Soluble epoxide hydrolase deficiency or inhibition enhances murine hypoxic pulmonary vasoconstriction after lipopolysaccharide challenge.
Hypoxic pulmonary vasoconstriction (HPV) is the response of the pulmonary vasculature to low levels of alveolar oxygen. HPV improves systemic arterial oxygenation by matching pulmonary perfusion to ventilation during alveolar hypoxia and is impaired in lung diseases such as the acute respiratory distress syndrome (ARDS) and in experimental models of endotoxemia. Epoxyeicosatrienoic acids (EETs) are pulmonary vasoconstrictors, which are metabolized to less vasoactive dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). We hypothesized that pharmacological inhibition or a congenital deficiency of sEH in mice would reduce the metabolism of EETs and enhance HPV in mice after challenge with lipopolysaccharide (LPS). HPV was assessed 22 h after intravenous injection of LPS by measuring the percentage increase in the pulmonary vascular resistance of the left lung induced by left mainstem bronchial occlusion (LMBO). After LPS challenge, HPV was impaired in sEH+/+, but not in sEH-/-mice or in sEH+/+mice treated acutely with a sEH inhibitor. Deficiency or pharmacological inhibition of sEH protected mice from the LPS-induced decrease in systemic arterial oxygen concentration (PaO2) during LMBO. In the lungs of sEH-/-mice, the LPS-induced increase in DHETs and cytokines was attenuated. Deficiency or pharmacological inhibition of sEH protects mice from LPS-induced impairment of HPV and improves the PaO2after LMBO. After LPS challenge, lung EET degradation and cytokine expression were reduced in sEH-/-mice. Inhibition of sEH might prove to be an effective treatment for ventilation-perfusion mismatch in lung diseases such as ARDS.
Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
Martin
M
Wepler
Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
Arkadi
A
Beloiartsev
Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
Mary D
MD
Buswell
Harvard Medical School, Boston, Massachusetts.|Center for Vascular Biology Research and Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Dipak
D
Panigrahy
Harvard Medical School, Boston, Massachusetts.|Cardiology Division and Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Rajeev
R
Malhotra
Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
Emmanuel S
ES
Buys
Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinik Ulm, Ulm, Germany.
Peter
P
Radermacher
Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
Fumito
F
Ichinose
Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.|Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; and.
Donald B
DB
Bloch
Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts; wzapol@mgh.harvard.edu.|Harvard Medical School, Boston, Massachusetts.
Warren M
WM
Zapol
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001784:Blood Gas Analysis; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000378:metabolism; D006439:Hemodynamics; D000860:Hypoxia / Q000150:complications / Q000201:enzymology* / Q000503:physiopathology*; D008070:Lipopolysaccharides; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000378:metabolism; D011651:Pulmonary Artery / Q000201:enzymology* / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D014661:Vasoconstriction
D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D016718:Arachidonic Acid; D004851:Epoxide Hydrolases; D010100:Oxygen
endotoxemia; hypoxic pulmonary vasoconstriction; knockout and inhibition; mice; soluble epoxide hydrolase