High concentrations of oxygen and increased airway pressure are administered to most preterm neonates with respiratory distress syndrome. Among the survivors, 20 percent to 30 percent develop a form of chronic lung disease called bronchopulmonary dysplasia (BPD). Tissue damage 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 blocking injury in cell culture and whole animal models of oxidative stress. Preliminary results now suggest that these SOD mimetics will be efficacious in protecting against the oxidative stress component of BPD in premature infants. We propose designing, synthesizing, and characterizing Mn(III)-porphyrins with high SOD activity that can be delivered to critical targets located in the intracellular and extracellular spaces of the lung. The efficacy of the new SOD mimetics will be tested in BPD through use of the Bronchopulmonary Resource Center in San Antonio. Our specific goals in this proposal are to 1) determine the pharmacokinetic/toxicity profiles of our existing lead SOD mimetics; 2) design and develop new SOD mimetics; 3) screen new SOD mimetics in nonprimate models of oxidative injury; 4) test SOD mimetics in baboon BPD; and, 5) determine the mode of action of SOD mimetics in the BPD model. We expect these studies to provide new insights on the role of oxidative stress in BPD and to provide a novel new therapeutic approach to reduce the impact of this devastating disease in premature infants.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL063397-04
Application #
6527213
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M1))
Program Officer
Berberich, Mary Anne
Project Start
1999-08-01
Project End
2003-09-29
Budget Start
2002-08-01
Budget End
2003-09-29
Support Year
4
Fiscal Year
2002
Total Cost
$346,148
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
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