Effects of Heat Shock Protein 90 Inhibition In the Lungs

Abstract

Inhibition of Hsp90 is associated with anti-inflammatory effects. We employed human lung microvascular endothelial cells to investigate the effects of the Hsp90 inhibitors 17-AAG, AUY-922 and 17-DMAG in the unfolded protein response (UPR) and viability of lung cells. Our observations indicate that moderate doses of those compounds trigger the activation of the UPR without inducing lethal effects in vitro . Indeed, AUY-922 triggered UPR activation in the lungs of C57BL/6 mice. UPR has been previously involved in the enhancement of the lung endothelial barrier function. Thus, the present study suggests that the barrier protective effects of Hsp90 inhibition in the lung microvasculature are highly probable to be associated with the activation of the UPR. Hence, the development of novel compounds which stochastically capacitate the repairing elements of UPR, may deliver new therapeutic possibilities against the severities of the acute respiratory distress syndrome.

P53 in the impaired lungs

“…UPR directly regulates the expression levels of P53 in the lung endothelium [ 60 ]. Recent studies suggested that the endothelial barrier enhancing effects of Hsp90 inhibitors and growth hormone-releasing hormone (GHRH) antagonists might be associated with UPR mediated P53 expression [ [69] , [70] , [71] ]. GHRH antagonist induces the expression of P53 and suppresses the major inflammatory extracellular signal-regulated kinases 1/2 (ERK1/2), Janus kinase 2 (JAK2), and signal transducer and activator of transcription 3 (STAT3) pathways in lung microvascular endothelial cells which express GHRH receptors [ 37 ].…”

Unfolded protein response in the COVID-19 context

“…Bovine pulmonary artery endothelial cells treated with this mannosidase inhibitor exerted hyper-permeability responses [6] . Heat shock protein 90 (Hsp90) inhibitors are UPR inducers [ 7 , 8 ] . It was recently reported that Luminespib (AUY-922), an advanced Hsp90 inhibitor, counteracts the Kifunensine-Induced lung endothelial barrier dysfunction [ 9 ].…”

P53 is Subjected to Lipoteichoic Acid-Induced Phosphorylation in the Lungs

“… 1 P53 protects the endothelium cells against the lipopolysaccharide (LPS)-induced endothelial hyperpermeability by reducing the generation of the reactive oxygen species, 2 by suppressing the inflammatory RhoA/MLC2 pathway, 3 and by inducing the repairing activities of the unfolded protein response in the lungs. 4 5 …”

“…1 P53 protects the endothelium cells against the lipopolysaccharide (LPS)-induced endothelial hyperpermeability by reducing the generation of the reactive oxygen species, 2 by suppressing the inflammatory RhoA/MLC2 pathway, 3 and by inducing the repairing activities of the unfolded protein response in the lungs. 4,5 Lung endothelial barrier dysfunction is both a cause and a consequence of severe lung inflammatory disease, including Fig. 1 (A-F) Western blot analysis of phosphorylated P53 (pP53 ser392 , pP53 ser46 , pP53 ser15 , pP53 ser33 ) and total P53 expression after treatment of bovine pulmonary artery endothelial cell (BPAEC) with either lipoteichoic acid (LTA) (10 µg/mL) or vehicle (VEH) (phosphate-buffered saline [PBS]) for 2, 4, and 6 hours.…”