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

Mohammad S Akhter,Nektarios Barabutis,Khadeja-Tul Kubra,Mohammad A Uddin

doi:10.3390/ph14060522

Mohammad S Akhter, Nektarios Barabutis + Show 2 more

Open Access

https://doi.org/10.3390/ph14060522

Copy DOI

Journal: Pharmaceuticals	Publication Date: May 29, 2021
Citations: 16	License type: CC BY 4.0

Affiliation: University of Louisiana at Monroe

Abstract

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.

Highlights

Human lungs encounter different atmospheric insults, as well as toxic molecules circulating in the blood
extracellular signalregulated kinase1/2 (ERK1/2) is a member of the mitogen-activated protein kinase (MAPK) family, and it is activated through phosphorylation
(1.6 mg/kg) for 24 h showed an elevation of the phosphorylated ERK1/2 expression levels in lung tissues as compared to the vehicle-treated mice

Summary

Introduction

Human lungs encounter different atmospheric insults, as well as toxic molecules circulating in the blood. Direct lung injury causes local damage to the lung epithelium, while indirect injury results in damage to the lung endothelium [1]. Both direct and indirect lung injuries trigger inflammation in lung epithelial and endothelial cells, leading to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The pulmonary vasculature is a mono-layered, non-fenestrated endothelial cell lining, which selectively permits the transport of fluids and solutes between the vasculature and the interstitium. The epithelium layer forms a very tight barrier, which prohibits the transfer of small molecules to the alveolar space but allows the oxygen and carbon dioxide exchange [2].

Methods

Results

Discussion

Conclusion