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Supersulphide airway protection in viral and chronic lung diseases

ABSTRACT: Supersulphides (inorganic and organic sulphides with sulphur catenation) manifest diverse physiological functions. These supersulphides are mainly generated from mitochondrial cysteinyl-tRNA synthetase (CARS2) that functions as a principal cysteine persulphide synthase (CPERS). Here we found powerful protective functions of supersulphides in viral airway infections (influenza and COVID-19) and chronic lung diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and aged lungs. Enhanced supersulphide exhalation also occurred from human airways in COVID-19 as well as the hamster model of SARS-CoV-2 infection, as identified by breath supersulphur-omics that we developed herein. The lung damage related to oxidative stress and inflammation in mouse models of COPD, IPF, and ageing and the lethal effects that resulted were mitigated by endogenous supersulphides, supplied via CARS2/CPERS or exogenously by the supersulphide donor glutathione trisulphide. Our findings thus elucidated the airway protective role of supersulphides and their therapeutic potential in viral and chronic lung diseases.

INSTRUMENT(S): 6520A Quadrupole Time-of-Flight LC/MS

ORGANISM(S): Escherichia Coli

SUBMITTER: Seiryo Ogata

LAB HEAD: Takaaki Akaike

PROVIDER: PXD043607 | Pride | 2023-07-14

REPOSITORIES: Pride

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Project description:BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time. METHODS: In order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions x 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans. RESULTS: We identified 127 genes whose expression levels were significantly associated with regional emphysema severity while controlling for gene expression differences between individuals. Genes increasing in expression with increasing emphysematous destruction included those involved in inflammation, such as the B-cell receptor signaling pathway, while genes decreasing in expression were enriched in tissue repair processes, including the transforming growth factor beta (TGF beta) pathway, actin organization, and integrin signaling. We found concordant differential expression of these emphysema severity-associated genes in four cross-sectional studies of COPD. Using the Connectivity Map, we identified GHK as a compound that can reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGF beta pathway activation. Treatment of human fibroblasts with GHK recapitulated TGF beta-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin beta1. Furthermore, addition of GHK or TGF beta restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD. CONCLUSIONS: These results demonstrate that gene-expression changes associated with regional emphysema severity within an individualÂ¿s lung can provide insights into emphysema pathogenesis and identify novel therapeutic opportunities for this deadly disease. They also suggest the need for additional studies to examine the mechanisms by which TGF beta and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression. Paired samples were obtained from 8 regions at regular intervals between the apex and base of each explanted lung from six patients with severe COPD and two donors. The degree of emphysematous destruction was quantified in one sample from each region by mean linear intercept (Lm), while gene expression was profiled in the adjacent sample from the same region using the Affymetrix Human Exon 1.0 ST GeneChip. Human fibroblast cell lines (HLF-1) were treated with GHK or TGF-Beta1 for 48 hours and profiled using the Affymetrix Human Gene 1.0 ST GeneChip.

			Action	DRS
	3CLpro.bin	Other
	3CLpro_bioconfirm.bin	Other
	PLpro.bin	Other
	PLpro_bioconfirm.bin	Other
	Sample_description.csv	Csv

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Supersulphide airway protection in viral and chronic lung diseases

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