TY - JOUR
T1 - Pathologic Fibroblasts in Idiopathic Subglottic Stenosis Amplify Local Inflammatory Signals
AU - Morrison, Robert J.
AU - Katsantonis, Nicolas George
AU - Motz, Kevin M.
AU - Hillel, Alexander T.
AU - Garrett, C. Gaelyn
AU - Netterville, James L.
AU - Wootten, Christopher T.
AU - Majka, Susan M.
AU - Blackwell, Timothy S.
AU - Drake, Wonder P.
AU - Gelbard, Alexander
N1 - Funding Information:
Sponsorships: North American Airway Collaborative. Funding source: Research in the North American Airway Collaborative is made possible by infrastructure supported by the Patient-Centered Outcomes Research Institute (award 1409-22214). We acknowledge the resources provided by the Bobby R. Alford Endowed Research Grant, American Academy of Otolaryngology— Head and Neck Surgery Foundation. We also acknowledge the Vanderbilt genomics core laboratory VANTAGE (Vanderbilt Technologies for Advanced Genomics), supported by an American Recovery and Reinvestment Act–funded National Institutes of Health award, as well as the Translational Pathology Shared Resource, supported by a Cancer Center Support grant (2P30 CA068485-14) from the National Cancer Institute / National Institutes of Health. The content is solely the responsibility of the authors.
Publisher Copyright:
© American Academy of Otolaryngology–Head and Neck Surgery Foundation 2018.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Objective: To characterize the phenotype and function of fibroblasts derived from airway scar in idiopathic subglottic stenosis (iSGS) and to explore scar fibroblast response to interleukin 17A (IL-17A). Study Design: Basic science. Setting: Laboratory. Subjects and Methods: Primary fibroblast cell lines from iSGS subjects, idiopathic pulmonary fibrosis subjects, and normal control airways were utilized for analysis. Protein, molecular, and flow cytometric techniques were applied in vitro to assess the phenotype and functional response of disease fibroblasts to IL-17A. Results: Mechanistically, IL-17A drives iSGS scar fibroblast proliferation (P <.01), synergizes with transforming growth factor ß1 to promote extracellular matrix production (collagen and fibronectin; P =.04), and directly stimulates scar fibroblasts to produce chemokines (chemokine ligand 2) and cytokines (IL-6 and granulocyte-macrophage colony-stimulating factor) critical to the recruitment and differentiation of myeloid cells (P <.01). Glucocorticoids abrogated IL-17A-dependent iSGS scar fibroblast production of granulocyte-macrophage colony-stimulating factor (P =.02). Conclusion: IL-17A directly drives iSGS scar fibroblast proliferation, synergizes with transforming growth factor ß1 to promote extracellular matrix production, and amplifies local inflammatory signaling. Glucocorticoids appear to partially abrogate fibroblast-dependent inflammatory signaling. These results offer mechanistic support for future translational study of clinical reagents for manipulation of the IL-17A pathway in iSGS patients.
AB - Objective: To characterize the phenotype and function of fibroblasts derived from airway scar in idiopathic subglottic stenosis (iSGS) and to explore scar fibroblast response to interleukin 17A (IL-17A). Study Design: Basic science. Setting: Laboratory. Subjects and Methods: Primary fibroblast cell lines from iSGS subjects, idiopathic pulmonary fibrosis subjects, and normal control airways were utilized for analysis. Protein, molecular, and flow cytometric techniques were applied in vitro to assess the phenotype and functional response of disease fibroblasts to IL-17A. Results: Mechanistically, IL-17A drives iSGS scar fibroblast proliferation (P <.01), synergizes with transforming growth factor ß1 to promote extracellular matrix production (collagen and fibronectin; P =.04), and directly stimulates scar fibroblasts to produce chemokines (chemokine ligand 2) and cytokines (IL-6 and granulocyte-macrophage colony-stimulating factor) critical to the recruitment and differentiation of myeloid cells (P <.01). Glucocorticoids abrogated IL-17A-dependent iSGS scar fibroblast production of granulocyte-macrophage colony-stimulating factor (P =.02). Conclusion: IL-17A directly drives iSGS scar fibroblast proliferation, synergizes with transforming growth factor ß1 to promote extracellular matrix production, and amplifies local inflammatory signaling. Glucocorticoids appear to partially abrogate fibroblast-dependent inflammatory signaling. These results offer mechanistic support for future translational study of clinical reagents for manipulation of the IL-17A pathway in iSGS patients.
KW - IL-17
KW - IL-17A
KW - fibroblast
KW - iSGS
KW - idiopathic subglottis stenosis
KW - laryngotracheal stenosis
KW - tracheal stenosis
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U2 - 10.1177/0194599818803584
DO - 10.1177/0194599818803584
M3 - Article
C2 - 30322354
AN - SCOPUS:85059591382
SN - 0194-5998
VL - 160
SP - 107
EP - 115
JO - Otolaryngology - Head and Neck Surgery
JF - Otolaryngology - Head and Neck Surgery
IS - 1
ER -