Differential anti-inflammatory effects of immunosuppressive drugs: Cyclosporin, rapamycin and FK-506 on inducible nitric oxide synthase, nitric oxide, cyclooxygenase-2 and PGE2 production

Attur, Mukundan; Patel, Rajesh N.; Thakker, Geeta D.; Vyas, Pranav; Levartovsky, David; Patel, Prakash D.; Naqvi, Syed Asif Ali; Raza, Rizwan; Patel, KJ; Abramson, David C.; Bruno, Giovanni; Abramson, S.B.; Amin, Ashok R.

doi:10.1007/pl00000199

Cited by 118 publications

(78 citation statements)

References 63 publications

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“…Additionally, a recent provocative report demonstrated that cyclosporine directly influenced respiratory epithelial cells to secrete factors that enhance fibroblast proliferation (41). Although it is not known what factors were liberated that promoted fibroblast proliferation in this study, cyclosporine inhibition of PGE 2 release could culminate in airway fibrosis (41)(42)(43)(44)(45). Therefore, it has been postulated that the influence of cyclosporine on epithelium could contribute to the development of fibrotic lung disease (obliterative bronchiolitis) after lung transplantation (41).…”

Section: Discussionmentioning

confidence: 79%

Simultaneous LFA-1 and CD40 Ligand Antagonism Prevents Airway Remodeling in Orthotopic Airway Transplantation: Implications for the Role of Respiratory Epithelium as a Modulator of Fibrosis

Murakawa

Kerklo

Zamora

et al. 2005

The Journal of Immunology

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Airway remodeling is a prominent feature of certain immune-mediated lung diseases such as asthma and chronic lung transplant rejection. Under conditions of airway inflammation, the respiratory epithelium may serve an important role in this remodeling process. Given the proposed role of respiratory epithelium in nonspecific injury models, we investigated the respiratory epithelium in an immune-specific orthotopic airway transplant model. MHC-mismatched tracheal transplants in mice were used to generate alloimmune-mediated airway lesions. Attenuation of this immune injury and alteration of antidonor reactivity were achieved by the administration of combined anti-LFA-1/anti-CD40L mAbs. By contrast, without immunotherapy, transplanted airways remodeled with a flattening of respiratory epithelium and significant subepithelial fibrosis. Unopposed alloimmune injury for 10 days was associated with subsequent epithelial transformation and subepithelial fibrosis that could not be reversed with immunotherapy. The relining of donor airways with recipient-derived epithelium was delayed with immunotherapy resulting in partially chimeric airways by 28 days. Partial epithelial cell chimerism was sufficient to prevent luminal fibrosis. However, epithelial chimerism was also associated with airway remodeling. Therefore, there appears to be an intimate relationship between the morphology and level of chimerism of the respiratory epithelium and the degree of airway remodeling following alloimmune injury.

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Section: Discussionmentioning

confidence: 79%

Simultaneous LFA-1 and CD40 Ligand Antagonism Prevents Airway Remodeling in Orthotopic Airway Transplantation: Implications for the Role of Respiratory Epithelium as a Modulator of Fibrosis

Murakawa

Kerklo

Zamora

et al. 2005

The Journal of Immunology

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“…Rapamycin inhibits tumor growth by not only suppressing angiogenesis (49) but also preventing the proliferation of cancer cells (50). Moreover, rapamycin enhanced the apoptosis of chemotherapy-resistant tumor cells (34) and reduced inflammation by regulating arginase, iNOS, and ROS (35,36). In MDSCs, rapamycin enhanced gemcitabine-induced apoptosis in vitro (C.-Y.…”

Section: Discussionmentioning

confidence: 99%

“…We sought to find a chemical inhibitor that regulates FKBP51 function for more in-depth analysis of the role of FKBP51 in MDSCs, and several reports demonstrated that FK506 and rapamycin inhibit the peptidyl-prolyl isomerase (PPIase) function of FKBP51 (33,34) and regulate inflammation (35,36). Thus, we tested whether FK506 and rapamycin could inhibit the suppressive activity of MDSCs.…”

Section: A Chemical Inhibitor Of Fkbp51 Rapamycin Reduces the Supprmentioning

confidence: 99%

Functional Changes in Myeloid-Derived Suppressor Cells (MDSCs) during Tumor Growth: FKBP51 Contributes to the Regulation of the Immunosuppressive Function of MDSCs

Kim

Lee

et al. 2012

The Journal of Immunology

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Myeloid-derived suppressor cells (MDSCs) are increased by tumor-derived factors and suppress anti-tumor immunity. MDSCs obtained at a late time point after tumor injection had stronger suppressive activity than MDSCs obtained at an early time point, as measured by T cell proliferation assays. To find factors in MDSCs that change during tumor growth, we analyzed gene expression profiles from MDSCs at different time points after tumor injection. We found that immune response-related genes were downregulated but protumor function-related genes were upregulated in both monocytic MDSCs (Mo-MDSCs) and polymorphonuclear granulocytic MDSCs (PMN-MDSCs) at the late time point. Among differentially expressed genes, FK506 binding protein 51 (FKBP51), which is a member of the immunophilin protein family and plays a role in immunoregulation, was increased in the Mo-MDSCs and PMN-MDSCs isolated from the late time points. Experiments using small interfering RNA and a chemical inhibitor of FKBP51 revealed that FKBP51 contributes to the regulation of the suppressive function of MDSCs by increasing inducible NO synthase, arginase-1, and reactive oxygen species levels and enhancing NF-κB activity. Collectively, our data suggest that FKBP51 is a novel molecule that can be targeted to regulate the immunosuppressive function of MDSCs.

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“…[85][86][87][88][89][90] In addition, sirolimus has been shown to inhibit VEGF-induced microvascular permeability, and reduces protein kinase C (PKC) activity, [85][86][87][88][89][90][91] as well as reduces the expression of inflammatory cytokines. 92,93 Recently, a phase 1 study of subconjunctival and intravitreal sirolimus in DMO was reported by Dugel et al 94 No non-ocular adverse events were noted, and the systemic exposure to sirolimus was low. There were no serious ocular adverse events reported.…”

Section: Angiopoietin (Ang)-2 Blockagementioning

confidence: 99%

A review of therapies for diabetic macular oedema and rationale for combination therapy

Amoaku

Saker

Stewart

2015

Eye

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Diabetic macular oedema (DMO) is responsible for significant visual impairment in diabetic patients. The primary cause of DMO is fluid leakage resulting from increased vascular permeability through contributory anatomical and biochemical changes. These include endothelial cell (EC) death or dysfunction, pericyte loss or dysfunction, thickened basement membrane, loss or dysfunction of glial cells, and loss/change of EC Glycocalyx. The molecular changes include increased reactive oxygen species, pro-inflammatory changes: advanced glycation end products, intracellular adhesion molecule-1, Complement 5-9 deposition and cytokines, which result in increased paracellular permeability, tight junction disruption, and increased transcellular permeability. Laser photocoagulation has been the mainstay of treatment until recently when pharmacological treatments were introduced. The current treatments for DMO target reducing vascular leak in the macula once it has occurred, they do not attempt to treat the underlying pathology. These pharmacological treatments are aimed at antagonising vascular endothelial growth factor (VEGF) or non-VEGF inflammatory pathways, and include intravitreal injections of anti-VEGFs (ranibizumab, aflibercept or bevacizumab) or steroids (fluocinolone, dexamethasone or triamcinolone) as single therapies. The available evidence suggests that each individual treatment modality in DMO does not result in a completely dry macula in most cases. The ideal treatment for DMO should improve vision and improve morphological changes in the macular (eg, reduce macular oedema) for a significant duration, reduced adverse events, reduced treatment burden and costs, and be well tolerated by patients. This review evaluates the individual treatments available as monotherapies, and discusses the rationale and potential for combination therapy in DMO.

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Differential anti-inflammatory effects of immunosuppressive drugs: Cyclosporin, rapamycin and FK-506 on inducible nitric oxide synthase, nitric oxide, cyclooxygenase-2 and PGE2 production

Cited by 118 publications

References 63 publications

Simultaneous LFA-1 and CD40 Ligand Antagonism Prevents Airway Remodeling in Orthotopic Airway Transplantation: Implications for the Role of Respiratory Epithelium as a Modulator of Fibrosis

Simultaneous LFA-1 and CD40 Ligand Antagonism Prevents Airway Remodeling in Orthotopic Airway Transplantation: Implications for the Role of Respiratory Epithelium as a Modulator of Fibrosis

Functional Changes in Myeloid-Derived Suppressor Cells (MDSCs) during Tumor Growth: FKBP51 Contributes to the Regulation of the Immunosuppressive Function of MDSCs

A review of therapies for diabetic macular oedema and rationale for combination therapy

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