Inhibition of Pendrin by a small molecule reduces Lipopolysaccharide-induced acute Lung Injury.

Abstract

Rationale: Pendrin is encoded by SLC26A4 and its mutation leads to congenital hearing loss. Additionally, pendrin is up-regulated in inflammatory airway diseases such as chronic obstructive pulmonary disease, allergic rhinitis, and asthma. In this study, the effects of a novel pendrin inhibitor, YS-01, were investigated in an LPS-induced acute lung injury (ALI) mice model, and the mechanism underlying the effect of YS-01 was examined. Methods: Lipopolysaccharide (LPS, 10 mg/kg) was intranasally instilled in wild type (WT) and pendrin-null mice. YS-01 (10 mg/kg) was administered intra-peritoneally before or after LPS inhalation. Lung injury parameters were assessed in the lung tissue and bronchoalveolar lavage fluid (BALF). Pendrin levels in the BALF of 41 patients with acute respiratory distress syndrome (ARDS) due to pneumonia and 25 control (solitary pulmonary nodule) patients were also measured. Results: LPS instillation induced lung injury in WT mice but not in pendrin-null mice. Pendrin expression was increased by LPS stimulation both in vitro and in vivo. YS-01 treatment dramatically attenuated lung injury and reduced BALF cell counts and protein concentration after LPS instillation in WT mice. Proinflammatory cytokines and NF-κB activation were suppressed by YS-01 treatment in LPS-induced ALI mice. In BALF of patients whose ARDS was caused by pneumonia, pendrin expression was up-regulated compared to that in controls (mean, 24.86 vs. 6.83 ng/mL, P < 0.001). Conclusions: A novel pendrin inhibitor, YS-01, suppressed lung injury in LPS-induced ALI mice and our data provide a new strategy for the treatment of inflammatory airway diseases including sepsis-induced ALI.

• Authors: Eun Hye Lee, Mi Hwa Shin, Mia Gi, Jinhong Park, Doona Song, Young-Min Hyun, Ji-Hwan Ryu, Je Kyung Seong, Yoon Jeon, Gyoonhee Han, Wan Namkung, Moo Suk Park, Jae Young Choi
• Journal: Theranostics (Theranostics) Vol. 10 Issue 22 Pg. 9913-9922 ( 2020) ISSN: 1838-7640 [Electronic] Australia
• PMID: 32929324 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Cytokines
• Lipopolysaccharides
• NF-kappa B
• Oxazoles
• Slc26a4 protein, mouse
• Small Molecule Libraries
• Sulfate Transporters
• YS-01

Topics

• Acute Lung Injury (chemically induced, drug therapy, metabolism)
• Aged
• Animals
• Bronchoalveolar Lavage Fluid
• Cytokines (metabolism)
• Disease Models, Animal
• Female
• Gene Expression Regulation (drug effects)
• Humans
• Inflammation (drug therapy, metabolism)
• Lipopolysaccharides (pharmacology)
• Lung (drug effects, metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• NF-kappa B (metabolism)
• Oxazoles (pharmacology)
• Pneumonia (drug therapy, metabolism)
• Respiratory Distress Syndrome (chemically induced, drug therapy, metabolism)
• Signal Transduction (drug effects)
• Small Molecule Libraries (pharmacology)
• Sulfate Transporters (antagonists & inhibitors)
• Up-Regulation (drug effects)