trichostatin-a and Postoperative-Complications

Rotator cuff (RC) muscle fatty infiltration (FI) is an important factor that determines the clinical outcome of patients with RC repair. There is no effective treatment for RC muscle FI at this time. The goal of this study is to define the role Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor in regulating muscle fibro/adipogenic progenitors (FAPs) adipogenesis and treating muscle fatty degeneration after massive RC tears in a mouse model. We hypothesize that TSA reduces muscle FI after massive RC tears. HDAC activity was measured in FAPs in RC muscle after tendon/nerve transection or sham surgery. FAPs were treated with TSA for 2 weeks and FAP adipogenesis was evaluated with perilipin and Oil Red O staining, as well as reverse transcript-polymerase chain reaction for adipogenesis-related genes. About 0.5 mg/kg TSA or dimethyl sulfoxide was administered to C57B/L6 mice with massive rotator cuff tears through daily intraperitoneal injection for 6 weeks. Supraspinatus muscles were harvested for biochemical and histology analysis. We found that FAPs showed significantly higher HDAC activity after RC tendon/nerve transection. TSA treatment significantly reduced HDAC activity and inhibited adipogenesis of FAPs. TSA also abolished the role of bone morphogenetic protein-7 in inducing FAP adipogenesis and promoted FAP brown/beige adipose tissue (BAT) differentiation. TSA injection significantly increased histone H3 acetylation and reduced FI of rotator cuff muscles after massive tendon tears. Results from this study showed that TSA can regulate FAP adipogenesis and promote FAP BAT differentiation epigenetically. HDAC inhibition may be a new treatment strategy to reduce muscle FI after RC tears and repair.

Topics: Adipogenesis; Animals; Bone Morphogenetic Protein 7; Cells, Cultured; Drug Evaluation, Preclinical; Female; Fibrosis; Histone Deacetylase Inhibitors; Hydroxamic Acids; Mice, Inbred C57BL; Postoperative Complications; Rotator Cuff Injuries; Stem Cells

Excessive neuroinflammatory responses play important roles in the development of postoperative cognitive dysfunction (POCD). Neurofilaments (NFs) were essential to the structure of axon and nerve conduction; and the abnormal degradation of NFs were always accompanied with degenerative diseases, which were also characterized by excessive neuroinflammatory responses in brain. However, it is still unclear whether the NFs were involved in the POCD. In this study, the LC-MS/MS method was used to explore the neuroinflammatory response and NFs of POCD in aged rats. Moreover, trichostatin A (TSA), an inflammation-related drug, was selected to test whether it could improve the surgery-induced cognitive dysfunction, inflammatory responses and NFs. Evident cognitive dysfunction, excessive microglia activation, neuroinflammatory responses and upregulated NFs in hippocampus were observed in the POCD group. TSA pretreatment could significantly mitigate these changes. The KEGG analysis revealed that nine pathways were enriched in the TSA + surgery group (versus the surgery group). Among them, two signaling pathways were closely related with the changes of NFs proteins. In conclusion, surgery could impair the cognitive function and aggravate neuroinflammation and NFs. The TSA could significantly improve these changes which might be related to the activation of the "focal adhesion" and "ECM-receptor interaction" pathways.

Topics: Animals; Cognitive Dysfunction; Hippocampus; Hydroxamic Acids; Inflammation; Intermediate Filaments; Laparotomy; Microglia; Postoperative Complications; Rats

To investigate whether histone deacetylase (HDAC) activity is associated with postoperative scarring and to evaluate the effect of HDAC inhibition by topical trichostatin A (TSA) on conjunctival fibrosis after trabeculectomy in a rat model.. Trabeculectomy was performed on the left eye of Sprague-Dawley rats. In the first experiment, adenoviruses HDAC 1, HDAC 2, and green fluorescent protein were added to the subconjunctival space during trabeculectomy. Expression of α-smooth muscle actin (α-SMA) was evaluated. In the second experiment, rats undergoing trabeculectomy were randomized into control, vehicle control, steroid, 500 nmol/L TSA, and 1 μmol/L TSA groups. On postoperative day 14, bleb vascularity, toxic effect of topical TSA on corneal epithelium, expression of α-SMA, transforming growth factor (TGF)-β1, and phosphorylated-Smad2/3 and the infiltration of CD45+ cells were determined. Masson's trichrome staining and immunofluorescence staining for α-SMA and CD45 were also performed.. Overexpression of HDAC1 contributed to accelerated conjunctival fibrosis after trabeculectomy. HDAC inhibition by topical administration of 1 μmol/L TSA significantly decreased bleb vascularity, leukocyte infiltration, and expression of α-SMA and TGF-β1 in the conjunctiva. Its effectiveness on conjunctival fibrosis was comparable to that of topical steroid. Masson's trichrome staining showed decreased collagen deposition in the bleb tissues of steroid and 1 μmol/L TSA treatment groups. Topical TSA did not have any toxic effect on the corneal epithelium.. HDAC activity is involved in postoperative conjunctival fibrosis. HDAC inhibition by topical administration of TSA eye drops is a safe and effective therapeutic modality to modulate wound healing after trabeculectomy.

Topics: Actins; Administration, Ophthalmic; Animals; Blotting, Western; Conjunctiva; Disease Models, Animal; Fibrosis; Histone Deacetylase Inhibitors; Hydroxamic Acids; Leukocyte Common Antigens; Phosphorylation; Postoperative Complications; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Smad2 Protein; Smad3 Protein; Trabeculectomy; Transforming Growth Factor beta1

Acute graft-versus-host disease (aGVHD) is a rare but serious and life-threatening complication of liver transplantation (LTx). Previously, we have demonstrated that the development of aGVHD after LTx (LTx-aGVHD) is associated with a decreased percentage of regulatory T cells (Tregs) in the peripheral blood of recipients. Histone deacetylase inhibitors promote the production of Tregs and some, such as suberoylanilide hydroxamic acid and trichostatin A (TSA), are used to treat autoimmune diseases, including GVHD after bone marrow transplantation.. In this study, LTx-aGVHD rats were treated with TSA continuously for 7 days from day 8 to 14 after LTx. Subsequently, splenic T cells were used for in vitro investigations of the mechanism of action of transplantation.. All LTx-aGVHD rats developed typical LTx-aGVHD symptoms after TSA treatment and died from LTx-aGVHD. The percentage frequency of Tregs in peripheral blood mononuclear cells was slightly up-regulated after TSA treatment, whereas TSA dramatically down-regulated Foxp3 protein and mRNA levels both in vivo and in vitro. Furthermore, TSA impaired T-cell proliferation and production of proinflammatory and anti-inflammatory cytokines in vitro.. TSA does not abrogate LTx-aGVHD in rats due to down-regulation of Tregs.

Topics: Acute Disease; Animals; Cell Proliferation; Cells, Cultured; Cytokines; Disease Models, Animal; Forkhead Transcription Factors; Graft Rejection; Graft vs Host Disease; Histone Deacetylase Inhibitors; Hydroxamic Acids; Liver Transplantation; Male; Postoperative Complications; Rats; Rats, Inbred BN; Rats, Inbred Lew; RNA, Messenger; Spleen; T-Lymphocytes, Regulatory; Treatment Failure