PMID- 37292825
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231219
DP  - 2023 May 19
TI  - Idiopathic subglottic stenosis arises at the epithelial interface of host and 
      pathogen.
LID - rs.3.rs-2945067 [pii]
LID - 10.21203/rs.3.rs-2945067/v1 [doi]
AB  - BACKGROUND: Idiopathic subglottic stenosis (iSGS) is a rare fibrotic disease of 
      the proximal airway affecting adult Caucasian women nearly exclusively. 
      Life-threatening ventilatory obstruction occurs secondary to pernicious 
      subglottic mucosal scar. Disease rarity and wide geographic patient distribution 
      has previously limited substantive mechanistic investigation into iSGS 
      pathogenesis. RESULT: By harnessing pathogenic mucosa from an international iSGS 
      patient cohort and single-cell RNA sequencing, we unbiasedly characterize the 
      cell subsets in the proximal airway scar and detail their molecular phenotypes. 
      Results show that the airway epithelium in iSGS patients is depleted of basal 
      progenitor cells, and the residual epithelial cells acquire a mesenchymal 
      phenotype. Observed displacement of bacteria beneath the lamina propria provides 
      functional support for the molecular evidence of epithelial dysfunction. Matched 
      tissue microbiomes support displacement of the native microbiome into the lamina 
      propria of iSGS patients rather than disrupted bacterial community structure. 
      However, animal models confirm that bacteria are necessary for pathologic 
      proximal airway fibrosis and suggest an equally essential role for host adaptive 
      immunity. Human samples from iSGS airway scar demonstrate adaptive immune 
      activation in response to the proximal airway microbiome of both matched iSGS 
      patients and healthy controls. Clinical outcome data from iSGS patients suggests 
      surgical extirpation of airway scar and reconstitution with unaffected tracheal 
      mucosa halts the progressive fibrosis. CONCLUSION: Our data support an iSGS 
      disease model where epithelial alterations facilitate microbiome displacement, 
      dysregulated immune activation, and localized fibrosis. These results refine our 
      understanding of iSGS and implicate shared pathogenic mechanisms with distal 
      airway fibrotic diseases.
FAU - Gelbard, Alexander
AU  - Gelbard A
AD  - Vanderbilt University Medical Center.
FAU - Shilts, Meghan H
AU  - Shilts MH
AD  - Vanderbilt University Medical Center.
FAU - Strickland, Britton
AU  - Strickland B
AD  - Vanderbilt University Medical Center.
FAU - Motz, Kevin
AU  - Motz K
AD  - Johns Hopkins.
FAU - Tsai, Hsiu-Wen
AU  - Tsai HW
AD  - Johns Hopkins.
FAU - Boone, Helen
AU  - Boone H
AD  - Vanderbilt University Medical Center.
FAU - Drake, Wonder P
AU  - Drake WP
AD  - Vanderbilt University Medical Center.
FAU - Wanjalla, Celestine
AU  - Wanjalla C
AD  - Vanderbilt University Medical Center.
FAU - Smith, Paula Marincola
AU  - Smith PM
AD  - Vanderbilt University Medical Center.
FAU - Brown, Hunter
AU  - Brown H
AD  - Vanderbilt University Medical Center.
FAU - Ramierez, Marisol
AU  - Ramierez M
AD  - The Newcastle upon Tyne Hospitals NHS Foundation Trust.
FAU - Atkinson, James B
AU  - Atkinson JB
AD  - Vanderbilt University Medical Center.
FAU - Powell, Jason
AU  - Powell J
AD  - Newcastle University.
FAU - Simpson, John
AU  - Simpson J
AD  - Newcastle University.
FAU - Rajagopala, Seesandra V
AU  - Rajagopala SV
AD  - Vanderbilt University Medical Center.
FAU - Mallal, Simon
AU  - Mallal S
AD  - Vanderbilt University Medical Center.
FAU - Sheng, Quanhu
AU  - Sheng Q
AD  - Vanderbilt University Medical Center.
FAU - Hillel, Alexander T
AU  - Hillel AT
AD  - Johns Hopkins.
FAU - Das, Suman R
AU  - Das SR
AD  - Vanderbilt University Medical Center.
LA  - eng
GR  - R21 AI149262/AI/NIAID NIH HHS/United States
GR  - K23 DC020988/DC/NIDCD NIH HHS/United States
GR  - R01 HL146401/HL/NHLBI NIH HHS/United States
GR  - R21 AI142321/AI/NIAID NIH HHS/United States
GR  - R21 AI154016/AI/NIAID NIH HHS/United States
PT  - Preprint
DEP - 20230519
PL  - United States
TA  - Res Sq
JT  - Research square
JID - 101768035
PMC - PMC10246274
COIS- COMPETING INTERESTS The authors of this manuscript declare no financial or other 
      conflicts of interest to disclose as described by the journal Microbiome.
EDAT- 2023/06/09 06:41
MHDA- 2023/06/09 06:42
PMCR- 2023/06/07
CRDT- 2023/06/09 04:27
PHST- 2023/06/09 06:41 [pubmed]
PHST- 2023/06/09 06:42 [medline]
PHST- 2023/06/09 04:27 [entrez]
PHST- 2023/06/07 00:00 [pmc-release]
AID - rs.3.rs-2945067 [pii]
AID - 10.21203/rs.3.rs-2945067/v1 [doi]
PST - epublish
SO  - Res Sq [Preprint]. 2023 May 19:rs.3.rs-2945067. doi: 10.21203/rs.3.rs-2945067/v1.