Faculty Collaboration Database

Sterile inflammation induces vasculopathy and chronic lung injury in murine sickle cell disease. Free Radic Biol Med 2024 Mar;215:112-126

Date

02/10/2024

Pubmed ID

38336101

DOI

10.1016/j.freeradbiomed.2024.01.052

Scopus ID

2-s2.0-85187405718 (requires institutional sign-in at Scopus site)

Abstract

Murine sickle cell disease (SCD) results in damage to multiple organs, likely mediated first by vasculopathy. While the mechanisms inducing vascular damage remain to be determined, nitric oxide bioavailability and sterile inflammation are both considered to play major roles in vasculopathy. Here, we investigate the effects of high mobility group box-1 (HMGB1), a pro-inflammatory damage-associated molecular pattern (DAMP) molecule on endothelial-dependent vasodilation and lung morphometrics, a structural index of damage in sickle (SS) mice. SS mice were treated with either phosphate-buffered saline (PBS), hE-HMGB1-BP, an hE dual-domain peptide that binds and removes HMGB1 from the circulation via the liver, 1-[4-(aminocarbonyl)-2-methylphenyl]-5-[4-(1H-imidazol-1-yl)phenyl]-1H-pyrrole-2-propanoic acid (N6022) or N-acetyl-lysyltyrosylcysteine amide (KYC) for three weeks. Human umbilical vein endothelial cells (HUVEC) were treated with recombinant HMGB1 (r-HMGB1), which increases S-nitrosoglutathione reductase (GSNOR) expression by ∼80%, demonstrating a direct effect of HMGB1 to increase GSNOR. Treatment of SS mice with hE-HMGB1-BP reduced plasma HMGB1 in SS mice to control levels and reduced GSNOR expression in facialis arteries isolated from SS mice by ∼20%. These changes were associated with improved endothelial-dependent vasodilation. Treatment of SS mice with N6022 also improved vasodilation in SS mice suggesting that targeting GSNOR also improves vasodilation. SCD decreased protein nitrosothiols (SNOs) and radial alveolar counts (RAC) and increased GSNOR expression and mean linear intercepts (MLI) in lungs from SS mice. The marked changes in pulmonary morphometrics and GSNOR expression throughout the lung parenchyma in SS mice were improved by treating with either hE-HMGB1-BP or KYC. These data demonstrate that murine SCD induces vasculopathy and chronic lung disease by an HMGB1- and GSNOR-dependent mechanism and suggest that HMGB1 and GSNOR might be effective therapeutic targets for reducing vasculopathy and chronic lung disease in humans with SCD.

Author List

Rarick KR, Li K, Teng RJ, Jing X, Martin DP, Xu H, Jones DW, Hogg N, Hillery CA, Garcia G, Day BW, Naylor S, Pritchard KA Jr

Authors

Guilherme Garcia PhD Assistant Professor in the Biomedical Engineering department at Medical College of Wisconsin
Neil Hogg PhD Associate Dean, Professor in the Biophysics department at Medical College of Wisconsin
Xi-Gang Jing Research Scientist I in the Pediatrics department at Medical College of Wisconsin
Kevin Richard Rarick PhD Assistant Professor in the Pediatrics department at Medical College of Wisconsin
Ru-Jeng Teng MD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Anemia, Sickle Cell
Animals
Benzamides
Endothelial Cells
HMGB1 Protein
Humans
Inflammation
Lung Diseases
Lung Injury
Mice
Pyrroles
Vascular Diseases