piperidines and Cicatrix

Topics: Adult; Antineoplastic Agents; Cicatrix; Color; Drug Eruptions; Facial Dermatoses; Female; Humans; Pigmentation Disorders; Piperidines; Quinazolines

Esophageal endoscopic submucosal dissection (ESD) is an effective minimally invasive therapy for early esophageal cancer and high-grade Barrett dysplasia. However, esophageal stricture formation after circumferential or large ESD has limited its wide adoption. Mitomycin C (MMC), halofuginone (Hal), and transforming growth factor β3 (TGF-β3) exhibits antiscarring effects that may prevent post-ESD stricture formation.. Using endoscopic mucosectomy (EEM) technique, an 8- to 10-cm-long circumferential esophageal mucosal segment was excised in a porcine model. The site was either untreated (control, n = 6) or received 40 evenly distributed injections of antiscarring agent immediately and at weeks 1 and 2. High and low doses were used: MMC 5 mg (n = 2), 0.5 mg (n = 2); Hal 5 mg (n = 2), 1.5 mg (n = 2), 0.5 mg (n = 2); TGF-β3 2 μg (n = 2), 0.5 μg (n = 2). The degree of stricture formation was determined by the percentage reduction of the esophageal lumen on weekly fluoroscopic examination. Animals were euthanized when strictures exceeded 80 % or the animals were unable to maintain weight.. The control group had a luminal diameter reduction of 78.2 ± 10.9 % by 2 weeks and were euthanized by week 3. Compared at 2 weeks, the Hal group showed a decrease in mean stricture formation (68.4 % low dose, 57.7 % high dose), while both TGF-β3 dosage groups showed no significant change (65.3 % low dose, 76.2 % high dose). MMC was most effective in stricture prevention (53.6 % low dose, 35 % high dose). Of concern, the esophageal wall treated with high-dose MMC appeared to be necrotic and eventually led to perforation. In contrast, low dose MMC, TGF-β3 and Hal treated areas appeared re-epithelialized and healthy.. Preliminary data on MMC and Hal demonstrated promise in reducing esophageal stricture formation after EEM. More animal data are needed to perform adequate statistical analysis in order to determine overall efficacy of antiscarring therapy.

Topics: Angiogenesis Inhibitors; Animals; Cicatrix; Disease Models, Animal; Dissection; Drug Therapy, Combination; Esophageal Diseases; Esophageal Stenosis; Esophagoscopy; Follow-Up Studies; Injections; Intestinal Mucosa; Mitomycin; Nucleic Acid Synthesis Inhibitors; Piperidines; Quinazolinones; Swine; Transforming Growth Factor beta3; Wound Healing

Injury to the CNS leads to formation of scar tissue, which is important in sealing the lesion and inhibiting axon regeneration. The fibrotic scar that comprises a dense extracellular matrix is thought to originate from meningeal cells surrounding the CNS. However, using transgenic mice, we demonstrate that perivascular collagen1α1 cells are the main source of the cellular composition of the fibrotic scar after contusive spinal cord injury in which the dura remains intact. Using genetic lineage tracing, light sheet fluorescent microscopy, and antigenic profiling, we identify collagen1α1 cells as perivascular fibroblasts that are distinct from pericytes. Our results identify collagen1α1 cells as a novel source of the fibrotic scar after spinal cord injury and shift the focus from the meninges to the vasculature during scar formation.

Topics: Analysis of Variance; Animals; Antigens; Blood Vessels; CD13 Antigens; Cell Count; Cicatrix; Collagen Type I; Collagen Type I, alpha 1 Chain; Disease Models, Animal; Disease Progression; Female; Fibroblasts; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Green Fluorescent Proteins; Lectins; Leukocyte Common Antigens; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pericytes; Piperidines; Proteoglycans; Receptor, Platelet-Derived Growth Factor beta; Spinal Cord Injuries; Time Factors; Uracil

Urethral strictures are from periurethral spongiofibrosis that develops as a result of urethral trauma, disease, or iatrogenic injury. The spongy tissue that surrounds the strictured urethra has an altered ratio of collagen, with increased collagen type I relative to type III. We evaluated the ability of a urethral catheter that was coated with halofuginone (HF), a potent type I collagen inhibitor, to prevent spongiofibrosis formation in a rat model.. HF was coated on silicone catheters and release kinetics were measured. Success of impregnation was evaluated with scanning electron microscopy, serial weights, and drug elution data. Urethral strictures were induced in rats using electrocautery. Half the animals had placement of an HF-coated catheter while the others had uncoated silicone controls. Animals were sacrificed at predetermined time points, and urethral tissue was either processed for staining with Masson trichrome and anti-alpha-1 collagen or digested to determine HF concentration. Serum drug levels were also determined in treated animals. Slides were graded by a pathologist who was blinded to treatment to determine collagen deposition.. HF was coated successfully on silicone catheters. Local urethral concentration of HF was tenfold higher than serum concentration in treated rats. Animals with HF-coated catheters had no new type I collagen deposition after urethral injury. Control animals had increased periurethral collagen type I deposition, typical of urethral stricture formation.. HF can be coated successfully on silicone catheters. HF successfully inhibits periurethral type I collagen deposition after urethral injury. This may become an important therapy to prevent urethral stricture formation or recurrence after endoscopic therapy.

Topics: Animals; Catheters; Cicatrix; Collagen Type I; Disease Models, Animal; Male; Piperidines; Quinazolinones; Rats; Rats, Sprague-Dawley; Staining and Labeling; Stents; Urethra; Urethral Diseases

The aim of the study was to assess the antifibrotic effect of systemically applied halofuginone after subglottic injury.. After standardized trauma to subglottic area, rats were divided into two groups: a study group that received treatment and a control group that did not. The rats were treated with 0.1 mg/kg/day intraperitoneal halofuginone injection for 30 days. The larynx specimens were examined histopathologically under light microscope for epithelization, inflammation, necrosis, and fibrosis.. The fibrosis indexes of the treated group were significantly less than those of the control group (P < .01).. Systemically applied halofuginone hydrobromide decreases fibrosis/scar tissue formation secondary to experimentally induced acute subglottic trauma.

Topics: Animals; Cicatrix; Epithelium; Female; Fibrosis; Glottis; Injections, Intraperitoneal; Laryngitis; Laryngostenosis; Larynx; Male; Necrosis; Piperidines; Protein Synthesis Inhibitors; Quinazolinones; Random Allocation; Rats; Rats, Sprague-Dawley

It is a major interest in the field of hematopoietic stem cell transplantation to reduce scarring of healing wounds with overdeposition of collagen due to radiation injury or graft-versus-host disease. Halofuginone (HF) inhibits collagen alpha1(I) gene expression and overdeposition of collagen. We examined the effect of HF on the healing of full-depth incision wounds inflicted in normal skin or skin areas compromised by local preirradiation with 18 Gy. Preirradiation significantly decreased the tensile strength of the healing wounds at day 14 (by approximately 60%, p < 0.0001). In contrast, HF treatment did not significantly decrease the strength of wounds inflicted in both normal and preirradiated skin. Histological evaluation revealed that HF induced moderate thinning of the dermis accompanied by elevated thickness of the epidermis and enhanced rejoining of subdermal muscles in the wound area. HF only minimally reduced total collagen deposition in both groups, with minor changes in the level of more matured fibrillar collagen network. Our study demonstrates that HF does not significantly affect wound strength. This encourages the possible use of HF as an antifibrotic agent with minimal complications for post-hematopoietic stem cell transplantation complications including radiation toxicity and graft-versus-host disease.

Topics: Animals; Cicatrix; Collagen Type I; Drug Evaluation, Preclinical; Hematopoietic Stem Cell Transplantation; Mice; Mice, Inbred C3H; Piperidines; Quinazolinones; Skin; Specific Pathogen-Free Organisms; Tensile Strength; Transplantation Conditioning; Wound Healing; Wounds, Penetrating

Traumatic brain injury (TBI) causes neuronal apoptosis, inflammation, and reactive astrogliosis, which contribute to secondary tissue loss, impaired regeneration, and associated functional disabilities. Here, we show that up-regulation of cell cycle components is associated with caspase-mediated neuronal apoptosis and glial proliferation after TBI in rats. In primary neuronal and astrocyte cultures, cell cycle inhibition (including the cyclin-dependent kinase inhibitors flavopiridol, roscovitine, and olomoucine) reduced up-regulation of cell cycle proteins, limited neuronal cell death after etoposide-induced DNA damage, and attenuated astrocyte proliferation. After TBI in rats, flavopiridol reduced cyclin D1 expression in neurons and glia in ipsilateral cortex and hippocampus. Treatment also decreased neuronal cell death and lesion volume, reduced astroglial scar formation and microglial activation, and improved motor and cognitive recovery. The ability of cell cycle inhibition to decrease both neuronal cell death and reactive gliosis after experimental TBI suggests that this treatment approach may be useful clinically.

Topics: Animals; Apoptosis; Astrocytes; Brain Injuries; Caspase 3; Caspases; Cell Cycle; Cell Proliferation; Cell Survival; Cells, Cultured; Cicatrix; Cyclin D1; Cyclin-Dependent Kinases; DNA Damage; Etoposide; Flavonoids; Gene Expression Regulation; Male; Neuroglia; Neuroprotective Agents; Piperidines; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley

Topics: Animals; Autoradiography; Cicatrix; Cytoplasmic Granules; Feeding Behavior; Female; Glucose; Gold; Hypothalamus; Injections, Intraperitoneal; Malates; Mice; Necrosis; Nitrogen Mustard Compounds; Obesity; Piperidines; Time Factors