Heightened endoplasmic reticulum stress in the lungs of patients with chronic obstructive pulmonary disease: The role of Nrf2-regulated proteasomal activity

Deepti Malhotra, Rajesh Thimmulappa, Neeraj Vij, Ana Navas Acien, Thomas Sussan, Salim Merali, Li Zhang, Steven G. Kelsen, Allen Myers, Robert A Wise, Rubin Tuder, Shyam Biswal

Research output: Contribution to journalArticle

Abstract

Rationale: Nuclear factor erythroid 2-related factor 2 (Nrf2), an important regulator of lung antioxidant defenses, declines in chronic obstructive pulmonary disease (COPD). However, Nrf2 also regulates the proteasome system that degrades damaged and misfolded proteins. Because accumulation ofmisfolded proteins in the endoplasmic reticulum(ER) causes ER stress and ER stress-induced apoptosis, Nrf2 may potentially prevent ER stress-mediated apoptosis in COPD. Objectives: To determine whether Nrf2-regulated proteasome function affects ER stress-mediated apoptosis in COPD. Methods: We assessed the expression of Nrf2, Nrf2-dependent proteasomal subunits, proteasomal activity, markers of ER stress, and apoptosis in emphysematous lungs of mice exposed to cigarette smoke (CS) as well as peripheral lung tissues from normal control subjects and patients with COPD. Measurements and Main Results: Compared with wild-type mice, emphysematous lungs of CS-exposed Nrf2-deficient mice exhibited markedly lower proteasomal activity and elevated markers of ER stress and apoptosis. Furthermore, compared with normal control subjects, lungs of patients with mild and advanced COPD showed a marked decrease in the expression of Nrf2-regulated proteasomal subunits and total proteasomal activity. However, they were associated with greater levels of ER stress and apoptosismarkers. In vitro studies have demonstrated that enhancing proteasomal activity in Beas2B cells eitherby sulforaphane, anactivator of Nrf2, or overexpression of Nrf2-regulated proteasomal subunit PSMB6, significantly inhibited cigarette smoke condensate (CSC)-induced ER stress and cell death. Conclusions: Impaired Nrf2 signaling causes significant decline in proteasomal activity and heightens ER stress response in lungs of patients with COPD and CS-exposed mice. Accordingly, pharmacological approaches that augment Nrf2 activity may protect against COPD progression by both up-regulating antioxidant defenses and relieving ER stress.

Original languageEnglish (US)
Pages (from-to)1197-1207
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume180
Issue number12
DOIs
StatePublished - Dec 15 2009

Fingerprint

Endoplasmic Reticulum Stress
Chronic Obstructive Pulmonary Disease
Lung
Smoke
Tobacco Products
Apoptosis
Proteasome Endopeptidase Complex
Antioxidants
Endoplasmic Reticulum
Disease Progression
Proteins
Cell Death
Pharmacology

Keywords

  • Chronic obstructive pulmonary disease lungs
  • Endoplasmic reticulum stress
  • Nrf2
  • Proteasome system
  • Unfolded protein response

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Heightened endoplasmic reticulum stress in the lungs of patients with chronic obstructive pulmonary disease : The role of Nrf2-regulated proteasomal activity. / Malhotra, Deepti; Thimmulappa, Rajesh; Vij, Neeraj; Navas Acien, Ana; Sussan, Thomas; Merali, Salim; Zhang, Li; Kelsen, Steven G.; Myers, Allen; Wise, Robert A; Tuder, Rubin; Biswal, Shyam.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 180, No. 12, 15.12.2009, p. 1197-1207.

Research output: Contribution to journalArticle

Malhotra, Deepti ; Thimmulappa, Rajesh ; Vij, Neeraj ; Navas Acien, Ana ; Sussan, Thomas ; Merali, Salim ; Zhang, Li ; Kelsen, Steven G. ; Myers, Allen ; Wise, Robert A ; Tuder, Rubin ; Biswal, Shyam. / Heightened endoplasmic reticulum stress in the lungs of patients with chronic obstructive pulmonary disease : The role of Nrf2-regulated proteasomal activity. In: American Journal of Respiratory and Critical Care Medicine. 2009 ; Vol. 180, No. 12. pp. 1197-1207.
@article{e08b0784e49b4193a3169af1fbebae8b,
title = "Heightened endoplasmic reticulum stress in the lungs of patients with chronic obstructive pulmonary disease: The role of Nrf2-regulated proteasomal activity",
abstract = "Rationale: Nuclear factor erythroid 2-related factor 2 (Nrf2), an important regulator of lung antioxidant defenses, declines in chronic obstructive pulmonary disease (COPD). However, Nrf2 also regulates the proteasome system that degrades damaged and misfolded proteins. Because accumulation ofmisfolded proteins in the endoplasmic reticulum(ER) causes ER stress and ER stress-induced apoptosis, Nrf2 may potentially prevent ER stress-mediated apoptosis in COPD. Objectives: To determine whether Nrf2-regulated proteasome function affects ER stress-mediated apoptosis in COPD. Methods: We assessed the expression of Nrf2, Nrf2-dependent proteasomal subunits, proteasomal activity, markers of ER stress, and apoptosis in emphysematous lungs of mice exposed to cigarette smoke (CS) as well as peripheral lung tissues from normal control subjects and patients with COPD. Measurements and Main Results: Compared with wild-type mice, emphysematous lungs of CS-exposed Nrf2-deficient mice exhibited markedly lower proteasomal activity and elevated markers of ER stress and apoptosis. Furthermore, compared with normal control subjects, lungs of patients with mild and advanced COPD showed a marked decrease in the expression of Nrf2-regulated proteasomal subunits and total proteasomal activity. However, they were associated with greater levels of ER stress and apoptosismarkers. In vitro studies have demonstrated that enhancing proteasomal activity in Beas2B cells eitherby sulforaphane, anactivator of Nrf2, or overexpression of Nrf2-regulated proteasomal subunit PSMB6, significantly inhibited cigarette smoke condensate (CSC)-induced ER stress and cell death. Conclusions: Impaired Nrf2 signaling causes significant decline in proteasomal activity and heightens ER stress response in lungs of patients with COPD and CS-exposed mice. Accordingly, pharmacological approaches that augment Nrf2 activity may protect against COPD progression by both up-regulating antioxidant defenses and relieving ER stress.",
keywords = "Chronic obstructive pulmonary disease lungs, Endoplasmic reticulum stress, Nrf2, Proteasome system, Unfolded protein response",
author = "Deepti Malhotra and Rajesh Thimmulappa and Neeraj Vij and {Navas Acien}, Ana and Thomas Sussan and Salim Merali and Li Zhang and Kelsen, {Steven G.} and Allen Myers and Wise, {Robert A} and Rubin Tuder and Shyam Biswal",
year = "2009",
month = "12",
day = "15",
doi = "10.1164/rccm.200903-0324OC",
language = "English (US)",
volume = "180",
pages = "1197--1207",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "12",

}

TY - JOUR

T1 - Heightened endoplasmic reticulum stress in the lungs of patients with chronic obstructive pulmonary disease

T2 - The role of Nrf2-regulated proteasomal activity

AU - Malhotra, Deepti

AU - Thimmulappa, Rajesh

AU - Vij, Neeraj

AU - Navas Acien, Ana

AU - Sussan, Thomas

AU - Merali, Salim

AU - Zhang, Li

AU - Kelsen, Steven G.

AU - Myers, Allen

AU - Wise, Robert A

AU - Tuder, Rubin

AU - Biswal, Shyam

PY - 2009/12/15

Y1 - 2009/12/15

N2 - Rationale: Nuclear factor erythroid 2-related factor 2 (Nrf2), an important regulator of lung antioxidant defenses, declines in chronic obstructive pulmonary disease (COPD). However, Nrf2 also regulates the proteasome system that degrades damaged and misfolded proteins. Because accumulation ofmisfolded proteins in the endoplasmic reticulum(ER) causes ER stress and ER stress-induced apoptosis, Nrf2 may potentially prevent ER stress-mediated apoptosis in COPD. Objectives: To determine whether Nrf2-regulated proteasome function affects ER stress-mediated apoptosis in COPD. Methods: We assessed the expression of Nrf2, Nrf2-dependent proteasomal subunits, proteasomal activity, markers of ER stress, and apoptosis in emphysematous lungs of mice exposed to cigarette smoke (CS) as well as peripheral lung tissues from normal control subjects and patients with COPD. Measurements and Main Results: Compared with wild-type mice, emphysematous lungs of CS-exposed Nrf2-deficient mice exhibited markedly lower proteasomal activity and elevated markers of ER stress and apoptosis. Furthermore, compared with normal control subjects, lungs of patients with mild and advanced COPD showed a marked decrease in the expression of Nrf2-regulated proteasomal subunits and total proteasomal activity. However, they were associated with greater levels of ER stress and apoptosismarkers. In vitro studies have demonstrated that enhancing proteasomal activity in Beas2B cells eitherby sulforaphane, anactivator of Nrf2, or overexpression of Nrf2-regulated proteasomal subunit PSMB6, significantly inhibited cigarette smoke condensate (CSC)-induced ER stress and cell death. Conclusions: Impaired Nrf2 signaling causes significant decline in proteasomal activity and heightens ER stress response in lungs of patients with COPD and CS-exposed mice. Accordingly, pharmacological approaches that augment Nrf2 activity may protect against COPD progression by both up-regulating antioxidant defenses and relieving ER stress.

AB - Rationale: Nuclear factor erythroid 2-related factor 2 (Nrf2), an important regulator of lung antioxidant defenses, declines in chronic obstructive pulmonary disease (COPD). However, Nrf2 also regulates the proteasome system that degrades damaged and misfolded proteins. Because accumulation ofmisfolded proteins in the endoplasmic reticulum(ER) causes ER stress and ER stress-induced apoptosis, Nrf2 may potentially prevent ER stress-mediated apoptosis in COPD. Objectives: To determine whether Nrf2-regulated proteasome function affects ER stress-mediated apoptosis in COPD. Methods: We assessed the expression of Nrf2, Nrf2-dependent proteasomal subunits, proteasomal activity, markers of ER stress, and apoptosis in emphysematous lungs of mice exposed to cigarette smoke (CS) as well as peripheral lung tissues from normal control subjects and patients with COPD. Measurements and Main Results: Compared with wild-type mice, emphysematous lungs of CS-exposed Nrf2-deficient mice exhibited markedly lower proteasomal activity and elevated markers of ER stress and apoptosis. Furthermore, compared with normal control subjects, lungs of patients with mild and advanced COPD showed a marked decrease in the expression of Nrf2-regulated proteasomal subunits and total proteasomal activity. However, they were associated with greater levels of ER stress and apoptosismarkers. In vitro studies have demonstrated that enhancing proteasomal activity in Beas2B cells eitherby sulforaphane, anactivator of Nrf2, or overexpression of Nrf2-regulated proteasomal subunit PSMB6, significantly inhibited cigarette smoke condensate (CSC)-induced ER stress and cell death. Conclusions: Impaired Nrf2 signaling causes significant decline in proteasomal activity and heightens ER stress response in lungs of patients with COPD and CS-exposed mice. Accordingly, pharmacological approaches that augment Nrf2 activity may protect against COPD progression by both up-regulating antioxidant defenses and relieving ER stress.

KW - Chronic obstructive pulmonary disease lungs

KW - Endoplasmic reticulum stress

KW - Nrf2

KW - Proteasome system

KW - Unfolded protein response

UR - http://www.scopus.com/inward/record.url?scp=72549115279&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=72549115279&partnerID=8YFLogxK

U2 - 10.1164/rccm.200903-0324OC

DO - 10.1164/rccm.200903-0324OC

M3 - Article

C2 - 19797762

AN - SCOPUS:72549115279

VL - 180

SP - 1197

EP - 1207

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 12

ER -