Attenuation of pulmonary ACE2 activity impairs inactivation of des-arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)L17-L31
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume314
Issue number1
DOIs
StatePublished - Jan 1 2018

Fingerprint

Neutrophil Infiltration
Bradykinin
Lung
Pneumonia
CXC Chemokines
Lung Diseases
Chemokine CXCL5
Bradykinin Receptors
Chemokine CXCL2
angiotensin converting enzyme 2
Carboxypeptidases
Lung Injury
Renin-Angiotensin System
Protein C
Chemokines
Endotoxins
Angiotensin II
Respiratory System
Inhalation
Epithelium

Keywords

  • Angiotensin-converting enzyme 2
  • Bradykinin receptor B1
  • C-X-C motif chemokine 5
  • Endotoxin
  • Lung inflammation

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Attenuation of pulmonary ACE2 activity impairs inactivation of des-arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. / Sodhi, Chhinder; Wohlford-Lenane, Christine; Yamaguchi, Yukihiro; Prindle, Thomas; Fulton, William B.; Wang, Sanxia; McCray, Paul B.; Chappell, Mark; Hackam, David; Jia, Hongpeng.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 314, No. 1, 01.01.2018, p. L17-L31.

Research output: Contribution to journalArticle

@article{5d372fccbbbb4040bfb4d93deb319351,
title = "Attenuation of pulmonary ACE2 activity impairs inactivation of des-arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration",
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 = "Angiotensin-converting enzyme 2, Bradykinin receptor B1, C-X-C motif chemokine 5, Endotoxin, Lung inflammation",
author = "Chhinder Sodhi and Christine Wohlford-Lenane and Yukihiro Yamaguchi and Thomas Prindle and Fulton, {William B.} and Sanxia Wang and McCray, {Paul B.} and Mark Chappell and David Hackam and Hongpeng Jia",
year = "2018",
month = "1",
day = "1",
doi = "10.1152/ajplung.00498.2016",
language = "English (US)",
volume = "314",
pages = "L17--L31",
journal = "American Journal of Physiology",
issn = "1040-0605",
publisher = "American Physiological Society",
number = "1",

}

TY - JOUR

T1 - Attenuation of pulmonary ACE2 activity impairs inactivation of des-arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration

AU - Sodhi, Chhinder

AU - Wohlford-Lenane, Christine

AU - Yamaguchi, Yukihiro

AU - Prindle, Thomas

AU - Fulton, William B.

AU - Wang, Sanxia

AU - McCray, Paul B.

AU - Chappell, Mark

AU - Hackam, David

AU - Jia, Hongpeng

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Angiotensin-converting enzyme 2

KW - Bradykinin receptor B1

KW - C-X-C motif chemokine 5

KW - Endotoxin

KW - Lung inflammation

UR - http://www.scopus.com/inward/record.url?scp=85043467113&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85043467113&partnerID=8YFLogxK

U2 - 10.1152/ajplung.00498.2016

DO - 10.1152/ajplung.00498.2016

M3 - Article

C2 - 28935640

AN - SCOPUS:85043467113

VL - 314

SP - L17-L31

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 1040-0605

IS - 1

ER -