| Targeting Nrf2 Signaling Improves Bacterial Clearance by Alveolar Macrophages in Patients with COPD and in a Mouse Model. | |
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MedLine Citation:
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PMID: 21490276 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Patients with chronic obstructive pulmonary disease (COPD) have innate immune dysfunction in the lung largely due to defective macrophage phagocytosis. This deficiency results in periodic bacterial infections that cause acute exacerbations of COPD, a major source of morbidity and mortality. Recent studies indicate that a decrease in Nrf2 (nuclear erythroid-related factor 2) signaling in patients with COPD may hamper their ability to defend against oxidative stress, although the role of Nrf2 in COPD exacerbations has not been determined. Here, we test whether activation of Nrf2 by the phytochemical sulforaphane restores phagocytosis of clinical isolates of nontypeable Haemophilus influenza (NTHI) and Pseudomonas aeruginosa (PA) by alveolar macrophages from patients with COPD. Sulforaphane treatment restored bacteria recognition and phagocytosis in alveolar macrophages from COPD patients. Furthermore, sulforaphane treatment enhanced pulmonary bacterial clearance by alveolar macrophages and reduced inflammation in wild-type mice but not in Nrf2-deficient mice exposed to cigarette smoke for 6 months. Gene expression and promoter analysis revealed that Nrf2 increased phagocytic ability of macrophages by direct transcriptional up-regulation of the scavenger receptor MARCO. Disruption of Nrf2 or MARCO abrogated sulforaphane-mediated bacterial phagocytosis by COPD alveolar macrophages. Our findings demonstrate the importance of Nrf2 and its downstream target MARCO in improving antibacterial defenses and provide a rationale for targeting this pathway, via pharmacological agents such as sulforaphane, to prevent exacerbations of COPD caused by bacterial infection. |
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Authors:
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Christopher J Harvey; Rajesh K Thimmulappa; Sanjay Sethi; Xiaoni Kong; Lonny Yarmus; Robert H Brown; David Feller-Kopman; Robert Wise; Shyam Biswal |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Science translational medicine Volume: 3 ISSN: 1946-6242 ISO Abbreviation: Sci Transl Med Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-04-14 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101505086 Medline TA: Sci Transl Med Country: United States |
Other Details:
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Languages: eng Pagination: 78ra32 Citation Subset: IM |
Affiliation:
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Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, MD 21205, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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