The Experts below are selected from a list of 723 Experts worldwide ranked by ideXlab platform
Alexander T. Hillel - One of the best experts on this subject based on the ideXlab platform.
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quantitative assessment of the immune microenvironment in patients with iatrogenic Laryngotracheal Stenosis
2021Co-Authors: Ruth J Davis, Kevin Motz, Dacheng Ding, Alexander Gelbard, Ioan Lina, Benjamin Green, Elizabeth L Engle, Janis M Taube, Alexander T. HillelAbstract:ObjectiveIatrogenic Laryngotracheal Stenosis (iLTS) is characterized by fibroinflammatory narrowing of the upper airway and is most commonly caused by intubation injury. Evidence suggests a key rol...
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increased expression of pd 1 and pd l1 in patients with Laryngotracheal Stenosis
2021Co-Authors: Ruth J Davis, Dacheng Ding, Alexander Gelbard, Ioan Lina, Elizabeth L Engle, Janis M Taube, Alexander T. HillelAbstract:OBJECTIVES Laryngotracheal Stenosis (LTS) is a fibrotic condition of the upper airway. Recent evidence suggests dysregulated host immunity plays a role in LTS development and progression. The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis, targeted by paradigm-shifting immunotherapies for cancer treatment, has also recently been implicated in the pathogenesis of fibrotic pulmonary disease. However, a role for the PD-1/PD-L1 axis in the proximal airway fibrosis seen in LTS patients has not been explored. STUDY DESIGN Controlled ex vivo study. METHODS Expression of PD-1, PD-L1, CD4, and CD8 were evaluated using immunohistochemical staining of cricotracheal resection specimens from postintubation iatrogenic Laryngotracheal Stenosis (iLTS), idiopathic subglottic Stenosis (iSGS) patients, and normal controls derived from rapid autopsy (n = 8 per group). Fibroblasts derived from iLTS scar were also treated with transforming growth factor beta 1 (TGFβ1) and analyzed for PD-L1 expression by quantitative real-time polymerase chain reaction (n = 6). RESULTS iLTS specimens exhibited increased expression of PD-1, PD-L1, and CD4 (all P < .0167) compared to controls, whereas iSGS specimens exhibited increased expression of PD-1 and CD4 (P < .0167) compared to controls. PD-1, PD-L1, and CD4 showed periepithelial patterns of expression in both disease cohorts. TGFβ1 treatment of iLTS fibroblasts increased expression of PD-L1 (the cognate ligand for PD-1). CONCLUSION Expression of both PD-1 and its ligand PD-L1 are significantly greater in patients with iLTS compared to controls, and PD-1 expression is also elevated in patients with iSGS. Given published evidence implicating the PD-1/PD-L1 axis in pulmonary fibrosis, this suggests a possible role for checkpoint inhibitors targeting the PD-1/PD-L1 axis for the treatment of LTS. LEVEL OF EVIDENCE N/A Laryngoscope, 131:967-974, 2021.
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design of a biocompatible drug eluting tracheal stent in mice with Laryngotracheal Stenosis
2020Co-Authors: Madhavi Duvvuri, Kevin Motz, Dacheng Ding, Hsiuwen Tsai, Ioan Lina, Andrew G Lee, Alexander T. HillelAbstract:Laryngotracheal Stenosis (LTS) is a pathologic narrowing of the subglottis and trachea leading to extrathoracic obstruction and significant shortness of breath. LTS results from mucosal injury from a foreign body in the trachea, leading to tissue damage and a local inflammatory response that goes awry, leading to the deposition of pathologic scar tissue. Treatment for LTS is surgical due to the lack of effective medical therapies. The purpose of this method is to construct a biocompatible stent that can be miniaturized to place into mice with LTS. We demonstrated that a PLLA-PCL (70% poly-L-lactide and 30% polycaprolactone) construct had optimal biomechanical strength, was biocompatible, practicable for an in vivo placement stent, and capable of eluting drug. This method provides a drug delivery system for testing various immunomodulatory agents to locally inhibit inflammation and reduce airway fibrosis. Manufacturing the stents takes 28-30 h and can be reproduced easily, allowing for experiments with large cohorts. Here we incorporated the drug rapamycin within the stent to test its effectiveness in reducing fibrosis and collagen deposition. Results revealed that PLLA-PCL tents showed reliable rapamycin release, were mechanically stable in physiological conditions, and were biocompatible, inducing little inflammatory response in the trachea. Further, the rapamycin-eluting PLLA-PCL stents reduced scar formation in the trachea in vivo.
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inhibition of glutaminase to reverse fibrosis in iatrogenic Laryngotracheal Stenosis
2020Co-Authors: Hsiuwen Tsai, Michael K Murphy, Kevin Motz, Dacheng Ding, Michael Feeley, Ioan Lina, Dimitri Benner, Jody E Hooper, Alexander T. HillelAbstract:OBJECTIVES/HYPOTHESIS Glutamine metabolism is a critical energy source for iatrogenic Laryngotracheal Stenosis (iLTS) scar fibroblasts, and glutaminase (GLS) is an essential enzyme converting glutamine to glutamate. We hypothesize that the GLS-specific inhibitor BPTES will block glutaminolysis and reduce iLTS scar fibroblast proliferation, collagen deposition, and fibroblast metabolism in vitro. STUDY DESIGN Test-tube Lab Research. METHODS Immunohistochemistry of a cricotracheal resection (n = 1) and a normal airway specimen (n = 1) were assessed for GLS expression. GLS expression was assessed in brush biopsies of subglottic/tracheal fibrosis and normal airway from patients with iLTS (n = 6). Fibroblasts were isolated and cultured from biopsies of subglottic/tracheal fibrosis (n = 6). Fibroblast were treated with BPTES and BPTES + dimethyl α-ketoglutarate (DMK), an analogue of the downstream product of GLS. Fibroblast proliferation, gene expression, protein production, and metabolism were assessed in all treatment conditions and compared to control. RESULTS GLS was overexpressed in brush biopsies of iLTS scar specimens (P = .029) compared to normal controls. In vitro, BPTES inhibited iLTS scar fibroblast proliferation (P = .007), collagen I (Col I) (P < .0001), collagen III (P = .004), and α-smooth muscle actin (P = .0025) gene expression and protein production (P = .031). Metabolic analysis demonstrated that BPTES reduced glycolytic reserve (P = .007) but had no effects on mitochondrial oxidative phosphorylation. DMK rescued BPTES inhibition of Col I gene expression (P = .0018) and protein production (P = .021). CONCLUSIONS GLS is overexpressed in iLTS scar. Blockage of GLS with BPTES significantly inhibits iLTS scar fibroblasts proliferation and function, demonstrating a critical role for GLS in iLTS. Targeting GLS to inhibit glutaminolysis may be a successful strategy to reverse scar formation in the airway. LEVEL OF EVIDENCE NA Laryngoscope, 2020.
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Laryngotracheal Microbiota in Adult Laryngotracheal Stenosis.
2019Co-Authors: Alexander T. Hillel, Sharon S. Tang, Camila Carlos, Joseph H. Skarlupka, Madhu Gowda, Linda X. Yin, Kevin M. Motz, Cameron R. Currie, Garret Suen, Susan L. ThibeaultAbstract:Laryngotracheal Stenosis is an obstructive respiratory disease that leads to voicing difficulties and dyspnea with potential life-threatening consequences. The majority of incidences are due to iatrogenic etiology from endotracheal tube intubation; however, airway scarring also has idiopathic causes. While recent evidence suggests a microbial contribution to mucosal inflammation, the microbiota associated with different types of Stenosis has not been characterized. High-throughput sequencing of the V4 region of the16S rRNA gene was performed to characterize the microbial communities of 61 swab samples from 17 iatrogenic and 10 adult idiopathic Stenosis patients. Nonscar swabs from Stenosis patients were internal controls, and eight swabs from four patients without Stenosis represented external controls. Significant differences in diversity were observed between scar and nonscar samples and among sample sites, with decreased diversity detected in scar samples and the glottis region. Permutational analysis of variance (PERMANOVA) results revealed significant differences in community composition for scar versus nonscar samples, etiology type, sample site, groups (iatrogenic, idiopathic, and internal and external controls), and individual patients. Pairwise Spearman's correlation revealed a strong inverse correlation between Prevotella and Streptococcus among all samples. Finally, bacteria in the family Moraxellaceae were found to be distinctly associated with idiopathic Stenosis samples in comparison with external controls. Our findings suggest that specific microbiota and community shifts are present with Laryngotracheal Stenosis in adults, with members of the family Moraxellaceae, including the known pathogens Moraxella and Acinetobacter, identified in idiopathic scar. Further work is warranted to elucidate the contributing role of bacteria on the pathogenesis of Laryngotracheal Stenosis.IMPORTANCE The Laryngotracheal region resides at the intersection between the heavily studied nasal cavity and lungs; however, examination of the microbiome in chronic inflammatory conditions of the subglottis and trachea remains scarce. To date, studies have focused on the microbiota of the vocal folds, or the glottis, for laryngeal carcinoma, as well as healthy larynges, benign vocal fold lesions, and larynges exposed to smoking and refluxate. In this study, we seek to examine the structure and composition of the microbial community in adult Laryngotracheal Stenosis of various etiologies. Due to the heterogeneity among the underlying pathogenesis mechanisms and clinical outcomes seen in Laryngotracheal Stenosis disease, we hypothesized that different microbial profiles will be detected among various Stenosis etiology types. Understanding differences in the microbiota for subglottic Stenosis subtypes may shed light upon etiology-specific biomarker identification and offer novel insights into management approaches for this debilitating disease.
Dacheng Ding - One of the best experts on this subject based on the ideXlab platform.
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quantitative assessment of the immune microenvironment in patients with iatrogenic Laryngotracheal Stenosis
2021Co-Authors: Ruth J Davis, Kevin Motz, Dacheng Ding, Alexander Gelbard, Ioan Lina, Benjamin Green, Elizabeth L Engle, Janis M Taube, Alexander T. HillelAbstract:ObjectiveIatrogenic Laryngotracheal Stenosis (iLTS) is characterized by fibroinflammatory narrowing of the upper airway and is most commonly caused by intubation injury. Evidence suggests a key rol...
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increased expression of pd 1 and pd l1 in patients with Laryngotracheal Stenosis
2021Co-Authors: Ruth J Davis, Dacheng Ding, Alexander Gelbard, Ioan Lina, Elizabeth L Engle, Janis M Taube, Alexander T. HillelAbstract:OBJECTIVES Laryngotracheal Stenosis (LTS) is a fibrotic condition of the upper airway. Recent evidence suggests dysregulated host immunity plays a role in LTS development and progression. The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis, targeted by paradigm-shifting immunotherapies for cancer treatment, has also recently been implicated in the pathogenesis of fibrotic pulmonary disease. However, a role for the PD-1/PD-L1 axis in the proximal airway fibrosis seen in LTS patients has not been explored. STUDY DESIGN Controlled ex vivo study. METHODS Expression of PD-1, PD-L1, CD4, and CD8 were evaluated using immunohistochemical staining of cricotracheal resection specimens from postintubation iatrogenic Laryngotracheal Stenosis (iLTS), idiopathic subglottic Stenosis (iSGS) patients, and normal controls derived from rapid autopsy (n = 8 per group). Fibroblasts derived from iLTS scar were also treated with transforming growth factor beta 1 (TGFβ1) and analyzed for PD-L1 expression by quantitative real-time polymerase chain reaction (n = 6). RESULTS iLTS specimens exhibited increased expression of PD-1, PD-L1, and CD4 (all P < .0167) compared to controls, whereas iSGS specimens exhibited increased expression of PD-1 and CD4 (P < .0167) compared to controls. PD-1, PD-L1, and CD4 showed periepithelial patterns of expression in both disease cohorts. TGFβ1 treatment of iLTS fibroblasts increased expression of PD-L1 (the cognate ligand for PD-1). CONCLUSION Expression of both PD-1 and its ligand PD-L1 are significantly greater in patients with iLTS compared to controls, and PD-1 expression is also elevated in patients with iSGS. Given published evidence implicating the PD-1/PD-L1 axis in pulmonary fibrosis, this suggests a possible role for checkpoint inhibitors targeting the PD-1/PD-L1 axis for the treatment of LTS. LEVEL OF EVIDENCE N/A Laryngoscope, 131:967-974, 2021.
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glutamine inhibition reduces iatrogenic Laryngotracheal Stenosis
2021Co-Authors: Hsiuwen Tsai, Michael K Murphy, Kevin Motz, Dacheng Ding, Michael Feeley, Ioan Lina, Liam Chung, Jennifer H ElisseeffAbstract:OBJECTIVE/HYPOTHESIS Glutamine inhibition has been demonstrated an antifibrotic effect in iatrogenic Laryngotracheal Stenosis (iLTS) scar fibroblasts in vitro. We hypothesize that broadly active glutamine antagonist, DON will reduce collagen formation and fibrosis-associated gene expression in iLTS mice. STUDY DESIGN Prospective controlled animal study. METHODS iLTS in mice were induced by chemomechanical injury of the trachea using a bleomycin-coated wire brush. PBS or DON (1.3 mg/kg) were administered by intraperitoneal injection (i.p.) every other day. Laryngotracheal complexes were harvested at days 7 and 14 after the initiation of DON treatment for the measurement of lamina propria thickness, trichrome stain, immunofluorescence staining of collagen 1, and fibrosis-associated gene expression. RESULTS The study demonstrated that DON treatment reduced lamina propria thickness (P = .025) and collagen formation in trichrome stain and immunofluorescence staining of collagen 1. In addition, DON decreased fibrosis-associated gene expression in iLTS mice. At day 7, DON inhibited Col1a1 (P < .0001), Col3a1 (P = .0046), Col5a1 (P < .0001), and Tgfβ (P = .023) expression. At day 14, DON reduced Co1a1 (P = .0076) and Tgfβ (P = .023) expression. CONCLUSIONS Broadly active glutamine antagonist, DON, significantly reduces fibrosis in iLTS mice. These results suggest that the concept of glutamine inhibition may be a therapeutic option to reduce fibrosis in the Laryngotracheal Stenosis. LEVEL OF EVIDENCE N/A Laryngoscope, 131:E2125-E2130, 2021.
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design of a biocompatible drug eluting tracheal stent in mice with Laryngotracheal Stenosis
2020Co-Authors: Madhavi Duvvuri, Kevin Motz, Dacheng Ding, Hsiuwen Tsai, Ioan Lina, Andrew G Lee, Alexander T. HillelAbstract:Laryngotracheal Stenosis (LTS) is a pathologic narrowing of the subglottis and trachea leading to extrathoracic obstruction and significant shortness of breath. LTS results from mucosal injury from a foreign body in the trachea, leading to tissue damage and a local inflammatory response that goes awry, leading to the deposition of pathologic scar tissue. Treatment for LTS is surgical due to the lack of effective medical therapies. The purpose of this method is to construct a biocompatible stent that can be miniaturized to place into mice with LTS. We demonstrated that a PLLA-PCL (70% poly-L-lactide and 30% polycaprolactone) construct had optimal biomechanical strength, was biocompatible, practicable for an in vivo placement stent, and capable of eluting drug. This method provides a drug delivery system for testing various immunomodulatory agents to locally inhibit inflammation and reduce airway fibrosis. Manufacturing the stents takes 28-30 h and can be reproduced easily, allowing for experiments with large cohorts. Here we incorporated the drug rapamycin within the stent to test its effectiveness in reducing fibrosis and collagen deposition. Results revealed that PLLA-PCL tents showed reliable rapamycin release, were mechanically stable in physiological conditions, and were biocompatible, inducing little inflammatory response in the trachea. Further, the rapamycin-eluting PLLA-PCL stents reduced scar formation in the trachea in vivo.
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inhibition of glutaminase to reverse fibrosis in iatrogenic Laryngotracheal Stenosis
2020Co-Authors: Hsiuwen Tsai, Michael K Murphy, Kevin Motz, Dacheng Ding, Michael Feeley, Ioan Lina, Dimitri Benner, Jody E Hooper, Alexander T. HillelAbstract:OBJECTIVES/HYPOTHESIS Glutamine metabolism is a critical energy source for iatrogenic Laryngotracheal Stenosis (iLTS) scar fibroblasts, and glutaminase (GLS) is an essential enzyme converting glutamine to glutamate. We hypothesize that the GLS-specific inhibitor BPTES will block glutaminolysis and reduce iLTS scar fibroblast proliferation, collagen deposition, and fibroblast metabolism in vitro. STUDY DESIGN Test-tube Lab Research. METHODS Immunohistochemistry of a cricotracheal resection (n = 1) and a normal airway specimen (n = 1) were assessed for GLS expression. GLS expression was assessed in brush biopsies of subglottic/tracheal fibrosis and normal airway from patients with iLTS (n = 6). Fibroblasts were isolated and cultured from biopsies of subglottic/tracheal fibrosis (n = 6). Fibroblast were treated with BPTES and BPTES + dimethyl α-ketoglutarate (DMK), an analogue of the downstream product of GLS. Fibroblast proliferation, gene expression, protein production, and metabolism were assessed in all treatment conditions and compared to control. RESULTS GLS was overexpressed in brush biopsies of iLTS scar specimens (P = .029) compared to normal controls. In vitro, BPTES inhibited iLTS scar fibroblast proliferation (P = .007), collagen I (Col I) (P < .0001), collagen III (P = .004), and α-smooth muscle actin (P = .0025) gene expression and protein production (P = .031). Metabolic analysis demonstrated that BPTES reduced glycolytic reserve (P = .007) but had no effects on mitochondrial oxidative phosphorylation. DMK rescued BPTES inhibition of Col I gene expression (P = .0018) and protein production (P = .021). CONCLUSIONS GLS is overexpressed in iLTS scar. Blockage of GLS with BPTES significantly inhibits iLTS scar fibroblasts proliferation and function, demonstrating a critical role for GLS in iLTS. Targeting GLS to inhibit glutaminolysis may be a successful strategy to reverse scar formation in the airway. LEVEL OF EVIDENCE NA Laryngoscope, 2020.
Robin T. Cotton - One of the best experts on this subject based on the ideXlab platform.
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diagnosis and management of Laryngotracheal Stenosis
2018Co-Authors: Matthew M Smith, Robin T. CottonAbstract:ABSTRACTIntroduction: Laryngotracheal Stenosis comprises a broad spectrum of congenital and acquired conditions that commonly cause pediatric airway obstruction. Although the majority of these cond...
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pediatric Laryngotracheal Stenosis and airway reconstruction a review of voice outcomes assessment and treatment issues
2006Co-Authors: Robin T. Cotton, Susan Baker, Lisa Kelchner, Barbara Weinrich, Linda Lee, Paul Willging, Karen B ZurAbstract:Summary Laryngotracheal Stenosis is defined as a congenital or acquired narrowing of the airway. Congenital causes may include subglottic membranous or cartilaginous narrowing. Acquired causes may include trauma due to prolonged endotracheal or tracheal intubation or Laryngotracheal injury. Although advances have been made over the past 30 years in reconstructive surgeries to improve airway patency in these patients, long-term laryngeal function for voice production is not well defined in this population. This review examines causes, symptoms and signs, and methods for diagnosing Laryngotracheal Stenosis. Surgical management procedures are briefly summarized. The current literature on voice outcomes is summarized. The predominant voice characteristics in the population are presented, although results are challenged by the heterogeneity of voice presentation and paucity of data from instrumental measures. Considerations for subjective and instrumental assessment, measures of quality of life, instrumental methods, and treatment options specific to the needs of this population are discussed. Research strategies to identify long-term outcomes of surgical and behavioral treatments in this population are posed.
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cricotracheal resection as a primary procedure for Laryngotracheal Stenosis in children
2000Co-Authors: Benjamin E J Hartley, Michael J Rutter, Robin T. CottonAbstract:Abstract Objective: Cricotracheal resection (CTR) is being increasingly used in the treatment of children with severe Laryngotracheal Stenosis. In this institution the majority of children are treated with CTR as a salvage procedure having undergone previous unsuccessful Laryngotracheal reconstruction (LTR). Selected children have undergone CTR as a primary procedure (without previous LTR). The objective of this study is to examine the outcome for children undergoing cricotracheal resection as a primary procedure for severe Laryngotracheal Stenosis. Method: analysis from prospectively collected database. Results: 17 patients underwent CTR without previous LTR or anterior cricoid split between October 1994 and September 1998. All the patients had grade 3 or 4 Stenosis. After a minimum of 1 year follow up 15 children are decannulated. Five children required further surgery to achieve this. Two children still have tracheostomies. Both had extended procedures. One included bilateral arytenoid abduction for bilateral vocal cord paralysis in a patient with quadraparesis following transverse myelitis. The other child, who suffered from multiple congenital anomalies, underwent a concurrent posterior cricoid cartilage graft. Nine patients had good voice post-operatively, five had acceptable voice and three had weak or no voice. Conclusion: the early experience for CTR in children as a primary procedure achieved an overall decannulation rate of 88% after 1 year follow up in children with severe Laryngotracheal Stenosis. Five children required further surgery to achieve this. The voice outcome was variable. CTR is an alternative primary procedure to LTR for severe Laryngotracheal Stenosis in children. The relative indications for these procedures are discussed.
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Progressive Laryngotracheal Stenosis with short stature and arthropathy.
1998Co-Authors: Robert J. Hopkin, Robin T. Cotton, Leonard O. Langer, Howard M. SaalAbstract:Laryngotracheal Stenosis is rare in adults, especially in the absence of a malignancy. It is most commonly caused by fibrosis following endotracheal intubation or tracheal trauma. Other conditions causing progressive airway narrowing include the mucopolysaccharidoses and autoimmune disorders. With the exception of storage diseases, there are no well-defined genetic disorders with progressive airway narrowing as a common complication. We have evaluated three unrelated individuals with this potentially life-threatening finding, all of whom have a previously unrecognized condition. Each patient had short stature and joint stiffness with no evidence for infectious, inflammatory, or metabolic diseases as a cause of their condition. None of our patients had clinical findings indicative of known skeletal dysplasias or storage diseases. They had minor facial anomalies which included deeply set eyes, bushy eyebrows, and flat midface. Given the unique findings of our patients including adult onset critical tracheal Stenosis, short stature, progressive joint limitation, and distinct facial anomalies, we conclude that they have a previously undescribed condition.
Kevin Motz - One of the best experts on this subject based on the ideXlab platform.
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quantitative assessment of the immune microenvironment in patients with iatrogenic Laryngotracheal Stenosis
2021Co-Authors: Ruth J Davis, Kevin Motz, Dacheng Ding, Alexander Gelbard, Ioan Lina, Benjamin Green, Elizabeth L Engle, Janis M Taube, Alexander T. HillelAbstract:ObjectiveIatrogenic Laryngotracheal Stenosis (iLTS) is characterized by fibroinflammatory narrowing of the upper airway and is most commonly caused by intubation injury. Evidence suggests a key rol...
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glutamine inhibition reduces iatrogenic Laryngotracheal Stenosis
2021Co-Authors: Hsiuwen Tsai, Michael K Murphy, Kevin Motz, Dacheng Ding, Michael Feeley, Ioan Lina, Liam Chung, Jennifer H ElisseeffAbstract:OBJECTIVE/HYPOTHESIS Glutamine inhibition has been demonstrated an antifibrotic effect in iatrogenic Laryngotracheal Stenosis (iLTS) scar fibroblasts in vitro. We hypothesize that broadly active glutamine antagonist, DON will reduce collagen formation and fibrosis-associated gene expression in iLTS mice. STUDY DESIGN Prospective controlled animal study. METHODS iLTS in mice were induced by chemomechanical injury of the trachea using a bleomycin-coated wire brush. PBS or DON (1.3 mg/kg) were administered by intraperitoneal injection (i.p.) every other day. Laryngotracheal complexes were harvested at days 7 and 14 after the initiation of DON treatment for the measurement of lamina propria thickness, trichrome stain, immunofluorescence staining of collagen 1, and fibrosis-associated gene expression. RESULTS The study demonstrated that DON treatment reduced lamina propria thickness (P = .025) and collagen formation in trichrome stain and immunofluorescence staining of collagen 1. In addition, DON decreased fibrosis-associated gene expression in iLTS mice. At day 7, DON inhibited Col1a1 (P < .0001), Col3a1 (P = .0046), Col5a1 (P < .0001), and Tgfβ (P = .023) expression. At day 14, DON reduced Co1a1 (P = .0076) and Tgfβ (P = .023) expression. CONCLUSIONS Broadly active glutamine antagonist, DON, significantly reduces fibrosis in iLTS mice. These results suggest that the concept of glutamine inhibition may be a therapeutic option to reduce fibrosis in the Laryngotracheal Stenosis. LEVEL OF EVIDENCE N/A Laryngoscope, 131:E2125-E2130, 2021.
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design of a biocompatible drug eluting tracheal stent in mice with Laryngotracheal Stenosis
2020Co-Authors: Madhavi Duvvuri, Kevin Motz, Dacheng Ding, Hsiuwen Tsai, Ioan Lina, Andrew G Lee, Alexander T. HillelAbstract:Laryngotracheal Stenosis (LTS) is a pathologic narrowing of the subglottis and trachea leading to extrathoracic obstruction and significant shortness of breath. LTS results from mucosal injury from a foreign body in the trachea, leading to tissue damage and a local inflammatory response that goes awry, leading to the deposition of pathologic scar tissue. Treatment for LTS is surgical due to the lack of effective medical therapies. The purpose of this method is to construct a biocompatible stent that can be miniaturized to place into mice with LTS. We demonstrated that a PLLA-PCL (70% poly-L-lactide and 30% polycaprolactone) construct had optimal biomechanical strength, was biocompatible, practicable for an in vivo placement stent, and capable of eluting drug. This method provides a drug delivery system for testing various immunomodulatory agents to locally inhibit inflammation and reduce airway fibrosis. Manufacturing the stents takes 28-30 h and can be reproduced easily, allowing for experiments with large cohorts. Here we incorporated the drug rapamycin within the stent to test its effectiveness in reducing fibrosis and collagen deposition. Results revealed that PLLA-PCL tents showed reliable rapamycin release, were mechanically stable in physiological conditions, and were biocompatible, inducing little inflammatory response in the trachea. Further, the rapamycin-eluting PLLA-PCL stents reduced scar formation in the trachea in vivo.
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inhibition of glutaminase to reverse fibrosis in iatrogenic Laryngotracheal Stenosis
2020Co-Authors: Hsiuwen Tsai, Michael K Murphy, Kevin Motz, Dacheng Ding, Michael Feeley, Ioan Lina, Dimitri Benner, Jody E Hooper, Alexander T. HillelAbstract:OBJECTIVES/HYPOTHESIS Glutamine metabolism is a critical energy source for iatrogenic Laryngotracheal Stenosis (iLTS) scar fibroblasts, and glutaminase (GLS) is an essential enzyme converting glutamine to glutamate. We hypothesize that the GLS-specific inhibitor BPTES will block glutaminolysis and reduce iLTS scar fibroblast proliferation, collagen deposition, and fibroblast metabolism in vitro. STUDY DESIGN Test-tube Lab Research. METHODS Immunohistochemistry of a cricotracheal resection (n = 1) and a normal airway specimen (n = 1) were assessed for GLS expression. GLS expression was assessed in brush biopsies of subglottic/tracheal fibrosis and normal airway from patients with iLTS (n = 6). Fibroblasts were isolated and cultured from biopsies of subglottic/tracheal fibrosis (n = 6). Fibroblast were treated with BPTES and BPTES + dimethyl α-ketoglutarate (DMK), an analogue of the downstream product of GLS. Fibroblast proliferation, gene expression, protein production, and metabolism were assessed in all treatment conditions and compared to control. RESULTS GLS was overexpressed in brush biopsies of iLTS scar specimens (P = .029) compared to normal controls. In vitro, BPTES inhibited iLTS scar fibroblast proliferation (P = .007), collagen I (Col I) (P < .0001), collagen III (P = .004), and α-smooth muscle actin (P = .0025) gene expression and protein production (P = .031). Metabolic analysis demonstrated that BPTES reduced glycolytic reserve (P = .007) but had no effects on mitochondrial oxidative phosphorylation. DMK rescued BPTES inhibition of Col I gene expression (P = .0018) and protein production (P = .021). CONCLUSIONS GLS is overexpressed in iLTS scar. Blockage of GLS with BPTES significantly inhibits iLTS scar fibroblasts proliferation and function, demonstrating a critical role for GLS in iLTS. Targeting GLS to inhibit glutaminolysis may be a successful strategy to reverse scar formation in the airway. LEVEL OF EVIDENCE NA Laryngoscope, 2020.
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engineering an immunomodulatory drug eluting stent to treat Laryngotracheal Stenosis
2019Co-Authors: Madhavi Duvvuri, Kevin Motz, Dacheng Ding, Michael Feeley, Jennifer H Elisseeff, Michael Murphy, Andrew G Lee, Alexander T. HillelAbstract:Objective: Develop a drug-eluting stent construct with a reliable drug-release profile and adequate mechanically stability for a trial in a small animal model of Laryngotracheal Stenosis (LTS), a debilitating pathologic narrowing of the airway leading to significant shortness of breath. Methods: Biodegradable, biocompatible stents containing 1.0% rapamycin made of PLLA-PCL (70% Poly-L-Lactide and 30% Polycaprolactone blend) and 50 : 50 PDLGA (Poly(DL-lactide-co-glycolide)) were compared. Mechanical strength testing and drug elution rates using high performance liquid chromatography analysis (HPLC) was assessed. Next, efficacy of stent elution on LTS derived scar fibroblasts. Finally, stents were placed in situ in an LTS mouse model. Results: The PLLA-PCL stent construct exhibited greater mechanical strength compared to the PDLGA stent over a 4-week period (Young's Modulus (PLLA-PCL) = 13.82; Young's Modulus (PDLGA) = 4.015). Moreover, the PLLA-PCL stent showed a reliable rapamycin release profile for 6 weeks (30% elution for PLLA-PCL stents compared to <1% elution for PDLGA). Collagen 1 (p < 0.05) and fibroblast cell proliferation were decreased in vitro when treated with the rapamycin stent. In vivo, the rapamycin stent reduced lamina propria thickness (p < 0.05) and collagen 1(p < 0.05), collagen 3, TGF-B (p < 0.05) and a-SMA (p < 0.05). Conclusions: The PLLA-PCL construct demonstrated superior mechanical strength and greater drug elution compared to PDLGA stents. We demonstrated the feasibility of testing this drug-eluting stent in vivo, showing that the rapamycin-eluting stent treats fibrosis. To our knowledge this is the first study to deploy a drug-eluting stent to treat tracheal pathology in an animal model. Optimization of a rapamycin-eluting PLLA-PCL stent for translational investigation will lead to improved treatment strategies of LTS.
Koen F M Joosten - One of the best experts on this subject based on the ideXlab platform.
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voice outcome and voice related quality of life after surgery for pediatric Laryngotracheal Stenosis
2017Co-Authors: Bas Pullens, Marieke M Hakkesteegt, Hans L J Hoeve, M K Timmerman, Koen F M JoostenAbstract:Objectives To evaluate the long-term outcome of voice quality and voice-related quality of life after open airway surgery for pediatric Laryngotracheal Stenosis. Study Design Prospective cohort study. Methods Children under the age of 18 years at time of follow-up and with a history of open airway surgery for acquired Laryngotracheal Stenosis were included in this analysis. To assess voice-related quality of life, the pediatric voice handicap (pVHI) index was completed by the patients' parents. The dysphonia severity index (DSI) was used as an objective measurement for voice quality. Results Fifty-five parents completed the pVHI, and 38 children completed the DSI. This showed high pVHI values and low total DSI scores, indicating significant voice disturbance. After multivariate analysis, the presence of comorbidities and glottic involvement of the Stenosis are associated with poor long-term voice-related quality of life. Conclusion Significant voice disturbance is common after surgery for pediatric Laryngotracheal Stenosis. Glottic involvement of the Stenosis and comorbidities is associated with poor voice-related quality of life. Evaluation of pre- and postoperative voice quality and voice-related quality of life is advised for children treated for Laryngotracheal Stenosis. Level of Evidence 2B. Laryngoscope, 127:1707–1711, 2017
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long term functional airway assessment after open airway surgery for Laryngotracheal Stenosis
2016Co-Authors: Bas Pullens, M K Timmerman, Marielle W Pijnenburg, Hans J Hoeve, Robert Baatenburg J De Jong, Corinne Buysse, Marc P Van Der Schroeff, Koen F M JoostenAbstract:Objectives/Hypothesis The purpose of this study was to evaluate our patient-reported and objective long-term outcomes of patients treated for Laryngotracheal Stenosis. Study Design Prospective cohort study. Methods Sixty-five patients were evaluated after a median follow-up of 7 years after surgery. Follow-up measurements consisted of pulmonary function testing, Bruce treadmill test, and Child Health Questionnaires (CHQ). Results Pulmonary function tests were available in 43 patients, and 30/43 had abnormal forced expiratory volume in 1 second/forced inspiratory volume in 1 second (FIV1), 25/43 had abnormal FIV1/maximum vital capacity, and 24/43 had abnormal peak expiratory flow. One-third of patients had reduced exercise tolerance. CHQ revealed significant positive correlations with pulmonary function results and exercise tolerance. Multivariate analysis showed that glottic involvement of the Stenosis and the presence of comorbidities at time of surgery are the only factors for poor long-term functional outcome. Conclusions The majority of patients show deficits in pulmonary function and exercise tolerance related to lower scores of quality of life. Glottic involvement of the Stenosis and the presence of comorbidities are the only significant factors for poor functional outcome. Long-term multidisciplinary follow up is mandatory after surgery for Laryngotracheal Stenosis. Level of Evidence 2B. Laryngoscope, 2015
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characteristics and surgical outcome of 98 infants and children surgically treated for a Laryngotracheal Stenosis after endotracheal intubation excellent outcome for higher grades of Stenosis after ss ltr
2014Co-Authors: Bas Pullens, M K Timmerman, L J Hoeve, M P Van Der Schroeff, Koen F M JoostenAbstract:Abstract Introduction To describe the characteristics and surgical outcome of 98 infants and children treated for an acquired laryngeal Stenosis after intubation for respiratory support. Material and methods We retrospectively reviewed our data from the last 18 years (1994–2013) concerning infants and children with an acquired Laryngotracheal Stenosis who were treated in our hospital with a Laryngotracheal reconstruction or a cricotracheal resection. Outcome was defined by decannulation ratio. Results Of the 98 infants and children who were studied, 54% were preterm, 18% neonates, 13% infants and 14% children. Ninety-one SS-LTR’s, two DS-LTR’s and five CTR’s were performed as primary surgery; three revision operations were performed (DS-LTR). Seventy-seven children had a tracheostomy prior to surgery; decannulation ratio was 93% after primary surgery and 95% after inclusion of revision surgery. For SS-LTR, the decannulation ratio was 93%, including grade III Stenosis with comorbidities. Male sex and glottic involvement of the Stenosis are correlated to failure of decannulation. Intubation in the term neonatal period is correlated to complicated post-operative course after SS-LTR. Conclusions Excellent results of surgery for acquired Laryngotracheal Stenosis can be obtained with a high decannulation rate. Even for higher grades of Stenosis with comorbidities and glottic involvement, an SS-LTR is an effective surgical treatment for acquired laryngeal Stenosis.
