This grant proposes preclinical studies to improve the utility and efficacy of inhaled nitric oxide (NO). This laboratory has reported pioneering studies providing evidence that inhaled NO gas produces selective Pulmonary vasodilation. Inhaling low levels of NO has been shown to selectively reverse pulmonary vasoconstriction due to hypoxia and other stimuli and increase systemic oxygenation by selectively vasodilating ventilated lung regions in patients and animal models of acute lung injury. Since1999, over 120,000 patients per year have breathed low levels of NO to treat pulmonary hypertension and acute respiratory failure. Unfortunately, approximately 40% of patients do not respond to NO inhalation with pulmonary vasodilation and improved oxygenation. The etiology of this variable response remains incompletely understood. Studies supported by this grant will have four aims: (1) identify mediators of the impaired hypoxic pulmonary vasoconstriction (HPV) due to endotoxin-induced lung injury, (2) elucidate the roles of NO, leukotrienes, and reactive oxygen species in the impairment of HPV associated with ventilator-induced lung injury (VILI), (3) examine the role of leukotrienes in the impairment of pulmonary vascular responsiveness to inhaled NO in acute lung injury, and (4) evaluate the impact of inhibitors of leukotriene signaling, as well as nitric oxide inhalation, on the development of VILI. Studies proposed in the first three acute lung injury due to endotoxemia and high tidal volume ventilation. New therapeutic approaches developed as a result of studies in mice will be tested in a second species, the lamb, as a key next step before bringing these new strategies to the patient bedside. By understanding the nature of the interaction of endogenous and inhaled NO and leukotriene synthesis in the pulmonary vascular dysfunction associated with acute lung injury, the proposed studies should enhance the utility of inhaled NO therapy in acute lung injury.
| Vaporidi, Katerina; Vergadi, Eleni; Kaniaris, Evangelos et al. (2012) Pulmonary microRNA profiling in a mouse model of ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 303:L199-207 |
| Petersen, Bodil; Austen, K Frank; Bloch, Kenneth D et al. (2011) Cysteinyl leukotrienes impair hypoxic pulmonary vasoconstriction in endotoxemic mice. Anesthesiology 115:804-11 |
| Steinbicker, Andrea U; Liu, Heling; Jiramongkolchai, Kim et al. (2011) Nitric oxide regulates pulmonary vascular smooth muscle cell expression of the inducible cAMP early repressor gene. Nitric Oxide 25:294-302 |
| Yu, Binglan; Shahid, Mohd; Egorina, Elena M et al. (2010) Endothelial dysfunction enhances vasoconstriction due to scavenging of nitric oxide by a hemoglobin-based oxygen carrier. Anesthesiology 112:586-94 |
| Vaporidi, Katerina; Francis, Roland C; Bloch, Kenneth D et al. (2010) Nitric oxide synthase 3 contributes to ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 299:L150-9 |
| Buys, Emmanuel S; Cauwels, Anje; Raher, Michael J et al. (2009) sGC(alpha)1(beta)1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models. Am J Physiol Heart Circ Physiol 297:H654-63 |
| Yu, Binglan; Volpato, Gian Paolo; Chang, Keqin et al. (2009) Prevention of the pulmonary vasoconstrictor effects of HBOC-201 in awake lambs by continuously breathing nitric oxide. Anesthesiology 110:113-22 |
| Yu, Binglan; Bloch, Kenneth D; Zapol, Warren M (2009) Hemoglobin-based red blood cell substitutes and nitric oxide. Trends Cardiovasc Med 19:103-7 |
| Volpato, Gian Paolo; Searles, Robert; Yu, Binglan et al. (2008) Inhaled hydrogen sulfide: a rapidly reversible inhibitor of cardiac and metabolic function in the mouse. Anesthesiology 108:659-68 |
| Derumeaux, Genevieve; Ichinose, Fumito; Raher, Michael J et al. (2008) Myocardial alterations in senescent mice and effect of exercise training: a strain rate imaging study. Circ Cardiovasc Imaging 1:227-34 |
Showing the most recent 10 out of 104 publications
