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

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.

Ex Vivo Evaluation of Glutamine Treatment in Sepsis and Trauma in a Human Peripheral Blood Mononuclear Cells Model

“…High MCP-1 levels are associated with organ failure and poor outcome, while blocking MCP-1 synthesis protects mice from sepsis [ 66 ]. In a murine sepsis model, the LPS-induced MCP-1 in the lungs was significantly downregulated with the HSP90α inhibitor AUY-922 by counteracting main pro-inflammatory pathways [ 67 ].…”

Mechanistic insights into targeting caspase‐3 activation and alveolar macrophage pyroptosis by Ephedra and bitter almond compounds for treating pediatric pneumonia via network pharmacology and bioinformatics

“…The membrane was blocked with 5% BSA at room temperature for 1 h, followed by incubation with corresponding antibody solutions: Caspase‐3 (ab32351, 1:1000; Abcam, UK), ASC (ab283684, 1:1000; Abcam, UK), caspase‐1 p20 (sc‐398715; 1:1000; Santa Cruz, USA), IL‐18 (ab243091, 1:1000; Abcam, UK), IL‐1β (ab254360, 1:1000; Abcam, UK), GSDMD FL (ab219800, 1:1000; Abcam, UK), GSDMD CL (ab215203, 1:1000; Abcam, UK), and β‐actin (ab8226, 1:1000; Abcam, UK) at 4°C overnight. The next day, the membrane was taken out and equilibrated at room temperature on a shaker for 1 h. After shaking in TBST (0.1% Tween 20) for three times, it was incubated with secondary antibody at room temperature for 1 h. After three washes with TBST, the developing solution was mixed in a 1:1 ratio and evenly dropped onto the membrane surface for imaging using a gel imaging system (Akhter et al., 2021). Protein strips were scanned in grayscale using AlphaView SA software (Version: 3.4.0).…”

Hsp90 inhibition protects brain endothelial cells against LPS‐induced injury

“…15,16 It also suppresses the activation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3), and mitogen-activated protein kinases (MAPKs) pathways in endothelial cells. Those cascades mediate inflammatory responses in the endothelium, 17 suggesting that Hsp90 inhibitors may be of therapeutic value in diseases related to lung endothelial barrier dysfunction (e.g., acute respiratory distress syndrome [ARDS] and sepsis) and BBB breakdown (e.g., Parkinson's 18 and Huntington's disease 19 ). Moreover, inhibition of Hsp90 exerts antioxidative properties by suppressing H 2 O 2induced generation of reactive oxygen species (ROS) in human cerebral microvascular endothelial cells (hCMEC/ D3).…”