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GPR68 Mediates Lung Endothelial Dysfunction Caused by Bacterial Inflammation and Tissue Acidification
Pratap Karki1, Yunbo Ke2, Chenou Zhang1
1Division of Pulmonary and Critical Care, Department of Medicine, UMSOM Lung Biology Program, University of Maryland School of Medicine, 20 Penn Street, HSF-2, Room S143, Baltimore, MD 21201, USA.
Cells
|January 8, 2025
Summary
Tissue acidification increases human pulmonary endothelial cell permeability and inflammation via GPR68. This proton-sensing receptor exacerbates LPS-induced endothelial dysfunction, highlighting its role in inflammatory diseases.
Area of Science:
- Cell Biology
- Physiology
- Immunology
Background:
- Tissue acidification is linked to inflammatory conditions.
- Proton-sensing G protein-coupled receptors (GPCRs), including GPR68, respond to low pH.
- GPR68 is implicated in chronic inflammatory diseases.
Purpose of the Study:
- To investigate the impact of extracellular acidification on human pulmonary endothelial cell (EC) permeability and inflammation.
- To explore the synergistic effects of acidosis on lipopolysaccharide (LPS)-induced endothelial dysfunction.
- To determine the role of GPR68 in mediating these acid-induced effects.
Main Methods:
- Human pulmonary endothelial cells were exposed to acidic conditions (pH 6.5).
- Endothelial permeability was assessed by transendothelial electrical resistance and VE-cadherin staining.
- Inflammatory markers (VCAM-1, ICAM-1, cytokines) were measured via mRNA, protein expression, and ELISA.
- GPR68 expression and function were evaluated using a specific inhibitor (OGM-8345).
- Synergistic effects with LPS were examined in macrovascular and microvascular ECs.
Main Results:
- Acidification (pH 6.5) delayed EC permeability increase and disrupted VE-cadherin.
- Acidic pH induced endothelial inflammation, upregulating adhesion molecules and pro-inflammatory cytokines.
- Acidic pH selectively increased GPR68 expression; its inhibition reversed acidosis-induced effects.
- Acidic pH exacerbated LPS-induced EC permeability and inflammation, effects suppressed by the GPR68 inhibitor.
Conclusions:
- GPR68 is a key mediator of acidic pH-induced human pulmonary vascular endothelial cell dysfunction.
- Tissue acidification potentiates LPS-induced endothelial injury through GPR68.
- Targeting GPR68 may offer therapeutic strategies for inflammatory conditions involving tissue acidosis.
