Dataset Information

Ablation or Inhibition of Protein Disulfide Isomerase A3 (PDIA3) in Aberrant Club Cells Attenuates Osteopontin (SPP1) Production and Pulmonary Fibrosis

ABSTRACT: Rationale: The role of club cells in the pathology of Idiopathic Pulmonary Fibrosis IPF is not well understood. PDIA3, an endoplasmic reticulum (ER) based redox chaperone catalyzes the cysteine disulfide bonds (-S-S-) in various fibrosis-related proteins; however, mechanisms of action of PDIA3 in pulmonary fibrosis is not fully elucidated. Objectives: To examine the role of club cells and PDIA3 in the pathogenesis of pulmonary fibrosis (PF) and therapeutic potential of inhibition of PDIA3 in PF. Methods: The impact of PDIA3 and aberrant club cells in PF was studied by retrospective analysis of human transcriptome data from LGRC, and specific deletion and inhibition of PDIA3 in club cells and blocking Osteopontin (SPP1) downstream of PDIA3 in mice. Measurements and Main Results: The PDIA3 along with club cell secretory protein (SCGB1A1 or CCSP) signatures are upregulated in IPF compared to control patients, and PDIA3 increases correlate with a decrease in lung function in IPF patients. The Bleomycin (BLM) model of PF showed increases in aberrant CCSP and PDIA3 positive cells in the lung parenchyma. Ablation of Pdia3, specifically in CCSP cells, decreases CCSP cells along with PF in mice. The therapeutic administration of a PDI inhibitor LOC14 reversed the BLM-induced CCSP cells and PF in mice. The proteomic screen of the PDIA3 partners revealed SPP1 as a major interactor in PF. Blocking SPP1 attenuated the development of PF in mice. Conclusions: Collectively, this study demonstrates a new relationship of club cells, with PDIA3, SPP1, and a putative pathological function of club cells in pulmonary fibrosis.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Lung, Epithelial Cell

DISEASE(S): Idiopathic Pulmonary Fibrosis,Pulmonary Fibrosis

SUBMITTER: Ying Wai Lam

LAB HEAD: Vikas Anathy

PROVIDER: PXD021715 | Pride | 2021-11-11

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Clarissa_QE_0146_IgG_PBS_Sample_1.raw	Raw
	Clarissa_QE_0162_IP_BLM24d_Sample_8.raw	Raw
	Clarissa_QE_0165_IP_BLM14d_Sample_4.raw	Raw
	Clarissa_QE_0167_IP_NegCNTL_Sample_10.raw	Raw
	Clarissa_QE_0169_IgG_BLM14d_Sample_4.raw	Raw

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Publications

Inhibition of PDIA3 in club cells attenuates osteopontin production and lung fibrosis.

Kumar Amit A Elko Evan E Bruno Sierra R SR Mark Zoe F ZF Chamberlain Nicolas N Mihavics Bethany Korwin BK Chandrasekaran Ravishankar R Walzer Joseph J Ruban Mona M Gold Clarissa C Lam Ying Wai YW Ghandikota Sudhir S Jegga Anil G AG Gomez Jose L JL Janssen-Heininger Yvonne Mw YM Anathy Vikas V

Thorax 20210816 7

<h4>Background</h4>The role of club cells in the pathology of idiopathic pulmonary fibrosis (IPF) is not well understood. Protein disulfide isomerase A3 (PDIA3), an endoplasmic reticulum-based redox chaperone required for the functions of various fibrosis-related proteins; however, the mechanisms of action of PDIA3 in pulmonary fibrosis are not fully elucidated.<h4>Objectives</h4>To examine the role of club cells and PDIA3 in the pathology of pulmonary fibrosis and the therapeutic potential of i ...[more]

PMID: 34400514

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