Effect of calcineurin inhibitors on extracellular matrix turnover in isolated human glomeruli

Esposito, Ciro; Foschi, Annalisa; Parrilla, Bina; Cornacchia, Flavia; Fasoli, Gianluca; Plati, Annarita; Mauri, Andreana De; Mazzullo, Tiziana; R, Scudellaro; Canton, Antonio Dal

doi:10.1016/j.transproceed.2004.03.013

Cited by 18 publications

(13 citation statements)

References 5 publications

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“…On the other hand, some data have suggested that cyclosporine (CsA) and tacrolimus (FK), the 2 calcineurin inhibitors most widely used in organ transplantation, could influence TGFβ 1 expression in the liver differently, in such a manner that CsA would markedly increase TGFβ 1 expression, whereas FK would not have this effect 17, 18. This differential effect of the 2 calcineurin inhibitors on TGFβ 1 has also been reported in different studies involving patients with transplantation of other organs,19–24 albeit not in all 25–27. Therefore, another objective of the present study was to investigate whether the expression of αSMA and TGFβ 1 was different in liver transplant recipients with hepatitis C recurrence treated with CsA or FK.…”

supporting

confidence: 74%

“…Overall, from our results it appears that mechanisms other than an overactivation of HSC and an overexpression of TGFβ 1 are probably involved in the accelerated hepatic fibrosis in LT patients with hepatitis C recurrence. For example, impairment of extracellular matrix degradation could be one of such mechanisms, as it can be speculated from some studies reporting that CsA can increase the expression of tissue inhibitors of metalloproteinases in fibroblasts and isolated glomeruli in humans 20, 35. Conversely, in spite of a similar amount of activated HSC in LT and non‐LT patients, a higher fibrogenesis in the former cannot completely be ruled out because of the possibility of a higher synthesis of collagen per cell in LT patients.…”

Section: Discussionmentioning

confidence: 99%

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Hepatic stellate cell activation in liver transplant patients with hepatitis C recurrence and in non-transplanted patients with chronic hepatitis C

et al. 2007

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The pathogenic mechanisms of accelerated graft fibrosis in hepatitis C recurrence after liver transplantation (LT) are not well established. The aim of the study was to assess whether a greater activation of hepatic stellate cells (HSC), the major collagen-producing cells in the liver, can occur in these patients as compared to non-LT patients with chronic hepatitis C. We determined the amount of activated HSC by computer-based morphometric analysis of ␣-smooth muscle actin (␣SMA)-positive cells and the hepatic TGF␤ 1 expression by immunohistochemistry in 46 LT patients with hepatitis C recurrence, 35 non-LT patients with chronic hepatitis C, and 16 controls. Hepatic ␣SMA and TGF␤ 1 expression was higher in LT patients with hepatitis C recurrence than in controls and was correlated with fibrosis stage and progression rate. No significant difference in ␣SMA and TGF␤ 1 expression was observed between LT and non-LT patients with hepatitis C, with the exception of a higher transforming growth factor ␤-1 (TGF␤ 1 ) expression in non-LT patients in the early stages of fibrosis. LT patients receiving cyclosporine (CsA) or tacrolimus (FK) had a similar fibrosis progression rate and ␣SMA and TGF␤ 1 expression. In conclusion, the accelerated fibrosis observed in LT patients with hepatitis C recurrence does not seem to be related to a greater amount of activated HSC and TGF␤ 1 expression in the grafts of these patients as compared to non-LT patients with chronic hepatitis C. In LT patients, the amount of activated HSC and TGF␤ 1 expression correlated with fibrosis stage and progression, without any apparent influence of the type of calcineurin inhibitor administered. Liver Transpl 13:1017Transpl 13: -1027Transpl 13: , 2007.Received December 7, 2006; accepted February 26, 2007. Hepatitis C recurrence is one of the most important problems in patients with liver transplantation (LT) for hepatitis C virus (HCV)-related liver disease. At present, liver disease caused by HCV is the leading indication for LT in Western countries. 1 The recurrence of HCV infection occurs almost universally and is followed by chronic hepatitis in the graft in most patients. 2,3 It is important to note that, whereas the course of chronic hepatitis C in immune competent subjects is often indolent, the graft lesion in LT patients with hepatitis C recurrence progresses very rapidly in a substantial proportion of cases, with a probability of cirrhosis in up to 30 to 40% of patients at 5 yr after transplantation. 4 Consequently, hepatitis C recurrence has been shown to have a negative impact on survival of patients receiving a liver transplant for HCV-related liver disease. 5

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supporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Hepatic stellate cell activation in liver transplant patients with hepatitis C recurrence and in non-transplanted patients with chronic hepatitis C

et al. 2007

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“…These distinctions may correlate with the individual toxicity profiles of cyclosporin and tacrolimus. Cyclosporin worsened ischemia reperfusion, endothelial cell toxicity, reactive oxygen species injury and promoted fibrogenesis of renal tissue and airway epithelium to a greater extent than tacrolimus (13,(35)(36)(37). Tacrolimus altered islet cell insulin secretion more so than cyclosporin (38).…”

Section: Discussionmentioning

confidence: 99%

Calcineurin Inhibitor Effects on Growth and Phenotype of Human Airway Epithelial Cells In Vitro

Neuringer

Sloan

Budd

et al. 2005

American Journal of Transplantation

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Calcineurin inhibitors (CIs) cyclosporin and tacrolimus form the basis for immunosuppression in lung transplantation, yet also exert biological effects on nonlymphoid tissue. With the advent of inhaled cyclosporin, we hypothesize that the airway epithelium is also subject to CI effects at high doses. The aim of this study was to identify human tracheobronchial epithelial cell (hTBEC) calcineurin gene expression and quantify effects of CIs on hTBEC growth, interleukin-1-b stimulated IL-8 production and hTBEC phenotype. Cyclophillin B and FK-associated binding protein, calcineurin A (a and b ), and NFATC3 and NFAT5 were detected in hTBEC cultures by RT-PCR. Acute and chronic cyclosporine treatment 1000 ng/mL significantly inhibited hTBEC proliferation, while tacrolimus did not (range of 10 ng/mL to 1000 ng/mL for acute treatment, 50 ng/mL for chronic treatment). Cyclosporin at 10 000 ng/mL significantly increased LDH release by well-differentiated hTBEC cultures (n = 6) and trended towards significance at 1000 ng/mL. IL1-b stimulated IL-8 production was significantly increased in rapidly growing hTBEC cultures (n = 8) treated with cyclosporin (p = 0.049). Prolonged treatment of welldifferentiated hTBECs at air-liquid-interface (ALI) with cyclosporin 1000 ng/mL significantly reduced intact multilayered mucociliary epithelium (p = 0.009). Inhibition of hTBEC growth, stimulation of IL-8 production and long-term effects on mucociliary phenotype and intact multi-layered epithelium suggest that cyclosporin may have a direct toxic effect on airway epithelium after transplantation.

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“…For instance, correlative data supports a role for TIMP2 in protecting the ECM from proteolysis in fracture healing [30], keloids [31], liver [32,33], kidneys [34,35], Dupuytren's contracture [36,37], and in heart tissues [38][39][40][41][42]. As a specific example, patients suffering from Dupuytren's contracture, a disease caused by excessive ECM deposition leading to fixed flexion of joints in the hand, have a disruption in the balance between TIMP2 and MMP2 in favor of TIMP2, which suggests that increased TIMP2 is associated with pathophysiological ECM accumulation [36,37].…”

Section: Timp2 Direct Inhibition Of Ecm Proteolysis By Timp2mentioning

confidence: 98%

The role of TIMPs in regulation of extracellular matrix proteolysis

2015

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Tissue inhibitors of metalloproteinases (TIMPs), which inhibit matrix metalloproteinases (MMPs) as well as the closely related, a disintegrin and metalloproteinases (ADAMs) and ADAMs with thrombospondin motifs (ADAMTSs), were traditionally thought to control extracellular matrix (ECM) proteolysis through direct inhibition of MMP-dependent ECM proteolysis. This classical role for TIMPs suggests that increased TIMP levels results in ECM accumulation (or fibrosis), whereas loss of TIMPs leads to enhanced matrix proteolysis. Mice lacking TIMP family members have provided support for such a role; however, studies with these TIMP deficient mice have also demonstrated that loss of TIMPs can often be associated with an accumulation of ECM. Collectively, these studies suggest that the divergent roles of TIMPs in matrix accumulation and proteolysis, which together can be referred to as ECM turnover, are dependent on the TIMP, specific tissue, and local tissue environment (i.e. health vs. injury/disease). Ultimately, these combined factors dictate the specific metalloproteinases being regulated by a given TIMP, and it is likely the diversity of metalloproteinases and their physiological substrates that determines whether TIMPs inhibit matrix proteolysis or accumulation. In this review, we discuss the evidence for the dichotomous roles of TIMPs in ECM turnover highlighting some of the common findings between different TIMP family members. Importantly, while we now have a better understanding of the role of TIMPs in regulating ECM turnover, much remains to be determined. Data on the specific metalloproteinases inhibited by different TIMPs in vivo remains limited and must be the focus of future studies.

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Effect of calcineurin inhibitors on extracellular matrix turnover in isolated human glomeruli

Cited by 18 publications

References 5 publications

Hepatic stellate cell activation in liver transplant patients with hepatitis C recurrence and in non-transplanted patients with chronic hepatitis C

Hepatic stellate cell activation in liver transplant patients with hepatitis C recurrence and in non-transplanted patients with chronic hepatitis C

Calcineurin Inhibitor Effects on Growth and Phenotype of Human Airway Epithelial Cells In Vitro

The role of TIMPs in regulation of extracellular matrix proteolysis

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