Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg(9) bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration

Chhinder P. Sodhi; Christine Wohlford-Lenane; Yukihiro Yamaguchi; Thomas Prindle; William B. Fulton; Sanxia Wang; Paul B. McCray; Mark Chappell; David J. Hackam; Hongpeng Jia

doi:10.1152/ajplung.00498.2016

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Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg(9) bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration

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Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg(9) bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration

Chhinder P. Sodhi, Christine Wohlford-Lenane, Yukihiro Yamaguchi, Thomas Prindle, William B. Fulton, Sanxia Wang, Paul B. McCray, Mark Chappell, David J. Hackam and Hongpeng Jia

American journal of physiology. Lung cellular and molecular physiology, Vol.314(1), pp.L17-L31

01/01/2018

DOI: 10.1152/ajplung.00498.2016

PMCID: PMC5866432

PMID: 28935640

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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-Arg(9) 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-alpha 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.

Life Sciences & Biomedicine

Physiology

Respiratory System

Science & Technology

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Title: Subtitle: Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg(9) bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration
Creators: Chhinder P. Sodhi - Johns Hopkins University
Christine Wohlford-Lenane - Roy J. and Lucille A. Carver College of Medicine
Yukihiro Yamaguchi - Johns Hopkins University
Thomas Prindle - Johns Hopkins University
William B. Fulton - Johns Hopkins University
Sanxia Wang - Johns Hopkins University
Paul B. McCray - Roy J. and Lucille A. Carver College of Medicine
Mark Chappell - Wake Forest University
David J. Hackam - Johns Hopkins University
Hongpeng Jia - Johns Hopkins University
Resource Type: Journal article
Publication Details: American journal of physiology. Lung cellular and molecular physiology, Vol.314(1), pp.L17-L31
Publisher: Amer Physiological Soc
DOI: 10.1152/ajplung.00498.2016
PMID: 28935640
PMCID: PMC5866432
ISSN: 1040-0605
eISSN: 1522-1504
Number of pages: 15
Grant note: 54759 / Center for Gene Therapy for Cystic Fibrosis (National Institute of Diabetes and Digestive and Kidney Diseases) P01AI060699 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) P30ES005605 / NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS) P30DK054759 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) 60699 / National Institute of Allergy and Infectious Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) R01GM078238 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
Language: English
Date published: 01/01/2018
Academic Unit: Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Internal Medicine
Record Identifier: 9984297318302771

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