elastin and Tracheal-Stenosis

The airway structures and messenger RNA expression of genes that regulate airway inflammation and remodeling may be altered in the trachea of patients with tracheobronchomalacia (TBM).. Fourteen tracheal specimens obtained from 2005 to 2018 were used in this study. Surgical resection specimens from patients with TBM and tracheal stenosis (TS) were compared with control tracheal specimens obtained from autopsy cases. We investigated the messenger RNA expression of genes encoding fibroblast growth factor (FGF) binding protein 2 (FGFBP2), FGF receptor R3 (FGFR3), interleukin-1β (IL1β), tumor growth factor-β1 (TGFβ1), tissue inhibitor of metalloproteinases 1 (TIMP1), and intercellular adhesion molecule 1 (ICAM1) as well as established markers of airway inflammation including interferon-γ (IFNγ) and tumor necrosis factor (TNF). The relative expression of target transcripts was assessed by quantitative real-time polymerase chain reaction. A histologic examination of the same resected airway specimens was performed on formalin-fixed paraffin-embedded tissue sections.. FGFBP2 and FGFR3 showed higher expression in TBM compared with TS and control groups (P < .05 and P < .01, respectively). Furthermore, both TGFβ1 and TIMP1 were elevated in TBM patients compared with control subjects (P < .05). Conversely ICAM1 was downregulated in TBM versus TS and control subjects (P < .05). IL1β, IFNγ, and TNF were increased in TBM, although it did not achieve statistical significance. Histologically compared with control airways both TBM and TS demonstrated submucosal fibrotic changes, with TBM additionally demonstrating alterations in elastin fiber quality and density in the posterior membrane.. Significant changes in gene expression are observed in the tracheal walls of patients with TBM and TS compared with control subjects.

Topics: Elastin; Fibroblast Growth Factors; Formaldehyde; Gene Expression; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interferon-gamma; Interleukin-1beta; Receptors, Fibroblast Growth Factor; RNA, Messenger; Tissue Inhibitor of Metalloproteinases; Tracheal Stenosis; Tracheobronchomalacia; Tumor Necrosis Factors

To define the inflammatory cell infiltrate preceding fibrosis in a laryngotracheal stenosis (LTS) murine model.. Prospective controlled murine study.. Laboratory.. Chemomechanical injury mice (n = 44) sustained bleomycin-coated wire-brush injury to the laryngotracheal complex while mechanical injury controls (n = 42) underwent phosphate-buffered saline (PBS)-coated wire-brush injury. Mock surgery controls (n = 34) underwent anterior transcervical tracheal exposure only. Inflammatory and fibrosis protein and gene expression were assessed in each condition. Immunohistochemistry served as a secondary outcome.. In chemomechanical injury mice, there was an upregulation of collagen I (P < .0001, P < .0001), Tgf-β (P = .0023, P = .0008), and elastin (P < .0001, P < .0001) on day 7; acute inflammatory gene Il1β (P = .0027, P = .0008) on day 1; and macrophage gene CD11b (P = .0026, P = .0033) on day 1 vs mechanical and mock controls, respectively. M1 marker inducible nitric oxide synthase (iNOS) expression decreased (P = .0014) while M2 marker Arg1 (P = .0002) increased on day 7 compared with mechanical controls. Flow cytometry demonstrated increased macrophages (P = .0058, day 4) and M1 macrophages (P = .0148, day 4; P = .0343, day 7; P = .0229, day 10) compared to mock controls. There were similarities between chemomechanical and mechanical injury mice with an increase in M2 macrophages at day 10 (P = .0196).. The bleomycin-induced LTS mouse model demonstrated increased macrophages involved with the development of fibrosis. Macrophage immunophenotype suggested that dysregulated M2 macrophages have a role in abnormal laryngotracheal wound healing. These data delineate inflammatory cells and signaling pathways in LTS that may potentially be modulated to lessen fibroblast proliferation and collagen deposition.

Topics: Animals; Bleomycin; Collagen; Disease Models, Animal; Elastin; Flow Cytometry; Gene Expression; Immunohistochemistry; Laryngostenosis; Larynx; Macrophages; Mice; Mice, Inbred C57BL; Prospective Studies; Trachea; Tracheal Stenosis; Transforming Growth Factor beta

Treatment of congenital tracheal stenosis/atresia remains essentially unresolved. Previous models of this disease entity have been restricted to rodents and the chick. We sought to establish the principles of a large, surgical animal model of this spectrum of fetal anomalies.. Fetal lambs (n = 8) underwent open surgery at 90-112 days gestation. Their cervical tracheas were encircled by a biocompatible polytetrafluoroethylene wrap, so as to extrinsically restrict their external diameter by 25%. Survivors (n = 7) were killed at different time points post-operatively before term. The manipulated tracheal segments were compared with their respective proximal portions (controls). Analyses included morphometry, histology and quantitative extracellular matrix measurements.. At necropsy, the typical gross appearance of tracheal stenosis/atresia was present in all manipulated tracheal segments. Histological findings included the virtual disappearance of the membranous portion of the trachea, along with infolding, fragmentation, and/or posterior fusion of cartilaginous rings, often with disappearance of the airway mucosa. There were significant decreases in diameter (P < 0.001) and total collagen levels (P = 0.005) on the manipulated trachea compared with the control portions. No significant differences were observed in overall elastin or glycosaminoglycan contents. A significant time-dependent increase in elastin was noted on the control, but not the experimental side.. In a surgical ovine model, controlled extrinsic compression of the fetal trachea leads to morphological and biochemical findings compatible with the congenital tracheal stenosis/atresia spectrum. This simple and easily reproducible prenatal model can be instrumental in the development of emerging therapies for these congenital anomalies.

Topics: Animals; Biocompatible Materials; Collagen; Disease Models, Animal; Elastin; Extracellular Matrix; Female; Fetus; Fluorocarbon Polymers; Organogenesis; Pregnancy; Sheep; Trachea; Tracheal Stenosis

Topics: Adult; Animals; Bronchoscopy; Elastin; Granulation Tissue; Humans; Infant; Male; Methods; Polymers; Postoperative Complications; Prostheses and Implants; Radiography; Sheep; Silicones; Sutures; Trachea; Tracheal Stenosis