Deuterated Arachidonic Acid Ameliorates Lipopolysaccharide-Induced Lung Damage in Mice
Alla Y. Molchanova,
Svetlana N. Rjabceva,
Tigran B. Melik-Kasumov,
Nikolay B. Pestov,
Plamena R. Angelova,
Vadim V. Shmanai,
Olga L. Sharko,
Andrei V. Bekish,
Genevieve James,
Hui Gyu Park,
Irina A. Udalova,
J. Thomas Brenna,
Mikhail S. Shchepinov
Affiliations
Alla Y. Molchanova
Institute of Physiology, National Academy of Sciences of Belarus, Academicheskaya 28, 220072 Minsk, Belarus
Svetlana N. Rjabceva
Institute of Physiology, National Academy of Sciences of Belarus, Academicheskaya 28, 220072 Minsk, Belarus
Tigran B. Melik-Kasumov
Institute of Physiology, National Academy of Sciences of Belarus, Academicheskaya 28, 220072 Minsk, Belarus
Nikolay B. Pestov
Laboratory of Tick-Borne Encephalitis and Other Viral Encephalitides, Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, Poselok Instituta Poliomielita 8 bd 17, Poselenie Moskovsky, 108819 Moscow, Russia
Plamena R. Angelova
Queen Square Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK
Vadim V. Shmanai
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Surganova 13, 220072 Minsk, Belarus
Olga L. Sharko
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Surganova 13, 220072 Minsk, Belarus
Andrei V. Bekish
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Surganova 13, 220072 Minsk, Belarus
Genevieve James
Departments of Pediatrics, of Chemistry, and of Nutrition, Dell Pediatric Research Institute, University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, USA
Hui Gyu Park
Departments of Pediatrics, of Chemistry, and of Nutrition, Dell Pediatric Research Institute, University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, USA
Irina A. Udalova
The Kennedy Institute of Rheumatology, University of Oxford, Oxford OX1 2JD, UK
J. Thomas Brenna
Departments of Pediatrics, of Chemistry, and of Nutrition, Dell Pediatric Research Institute, University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, TX 78723, USA
Arachidonic acid (ARA) is a major component of lipid bilayers as well as the key substrate for the eicosanoid cascades. ARA is readily oxidized, and its non-enzymatic and enzymatic oxidation products induce inflammatory responses in nearly all tissues, including lung tissues. Deuteration at bis-allylic positions substantially decreases the overall rate of ARA oxidation when hydrogen abstraction is an initiating event. To compare the effects of dosing of arachidonic acid (H-ARA) and its bis-allylic hexadeuterated form (D-ARA) on lungs in conventionally healthy mice and in an acute lung injury model, mice were dosed with H-ARA or D-ARA for six weeks through dietary supplementation and then challenged with intranasal lipopolysaccharide (LPS) for subsequent analysis of bronchoalveolar lavage fluid and lung tissue. Dosing on D-ARA resulted in successful incorporation of D-ARA into various tissues. D-ARA significantly reduced LPS-induced adverse effects on alveolar septal thickness and the bronchoalveolar area. Oral deuterated ARA is taken up efficiently and protects against adverse LPS-induced pathology. This suggests novel therapeutic avenues for reducing lung damage during severe infections and other pathological conditions with inflammation in the pulmonary system and other inflammatory diseases.
