This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Primary pulmonary hypertension (PPH) is a fatal disease of unclear etiology, characterized by progressive increase in pulmonary artery pressure. The long-term goal of this research is to determine the role of NO, oxidants and NO-oxidant chemical reaction products in pulmonary hypertension. Our preliminary data provide clear evidence that NO and NO reaction products (NO3-, S-nitrosothiols) are lower in lungs of PPH than healthy controls. We propose that the low levels of NO and its reaction products in PPH are due to decreased NO synthesis and increased NO consumption by reactions with oxidant species, leading to alternative reaction endproducts. We show that NO reaction products are strongly correlated in an inverse relationship to pulmonary artery pressures in PPH. Theoretical modeling and simulation of our data suggest that progression and mortality in PPH will be predicted by NO reaction products. These data indicate a possible role for NO and oxidants in the pathogenesis of PPH. We will test our hypotheses with 3 aims. First, we will extend our preliminary findings and obtain longitudinal data on pulmonary artery pressures, cardiac output and lung diffusion capacity in 30 PPH patients. The values of these factors at specific time points will be modeled as linear functions of the corresponding levels of NO and NO reaction products to test our hypothesis that NO reaction products are predictive of progression of PPH. Second, low NO levels in PPH may result from decreased nitric oxide synthase (NOS) levels or activity. NOS expression for all 3 isoforms will be quantitated and localized in PPH lungs in comparison to controls. NOS activity will be measured and posttranslational mechanisms regulating activity evaluated. Third, low NO in PPH may also result from increased consumption. We propose that oxidative consumption of NO is increased in PPH due to alterations in the reducing-oxidizing (redox) environment of the lung. Since oxidative status of the lung cannot be assessed directly, we will test this hypothesis by measures of (i) nitrotyrosine formation; (ii) Nuclear Factor kB, a transcription factor activated in inflammation through oxidant mechanisms; and (iii) antioxidant levels. Together, these experiments will define the mechanisms regulating NO levels and reactions in the lung, and provide a comprehensive picture regarding the role of NO and NO reaction products in PPH
Showing the most recent 10 out of 136 publications
