We have shown that patients with primary pulmonary hypertension (PPH) have low levels of nitric oxide (NO), a potent vasodilator, in exhaled breath suggesting a role for NO in the pathophysiology of pulmonary hypertension. The purpose of this proposed research is to determine the mechanism(s) for low NO in PPH. Potential mechanisms that will be addressedin the experiments are inhibition of NO production by CO and enzyme kinetic abnormalities affecting the sensitivity of NO synthase (NOS) to oxygen. We have previously shown that oxygen concentrations in the physiologic range determine the rate of NO synthesis in the lung. However, PPH individuals have low NO despite receiving supplemental oxygen therapy. This suggests that NO synthases in PPH may be less sensitive to oxygen and thus require higher than normal oxygen to produce NO. Furthermore, CO can directly affect endogenous NO synthesis. In preliminary data, CO in PPH is in the range that may lead to inhibition of NOS activity and NO generation. We hypothesize that NO is decreased in PPH perhaps as a consequence of high CO levels and/or impaired NO production in response to oxygen. As an extension of this hypothesis, we also propose that effective therapies such as epoprostenol, may act in part by increasing NO levels in PPH. To test this hypothesis, we propose the following specific aims:
Aim 1. Determine the levels of Carbon monoxide (CO) in relationship to NO and severity of disease in PPH.
Aim 2. Study the effect of oxygen and epoprostenol on NO levels in PPH in vivo.
Aim 3. Study the effect of 02 and CO on NOS expression and activity in vitro. Formal course work and education are incorporated into the training component of this proposal. The candidate will have direction from leaders in the field of lung biology and pulmonary hypertension through a mentoring group. Through the 5 year award, the candidate will develop his skills in (i) hypotheses-driven design of studies, (ii) analyses and interpretation of data, and (iii) writing of manuscripts, abstracts and presenting data at meetings. The training component of this proposal will lead to the candidate's transition to a fully independent investigator.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL068863-05
Application #
6914832
Study Section
Special Emphasis Panel (ZHL1-CSR-F (M2))
Program Officer
Colombini-Hatch, Sandra
Project Start
2002-07-10
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
5
Fiscal Year
2005
Total Cost
$126,630
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Dweik, Raed A; Sorkness, Ronald L; Wenzel, Sally et al. (2010) Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med 181:1033-41
Heresi, Gustavo A; Aytekin, Metin; Newman, Jennie et al. (2010) CXC-chemokine ligand 10 in idiopathic pulmonary arterial hypertension: marker of improved survival. Lung 188:191-7
Mashir, Alquam; Dweik, Raed A (2009) Exhaled breath analysis: The new interface between medicine and engineering. Adv Powder Technol 20:420-425
Heresi, Gustavo A; Dweik, Raed A (2009) Sarcoidosis-associated pulmonary hypertension. One size does not fit all. Chest 135:1410-1412
Grob, Natalia M; Dweik, Raed A (2008) Exhaled nitric oxide in asthma: progress since the introduction of standardized methodology. J Breath Res 2:37002
Grob, Natalia M; Laskowski, Daniel; Dweik, Raed A (2008) A technical report on exhaled nitric oxide measurement: asthma monitoring in athletes. J Breath Res 2:37027
Hunter, Gary W; Dweik, Raed A (2008) Applied breath analysis: an overview of the challenges and opportunities in developing and testing sensor technology for human health monitoring in aerospace and clinical applications. J Breath Res 2:1-7
Grob, Natalia M; Dweik, Raed A (2008) Exhaled nitric oxide in asthma. From diagnosis, to monitoring, to screening: are we there yet? Chest 133:837-9
Lara, Abigail; Khatri, Sumita B; Wang, Zeneng et al. (2008) Alterations of the arginine metabolome in asthma. Am J Respir Crit Care Med 178:673-81
Aytekin, Metin; Comhair, Suzy A A; de la Motte, Carol et al. (2008) High levels of hyaluronan in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 295:L789-99

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