Abstract
Acute lung injury is characterized by the infiltration of neutrophils into lungs and the subsequent impairment of lung function. Here we explored the role of TDAG8 in lung injury induced by lipopolysaccharide (LPS) administrated intratracheally. In this model, cytokines and chemokines released from resident macrophages are shown to cause neutrophilic inflammation in the lungs. We found that LPS treatment increased TDAG8 expression in the lungs and confirmed its expression in resident macrophages in bronchoalveolar lavage (BAL) fluids. LPS administration remarkably increased neutrophil accumulation without appreciable change in the resident macrophages, which was associated with increased penetration of blood proteins into BAL fluids, interstitial accumulation of inflammatory cells, and damage of the alveolar architecture. The LPS-induced neutrophil accumulation and the associated lung damage were enhanced in TDAG8-deficient mice as compared with those in wild-type mice. LPS also increased several mRNA and protein expressions of inflammatory cytokines and chemokines in the lungs or BAL fluids. Among these inflammatory mediators, mRNA and protein expression of KC (also known as CXCL1), a chemokine of neutrophils, were significantly enhanced by TDAG8 deficiency. We conclude that TDAG8 is a negative regulator for lung neutrophilic inflammation and injury, in part, through the inhibition of chemokine production.
Highlights
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are caused by several disorders, including pneumonia, sepsis, and aspiration of gastric contents, and are characterized by pulmonary edema due to increased permeability of the alveolar epithelial and endothelial barriers and the subsequent impairment of arterial oxygenation
Recent studies have shown that proton-sensing ovarian cancer G protein-coupled receptor 1 (OGR1) family G protein-coupled receptors (GPCRs), including OGR1, G protein-coupled receptor 4 (GPR4), and T-cell death-associated gene 8 (TDAG8 or GPR65), mediate cellular actions induced by alkaline and acidic pH of 8 to 6 through histidine residues in a variety of cell types [6,7,8]
We explored the role of proton-sensing TDAG8 in lung injury as induced by intratracheally administrated lipopolysaccharide (LPS) and found that TDAG8 is protective against lung neutrophilic inflammation and injury
Summary
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are caused by several disorders, including pneumonia, sepsis, and aspiration of gastric contents, and are characterized by pulmonary edema due to increased permeability of the alveolar epithelial and endothelial barriers and the subsequent impairment of arterial oxygenation. The accumulation of neutrophils in the lung microvasculature, interstitium, and bronchoalveolar space is believed to play a key role in ALI and ARDS [1,2,3]. Recent studies have shown that proton-sensing ovarian cancer G protein-coupled receptor 1 (OGR1) family G protein-coupled receptors (GPCRs), including OGR1 ( known as GPR68), G protein-coupled receptor 4 (GPR4), and T-cell death-associated gene 8 (TDAG8 or GPR65), mediate cellular actions induced by alkaline and acidic pH of 8 to 6 through histidine residues in a variety of cell types [6,7,8]. TDAG8 is mainly expressed in bone marrow-derived or hematopoietic cells [9] and has been shown to mediate the inhibition of extracellular acidification-induced inflammatory cytokine production in macrophages [10], the inhibition of superoxide anion production in neutrophils [11], and the survival response in eosinophils [12]. We explored the role of proton-sensing TDAG8 in lung injury as induced by intratracheally administrated lipopolysaccharide (LPS) and found that TDAG8 is protective against lung neutrophilic inflammation and injury
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
