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The Role of Cyclooxygenase-2 in Newborn Hyperoxic Lung Injury

Britt, Rodney Deon, Jr.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1350400061

Abstract Details

2012, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
Development of respiratory distress syndrome (RDS) adversely affects patient populations in neonatal and pediatric intensive care units. Patients with RDS require ventilation and oxygen therapy to maintain adequate tissue oxygenation. Preterm infants who develop RDS are at risk of developing the chronic lung disease, bronchopulmonary dysplasia (BPD). Lung ventilation and exposure to supraphysiological concentrations of oxygen contribute to the risk of developing BPD. Preterm infants with BPD have reduced alveolar and vascular development. Survivors of BPD have diminished lung function and are at risk of developing additional lung diseases such as asthma. Dysregulation of the inflammatory response is a significant contributing factor to BPD. Previous studies showed that cyclooxygenase-2 (COX-2) expression and leukocyte infiltration are increased in the lung during newborn hyperoxic exposure in mice. To determine the role of COX-2 in newborn hyperoxic lung injury, newborn pups were injected with aspirin (non-selective COX -2 inhibitor) and celecoxib (selective COX-2 inhibitor) during exposure to hyperoxia. We tested the hypothesis that COX-2 inhibition would (1) reduce macrophage infiltration and chemokine expression, (2) improve lung alveolarization, and (3) improve lung function in newborn mice exposed to hyperoxia. Our data suggest that COX-2 has a pro-inflammatory role in macrophage infiltration but is not involved in lung alveolarization during hyperoxic lung injury. Understanding the role of COX-2 in the developing lung during hyperoxic exposure may lead to therapeutic strategies to improve clinical outcomes and prevent development of BPD. The role of nonciliated airway epithelial cells, or Clara cells, during inflammation remains poorly understood. Studies have suggested that Clara cells are critical for regeneration of the airway epithelium and produce mediators which regulate inflammation. Through immuohistochemical analysis, we have found that Clara cells express COX-2. Mouse transformed Clara cells (MTCC) were utilized as an in vitro model to assess Clara cell responses to pro-inflammatory stimuli. We tested the hypothesis that lipopolysaccharide (LPS) would increase COX-2 and chemokine expression in MTCC. Our data show that LPS stimulation increases COX-2 and chemokine mRNA and protein expression, while increasing prostanoid levels. LPS also stimulates phosphorylation of mitogen activating protein kinases: p38, JNK, and ERK. Our data suggest that Clara cells may produce prostaglandins and chemotactic factors during inflammation. We speculate that Clara cells produce mediators to modulate leukocyte infiltration and the progression of inflammation during the pathogenesis of acute lung injury. Further characterization of Clara cell function may help identify therapeutic strategies to enhance regeneration of the airway epithelium in patients with chronic inflammatory lung diseases.
Lynette Rogers, PhD (Advisor)
Leif Nelin, MD (Committee Member)
Mark Hall, MD (Committee Member)
Douglas Kniss, PhD (Committee Member)
Bronchopulmonary Dysplasia; Cyclooxygenase-2; Clara cells; Aspirin

Recommended Citations

Citations

  • Britt, Jr., R. D. (2012). The Role of Cyclooxygenase-2 in Newborn Hyperoxic Lung Injury [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1350400061

    APA Style (7th edition)

  • Britt, Jr., Rodney. The Role of Cyclooxygenase-2 in Newborn Hyperoxic Lung Injury. 2012. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1350400061.

    MLA Style (8th edition)

  • Britt, Jr., Rodney. "The Role of Cyclooxygenase-2 in Newborn Hyperoxic Lung Injury." Doctoral dissertation, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1350400061

    Chicago Manual of Style (17th edition)

osu1350400061
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© 2012, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.