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Article

Elucidation of the Molecular Pathways Involved in the Protective Effects of AUY-922 in LPS-Induced Inflammation in Mouse Lungs

School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA 71201, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Giorgio Cozza and Félix Carvalho
Pharmaceuticals 2021, 14(6), 522; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060522
Received: 30 April 2021 / Revised: 20 May 2021 / Accepted: 26 May 2021 / Published: 29 May 2021
(This article belongs to the Special Issue Lung Injury and Repair)
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) cause thousands of deaths every year and are associated with high mortality rates (~40%) due to the lack of efficient therapies. Understanding the molecular mechanisms associated with those diseases will most probably lead to novel therapeutics. In the present study, we investigated the effects of the Hsp90 inhibitor AUY-922 in the major inflammatory pathways of mouse lungs. Mice were treated with LPS (1.6 mg/kg) via intratracheal instillation for 24 h and were then post-treated intraperitoneally with AUY-922 (10 mg/kg). The animals were examined 48 h after AUY-922 injection. LPS activated the TLR4-mediated signaling pathways, which in turn induced the release of different inflammatory cytokines and chemokines. AUY-922 suppressed the LPS-induced inflammation by inhibiting major pro-inflammatory pathways (e.g., JAK2/STAT3, MAPKs), and downregulated the IL-1β, IL-6, MCP-1 and TNFα. The expression levels of the redox regulator APE1/Ref1, as well as the DNA-damage inducible kinases ATM and ATR, were also increased after LPS treatment. Those effects were counteracted by AUY-922. Interestingly, this Hsp90 inhibitor abolished the LPS-induced pIRE1α suppression, a major component of the unfolded protein response. Our study elucidates the molecular pathways involved in the progression of murine inflammation and supports our efforts on the development of new therapeutics against lung inflammatory diseases and sepsis. View Full-Text
Keywords: acute lung injury; acute respiratory distress syndrome; Hsp90 inhibitor; P53; unfolded protein response acute lung injury; acute respiratory distress syndrome; Hsp90 inhibitor; P53; unfolded protein response
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MDPI and ACS Style

Akhter, M.S.; Uddin, M.A.; Kubra, K.-T.; Barabutis, N. Elucidation of the Molecular Pathways Involved in the Protective Effects of AUY-922 in LPS-Induced Inflammation in Mouse Lungs. Pharmaceuticals 2021, 14, 522. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060522

AMA Style

Akhter MS, Uddin MA, Kubra K-T, Barabutis N. Elucidation of the Molecular Pathways Involved in the Protective Effects of AUY-922 in LPS-Induced Inflammation in Mouse Lungs. Pharmaceuticals. 2021; 14(6):522. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060522

Chicago/Turabian Style

Akhter, Mohammad S., Mohammad A. Uddin, Khadeja-Tul Kubra, and Nektarios Barabutis. 2021. "Elucidation of the Molecular Pathways Involved in the Protective Effects of AUY-922 in LPS-Induced Inflammation in Mouse Lungs" Pharmaceuticals 14, no. 6: 522. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060522

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