Docosahexaenoic acid (DHA) is a long chain fatty acid that exhibits anti-inflammatory and immuno-modulating properties. Although the mechanisms involved are not completely understood, the anti-inflammatory properties of long chain fatty acids are thought to include effects on signaling pathways resulting in modified gene transcription. To date, a specific high affinity receptor for DHA has not been identified however DHA-mediated decreases in cytokine and chemokine production are likely due to receptor related mechanisms. Receptor for Advanced Glycation End Products (RAGE) is a """"""""Damage Associated Molecular Pattern"""""""" receptor and, as such, is able to engage classes of unrelated molecules using tertiary structure for ligand recognition. RAGE is highly expressed in lung;specifically epithelial type I cells, endothelial cells, and alveolar macrophages. RAGE protein expression is increased in the lungs of mice exposed to hyperoxia, and the increase is related to the severity of injury. Furthermore, RAGE knockout mice are protected from hyperoxic lung injury, indicating that RAGE-mediated events play a role in the development of lung injury. DHA is preferentially accreted by the third trimester human fetus to aid the maturation of neurological tissues. Extremely preterm infants are born prior to this accretion and are often not provided """"""""pre-formed"""""""" DHA in parenteral nutrition or receive low levels in milk from human milk banks. In addition, prematurely born infants often require life-sustaining therapies, including ventilatory support and high concentrations of oxygen and are at risk for inflammation associated with hyperoxic lung injury. Bronchopulmonary Dysplasia (BPD) is one of the most common diseases of prematurity and is closely linked to both maternal and infant inflammatory responses. Infants diagnosed with BPD have decreased lung alveolarization and often require respiratory support for a prolonged period of time. Furthermore, infants with BPD often exhibit delayed neurological development and are at risk for other medical problems that further impair their overall health. The central hypothesis is that DHA attenuates hyperoxia- induced lung injury by decreasing leukocyte chemotaxis, through altering RAGE expression and signaling pathways.
Aim 1 will test the hypothesis that DHA supplementation decreases inflammation through the modulation of soluble RAGE (sRAGE) levels and activity. sRAGE is generated by proteolytic cleavage of the extracellular domain of membrane-bound RAGE (mRAGE). sRAGE can enhance chemotaxis and promote maturation and differentiation of monocytes.
This aim will investigate the mechanisms by which DHA decreases sRAGE levels in the context of hyperoxia exposure.
Aim 2 will test the hypothesis that DHA supplementation alters RAGE-mediated signaling pathways. DHA can propagate or antagonize receptor- mediated signaling by either directly binding to the ligand domain or influencing the ability of ligand to bind or activate the receptor.
This aim will investigate the mechanisms by which DHA diminishes intracellular pro- inflammatory signaling.
Aim 3 will test the hypothesis that DHA supplementation to lactating women will provide DHA to preterm infants and result in decreased sRAGE expression and inflammatory responses in both the mother and the infant. These studies will investigate the influence of DHA on sRAGE levels in the context of preterm birth. The studies outlined in this proposal will combine an established newborn mouse model of hyperoxia exposure and arrested lung development with clinical investigations in preterm human infants to investigate the mechanisms by which DHA decreases inflammation and improves lung growth.

Public Health Relevance

Long chain fatty acids are efficacious in reducing inflammation in many diseases however the mechanisms of action are poorly understood. Preterm birth is associated with inflammation and the use of long chain fatty acids, such as docosahexeanoic acid (DHA), as an anti-inflammatory therapy has not been explored. The ultimate goal of this study is to identify mechanisms associated with the anti-inflammatory properties of DHA in the context of hyperoxic lung injury and preterm birth.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Research Project (R01)
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Special Emphasis Panel (ZAT1-SM (23))
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Hopp, Craig
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Nationwide Children's Hospital
United States
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Velten, Markus; Heyob, Kathryn M; Wold, Loren E et al. (2018) Perinatal inflammation induces sex-related differences in cardiovascular morbidities in mice. Am J Physiol Heart Circ Physiol 314:H573-H579
Copp, Kathleen; DeFranco, Emily A; Kleiman, Jeanne et al. (2018) Nutrition Support Team Guide to Maternal Diet for the Human-Milk-Fed Infant. Nutr Clin Pract 33:687-693
Ali, Mehboob; Heyob, Kathryn; Tipple, Trent E et al. (2018) Alterations in VASP phosphorylation and profilin1 and cofilin1 expression in hyperoxic lung injury and BPD. Respir Res 19:229
Rogers, Lynette K; Cismowski, Mary J (2018) Oxidative Stress in the Lung - The Essential Paradox. Curr Opin Toxicol 7:37-43
Valentine, Christina J; Morrow, Georgia; Reisinger, Amanda et al. (2017) Lactational Stage of Pasteurized Human Donor Milk Contributes to Nutrient Limitations for Infants. Nutrients 9:
Durrani-Kolarik, Shaheen; Pool, Caylie A; Gray, Ashley et al. (2017) miR-29b supplementation decreases expression of matrix proteins and improves alveolarization in mice exposed to maternal inflammation and neonatal hyperoxia. Am J Physiol Lung Cell Mol Physiol 313:L339-L349
Robbins, Mary E; Dakhlallah, Duaa; Marsh, Clay B et al. (2016) Of mice and men: correlations between microRNA-17?92 cluster expression and promoter methylation in severe bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 311:L981-L984
Graf, Amanda E; Lallier, Scott W; Waidyaratne, Gavisha et al. (2016) Maternal high fat diet exposure is associated with increased hepcidin levels, decreased myelination, and neurobehavioral changes in male offspring. Brain Behav Immun 58:369-378
Ali, Mehboob; Heyob, Kathryn; Rogers, Lynette K (2016) DHA-mediated regulation of lung cancer cell migration is not directly associated with Gelsolin or Vimentin expression. Life Sci 155:1-9
Thompson, Michael D; Cismowski, Mary J; Trask, Aaron J et al. (2016) Enhanced Steatosis and Fibrosis in Liver of Adult Offspring Exposed to Maternal High-Fat Diet. Gene Expr 17:47-59

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