Translational genomics of acquired laryngotracheal stenosis

Anis, Mursalin M.; Zhao, Zhigen; Khurana, Jasvir S.; Krynetskiy, Evgeny; Soliman, Ahmed M. S.

doi:10.1002/lary.24382

Cited by 15 publications

(15 citation statements)

References 17 publications

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“…39 Recent discoveries also highlight the potential for a genetic predisposition to laryngotracheal scar formation; one study found an association between a polymorphism in matrix metalloproteinase 1 (MMP1) and the formation of scar after intubation injury. 40 This discovery complements our finding of elevated MMP activity after hypoxic stimulation of normal laryngotracheal fibroblasts, suggesting that genetic predisposition may enhance the effects of hypoxia on the laryngotracheal ECM. Ultimately, we believe that iLTS is multi-factorial disease arising from a combination of genetic predisposition, hypoxic and mechanical tissue injury, and subsequent consequences on local microbiome and inflammation.…”

Section: Discussionsupporting

confidence: 75%

Fibroblasts in Hypoxic Conditions Mimic Laryngotracheal Stenosis

Yin

Motz²,

Samad

et al. 2017

Otolaryngol.--head neck surg.

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Objective To elucidate the role of hypoxia and inflammatory pathways in the pathogenesis of iatrogenic laryngotracheal stenosis (iLTS). Study Design 1) Examination of mucosal surface gene expression in human iLTS 2) In vitro comparison of normal and scar laryngotracheal fibroblasts under normoxic and hypoxic conditions Setting Tertiary care hospital in a research university, 2012–2016 Subjects and Methods Brush biopsies were obtained from normal laryngotracheal tissue and scar in iLTS patients; gene expression was compared. Fibroblasts were isolated from normal and scarred trachea and grown in vitro in either a 1% O2 or normoxic environment. Cell growth and gene and protein expression were compared. Statistical analysis utilized a multilevel mixed-effects model. Results Expression of IL-6 (Fold-change = 2.8, p<0.01), myofibroblast marker αSMA (Fold-change = 3.0, p=0.01), and MMP13 (Fold-change = 5.4, p=0.02) was significantly increased in scar biopsy samples compared to normal. Under hypoxic conditions in vitro, normal laryngotracheal fibroblasts proliferated significantly faster (n=8, p<0.01 each day). Expression of IL-6 (n=8, Fold-change = 2.6, p<0.01) increased significantly after 12 hours under hypoxia. Expression of αSMA (n=8, Fold-change= 2.0, p=0.03), COL1 (n=8, Fold-change = 1.1), and MMP13 (n=8, Fold-change = 1.6, p=0.01) increased significantly after 48 hours under hypoxia. Scar fibroblasts also proliferated significantly faster under hypoxic conditions, but did not display the same expression profile. Conclusion Human iLTS scar has a myofibroblast phenotype. Under hypoxic conditions in vitro, normal laryngotracheal fibroblasts can transdifferentiate into a similar phenotype. These changes may be mediated by IL-6, a fibrosis-related cytokine.

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Section: Discussionsupporting

confidence: 75%

Fibroblasts in Hypoxic Conditions Mimic Laryngotracheal Stenosis

Yin

Motz²,

Samad

et al. 2017

Otolaryngol.--head neck surg.

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“…). Inclusion criteria were 1) a history of endotracheal intubation for at least 3 days, 2) the intubation or tracheotomy had to have occurred at least 30 days before recruitment to ensure adequate time for ALTS to develop in susceptible subjects, and 3) laryngoscopy, bronchoscopy, or radiologic studies must have documented the presence or absence of ALTS in the medical record …”

Section: Methodsmentioning

confidence: 99%

“…This study excluded patients with congenital subglottic stenosis, idiopathic subglottic stenosis, chronic inflammatory and autoimmune diseases such as Wegener's granulomatosis, idiopathic pulmonary fibrosis, sarcoidosis, cicatricial pemphigoid, relapsing polychondritis, and patients who have received radiation therapy to the head or neck …”

Section: Methodsmentioning

confidence: 99%

“…SNP selection was done as described previously . Based on our current understanding of the pathophysiology of ALTS, candidate genes were selected that contribute to the inflammatory, proliferation, and remodeling phases of wound healing .…”

Section: Methodsmentioning

confidence: 99%

“…The TGFβ1 SNP (rs1800469) is functional in that it alters transcription factor binding to the TGFβ1 promoter, thus affecting transcription and plasma concentration of this cytokine . In previous work from our group, a functional SNP of an interstitial collagenase, matrix metalloproteinase (MMP)‐1 ( MMP1 ), was found to be associated with development of ALTS in a group of 76 patients . MMP‐1 and other MMPs are responsible for degradation of extracellular matrix components, and changes in expression of these enzymes may influence remodeling and development of stenosis .…”

Section: Introductionmentioning

confidence: 99%

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Determining Candidate Single Nucleotide Polymorphisms in Acquired Laryngotracheal Stenosis

et al. 2017

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The Incidence of Laryngotracheal Stenosis in Neonates With a History of Ventilator‐Associated Pneumonia

2019

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Objectives/HypothesisNeonatal patients requiring prolonged intubation are susceptible to both infection and laryngotracheal stenosis (LTS). This study investigated the effect of ventilator‐associated pneumonia (VAP) on the development of LTS in neonates.Study DesignRetrospective case–control study.MethodsThe incidence of LTS in neonates with VAP was compared with the incidence of LTS in matched intubated controls without VAP. Patients were treated at a tertiary‐care medical center from 2004 to 2014. Eligible patient records were assessed for the development of LTS. Demographics, medical comorbidities, infection characteristics, and treatment variables were compared using unpaired t test or χ2 test. Statistical significance was set a priori at P < .05.ResultsWhen comparing the VAP patients with matched non‐VAP controls, we found no significant differences in the incidence of LTS (VAP vs. non‐VAP, 8.3% vs. 6.7%; P = .73). In subgroup analysis of the VAP cohort, LTS and non‐LTS patients demonstrated similar VAP organisms on broncho‐alveolar lavage (Klebsiella pneumoniae, Pseudomonas aeroginosa, Escherichia coli, methicillin‐resistant Staphylococcus aureus, Streptococcus pneumoniae, and Enterobacter). Additionally, within the VAP cohort, LTS and non‐LTS patients showed similar gestational age (LTS vs. non‐LTS, 31.3 days vs. 28.1 days; P = .22), birth weight (LTS vs. non‐LTS, 1.6 kg vs. 1.2 kg; P = .33), and similar intubation duration (LTS vs. non‐LTS, 37.8 days vs. 27.5 days; P = .52).ConclusionsIn this neonatal cohort, VAP was not associated with an increased incidence of LTS. Given severity of the burden of LTS on the healthcare system, multi‐institutional longitudinal investigation into contributing risk factors for neonatal LTS is warranted.Level of EvidenceNA Laryngoscope, 130:2252–2255, 2020

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Translational genomics of acquired laryngotracheal stenosis

Cited by 15 publications

References 17 publications

Fibroblasts in Hypoxic Conditions Mimic Laryngotracheal Stenosis

Fibroblasts in Hypoxic Conditions Mimic Laryngotracheal Stenosis

Determining Candidate Single Nucleotide Polymorphisms in Acquired Laryngotracheal Stenosis

The Incidence of Laryngotracheal Stenosis in Neonates With a History of Ventilator‐Associated Pneumonia

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