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. 2020 Jan 17;25(2):195–197. doi: 10.1007/s12192-020-01069-1

Heat shock protein 90 inhibition in the inflamed lungs

Nektarios Barabutis 1,✉
PMCID: PMC7058811  PMID: 31950341

Abstract

Heat shock protein 90 is a highly conserved molecular chaperone, essential for cellular survival under diverse environments. Since this protein is employed by tumors to promote their prevalence, heat shock protein 90 inhibitors have been developed to oppose malignancies. The anti-cancer effects of those compounds appear to be associated with anti-inflammatory properties. Thus, ongoing laborious efforts investigate the possible application of those agents towards inflammatory disorders of the lungs, such as the acute respiratory distress syndrome.

Keywords: Acute lung injury, Acute respiratory distress syndrome, Inflammation

Acute lung injury

Human lungs are subjected to a plethora of stimuli, which may endanger the physiological respiratory function. Indirect (sepsis and trauma, shock, burn injury, mass transfusion) or direct (pneumonia, aspiration, lung contusion) pulmonary challenges, may lead to lung dysfunction, often associated with irreversible outcomes (Matthay et al. 2019). Indeed, the severe form of acute lung injury (ALI), namely the acute respiratory distress syndrome (ARDS), is associated with mortality rates up to 42%. Since this disorder is defined as a PaO2:FiO2 < 300 mmHg with bilateral opacities on chest radiograph devoid of a primary cardiac etiology, a diverse variety of etiologies are involved in this diagnosis (Sinha and Calfee 2019), and contribute towards the unsuccessful outcomes of randomized controlled trials (Matthay et al. 2017).

Lung endothelium in ARDS

The abnormal function of the lung endothelium is a major cause and consequence of ARDS. The thin cellular monolayer which separates the vascular lumen from the surrounding tissues is in control of the vascular wall and regulates the passage of fluid and nutrients through the corresponding tissues (Aman et al. 2016). In the cases of severe inflammation, there are structural changes in the lung endothelium, which affect the properties of this semi-permeable structure. Hence, the permeability of those cellular monolayers increases, causing pulmonary edema and respiratory failure (Englert et al. 2019).

Therapeutic approaches in ARDS

There is a lack of effective pharmacological agents able to counteract ARDS. Ventilator strategies are utilized to stabilize gas exchange, avoiding excessive lung injury. ARDS patients who have received lower tidal volumes (initial tidal volume of 6 mL/kg) compared with higher tidal volumes (initial tidal volume of 12 mL/kg) have experienced higher survival rates (Peck and Hibbert 2019). Prone positioning, sedation to prevent movement, fluid management, and extracorporeal membrane oxygenation are alternative methods towards ARDS treatment. However, the efficacy of those strategies towards lung endothelium repair is still unsatisfactory (Aretha et al. 2019).

Heat shock protein 90 inhibitors

Heat shock protein 90 is a molecular chaperone assisting in the maturation of a plethora of “client” proteins, regulators of crucial intracellular events, such as proliferation, differentiation, and adaption to diverse environmental challenges (Scieglinska et al. 2019). Moreover, it is involved in the progression of malignancies, and potentiates the activity of oncogenic “players” which are streaming carcinogenetic responses (Snigireva et al. 2019). Thus, the concept of Hsp90 inhibition appears to be an attractive anti-cancer strategy, since Hsp90 inhibitors suppress oncogenic pathways and demonstrate a higher selectivity for cancer versus normal cells (Butler et al. 2015). Since cancer and inflammation are interrelated processes, it was soon revealed that Hsp90 inhibition suppresses inflammation (Barabutis et al. 2018). The in vivo and in vitro application of Hsp90 inhibitors in experimental models of ALI have delivered promising results, since Hsp90 inhibitors appear to enhance and repair the injured inflamed lung endothelium (Antonov et al. 2008; Chatterjee et al. 2008). Moreover, those compounds recruit P53 to counteract the lipopolysaccharides (LPS)-induced endothelial barrier dysfunction, which represents an established model of ALI (Hulina et al. 2018).

P53 in the lungs

P53 is of crucial importance towards cancer prevention, protects the cells against both mild and severe intracellular and extracellular stresses, and it is closely associated with Hsp90 (Muller et al. 2004). A robust P53 induction due to Hsp90 inhibition delivers cellular death via apoptosis (Ayrault et al. 2009). Indeed, the mild induction of this 53 kDa protein is associated with anti-inflammatory responses (Cooks et al. 2014) in various tissues, including the lungs (Komarova et al. 2005). In case of the chronic LPS exposure, P53 facilitates lung inflammation by promoting senescence (Sagiv et al. 2018).

P53 augmentation due to Hsp90 inhibition

It appears that Hsp90 inhibition induces the expression of P53 in the lungs by diverse ways. P53 phosphorylation has been shown to destabilize P53 (Katayama et al. 2004). 17-DMAG counteracted the LPS-induced P53 phosphorylation in Ser. 6, Ser. 15, Ser. 33, and Ser. 392 in bovine pulmonary artery endothelial cells (Barabutis et al. 2019). In another study, 17-AAG suppressed the LPS-induced induction of the p53 negative regulator MDM4, as well as the LPS-trigerred MDM2 (another p53 negative regulator) phosphorylation in human lung microvascular endothelial cells (Barabutis et al. 2015).

Hsp90 inhibition induces the unfolded protein response element in lung cells

Unfolded protein response (UPR) is an endoplasmic reticulum (ER)–based cytoprotective mechanism, developed to prevent pathologies due to increased ER stress. The UPR positively affects the expression levels of P53 in lung cells (Akhter et al. 2019). Hsp90 inhibitors have been recently shown to capacitate its activation in both bovine and mice lung cells. Cells exposed to 17-AAG and AUY-922 activated the three branches of the UPR machinery, namely the protein kinase RNA-like ER kinase, the activating transcription factor 6, and the inositol-requiring enzyme-1α (Kubra et al. 2019). Moreover, they induced the UPR regulators immunoglobulin heavy-chain-binding protein, endoplasmic reticulum oxidoreductin-1alpha, and protein disulfide isomerase. Since UPR has been previously shown to be involved in repairing processes towards the endothelium (Barabutis 2019), it is probable that similar events may occur in the case of the inflamed lung. Thus, the investigation of the exact mechanisms that drive the induction of UPR by Hsp90 inhibition may contribute to new strategies against ARDS.

Funding information

This research is supported by the R&D, Research Competitiveness Subprogram (RCS) of the Louisiana Board of Regents through the Board of Regents Support Fund (LEQSF (2019-22)-RD-A-26) (PI:NB), and by the National Institute of General Medical Sciences (NIGMS) of the National Institute of Health (NIH) (5 P20GM103424-15, 3 P20GM103424-15S1).

Compliance with ethical standards

Conflict of interest

The author declares that there is no conflict of interest.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. Akhter MS, Uddin MA, Barabutis N. Unfolded protein response regulates P53 expression in the pulmonary endothelium. J Biochem Mol Toxicol. 2019;33:e22380. doi: 10.1002/jbt.22380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aman Jurjan, Weijers Ester M., van Nieuw Amerongen Geerten P., Malik Asrar B., van Hinsbergh Victor W. M. Using cultured endothelial cells to study endothelial barrier dysfunction: Challenges and opportunities. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2016;311(2):L453–L466. doi: 10.1152/ajplung.00393.2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Antonov A, Snead C, Gorshkov B, Antonova GN, Verin AD, Catravas JD. Heat shock protein 90 inhibitors protect and restore pulmonary endothelial barrier function. Am J Respir Cell Mol Biol. 2008;39:551–559. doi: 10.1165/rcmb.2007-0324OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Aretha Diamanto, Fligou Fotini, Kiekkas Panagiotis, Karamouzos Vasilis, Voyagis Gregorios. Extracorporeal Life Support: The Next Step in Moderate to Severe ARDS—A Review and Meta-Analysis of the Literature. BioMed Research International. 2019;2019:1–11. doi: 10.1155/2019/1035730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ayrault O, Godeny MD, Dillon C, Zindy F, Fitzgerald P, Roussel MF, Beere HM. Inhibition of Hsp90 via 17-DMAG induces apoptosis in a p53-dependent manner to prevent medulloblastoma. Proc Natl Acad Sci U S A. 2009;106:17037–17042. doi: 10.1073/pnas.0902880106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Barabutis N. Unfolded protein response supports endothelial barrier function. Biochimie. 2019;165:206–209. doi: 10.1016/j.biochi.2019.08.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Barabutis N, Dimitropoulou C, Birmpas C, Joshi A, Thangjam G, Catravas JD. p53 protects against LPS-induced lung endothelial barrier dysfunction. Am J Phys Lung Cell Mol Phys. 2015;308:L776–L787. doi: 10.1152/ajplung.00334.2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Barabutis Nektarios, Schally Andrew V., Siejka Agnieszka. P53, GHRH, inflammation and cancer. EBioMedicine. 2018;37:557–562. doi: 10.1016/j.ebiom.2018.10.034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Barabutis N, Uddin MA, Catravas JD. Hsp90 inhibitors suppress P53 phosphorylation in LPS - induced endothelial inflammation. Cytokine. 2019;113:427–432. doi: 10.1016/j.cyto.2018.10.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Butler L. M., Ferraldeschi R., Armstrong H. K., Centenera M. M., Workman P. Maximizing the Therapeutic Potential of HSP90 Inhibitors. Molecular Cancer Research. 2015;13(11):1445–1451. doi: 10.1158/1541-7786.MCR-15-0234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chatterjee A, Snead C, Yetik-Anacak G, Antonova G, Zeng J, Catravas JD. Heat shock protein 90 inhibitors attenuate LPS-induced endothelial hyperpermeability. Am J Phys Lung Cell Mol Phys. 2008;294:L755–L763. doi: 10.1152/ajplung.00350.2007. [DOI] [PubMed] [Google Scholar]
  12. Cooks T, Harris CC, Oren M. Caught in the cross fire: p53 in inflammation. Carcinogenesis. 2014;35:1680–1690. doi: 10.1093/carcin/bgu134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Englert JA, Bobba C, Baron RM (2019) Integrating molecular pathogenesis and clinical translation in sepsis-induced acute respiratory distress syndrome. JCI Insight 4 10.1172/jci.insight.124061 [DOI] [PMC free article] [PubMed]
  14. Hulina A, Grdic Rajkovic M, Jaksic Despot D, Jelic D, Dojder A, Cepelak I, Rumora L. Extracellular Hsp70 induces inflammation and modulates LPS/LTA-stimulated inflammatory response in THP-1 cells. Cell Stress Chaperones. 2018;23:373–384. doi: 10.1007/s12192-017-0847-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Katayama H, et al. Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet. 2004;36:55–62. doi: 10.1038/ng1279. [DOI] [PubMed] [Google Scholar]
  16. Komarova EA, et al. p53 is a suppressor of inflammatory response in mice. FASEB J. 2005;19:1030–1032. doi: 10.1096/fj.04-3213fje. [DOI] [PubMed] [Google Scholar]
  17. Kubra Khadeja-Tul, Uddin Mohammad A., Akhter Mohammad S., Barabutis Nektarios. Hsp90 inhibitors induce the unfolded protein response in bovine and mice lung cells. Cellular Signalling. 2020;67:109500. doi: 10.1016/j.cellsig.2019.109500. [DOI] [PubMed] [Google Scholar]
  18. Matthay MA, McAuley DF, Ware LB. Clinical trials in acute respiratory distress syndrome: challenges and opportunities. Lancet Respir Med. 2017;5:524–534. doi: 10.1016/S2213-2600(17)30188-1. [DOI] [PubMed] [Google Scholar]
  19. Matthay MA, Zemans RL, Zimmerman GA, Arabi YM, Beitler JR, Mercat A, Herridge M, Randolph AG, Calfee CS. Acute respiratory distress syndrome. Nat Rev Dis Primers. 2019;5:18. doi: 10.1038/s41572-019-0069-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Müller Lin, Schaupp Andreas, Walerych Dawid, Wegele Harald, Buchner Johannes. Hsp90 Regulates the Activity of Wild Type p53 under Physiological and Elevated Temperatures. Journal of Biological Chemistry. 2004;279(47):48846–48854. doi: 10.1074/jbc.M407687200. [DOI] [PubMed] [Google Scholar]
  21. Peck Tyler J, Hibbert Kathryn A. Recent advances in the understanding and management of ARDS. F1000Research. 2019;8:1959. doi: 10.12688/f1000research.20411.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Sagiv A, et al. p53 in bronchial club cells facilitates chronic lung inflammation by promoting senescence. Cell Rep. 2018;22:3468–3479. doi: 10.1016/j.celrep.2018.03.009. [DOI] [PubMed] [Google Scholar]
  23. Scieglinska D, Krawczyk Z, Sojka DR, Gogler-Piglowska A. Heat shock proteins in the physiology and pathophysiology of epidermal keratinocytes. Cell Stress Chaperones. 2019;24:1027–1044. doi: 10.1007/s12192-019-01044-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Sinha P, Calfee CS. Phenotypes in acute respiratory distress syndrome: moving towards precision medicine. Curr Opin Crit Care. 2019;25:12–20. doi: 10.1097/MCC.0000000000000571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Snigireva AV, Vrublevskaya VV, Skarga YY, Morenkov OS. Cell surface heparan sulfate proteoglycans are involved in the extracellular Hsp90-stimulated migration and invasion of cancer cells. Cell Stress Chaperones. 2019;24:309–322. doi: 10.1007/s12192-018-0955-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

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