Effects of combining selective PDE9 inhibition with inhaled nitric oxide on pulmonary gas exchange, mechanics, inflammation and lung injury in a murine model of ventilator induced lung injury.
Final Report Abstract
My research at the Anesthesia Center for Critical Care Research, led by Prof. Warren M. Zapol, at the Massachusetts General Hospital in Boston, USA, was based on the project "Effects of combining selective PDE9-inhibition with inhaled nitric oxide (iNO) on pulmonary gas exchange, mechanics, inflammation and lung injury in a murine model of ventilator-induced lung injury (VILI)". Acute respiratory distress syndrome (ARDS) is a severe, life-threatening reaction induced by injuries or acute infections in the lung. In ARDS, VILI contributes importantly to mortality. Inhaled NO is able to improve systemic arterial oxygenation, and exert anti-inflammatory effects in ARDS, but does not increase survival. The in vivo effects of iNO are mediated by the activation of soluble guanylate cyclase (sGC) and the following increase in cyclic guanosine monophosphate (cGMP), the latter one being metabolized by several phosphodiesterases (PDEs), including PDE9. In a murine model of VILI, treatment with low-dose iNO or PDE9-inhibition with BAY73-6691 intravenously improved lung compliance and survival compared to untreated mice. However, in mice with VILI, a combined therapy with iNO and BAY73-6691 intravenously decreased lung compliance and survival without changing the levels of inflammatory markers. Hypoxic pulmonary vasoconstriction (HPV) describes the physiological response to alveolar hypoxia and directs pulmonary blood flow toward well-ventilated regions and therefore matches perfusion with alveolar ventilation to maintain systemic arterial oxygenation. HPV is impaired in sepsis and ARDS and in experimental models after challenge with lipopolysaccharides (LPS). Epoxyeicosatrienoic acids (EETs) are pulmonary vasoconstrictors, which are metabolized by the enzyme soluble epoxide hydrolase (sEH). We measured HPV in mice in vivo and demonstrated that after LPS-challenge, HPV was preserved in mice with a congenital sEH deficiency (sEH-/- mice) and restored in wild-type (sEH+/+) mice treated with the sEH inhibitor IK-950, which was accompanied by increased levels of systemic arterial oxygenation in both groups. A challenge with LPS induced an increase in the degradation of lung 14,15- and 11,12-EETs and in pulmonary cytokine mRNA levels in sEH+/+ mice, but not in sEH-/- mice. Inhibitors of sEH might improve lung function and decrease pulmonary inflammation in patients with ARDS. In another mouse model we studied the contribution of the NO-sGC-cGMP pathway to anesthesia-induced unconsciousness in mice. We examined the loss and the return of the righting reflex (LORR and RORR) while sGCalpha1-deficient (sGCalpha1-/-) and wild-type mice where breathing sevoflurane. We conclude that sGCalpha1 deficiency increases the threshold of sevoflurane-induced LORR and RORR and that sevoflurane increases brain cGMP levels in wild-type mice, but not in sGCalpha1-/- mice. Our results suggest that patients with impaired NO-cGMP signaling secondary to genetic mutations affecting the NO-cGMP system may require higher anesthetic concentrations to induce unconsciousness. In sheep, we studied the effects of NO treatment of stored red blood cells (RBCs) before transfusion. The transfusion of packed RBCs stored for a longer duration is associated with increased pulmonary arterial pressure, decreased erythrocyte deformability, and survival rate. We demonstrated that NO treatment limited pulmonary hypertension, improved the deformability of stored RBCs and increased their survival after transfusion. Treating RBCs stored for a longer time with NO gas prior to transfusion might be a promising therapeutic approach to prevent pulmonary vasoconstriction and pulmonary hypertension.
Publications
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Exposure of Stored Packed Erythrocytes to Nitric Oxide Prevents Transfusion-associated Pulmonary Hypertension. Anesthesiology (2016). 5. 952 963
Muenster, Stefan; Beloiartsev, Arkadi; Yu, Binglan; Du, E.; Abidi, Sabia; Dao, Ming; Fabry, Gregor; Graw, Jan A.; Wepler, Martin; Malhotra, Rajeev; Fernandez, Bernadette O.; Feelisch, Martin; Bloch, Kenneth D.; Bloch, Donald B.; Zapol, Warren M.
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Soluble epoxide hydrolase deficiency or inhibition enhances murine hypoxic pulmonary vasoconstriction after lipopolysaccharide challenge. Am J Physiol Lung Cell Mol Physiol (2016). 6. L1213-L1221
Wepler, Martin; Beloiartsev, Arkadi; Buswell, Mary D.; Panigrahy, Dipak; Malhotra, Rajeev; Buys, Emmanuel S.; Radermacher, Peter; Ichinose, Fumito; Bloch, Donald B.; Zapol, Warren M.
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“Congenital Absence or Inhibition of Soluble Epoxide Hydrolase Enhances Hypoxic Pulmonary Vasoconstriction after Lipopolysaccharide Challenge”. Abstract A4785, ATS 2016, San Francisco, USA
Wepler M, Beloiartsev A, Panigrahy D, Malhotra R, Buys ES, Bloch DB, Ichinose F, Zapol WM
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„Sensitivity to Sevoflurane Anesthesia is decreased in Mice with a Congenital Deletion of Soluble Guanylate Cyclase Alpha-1”. Abstract OR021-A1108, ASA 2016, Chicago, USA
Nagasaka Y, Wepler M, Thoonen R, Sips PY, Allen K, Graw JA, Yao V, Muenster S, Brouckaert P, Miller K, Solt K, Buys ES, Ichinose F, Zapol WM
