PMID- 30322354 OWN - NLM STAT- MEDLINE DCOM- 20191024 LR - 20200501 IS - 1097-6817 (Electronic) IS - 0194-5998 (Print) IS - 0194-5998 (Linking) VI - 160 IP - 1 DP - 2019 Jan TI - Pathologic Fibroblasts in Idiopathic Subglottic Stenosis Amplify Local Inflammatory Signals. PG - 107-115 LID - 10.1177/0194599818803584 [doi] 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. FAU - Morrison, Robert J AU - Morrison RJ AD - 1 Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University, Nashville, Tennessee, USA. AD - 2 Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, USA. FAU - Katsantonis, Nicolas-George AU - Katsantonis NG AD - 1 Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University, Nashville, Tennessee, USA. FAU - Motz, Kevin M AU - Motz KM AD - 3 Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins, Baltimore, Maryland, USA. FAU - Hillel, Alexander T AU - Hillel AT AD - 3 Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins, Baltimore, Maryland, USA. FAU - Garrett, C Gaelyn AU - Garrett CG AD - 1 Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University, Nashville, Tennessee, USA. FAU - Netterville, James L AU - Netterville JL AD - 1 Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University, Nashville, Tennessee, USA. FAU - Wootten, Christopher T AU - Wootten CT AD - 1 Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University, Nashville, Tennessee, USA. FAU - Majka, Susan M AU - Majka SM AD - 4 Department of Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee, USA. FAU - Blackwell, Timothy S AU - Blackwell TS AD - 4 Department of Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee, USA. AD - 5 Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, USA. FAU - Drake, Wonder P AU - Drake WP AD - 6 Division of Infectious Disease, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA. FAU - Gelbard, Alexander AU - Gelbard A AD - 1 Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University, Nashville, Tennessee, USA. LA - eng GR - P01 HL092870/HL/NHLBI NIH HHS/United States GR - R01 HL136449/HL/NHLBI NIH HHS/United States GR - P30 CA068485/CA/NCI NIH HHS/United States GR - R01 HL146401/HL/NHLBI NIH HHS/United States GR - R01 HL117074/HL/NHLBI NIH HHS/United States GR - K24 HL127301/HL/NHLBI NIH HHS/United States GR - R01 HL116597/HL/NHLBI NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20181016 PL - England TA - Otolaryngol Head Neck Surg JT - Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery JID - 8508176 RN - 0 (Cytokines) RN - 0 (IL17A protein, human) RN - 0 (Interleukin-17) SB - IM MH - Biopsy, Needle MH - Case-Control Studies MH - Cell Proliferation/genetics MH - Cells, Cultured MH - Cicatrix/*pathology MH - Cytokines/metabolism MH - Enzyme-Linked Immunosorbent Assay/methods MH - Female MH - Fibroblasts/*pathology MH - Fibrosis/genetics/*pathology MH - Flow Cytometry/methods MH - Humans MH - Immunohistochemistry MH - Interleukin-17/*genetics MH - Laryngostenosis/genetics/*pathology MH - Male MH - Polymerase Chain Reaction/methods MH - Reference Values MH - Sensitivity and Specificity MH - Signal Transduction/genetics PMC - PMC6389372 MID - NIHMS1002559 OTO - NOTNLM OT - IL-17 OT - IL-17A OT - fibroblast OT - iSGS OT - idiopathic subglottis stenosis OT - laryngotracheal stenosis OT - tracheal stenosis COIS- Disclosures Competing interests: Alexander T. Hillel, Olympus, USA- consultant. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. EDAT- 2018/10/17 06:00 MHDA- 2019/10/28 06:00 PMCR- 2019/03/01 CRDT- 2018/10/17 06:00 PHST- 2018/10/17 06:00 [pubmed] PHST- 2019/10/28 06:00 [medline] PHST- 2018/10/17 06:00 [entrez] PHST- 2019/03/01 00:00 [pmc-release] AID - 10.1177/0194599818803584 [doi] PST - ppublish SO - Otolaryngol Head Neck Surg. 2019 Jan;160(1):107-115. doi: 10.1177/0194599818803584. Epub 2018 Oct 16.