Abstract
The role of Endoplasmic Reticulum Chaperone and Signaling Regulator BiP/GRP78 in acute inflammatory injury, particularly in the context of lung endothelium, is poorly defined. In his study, we monitored the effect of SubAB, a holoenzyme that cleaves and specifically inactivates BiP/GRP78 and its inactive mutant SubAA272B on lung inflammatory injury in an aerosolized LPS inhalation mouse model of acute lung injury (ALI). Analysis of lung homogenates and bronchoalveolar lavage (BAL) fluid showed that LPS-induced lung inflammation and injury were significantly inhibited in SubAB- but not in SubAA272B-treated mice. SubAB-treated mice were also protected from LPS-induced decrease in lung compliance. Gene transfer of dominant negative mutant of BiP in the lung endothelium protected against LPS-induced lung inflammatory responses. Consistent with this, stimulation of endothelial cells (EC) with thrombin caused an increase in BiP/GRP78 levels and inhibition of ER stress with 4-phenylbutyric acid (4-PBA) prevented this response as well as increase in VCAM-1, ICAM-1, IL-6, and IL-8 levels. Importantly, thrombin-induced Ca2+ signaling and EC permeability were also prevented upon BiP/GRP78 inactivation. The above EC responses are mediated by intracellular BiP/GRP78 and not by cell surface BiP/GRP78. Together, these data identify intracellular BiP/GRP78 as a novel regulator of endothelial dysfunction associated with ALI.
Highlights
The endoplasmic reticulum (ER) is a major site for the synthesis and maturation of secretory and membrane proteins and plays essential roles in physiological regulation of many cellular processes[21]
In order to test the possibility whether BiP/GRP78 is a critical player in mediating lung vascular inflammation and injury we first determined if BiP expression was regulated in an aerosolized bacterial LPS inhalation mouse model of acute lung injury (ALI)
Because BiP/GRP78 is a known mediator of ER stress, we investigated if the ER stress-BiP/GRP78 axis is critical to endothelial cells (EC) inflammation associated with ALI
Summary
The endoplasmic reticulum (ER) is a major site for the synthesis and maturation of secretory and membrane proteins and plays essential roles in physiological regulation of many cellular processes[21]. BiP/GRP78 (Binding Immunoglobulin Protein/78-kDa glucose-regulated protein), referred to as heat-shock protein A5 (HSPA5), is primarily regarded as an ER chaperone involved in protein folding and assembly, Ca2+ homeostasis, and regulating ER stress signaling. One of the pathways activated under UPR involves expression of ER chaperone BiP/GRP78 to assist in proper protein folding, maintain chaperone homeostasis, and support cell survival. Studies have shown that BiP/GRP78 is critical to embryonic development, aging, insulin-mediated signaling and pathological conditions, including cancer, diabetes, obesity and neurological disorders[24,25,26,27]. Our study identifies intracellular BiP/GRP78 as an important mediator of lung vascular inflammation and injury through its ability, at least in part, to activate EC inflammation and barrier disruption
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