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Acute Lung Injury Is Reduced in fat-1 Mice Endogenously Synthesizing n-3 Fatty Acids

¹ University of Giessen Lung Center, Medical Clinic II, Justus-Liebig-University Giessen, Giessen, Germany; ² Department of Veterinary Physiology, Justus-Liebig-University Giessen, Giessen, Germany; ³ Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and ⁴ Resolvyx Pharmaceuticals, Inc., Bedford, Massachusetts

Correspondence and requests for reprints should be addressed to Konstantin Mayer, M.D., University of Giessen Lung Center (UGLC), Medical Clinic II, Justus-Liebig-University Giessen, Klinikstr. 36, D-35392 Giessen, Germany. E-mail: konstantin.mayer{at}uglc.de

Rationale: Acute lung injury (ALI) remains an important cause of mortality in intensive care units. Inflammation is controlled by cytokines and eicosanoids derived from the n-6 fatty acid (FA) arachidonic acid (AA). The n-3 FA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and mediators derived from EPA and DHA possess reduced inflammatory potency.

Objectives: To determine whether the ability of fat-1 mice to endogenously convert n-6 to n-3 FA, and thus generate an increased ratio of n-3 to n-6 FA, impacts experimental ALI.

Methods: We investigated ALI induced by intratracheal instillation of endotoxin in fat-1 and wild-type (WT) mice, assessing leukocyte numbers, protein concentration, and prostaglandin and cytokine levels in bronchoalveolar lavage fluid, as well as free FA in plasma, and lung ventilator compliance. Body temperature and motor activity of mice—markers of sickness behavior—were also recorded.

Measurements and Main Results: In ALI, fat-1 mice exhibited significantly reduced leukocyte invasion, protein leakage, and macrophage inflammatory protein-2 and thromboxane B₂ levels in lavage fluid compared with WT mice. Free AA levels were increased in the plasma of WT mice in response to endotoxin, whereas EPA and DHA were increased in the fat-1 group. Ventilator compliance was significantly improved in fat-1 mice. Body temperature and motor activity were decreased in ALI. fat-1 Mice recovered body temperature and motor activity faster.

Conclusions: fat-1 Mice exhibited reduced features of ALI and sickness behavior. Increasing the availability of n-3 FA may thus be beneficial in critically ill patients with ALI.

Key Words: fat-1 mice • eicosapentaenoic acid • sickness behavior • inflammation • acute lung injury

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject n-3–Containing diets or lipid emulsions were reported to have beneficial effects on the acute lung injury (ALI) in experimental models and patients. Still, uncertainty exists if the supply of n-3 fatty acids (FAs) is of benefit per se or is just counteracting the negative effects of n-6 FAs supplied as controls. What This Study Adds to the Field ALI and signs of systemic inflammation as fever were ameliorated in mice endogenously synthesizing n-3 FA without dietary or parenteral nutritional intervention.

 

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