Inhaled [D-Ala2]-Dynorphin 1-6 Prevents Hyperacetylation and Release of High Mobility Group Box 1 in a Mouse Model of Acute Lung Injury.

Vladislav N Karkischenko,Nataliya V Petrova,Maxim S Nesterov,Veronika I Skvortsova,Igor A Pomytkin,Melik T Gasanov,Oxana V Alimkina,Yuriy V Fokin,Luis Horacio Gutiérrez-González

doi:10.1155/2021/4414544

Abstract

COVID-19 is a respiratory infection caused by the SARS-CoV-2 virus that can rapidly escalate to life-threatening pneumonia and acute respiratory distress syndrome (ARDS). Recently, extracellular high mobility group box 1 (HMGB1) has been identified as an essential component of cytokine storms that occur with COVID-19; HMGB1 levels correlate significantly with disease severity. Thus, the modulation of HMGB1 release may be vital for treating COVID-19. HMGB1 is a ubiquitous nuclear DNA-binding protein whose biological function depends on posttranslational modifications, its redox state, and its cellular localization. The acetylation of HMGB1 is a prerequisite for its translocation from the nucleus to the cytoplasm and then to the extracellular milieu. When released, HMGB1 acts as a proinflammatory cytokine that binds primarily to toll-like receptor 4 (TLR4) and RAGE, thereby stimulating immune cells, endothelial cells, and airway epithelial cells to produce cytokines, chemokines, and other inflammatory mediators. In this study, we demonstrate that inhaled [D-Ala2]-dynorphin 1-6 (leytragin), a peptide agonist of δ-opioid receptors, significantly inhibits HMGB1 secretion in mice with lipopolysaccharide- (LPS-) induced acute lung injury. The mechanism of action involves preventing HMGB1's hyperacetylation at critical lysine residues within nuclear localization sites, as well as promoting the expression of sirtuin 1 (SIRT1), an enzyme known to deacetylate HMGB1. Leytragin's effects are mediated by opioid receptors, since naloxone, an antagonist of opioid receptors, abrogates the leytragin effect on SIRT1 expression. Overall, our results identify leytragin as a promising therapeutic agent for the treatment of pulmonary inflammation associated with HMGB1 release. In a broader context, we demonstrate that the opioidergic system in the lungs may represent a promising target for the treatment of inflammatory lung diseases.

Highlights

Coronavirus disease 2019 (COVID-19) is a respiratory infection caused by the SARS-CoV-2 virus
The primary finding of our study is that leytragin, a peptide agonist of DOR, prevented high mobility group box 1 (HMGB1) release in the lungs of LPS-induced mice when administered by inhalation; this effect is mediated by opioid receptors, the upregulation of sirtuin 1 (SIRT1) expression, and the downregulation of HMGB1 hyperacetylation at critical lysine residues within nuclear localization sequences 1 (NLS1) and NLS2 sequences
We demonstrate that leytragin inhibited the LPS-induced hyperacetylation of HMGB1 at both NLS1 and NLS2, with the greatest effect being observed for HMGB1 molecules released into bronchoalveolar lavage (BAL)

Summary

Introduction

Coronavirus disease 2019 (COVID-19) is a respiratory infection caused by the SARS-CoV-2 virus. The average levels of HMGB1 were approximately 5- and 26-fold higher than the normal range in the peripheral blood of patients with nonsevere and severe COVID-19, respectively [8], reaching levels typically observed with severe sepsis [10]. These HMGB1 levels correlate significantly with the severity of clinical manifestations, such as the risk for intensive care unit admission and death, the severity of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), the degree of organic impairment, and peak Ddimer levels [9]; this finding points to extracellular HMGB1 as a possible major driver of inflammation in COVID-19

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