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Nitrated fatty acids reverse cigarette smoke-induced alveolar macrophage activation and inhibit protease activity via electrophilic S-alkylation

Reddy, AT and Lakshmi, SP and Muchumarri, RR and Reddy, RC (2016) Nitrated fatty acids reverse cigarette smoke-induced alveolar macrophage activation and inhibit protease activity via electrophilic S-alkylation. PLoS ONE, 11 (4).

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Abstract

© 2016, Public Library of Science. All rights reserved. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Nitrated fatty acids (NFAs), endogenous products of nonenzymatic reactions of NO-derived reactive nitrogen species with unsaturated fatty acids, exhibit substantial anti-inflammatory activities. They are both reversible electrophiles and peroxisome proliferator-activated receptor γ (PPARγ) agonists, but the physiological implications of their electrophilic activity are poorly understood. We tested their effects on inflammatory and emphysema-related biomarkers in alveolar macrophages (AMs) of smoke-exposed mice. NFA (10-nitro-oleic acid or 12-nitrolinoleic acid) treatment downregulated expression and activity of the inflammatory transcription factor NF-κB while upregulating those of PPARγ. It also downregulated production of inflammatory cytokines and chemokines and of the protease cathepsin S (Cat S), a key mediator of emphysematous septal destruction. Cat S downregulation was accompanied by decreased AM elastolytic activity, a major mechanism of septal destruction. NFAs downregulated both Cat S expression and activity in AMs of wild-type mice, but only inhibited its activity in AMs of PPARγ knockout mice, pointing to a PPARγ-independent mechanism of enzyme inhibition. We hypothesized that this mechanism was electrophilic S-alkylation of target Cat S cysteines, and found that NFAs bind directly to Cat S following treatment of intact AMs and, as suggested by in silico modeling and calculation of relevant parameters, elicit S-alkylation of Cys25 when incubated with purified Cat S. These results demonstrate that NFAs' electrophilic activity, in addition to their role as PPARγ agonists, underlies their protective effects in chronic obstructive pulmonary disease (COPD) and support their therapeutic potential in this disease.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Reddy, AT
Lakshmi, SP
Muchumarri, RR
Reddy, RC
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorSu, YunchaoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 April 2016
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 11
Number: 4
DOI or Unique Handle: 10.1371/journal.pone.0153336
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Critical Care Medicine
Refereed: Yes
Date Deposited: 31 Aug 2016 17:31
Last Modified: 24 Jan 2019 00:55
URI: http://d-scholarship.pitt.edu/id/eprint/28265

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