflammatory phenotype

et al. 2020

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“…Importantly, it has been proposed that the activation of VCAM-1 and P-selectin increase platelets function and thrombogenic capacity thereby caution must be taken when developing a target delivery system based on endothelial adhesion molecules [ 203 ]. Meanwhile, comparable levels of VCAM-1 and P-selectin are present in the vascular system of different tissues, some of them likely secreted by ECs following inflammation [ 204 ]. The broad distribution of VCAM-1 and P-selectin on the luminal surface of the vascular network, along with considerable serum levels of these proteins, raises the possibility of non-specific binding and exosome neutralization before BBB cross.…”

Section: Surface Modification Of Exosomes; An Efficient Strategy To Increase Bbb Crossmentioning

confidence: 99%

Exosomal delivery of therapeutic modulators through the blood–brain barrier; promise and pitfalls

et al. 2021

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Nowadays, a large population around the world, especially the elderly, suffers from neurological inflammatory and degenerative disorders/diseases. Current drug delivery strategies are facing different challenges because of the presence of the BBB, which limits the transport of various substances and cells to brain parenchyma. Additionally, the low rate of successful cell transplantation to the brain injury sites leads to efforts to find alternative therapies. Stem cell byproducts such as exosomes are touted as natural nano-drug carriers with 50–100 nm in diameter. These nano-sized particles could harbor and transfer a plethora of therapeutic agents and biological cargos to the brain. These nanoparticles would offer a solution to maintain paracrine cell-to-cell communications under healthy and inflammatory conditions. The main question is that the existence of the intact BBB could limit exosomal trafficking. Does BBB possess some molecular mechanisms that facilitate the exosomal delivery compared to the circulating cell? Although preliminary studies have shown that exosomes could cross the BBB, the exact molecular mechanism(s) beyond this phenomenon remains unclear. In this review, we tried to compile some facts about exosome delivery through the BBB and propose some mechanisms that regulate exosomal cross in pathological and physiological conditions.

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“…Previous studies have revealed that proposed biomarkers, VCAM-1, ICAM-1, and CD62P with higher concentrations are independently associated with fibrosis [26,27]. To investigate the role of LCG on the vascular fibrosis in DMED rats, the VCAM-1, ICAM-1, and CD62P levels in serum samples of rats were assayed with flow cytometry.…”

Section: Lcg Reduced Vascular Fibrosis Markers Expression In the Seramentioning

confidence: 99%

Couplet medicines of leech and centipede granules improve erectile dysfunction via inactivation of the CaSR/PLC/PKC signaling in streptozotocin-induced diabetic rats

et al. 2020

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Erectile dysfunction (ED) is one of the significant complications of diabetes mellitus (DM), and CASR plays an important role in cellular antiapoptosis and NO production in the vascular endothelium by activating PKC. The present study was aimed to investigate the efficacy of Leech and Centipede Granules (LCG) through the CaSR/PLC/PKC signaling. Fifty male Sprague-Dawley rats were treated with streptozotocin to induce the DM model. After 10 weeks, an apomorphine test was used to confirm DMED. Rats with DMED were administrated with LCG and U73122 for 4 weeks. Fasting blood glucose, body weight, insulin and glucagon levels were measured. Erectile function in rats was assessed by apomorphine. Serums were measured using enzyme-linked immunosorbent assay and flow cytometry, and penile tissues were harvested for histologic and the expression of related targets analyses. After treatment, fasting blood glucose, body weight, insulin, glucagon levels, and erectile function were significantly ameliorated in the LCG groups. The LOX-1, NOX, and EMPs concentrations were significantly decreased with LCG treatment. LCG also continuously increased NO and decreased ET-1 content in penile tissues. LCG and U73122 administration also improved penile fibrosis by significantly decreasing VCAM-1, ICAM-1, and CD62P. The data also showed that LCG reduced the apoptosis level in the penis. Furthermore, the inhibited activation of the CaSR/PLC/PKC pathway was observed in DMED rats with LCG treatment. Collectively, LCG significantly ameliorated erectile function of DMED rats via increased NO generation, inhibiting endothelial cells apoptosis and penile fibrosis, which might benefit from the suppression of CaSR/PLC/PKC pathway in DMED rats.

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Increased Soluble VCAM-1 and Normal P-Selectin in Cystic Fibrosis: a Cross-Sectional Study

Cited by 11 publications

References 84 publications

Transcriptomic analysis of CFTR-impaired endothelial cells reveals a pro-inflammatory phenotype

Transcriptomic analysis of CFTR-impaired endothelial cells reveals a pro-inflammatory phenotype

Exosomal delivery of therapeutic modulators through the blood–brain barrier; promise and pitfalls

Couplet medicines of leech and centipede granules improve erectile dysfunction via inactivation of the CaSR/PLC/PKC signaling in streptozotocin-induced diabetic rats

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