Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration
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Open Access
- 1 January 2018
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Lung Cellular and Molecular Physiology
- Vol. 314 (1), L17-L31
- https://doi.org/10.1152/ajplung.00498.2016
Abstract
Angiotensin-converting enzyme 2 (ACE2) is a terminal carboxypeptidase with important functions in the renin-angiotensin system and plays a critical role in inflammatory lung diseases. ACE2 cleaves single-terminal residues from several bioactive peptides such as angiotensin II. However, few of its substrates in the respiratory tract have been identified, and the mechanism underlying the role of ACE2 in inflammatory lung disease has not been fully characterized. In an effort to identify biological targets of ACE2 in the lung, we tested its effects on des-Arg9 bradykinin (DABK) in airway epithelial cells on the basis of the hypothesis that DABK is a biological substrate of ACE2 in the lung and ACE2 plays an important role in the pathogenesis of acute lung inflammation partly through modulating DABK/bradykinin receptor B1 (BKB1R) axis signaling. We found that loss of ACE2 function in mouse lung in the setting of endotoxin inhalation led to activation of the DABK/BKB1R axis, release of proinflammatory chemokines such as C-X-C motif chemokine 5 (CXCL5), macrophage inflammatory protein-2 (MIP2), C-X-C motif chemokine 1 (KC), and TNF-α from airway epithelia, increased neutrophil infiltration, and exaggerated lung inflammation and injury. These results indicate that a reduction in pulmonary ACE2 activity contributes to the pathogenesis of lung inflammation, in part because of an impaired ability to inhibit DABK/BKB1R axis-mediated signaling, resulting in more prompt onset of neutrophil infiltration and more severe inflammation in the lung. Our study identifies a biological substrate of ACE2 within the airways, as well as a potential new therapeutic target for inflammatory diseases.Keywords
This publication has 81 references indexed in Scilit:
- Neuropeptides activate TRPV1 in rheumatoid arthritis fibroblast-like synoviocytes and foster IL-6 and IL-8 productionAnnals Of The Rheumatic Diseases, 2013
- Function of the p38MAPK-HSP27 Pathway in Rat Lung Injury Induced by Acute Ischemic Kidney InjuryBioMed Research International, 2013
- LPS Increases MUC5AC by TACE/TGF-α/EGFR Pathway in Human Intrahepatic Biliary Epithelial CellBioMed Research International, 2013
- Blocking of Bradykinin Receptor B1 Protects from Focal Closed Head Injury in Mice by Reducing Axonal Damage and Astroglia ActivationJournal of Cerebral Blood Flow & Metabolism, 2012
- LPS-Stimulated Cytokine Production in Type I Cells Is Modulated by the Renin–Angiotensin SystemAmerican Journal of Respiratory Cell and Molecular Biology, 2012
- Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin‐(1–7) or an angiotensin II receptor antagonistThe Journal of Pathology, 2011
- Autoantibodies to angiotensin-converting enzyme 2 in patients with connective tissue diseasesArthritis Research & Therapy, 2010
- Ectodomain shedding of angiotensin converting enzyme 2 in human airway epitheliaAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2009
- JunD Protects the Liver from Ischemia/Reperfusion Injury by Dampening AP-1 Transcriptional ActivationOnline Journal of Public Health Informatics, 2008
- Clathrin-Dependent Entry of Severe Acute Respiratory Syndrome Coronavirus into Target Cells Expressing ACE2 with the Cytoplasmic Tail DeletedJournal of Virology, 2007