AUTHOR=Zhang Cancan , Xu Huisha , Netto Keilah G. , Sokulsky Leon A. , Miao Yiyan , Mo Zhongyuan , Meng Yan , Du Yingying , Wu Chengyong , Han Liyou , Zhang Lirong , Liu Chi , Zhang Guojun , Li Fuguang , Yang Ming 

TITLE=Inhibition of γ-glutamyl transferase suppresses airway hyperresponsiveness and airway inflammation in a mouse model of steroid resistant asthma exacerbation

JOURNAL=Frontiers in Immunology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1132939

DOI=10.3389/fimmu.2023.1132939

ISSN=1664-3224

ABSTRACT=Despite recent advance, there are limited treatments available for acute asthma exacerbations. Here, we demonstrate that GGsTop, a γ-glutamyl transferase inhibitor, attenuates hallmark features of the disease with a murine model of lipopolysaccharide (LPS) and ovalbumin (OVA) driven asthma exacerbation. Expression of inflammatory cytokines, mucus hypersecretion, collagen deposition, and airway hyperresponsiveness (AHR) were dramatically inhibited by GGsTop treatment. Using RNA-sequencing and pathway analysis, we demonstrated that the activation of TLR4/NFκB signaling pathway in airway was downregulated by GGsTop. Interestingly, further analysis revealed that GGsTop significantly inhibited not only IFNγ responses but also the expression of glucocorticoid-associated molecules, implicating that GGsTop profoundly attenuates inflammatory pathways. Overall, our study suggests that GGsTop is a viable treatment for asthma exacerbation by broadly inhibiting the activation of multiple inflammatory pathways.