Immunosuppressive Drugs Alter α1-Antitrypsin Production in Hepatocytes: Implications for Epithelial Gap Repair

Brami, Ido; Ini, Dor; Sassonker, Nofit; Zaknoun, Melodie; Zuckerman, Tsila; Lewis, Eli C.

doi:10.1016/j.bbmt.2019.12.764

Cited by 3 publications

(1 citation statement)

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“…However, at 48 h from injury, the difference between DEX and AAT-treated wells was profound: in the presence of DEX, gap closure was stunted and had barely advanced from the 6-h point. In contrast, cell migration in AAT-treated wells was as far advanced as the plentiful conditions of 10% FCS, agreeing with previously reported data using other cells types (e.g., Caco2 colon epithelial cells), drug concentrations (e.g., AAT at 0.1–0.5 mg/ml) and experimental protocols (e.g., 96-well plates) (13,20,21). Perhaps more intriguing is the combination of the two approaches; when cells were co-treated with AAT and DEX, the early point of 6 h depicted a profile of gap closure that was superior to AAT alone, and the point of gap closure at 48 h was markedly superior to that of DEX alone.…”

Section: Discussionsupporting

confidence: 91%

Trauma-Induced Vestibular Dysfunction: Improved Repair Under Local Treatment With α1-Antitrypsin

El-Saied,

Kaminer,

Kaplan

et al. 2024

Otol Neurotol

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Aim To characterize vestibular recovery in a mouse model of unilateral labyrinthotomy under local AAT and dexamethasone treatment. Background Alpha1-antitrypsin (AAT) is a circulating tissue-protective molecule that rises during inflammatory conditions and promotes inflammatory resolution. Its local concentration in human perilymph inversely correlates with the severity of inner ear dysfunction; concomitantly, mice that overexpress AAT and undergo inner ear trauma rapidly restore vestibular function. Locally applied AAT has yet to be examined in this context, nor has it been directly compared with anti-inflammatory corticosteroid treatment. Methods Wild-type mice C57BL/6 underwent a unilateral inner ear injury. Nine microliters of saline, clinical-grade AAT (180 μg/site), dexamethasone (4 mg/site), or both were applied locally on Days 0, 1, and 2 (n = 5/group). Vestibular function was assessed for 7 days. An in vitro human epithelial gap closure assay was performed using A549 cells in the presence of AAT and/or dexamethasone. Results Upon labyrinthotomy, all groups displayed severe vestibular dysfunction. Saline-treated mice showed the longest impairment. That group and the dexamethasone group displayed partial to no recovery, while AAT-treated mice exhibited complete recovery within 7 days; at this time point, dexamethasone-treated mice exhibited 50% recovery. Objective vestibular testing showed similar outcomes. In vitro, cotreatment with AAT and dexamethasone resulted in a gap closure dynamic that was superior to AAT alone at 6 h and superior to DEX alone at 48 h. Conclusion Locally applied AAT treatment is superior to locally applied dexamethasone in promoting vestibular recovery in vivo. Ongoing studies are exploring the potential advantages of AAT combined with early low-dose dexamethasone therapy.

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Section: Discussionsupporting

confidence: 91%

Trauma-Induced Vestibular Dysfunction: Improved Repair Under Local Treatment With α1-Antitrypsin

El-Saied,

Kaminer,

Kaplan

et al. 2024

Otol Neurotol

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A transepithelial pathway delivers succinate to macrophages, thus perpetuating their pro-inflammatory metabolic state

et al. 2021

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A transepithelial pathway delivers succinate to macrophages, thus perpetuating their proinflammatory metabolic state Graphical abstract Highlights d Succinate uptake is elevated in macrophages to perpetuate their pro-inflammatory state d Na + -dependent transporters mediate transepithelial succinate delivery into macrophages d Succinate concentrations are elevated in the serum and feces of IBD patients d Succinate-metabolizing bacteria are altered in IBD patients

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Restoration of FVIII Function and Phenotypic Rescue in Hemophilia A Mice by Transplantation of MSCs Derived From F8-Modified iPSCs

Qiu

Zhou

et al. 2021

Front. Cell Dev. Biol.

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Hemophilia A (HA), an X-linked recessive congenital bleeding disorder, affects 80%–85% of patients with hemophilia. Nearly half of severe cases of hemophilia are caused by a 0.6-Mb genomic inversion (Inv22) that disrupts F8. Although viral-based gene therapy has shown therapeutic effects for hemophilia B (HB), this promising approach is not applicable for HA at the present stage; this limitation is mainly due to the large size of F8 cDNA, which far exceeds the adeno-associated virus (AAV) packaging capacity. We previously reported an in situ genetic correction of Inv22 in HA patient-specific induced pluripotent stem cells (HA-iPSCs) by using TALENs. We also investigated an alternative strategy for targeted gene addition, in which cDNA of the B-domain deleted F8 (BDDF8) was targeted at the rDNA locus of HA-iPSCs using TALENickases to restore FVIII function. Mesenchymal stem cells (MSCs) have low immunogenicity and can secrete FVIII under physiological conditions; in this study, MSCs were differentiated from F8-corrected iPSCs, BDDF8-iPSCs, and HA-iPSCs. Differentiated MSCs were characterized, and FVIII expression efficacy in MSCs was verified in vitro. The three types of MSCs were introduced into HA mice via intravenous injection. Long-term engraftment with restoration of FVIII function and phenotypic rescue was observed in HA mice transplanted with F8-corrected iMSCs and BDDF8-iMSCs. Our findings suggest that ex vivo gene therapy using iMSCs derived from F8-modified iPSCs can be feasible, effective, and promising for the clinical translation of therapeutic gene editing of HA and other genetic birth defects, particularly those that involve large sequence variants.

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Immunosuppressive Drugs Alter α1-Antitrypsin Production in Hepatocytes: Implications for Epithelial Gap Repair

Cited by 3 publications

References 51 publications

Trauma-Induced Vestibular Dysfunction: Improved Repair Under Local Treatment With α1-Antitrypsin

Trauma-Induced Vestibular Dysfunction: Improved Repair Under Local Treatment With α1-Antitrypsin

A transepithelial pathway delivers succinate to macrophages, thus perpetuating their pro-inflammatory metabolic state

Restoration of FVIII Function and Phenotypic Rescue in Hemophilia A Mice by Transplantation of MSCs Derived From F8-Modified iPSCs

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