Cyclosporin A, apoptosis of BAL T-cells and expression of Bcl-2 inasthmatics

Sun, Yu; Khan, L N; Meng, Qiu; Barnes, Neil; Kay, A. B.

doi:10.1183/09031936.03.00098902

Cited by 23 publications

(16 citation statements)

References 30 publications

(53 reference statements)

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“…Also, infiltration of macrophages, and interstitial fibrosis were detected with CsA therapy at doses ranging from 25 to 50 mg/kg (Young et al 1995). In contrast, Ying et al (2003) reported that CsA is known to inhibit T-cell proliferation, induce apoptosis of CD4-positive T-cells and down regulate cytokine gene expression. Moreover, Tirkey et al (2005) that cyclosporine specifically and reversibly inhibits immunocompetent T-helper lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

“…It is a potent immunosuppressive drug that has been used in organ transplantation and in the management of a number of chronic inflammatory conditions, such as psoriasis, Crohn's disease and rheumatoid arthritis (Faulds et al 1993). Ying et al (2003) stated that patients must take this drug over their lifetime. Previous studies reported that a major limiting factor in the clinical use of CsA is chronic nephrotoxicity (Amore et al 2000;Han et al 2006).…”

Section: Introductionmentioning

confidence: 99%

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Prophylactic role of curcumin against cyclosporine-induced nephrotoxicity: Histological and immunohistological study

Fattah

He²,

Fa³

et al. 2010

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Abstract. This study aimed to investigate the possible protective role of curcumin against renal damage caused by administration of cyclosporine A (CsA) in adult male rats. For this purpose, 27 adult male albino rats were used and divided into three equal groups. Group I (control group) and group II (CsA-treated group) received a daily subcutaneous injection of CsA at a dose of 20 mg/kg b.w. Group III (prophylactic group) received a daily oral curcumin at a dose of 15 mg/kg b.w. simultaneously with CsA. After 21 days, all the animals were anaesthetized and the kidneys were rapidly removed and processed to prepare paraffin sections stained with H&E, PAS and Masson's trichrome. In addition, the glutathione S-transferase (GST) enzyme was detected immunohistochemically. The optical density and the area (in %) of positive GST immunoreactions were measured in the cytoplasm of renal tubules and glomeruli and the data were statistically analyzed. Examination of sections from CsA-treated group showed renal tubules with vacuolated cytoplasm and others with darkly stained pyknotic nuclei. Apical brush borders of proximal tubules were undefined and PAS positive granules were noticed in their cytoplasm. The renal corpuscles contained shrunken glomeruli with widening of their Bowman's spaces. Inflammatory cellular infiltrate and increase in the collagen fibers were observed between the renal tubules. In prophylactic group, the structure of renal tubules and corpuscles were preserved except few tubular darkly stained pyknotic nuclei. Numerous blood vessels, few cellular infiltration and thin collagen fibers were observed between the renal tubules. Statistical analysis of morphometric data showed significant increase in the optical density of GST immunoreactivity in the cells of renal tubules and glomeruli of CsAtreated group when compared with the control or prophylactic groups. However, a significant decrease in the area of GST immunoreactivity in sections from prophylactic group was observed when compared with control or CsA-treated groups. In conclusion, protective effect of curcumin against cyclosporine-induced nephrotoxicity in rats was proven based on the study of histological changes and GST immunoexpression. This study supposes the possible therapeutic applications of curcumin in CsA-treated patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prophylactic role of curcumin against cyclosporine-induced nephrotoxicity: Histological and immunohistological study

Fattah

He²,

Fa³

et al. 2010

gpb

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“…In the same way, tacrolimus, which is reliably absorbed from the gut, has a comparable mode of action though inhibition of calcineurin, thereby diminishing T-lymphocyte activation [6]. Furthermore, recent evidence indicates that CYA and tacrolimus induce apoptosis of CD4+ T-lymphocytes [12,13], and can be combined with rapamycin, which also promotes apoptosis, although tacrolimus plus rapamycin combined therapy appears to be superior [13]. Regarding the antiapoptotic Bcl-2 protein, CYA reduces the number of the Bcl-2-positive T cells [12].…”

Section: Cyclosporine A: Mechanisms Of Actionmentioning

confidence: 99%

“…Furthermore, recent evidence indicates that CYA and tacrolimus induce apoptosis of CD4+ T-lymphocytes [12,13], and can be combined with rapamycin, which also promotes apoptosis, although tacrolimus plus rapamycin combined therapy appears to be superior [13]. Regarding the antiapoptotic Bcl-2 protein, CYA reduces the number of the Bcl-2-positive T cells [12]. The apoptotic activity of CYA is possibly mediated by the inhibition of cytokine release and the subsequent activation of ICE-like proteins (ICE is an acronym for IL-1β converting enzyme of caspase 1), known to play a chief role triggering the apoptotic cascade [14].…”

Section: Cyclosporine A: Mechanisms Of Actionmentioning

confidence: 99%

Immunomodulatory benefits of cyclosporine A in inflammatory bowel disease

Kountouras

Zavos

Chatzopoulos

2004

J Cellular Molecular Medi

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Etiopathogenesis of mucosal inflammation in inflammatory bowel disease remains a complex and enigmatic field; various factors (genetic, environmental and microbial) trigger an event that activates intestinal immune and nonimmune systems culminating in inflammation and tissue injury. Specifically, both innate and adaptive immune systems seem to play important roles in the pathophysiology of this disease. Cyclosporine A represents a macrolide immune modulator with primary inhibitory effects on T helper lymphocyte production of interleukin-2, and other cytokines leading to altered T-lymphocyte and B-lymphocyte function. The diversity of its therapeutic outcome reported in inflammatory bowel disease may be due to the intricate immuno-pathogenic profile of the disease and the variety of the applied dose-dependent courses of therapy. Cyclosporine A exerts additional actions on other components of the inflammatory infiltrate, including neutrophils and mast cells, thereby appearing to be a multi-dynamic therapeutic approach, although with potential drawbacks, that may be applied alone or combined with other immunomodulatory agents in inflammatory bowel disease patients. Because cyclosporine A induces apoptosis of T-lymphocytes responsible for perpetuation of the chronic inflammatory process in the disease with potential tumorigenic effect, it may exert a further inhibitory effect on cancer development in inflammatory bowel disease patients, and can be combined with other relative agents, such as rapamycin, which also promotes T-lymphocyte apoptosis. Therefore, recently established multifactorial action of cyclosporine A in relation to the pathogenesis of the disease can open new horizons for prospective, controlled trials in large cohorts, aiming to emphasize cyclosporine A's potential.

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“…On the other hand, calcineurin-deficient mice expressed a lower level of Bcl-2 in naïve T cells and were characterized by a moderate lymphopenia, indicating that Bcl-2 expression in naïve T cells also depends on the activity of the calcineurin-NFAT pathway [17]. A similar phenomenon was observed in T cells isolated from bronchoalveolar lavage fluid in asthmatic patients treated with cyclosporine A (CsA) [18].…”

Section: Introductionmentioning

confidence: 74%

Synergistic Bcl-2 inhibition by ABT-737 and cyclosporine A

et al. 2012

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Survival of lymphocytes and melanocyte stem cells critically depends on B cell lymphoma 2 (Bcl-2). In T lymphocytes, a basal calcineurin activity maintains Bcl-2 expression in naïve cells, and the activation of the calcineurin pathway orchestrates the regulation of the intrinsic apoptosis pathway after antigen recognition. Therefore, calcineurin inhibitors might potentiate the pro-apoptotic effect of pharmacological Bcl-2 inhibitors on lymphatic cells. In vitro, a reduced Bcl-2 expression in lymphocytes exposed to calcineurin inhibitors increased their sensitivity to the small molecule Bcl-2 inhibitor ABT-737. This correlated with an augmented pro-apoptotic activity of ABT-737 on lymphocytes in combination with cyclosporine A in naïve mice in vivo. Interestingly, similar processes were observed in melanocytes. ABT-737 induced a fur depigmentation at the site of injection, and this effect was expanded to a generalized depigmentation in combination with cyclosporine A. Thus, inhibiting calcineurin increases the pro-apoptotic potency of ABT-737 in cells depending on Bcl-2 for survival. The increased efficacy of Bcl-2 inhibitors in combination with cyclosporine A might be relevant to exploit their anti-neoplastic and immuno-modulatory properties.

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Cyclosporin A, apoptosis of BAL T-cells and expression of Bcl-2 inasthmatics

Cited by 23 publications

References 30 publications

Prophylactic role of curcumin against cyclosporine-induced nephrotoxicity: Histological and immunohistological study

Prophylactic role of curcumin against cyclosporine-induced nephrotoxicity: Histological and immunohistological study

Immunomodulatory benefits of cyclosporine A in inflammatory bowel disease

Synergistic Bcl-2 inhibition by ABT-737 and cyclosporine A

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