Elevated concentrations of oxygen and increased airway pressure are administered to preterm neonates with respiratory distress syndrome. Among the survivors, 20% to 30% develop a form of chronic lung disease called bronchopulmonary dysplasia (BPD) and which is now characterized by poor alveolarization and vascularization. Tissue injury caused by the superoxide anion (O2-) and other free oxygen radicals has been implicated in the pathogenesis of BPD. We have synthesized a class of novel, small Mn(III) porphyrin mimetics of superoxide dismutase (SOD) and catalase. These compounds have been shown to be effective in a variety of animal models of oxidative stress. Recent work has shown that AEOL 10113 by IV infusion decreases inflammation and fibrosis in the 140-day gestation plus 10 days 100% neonatal baboon model of BPD. AEOL 10113 also enhances alveolarization in the 125-day gestation model of BPD receiving PRN O2 for 14 days. Based on this preliminary work we hypothesize that: 1) An effective antioxidant mimetic with optimum dose to the lung will reduce or prevent impairment of alveolarization in premature infants, 2) Creating a more reducing environment in the lung during the first few weeks following premature delivery will have a long term benefit on lung development - permanently improving lung structure and function, and 3) BPD is a complex, multifactoral disease in which multiple therapeutic approaches are likely to be required to optimize therapy and result in normal lung structure and function. We thus propose 1) optimizing lung delivery by use of an aerosol to give highest therapeutic benefit with the lower risk of toxicity, 2) defining the dose-response relationship for AEOL 10113 in the 125-day gestation, 21-day follow-up model, 3) evaluating two new antioxidant mimetics in the 125-day gestation model, 4) extending the 125-day gestation model to a 6-month follow-up to show long term therapeutic benefit, and 5) evaluate the potential advantages of combination therapy. We believe that it should be possible to use this therapeutic strategy of a low molecular catalytic antioxidant in a human clinical trial, but it is critical to use the baboon model to optimize conditions and minimize possible toxicities.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01HL063397-05
Application #
6733415
Study Section
Special Emphasis Panel (ZHL1-CSR-P (S2))
Program Officer
Berberich, Mary Anne
Project Start
1999-08-01
Project End
2007-08-31
Budget Start
2003-09-30
Budget End
2004-08-31
Support Year
5
Fiscal Year
2003
Total Cost
$384,641
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Ash, Samuel Y; Harmouche, Rola; Putman, Rachel K et al. (2017) Clinical and Genetic Associations of Objectively Identified Interstitial Changes in Smokers. Chest 152:780-791
Jungsuwadee, Paiboon; Weaver, Michael R; Gally, Fabienne et al. (2012) The metalloporphyrin antioxidant, MnTE-2-PyP, inhibits Th2 cell immune responses in an asthma model. Int J Mol Sci 13:9785-97
Karaaslan, Cagatay; Hirakawa, Hiroshi; Yasumatsu, Ryuji et al. (2011) Elastase inhibitory activity of airway ?1-antitrypsin is protected by treatment with a catalytic antioxidant in a baboon model of severe bronchopulmonary dysplasia. Pediatr Res 70:363-7
McCurnin, Donald C; Pierce, Richard A; Willis, Brigham C et al. (2009) Postnatal estradiol up-regulates lung nitric oxide synthases and improves lung function in bronchopulmonary dysplasia. Am J Respir Crit Care Med 179:492-500
Patel, Manisha; Li, Qing-You; Chang, Ling-Yi et al. (2005) Activation of NADPH oxidase and extracellular superoxide production in seizure-induced hippocampal damage. J Neurochem 92:123-31
Kinnula, Vuokko L; Crapo, James D (2003) Superoxide dismutases in the lung and human lung diseases. Am J Respir Crit Care Med 167:1600-19
Chang, Ling-Yi L; Subramaniam, Meera; Yoder, Bradley A et al. (2003) A catalytic antioxidant attenuates alveolar structural remodeling in bronchopulmonary dysplasia. Am J Respir Crit Care Med 167:57-64
Ross, Aron D; Sheng, Huaxin; Warner, David S et al. (2002) Hemodynamic effects of metalloporphyrin catalytic antioxidants: structure-activity relationships and species specificity. Free Radic Biol Med 33:1657-69