Niu, Mengya, Zhang, Xiuli, Wu, Zengkai, Li, Bin, Bao, Jingpiao, Dai, Juanjuan, Yang, Zihan, Zeng, Yue, Li, Liang, Pandol, Stephen et al (show 2 more authors)
(2024)
Neutrophil-specific ORAI1 Calcium Channel Inhibition Reduces Pancreatitis-associated Acute Lung Injury.
Function (Oxford, England), 5 (1).
zqad061-.
Abstract
Acute pancreatitis is initiated within pancreatic exocrine cells and sustained by dysregulated systemic inflammatory responses mediated by neutrophils. Store-operated Ca<sup>2+</sup> entry (SOCE) through ORAI1 channels in pancreatic acinar cells triggers acute pancreatitis, and ORAI1 inhibitors ameliorate experimental acute pancreatitis, but the role of ORAI1 in pancreatitis-associated acute lung injury has not been determined. Here, we showed mice with pancreas-specific deletion of <i>Orai1</i> (<i>Orai1<sup>ΔPdx1</sup></i>, ∼70% reduction in the expression of Orai1) are protected against pancreatic tissue damage and immune cell infiltration, but not pancreatitis-associated acute lung injury, suggesting the involvement of unknown cells that may cause such injury through SOCE via ORAI1. Genetic (<i>Orai1<sup>ΔMRP8</sup></i>) or pharmacological inhibition of ORAI1 in murine and human neutrophils decreased Ca<sup>2+</sup> influx and impaired chemotaxis, reactive oxygen species production, and neutrophil extracellular trap formation. Unlike pancreas-specific <i>Orai1</i> deletion, mice with neutrophil-specific deletion of <i>Orai1</i> (<i>Orai1<sup>ΔMRP8</sup></i>) were protected against pancreatitis- and sepsis-associated lung cytokine release and injury, but not pancreatic injury in experimental acute pancreatitis. These results define critical differences between contributions from different cell types to either pancreatic or systemic organ injury in acute pancreatitis. Our findings suggest that any therapy for acute pancreatitis that targets multiple rather than single cell types is more likely to be effective.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Neutrophils, Animals, Humans, Mice, Pancreatitis, Acute Disease, Acute Lung Injury, ORAI1 Protein |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 06 Feb 2024 09:39 |
| Last Modified: | 06 Feb 2024 09:39 |
| DOI: | 10.1093/function/zqad061 |
| Open Access URL: | https://doi.org/10.1093/function/zqad061 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3178425 |
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