Chiara Cipollina1, Serena Di Vincenzo2, Stefania Gerbino3, Liboria Siena4, Mark Gjomarkaj4, Elisabetta Pace4. 1. Fondazione Ri.MED, Via Bandiera 11, Palermo, Italy; Istituto di Biomedicina e Immunologia Molecolare (IBIM), Consiglio Nazionale delle Ricerche (CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy. Electronic address: chiara.cipollina@gmail.com. 2. Istituto di Biomedicina e Immunologia Molecolare (IBIM), Consiglio Nazionale delle Ricerche (CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy; Scienze e Biotecnologie Mediche e Sperimentali, Pneumologia Sperimentale e Clinica, Università degli Studi di Palermo, Palermo, Italy. 3. Istituto di Biomedicina e Immunologia Molecolare (IBIM), Consiglio Nazionale delle Ricerche (CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy; Dipartimento di Scienze Motorie, Università degli Studi di Palermo, Palermo, Italy. 4. Istituto di Biomedicina e Immunologia Molecolare (IBIM), Consiglio Nazionale delle Ricerche (CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy.
Abstract
BACKGROUND: 17-Oxo-DHA is an endogenous electrophilic derivative of the omega-3 fatty acid docosahexaenoic acid (DHA) which is generated in activated macrophages by the action of cyclooxygenase-2. METHODS: The ability of 17-oxo-DHA to control inflammation and oxidative stress was tested in human macrophages (THP-1) and bronchial epithelial cell line (16HBE) stimulated with cigarette smoke extract (CSE) and lipopolysaccharide (LPS). All data were further confirmed using primary bronchial epithelial cells, alveolar macrophages and peripheral blood mononuclear cells. RESULTS: 17-Oxo-DHA was a strong inducer of the anti-oxidant response promoting Nrf2 nuclear accumulation, leading to the expression of heme oxygenase 1 and more than doubling glutathione levels. This resulted in suppression of CSE-induced ROS generation in macrophages. In macrophages, 17-oxo-DHA potently suppressed TNFα release in response to LPS, CSE and IL-1β acting at transcriptional level via a mechanism independent of Nrf2. Externally supplemented 17-oxo-DHA displayed the same effects in the presence of the Cox-inhibitor indomethacin. The non-electrophilic 17-oxo-DHA precursor DHA did not show any biological actions, indicating that the electrophilic moiety was required for this compound to become bioactive. CONCLUSIONS: 17-Oxo-DHA promotes cytoprotective actions both in immune and structural cells. In immune cells, 17-oxo-DHA is effective in contrasting CSE- and LPS-induced oxidative damage and inflammation acting via multiple independent pathways. GENERAL SIGNIFICANCE: Herein we provide insights on how the novel endogenous electrophilic DHA-derivative 17-oxo-DHA promotes anti-oxidant and anti-inflammatory actions. Data herein reported indicate that 17-oxo-DHA is an attractive lead compound for the development of new treatments for cigarette smoke-related airway inflammatory disorders.
BACKGROUND:17-Oxo-DHA is an endogenous electrophilic derivative of the omega-3 fatty aciddocosahexaenoic acid (DHA) which is generated in activated macrophages by the action of cyclooxygenase-2. METHODS: The ability of 17-oxo-DHA to control inflammation and oxidative stress was tested in human macrophages (THP-1) and bronchial epithelial cell line (16HBE) stimulated with cigarette smoke extract (CSE) and lipopolysaccharide (LPS). All data were further confirmed using primary bronchial epithelial cells, alveolar macrophages and peripheral blood mononuclear cells. RESULTS:17-Oxo-DHA was a strong inducer of the anti-oxidant response promoting Nrf2 nuclear accumulation, leading to the expression of heme oxygenase 1 and more than doubling glutathione levels. This resulted in suppression of CSE-induced ROS generation in macrophages. In macrophages, 17-oxo-DHA potently suppressed TNFα release in response to LPS, CSE and IL-1β acting at transcriptional level via a mechanism independent of Nrf2. Externally supplemented 17-oxo-DHA displayed the same effects in the presence of the Cox-inhibitor indomethacin. The non-electrophilic 17-oxo-DHA precursor DHA did not show any biological actions, indicating that the electrophilic moiety was required for this compound to become bioactive. CONCLUSIONS:17-Oxo-DHA promotes cytoprotective actions both in immune and structural cells. In immune cells, 17-oxo-DHA is effective in contrasting CSE- and LPS-induced oxidative damage and inflammation acting via multiple independent pathways. GENERAL SIGNIFICANCE: Herein we provide insights on how the novel endogenous electrophilic DHA-derivative 17-oxo-DHA promotes anti-oxidant and anti-inflammatory actions. Data herein reported indicate that 17-oxo-DHA is an attractive lead compound for the development of new treatments for cigarette smoke-related airway inflammatory disorders.
Authors: Jiong Hu; Alexandra Geyer; Sarah Dziumbla; Khader Awwad; Darryl C Zeldin; Wolf-Hagen Schunck; Rüdiger Popp; Timo Frömel; Ingrid Fleming Journal: Prostaglandins Other Lipid Mediat Date: 2017-04-23 Impact factor: 3.072
Authors: Amanda Croasdell; Thomas H Thatcher; R Matthew Kottmann; Romain A Colas; Jesmond Dalli; Charles N Serhan; Patricia J Sime; Richard P Phipps Journal: Am J Physiol Lung Cell Mol Physiol Date: 2015-08-21 Impact factor: 5.464
Authors: Grace Y Sun; Agnes Simonyi; Kevin L Fritsche; Dennis Y Chuang; Mark Hannink; Zezong Gu; C Michael Greenlief; Jeffrey K Yao; James C Lee; David Q Beversdorf Journal: Prostaglandins Leukot Essent Fatty Acids Date: 2017-03-10 Impact factor: 3.015