Reactive oxygen species/hypoxia-inducible Factor-1a/Platelet-Derived Growth Factor-BB autocrine loop contributes to cocaine-mediated alveolar epithelial barrier damage

Lu Yang, Xufeng Chen, Samantha M Simet Chadwick, Guoku Hu, Yu Cai, Fang Niu, Yeonhee Kook, Shilpa J Buch

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Abuse of psychostimulants, such as cocaine, has been shown to be closely associated with complications of the lung, such as pulmonary hypertension, edema, increased inflammation, and infection. However, the mechanism by which cocaine mediates impairment of alveolar epithelial barrier integrity that underlies various pulmonary complications has not been well determined. Herein, we investigate the role of cocaine in disrupting the alveolar epithelial barrier function and the associated signaling cascade. Using the combinatorial electric cell-substrate impedance sensing and FITCdextran permeability assays, we demonstrated cocaine-mediated disruption of the alveolar epithelial barrier, as evidenced by increased epithelial monolayer permeability with a concomitant loss of the tight junction protein zonula occludens-1 (Zo-1) in both mouse primary alveolar epithelial cells and the alveolar epithelial cell line, L2 cells. To dissect the signaling pathways involved in this process, we demonstrated that cocaine-mediated induction of permeability factors, platelet-derived growth factor (PDGF-BB) and vascular endothelial growth factor, involved reactive oxygen species (ROS)-dependent induction of hypoxia-inducible factor (HIF)-1a. Interestingly, we demonstrated that ROS-dependent induction of another transcription factor, nuclear factor erythroid-2-related factor-2, that did not play a role in cocaine-mediated barrier dysfunction. Importantly, this study identifies, for the first time, that ROS/HIF-1a/PDGF-BB autocrine loop contributes to cocaine-mediated barrier disruption via amplification of oxidative stress and downstream signaling. Corroboration of these cell culture findings in vivo demonstrated increased permeability of the alveolar epithelial barrier, loss of expression of Zo-1, and a concomitantly increased expression of both HIF-1a and PDGF-BB. Pharmacological blocking of HIF-1a significantly abrogated cocaine-mediated loss of Zo-1. Understanding the mechanism(s) by which cocaine mediates barrier dysfunction could provide insights into the development of potential therapeutic targets for cocaine-mediated pulmonary hypertension.

Original languageEnglish (US)
Pages (from-to)736-748
Number of pages13
JournalAmerican journal of respiratory cell and molecular biology
Volume55
Issue number5
DOIs
StatePublished - Nov 2016

Fingerprint

Cocaine
Reactive Oxygen Species
Tight Junctions
Permeability
Alveolar Epithelial Cells
Pulmonary Hypertension
NF-E2 Transcription Factor
Hypoxia
platelet-derived growth factor BB
Electric batteries
Tight Junction Proteins
Lung
Oxidative stress
Platelet-Derived Growth Factor
Pulmonary Edema
Electric Impedance
Cell culture
Vascular Endothelial Growth Factor A
Amplification
Monolayers

Keywords

  • Alveolar epithelium
  • Cocaine
  • Hypoxia-inducible factor-1a
  • Platelet-derived growth factor-BB
  • Reactive oxygen species

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

@article{f917da1c36ff489a853969e3988d7ee8,
title = "Reactive oxygen species/hypoxia-inducible Factor-1a/Platelet-Derived Growth Factor-BB autocrine loop contributes to cocaine-mediated alveolar epithelial barrier damage",
abstract = "Abuse of psychostimulants, such as cocaine, has been shown to be closely associated with complications of the lung, such as pulmonary hypertension, edema, increased inflammation, and infection. However, the mechanism by which cocaine mediates impairment of alveolar epithelial barrier integrity that underlies various pulmonary complications has not been well determined. Herein, we investigate the role of cocaine in disrupting the alveolar epithelial barrier function and the associated signaling cascade. Using the combinatorial electric cell-substrate impedance sensing and FITCdextran permeability assays, we demonstrated cocaine-mediated disruption of the alveolar epithelial barrier, as evidenced by increased epithelial monolayer permeability with a concomitant loss of the tight junction protein zonula occludens-1 (Zo-1) in both mouse primary alveolar epithelial cells and the alveolar epithelial cell line, L2 cells. To dissect the signaling pathways involved in this process, we demonstrated that cocaine-mediated induction of permeability factors, platelet-derived growth factor (PDGF-BB) and vascular endothelial growth factor, involved reactive oxygen species (ROS)-dependent induction of hypoxia-inducible factor (HIF)-1a. Interestingly, we demonstrated that ROS-dependent induction of another transcription factor, nuclear factor erythroid-2-related factor-2, that did not play a role in cocaine-mediated barrier dysfunction. Importantly, this study identifies, for the first time, that ROS/HIF-1a/PDGF-BB autocrine loop contributes to cocaine-mediated barrier disruption via amplification of oxidative stress and downstream signaling. Corroboration of these cell culture findings in vivo demonstrated increased permeability of the alveolar epithelial barrier, loss of expression of Zo-1, and a concomitantly increased expression of both HIF-1a and PDGF-BB. Pharmacological blocking of HIF-1a significantly abrogated cocaine-mediated loss of Zo-1. Understanding the mechanism(s) by which cocaine mediates barrier dysfunction could provide insights into the development of potential therapeutic targets for cocaine-mediated pulmonary hypertension.",
keywords = "Alveolar epithelium, Cocaine, Hypoxia-inducible factor-1a, Platelet-derived growth factor-BB, Reactive oxygen species",
author = "Lu Yang and Xufeng Chen and {Simet Chadwick}, {Samantha M} and Guoku Hu and Yu Cai and Fang Niu and Yeonhee Kook and Buch, {Shilpa J}",
year = "2016",
month = "11",
doi = "10.1165/rcmb.2016-0096OC",
language = "English (US)",
volume = "55",
pages = "736--748",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "5",

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TY - JOUR

T1 - Reactive oxygen species/hypoxia-inducible Factor-1a/Platelet-Derived Growth Factor-BB autocrine loop contributes to cocaine-mediated alveolar epithelial barrier damage

AU - Yang, Lu

AU - Chen, Xufeng

AU - Simet Chadwick, Samantha M

AU - Hu, Guoku

AU - Cai, Yu

AU - Niu, Fang

AU - Kook, Yeonhee

AU - Buch, Shilpa J

PY - 2016/11

Y1 - 2016/11

N2 - Abuse of psychostimulants, such as cocaine, has been shown to be closely associated with complications of the lung, such as pulmonary hypertension, edema, increased inflammation, and infection. However, the mechanism by which cocaine mediates impairment of alveolar epithelial barrier integrity that underlies various pulmonary complications has not been well determined. Herein, we investigate the role of cocaine in disrupting the alveolar epithelial barrier function and the associated signaling cascade. Using the combinatorial electric cell-substrate impedance sensing and FITCdextran permeability assays, we demonstrated cocaine-mediated disruption of the alveolar epithelial barrier, as evidenced by increased epithelial monolayer permeability with a concomitant loss of the tight junction protein zonula occludens-1 (Zo-1) in both mouse primary alveolar epithelial cells and the alveolar epithelial cell line, L2 cells. To dissect the signaling pathways involved in this process, we demonstrated that cocaine-mediated induction of permeability factors, platelet-derived growth factor (PDGF-BB) and vascular endothelial growth factor, involved reactive oxygen species (ROS)-dependent induction of hypoxia-inducible factor (HIF)-1a. Interestingly, we demonstrated that ROS-dependent induction of another transcription factor, nuclear factor erythroid-2-related factor-2, that did not play a role in cocaine-mediated barrier dysfunction. Importantly, this study identifies, for the first time, that ROS/HIF-1a/PDGF-BB autocrine loop contributes to cocaine-mediated barrier disruption via amplification of oxidative stress and downstream signaling. Corroboration of these cell culture findings in vivo demonstrated increased permeability of the alveolar epithelial barrier, loss of expression of Zo-1, and a concomitantly increased expression of both HIF-1a and PDGF-BB. Pharmacological blocking of HIF-1a significantly abrogated cocaine-mediated loss of Zo-1. Understanding the mechanism(s) by which cocaine mediates barrier dysfunction could provide insights into the development of potential therapeutic targets for cocaine-mediated pulmonary hypertension.

AB - Abuse of psychostimulants, such as cocaine, has been shown to be closely associated with complications of the lung, such as pulmonary hypertension, edema, increased inflammation, and infection. However, the mechanism by which cocaine mediates impairment of alveolar epithelial barrier integrity that underlies various pulmonary complications has not been well determined. Herein, we investigate the role of cocaine in disrupting the alveolar epithelial barrier function and the associated signaling cascade. Using the combinatorial electric cell-substrate impedance sensing and FITCdextran permeability assays, we demonstrated cocaine-mediated disruption of the alveolar epithelial barrier, as evidenced by increased epithelial monolayer permeability with a concomitant loss of the tight junction protein zonula occludens-1 (Zo-1) in both mouse primary alveolar epithelial cells and the alveolar epithelial cell line, L2 cells. To dissect the signaling pathways involved in this process, we demonstrated that cocaine-mediated induction of permeability factors, platelet-derived growth factor (PDGF-BB) and vascular endothelial growth factor, involved reactive oxygen species (ROS)-dependent induction of hypoxia-inducible factor (HIF)-1a. Interestingly, we demonstrated that ROS-dependent induction of another transcription factor, nuclear factor erythroid-2-related factor-2, that did not play a role in cocaine-mediated barrier dysfunction. Importantly, this study identifies, for the first time, that ROS/HIF-1a/PDGF-BB autocrine loop contributes to cocaine-mediated barrier disruption via amplification of oxidative stress and downstream signaling. Corroboration of these cell culture findings in vivo demonstrated increased permeability of the alveolar epithelial barrier, loss of expression of Zo-1, and a concomitantly increased expression of both HIF-1a and PDGF-BB. Pharmacological blocking of HIF-1a significantly abrogated cocaine-mediated loss of Zo-1. Understanding the mechanism(s) by which cocaine mediates barrier dysfunction could provide insights into the development of potential therapeutic targets for cocaine-mediated pulmonary hypertension.

KW - Alveolar epithelium

KW - Cocaine

KW - Hypoxia-inducible factor-1a

KW - Platelet-derived growth factor-BB

KW - Reactive oxygen species

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