2. Academic Validation
  3. Airway and parenchyma transcriptomics in a house dust mite model of experimental asthma

Airway and parenchyma transcriptomics in a house dust mite model of experimental asthma

  • Respir Res. 2023 Jan 25;24(1):32. doi: 10.1186/s12931-022-02298-x.
Xiaofan Tu # 1,  Henry M Gomez # 1,  Richard Y Kim 1 2,  Alexandra C Brown 1,  Emma de Jong 3,  Izabela Galvao 4,  Alen Faiz 2,  Anthony Bosco 5,  Jay C Horvat 1,  Philip Hansbro # 6 7,  Chantal Donovan # 8 9
Affiliations

Affiliations

  • 1 Priority Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia.
  • 2 Faculty of Science, School of Life Sciences, University of Technology Sydney, Sydney, NSW, Australia.
  • 3 Centre for Health Research, Telethon Kids Institute, The University of Western Australia, Nedlands, WA, Australia.
  • 4 Centre for Inflammation, Faculty of Science, School of Life Sciences, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia.
  • 5 Asthma and Airway Disease Research Center, University of Arizona, Arizona, USA.
  • 6 Priority Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia. [email protected].
  • 7 Centre for Inflammation, Faculty of Science, School of Life Sciences, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia. [email protected].
  • 8 Priority Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Newcastle, NSW, Australia. [email protected].
  • 9 Faculty of Science, School of Life Sciences, University of Technology Sydney, Sydney, NSW, Australia. [email protected].
  • # Contributed equally.
PMID: 36698141 DOI: 10.1186/s12931-022-02298-x
Abstract

Lung transcriptomics studies in asthma have provided valuable information in the whole lung context, however, deciphering the individual contributions of the airway and parenchyma in disease pathogenesis may expedite the development of novel targeted treatment strategies. In this study, we performed transcriptomics on the airway and parenchyma using a house dust Mite (HDM)-induced model of experimental asthma that replicates key features of the human disease. HDM exposure increased the expression of 3,255 genes, of which 212 were uniquely increased in the airways, 856 uniquely increased in the parenchyma, and 2187 commonly increased in both compartments. Further interrogation of these genes using a combination of network and transcription factor enrichment analyses identified several transcription factors that regulate airway and/or parenchymal gene expression, including transcription factor EC (TFEC), transcription factor PU.1 (SPI1), H2.0-like homeobox (HLX), metal response element binding transcription factor-1 (MTF1) and E74-like factor 4 (ets domain transcription factor, ELF4) involved in controlling innate immune responses. We next assessed the effects of inhibiting lung SPI1 responses using commercially available DB1976 and DB2313 on key disease outcomes. We found that both compounds had no protective effects on airway inflammation, however DB2313 (8 mg/kg) decreased mucus secreting cell number, and both DB2313 (1 mg/kg) and DB1976 (2.5 mg/kg and 1 mg/kg) reduced small airway collagen deposition. Significantly, both compounds decreased airway hyperresponsiveness. This study demonstrates that SPI1 is important in HDM-induced experimental asthma and that its pharmacological inhibition reduces HDM-induced airway collagen deposition and hyperresponsiveness.

Keywords

AHR; Asthma; House dust mite; Remodeling; SPI1; Transcriptomics.

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