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. This proposal focuses on the role of the glycosaminoglycan hyaluronan (hyaluronic acid, HA) and the pulmonary collectins SP-A and SP-D in inflammation and Bronchopulmonary Dysplasia BPD) in baboon models of preterm birth and ventilation. Data from our laboratory, using the rodent model of bleomycin-induced lung injury, indicates increased lung HA in association with macrophage accumulation. Administration of HA-binding peptide to bleomycin-injured animals decreases inflammation and fibrosis. In addition, we have found increases in tracheal aspirate HA concentrations that correlate with inflammation and are predictive of death or BPD in human preterm infants with lung disease. Oxidative and nitrative stresses are critical mediators of lung injury and inflammation. Proteins constitute a major target of reactivity for reactive oxygen (ROS) and nitrogen species (RNS) forming distinct protein adducts such as 3-nitrotyrosine-modified surfactant proteins, in particular SP-A and SP-D. Further, ROS and RNS have been shown to fragment HA into lower molecular weight (LMW) forms that promote macrophage activation, cytokine gene expression and chemotaxis. Preliminary data indicate differential localization and expression of 3-nitrotyrosine in rodent lungs injured with bleomycin and infant lungs with BPD. The program for Collaborative Research on BPD provides a unique opportunity to test the mechanistic contribution of HA and pulmonary collectins to the development of BPD. Using the baboon models of BPD, we will test the hypothesis that elevated concentrations of LMW HA and post-translational modification of pulmonary collectins, occurring as a result of oxidative, nitrative and nitrosative stresses associated with preterm birth and ventilation, are integral to and promote the inflammatory process that precedes the development of BPD. Therapies that limit the production or effects of LMW HA and modified collectins will limit the incidence and/or severity of BPD.
Aim 1 will characterize the developmental and postnatal expression of HA and its receptors in relation to inflammation and markers of oxidation, nitration and nitrosylation in the baboon models.
Aim 2 will focus on determining surfactant composition, content and function, as well as the changes in oxidation, nitration and nitrosylation of SP-A an SP-D in the baboon models.
Aim 3 will examine the effects of potential therapies, including SOD mimetics, inhaled NO and HA-binding peptides on the inflammatory, HA and surfactant changes in the baboon BPD models. The experiments described in this proposal will define the contribution of LMW HA and pulmonary collectins to the outcomes of these models and are a pre-requisite to further development of novel HA-based therapeutics to limit the incidence and/or severity of BPD in humans.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR013986-08
Application #
7349839
Study Section
Special Emphasis Panel (ZRR1-CM-8 (01))
Project Start
2006-05-01
Project End
2007-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
8
Fiscal Year
2006
Total Cost
$29,367
Indirect Cost
Name
Texas Biomedical Research Institute
Department
Type
DUNS #
007936834
City
San Antonio
State
TX
Country
United States
Zip Code
78245
Shelton, Elaine L; Waleh, Nahid; Plosa, Erin J et al. (2018) Effects of antenatal betamethasone on preterm human and mouse ductus arteriosus: comparison with baboon data. Pediatr Res 84:458-465
Perminov, Ekaterina; Mangosing, Sara; Confer, Alexandra et al. (2018) A case report of ovotesticular disorder of sex development (OT-DSD) in a baboon (Papio spp.) and a brief review of the non-human primate literature. J Med Primatol 47:192-197
Jensen, Jeffrey T; Hanna, Carol; Mishler, Emily et al. (2018) Effect of menstrual cycle phase and hormonal treatments on evaluation of tubal patency in baboons. J Med Primatol 47:40-45
Confer, Alexandra; Owston, Michael A; Kumar, Shyamesh et al. (2018) Multiple endocrine neoplasia-like syndrome in 24 baboons (Papio spp.). J Med Primatol 47:434-439
Mustonen, Allison; Gonzalez, Olga; Mendoza, Elda et al. (2018) Uremic encephalopathy in a rhesus macaque (Macaca mulatta): A case report and a brief review of the veterinary literature. J Med Primatol :
Koistinen, Keith; Mullaney, Lisa; Bell, Todd et al. (2018) Coccidioidomycosis in Nonhuman Primates: Pathologic and Clinical Findings. Vet Pathol 55:905-915
Mahaney, Michael C; Karere, Genesio M; Rainwater, David L et al. (2018) Diet-induced early-stage atherosclerosis in baboons: Lipoproteins, atherogenesis, and arterial compliance. J Med Primatol 47:3-17
Mangosing, Sara; Perminov, Ekaterina; Gonzalez, Olga et al. (2018) Uterine Tumors Resembling Ovarian Sex Cord Tumors in Four Baboons ( Papio spp.). Vet Pathol 55:753-758
Joganic, Jessica L; Willmore, Katherine E; Richtsmeier, Joan T et al. (2018) Additive genetic variation in the craniofacial skeleton of baboons (genus Papio) and its relationship to body and cranial size. Am J Phys Anthropol 165:269-285
Kumar, Shyamesh; Laurence, Hannah; Owston, Michael A et al. (2017) Natural pathology of the captive chimpanzee (Pan troglodytes): A 35-year review. J Med Primatol 46:271-290

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