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Heightened Endoplasmic Reticulum Stress in the Lungs of Patients with Chronic Obstructive Pulmonary Disease

The Role of Nrf2-Regulated Proteasomal Activity

¹ Environmental Health Sciences, Johns Hopkins School of Public Health; ² Department of Pediatrics and Division of Pulmonary Medicine, ⁷ Division of Pulmonary and Critical Care Medicine, Department of Medicine, ⁸ Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, Maryland; ³ Department of Biochemistry and Department of Medicine, Division of Pulmonary and Critical Care Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania; ⁴ Division of Pulmonary and Critical Care Medicine, University of Colorado Denver, School of Medicine, Aurora, Colorado; ⁵ The Johns Hopkins Asthma and Allergy Center; and ⁶ Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Shyam Biswal, Ph.D., Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Room E7624, 615 North Wolfe St., Baltimore, MD 21205. E-mail: sbiswal{at}jhsph.edu

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 of misfolded 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 apoptosis markers. In vitro studies have demonstrated that enhancing proteasomal activity in Beas2B cells either by sulforaphane, an activator 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.

Key Words: Nrf2 • proteasome system • endoplasmic reticulum stress • unfolded protein response • chronic obstructive pulmonary disease lungs

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Chronic obstructive pulmonary disease (COPD) continues to be a leading cause of death worldwide, but there are no successful treatment options available. Recent publications have highlighted the importance of defective nuclear factor erythroid 2–related factor 2 (Nrf2)-regulated antioxidant pathway as a mechanism of COPD pathogenesis. What This Study Adds to the Field The decline in Nrf2-dependent proteasomal activity in lungs of patients with COPD leads to an increase in endoplasmic reticulum stress, an unfolded protein response, and cell death that may participate in COPD progression.