Oxygen and Barotrauma Effects on Human Airway Epithelium
Target Investigator:
Aaron C. Chidekel, MD
Chief – Division of Pulmonary Medicine – Wilmington
Collaborators: Yan Zhu, M.D. Nemours Biomedical Research
Mentors: Thomas H. Shaffer, MS.E., Ph.D., Nemours Biomedical Research
Vineet Bhandari, M.D., Yale University
Marla R. Wolfson, Ph.D., Temple University School of Medicine

 

Despite remarkable advances in perinatal and neonatal intensive care, chronic lung disease remains a common occurrence after premature birth or critical illness in the neonatal period or early infancy. Chronic lung disease of infancy (CLDI), as it is now frequently referred to, encompasses a heterogeneous group of conditions stemming from severe illness in the neonatal period or early in life, which often includes disorders other than those primarily affecting the lung. Contributing to the complexity and heterogeneity of CLDI is the fact that, in addition to the underlying condition and susceptibility of the individual neonate or infant, the therapies necessary to support these smallest and sickest of patients often play a role in the incitement and progression of lung injury. Technology such as oxygen therapy, mechanical ventilation and barotrauma, contribute to the pathogenesis of chronic lung disease in ways that are incompletely understood.

The central hypothesis of this project is that the airway epithelium is a critical response element in the pathogenesis and progression of BPD and CLDI. The overall aim of the proposal is to further elucidate the specific role of the airway epithelium in these processes and whether it can be manipulated with specific treatment strategies. Specific Aim 1: To determine the role of the airway epithelium, as modeled by human Calu-3 cells, in the pulmonary inflammatory response to hyperoxia and/or barotrauma. Specific Aim 2: To study the potential protective effects of pharmacological agents on the response of Calu-3 cells to hyperoxia and barotrauma.

Figure 1. This figure demonstrates the alterations in epithelial barrier of the Calu-3 cell line. Transepithelial resistance (TER) is plotted as a function of oxygen exposure and time. As shown, TER significantly decreases with increasing oxygen exposure and time.
Figure 2. Inflammation (IL-6) in apical surface fluid (ASF). This figure demonstrates the inflammatory response of the Calu-3 cell line as a function of oxygen exposure and time. As shown, IL-6 significantly increases with increasing oxygen exposure at 24 hrs. By 72 hrs., the inflammatory response, although elevated is less than at 24 hrs.

Related Publications:

    Babu PB, Chidekel A, Shaffer TH: Association of interleukin-8 with inflammatory and innate immune components in bronchoalveolar lavage of children with chronic respiratory diseases. Clin Chim Acta. Dec;350(1-2):195-200, 2004.
    Babu PB, Chidekel A, Shaffer TH: Hyperoxia-induced changes in human airway epithelial cells: the protective effect of perflubron. Pediatr Crit Care Med. Mar;6(2):188-94, 2005.
    Miller TL, Touch SM, Singhaus CJ, Ramesh Babu PB, Chidekel A, Shaffer TH: Expression of Matrix Metalloproteinases 2, 7 and 9 and Their Tissue Inhibitors 1 and 2 in Developing Rabbit Tracheae. Biol Neonate. Nov 24;89(4):236-243, Epub ahead of print, 2005.
    Miller TL, Zhu Y, Markwardt S, Singhaus CJ, Chidekel AC, Shaffer TH: Dissociation between the effects of oxygen and pressure on matrix metalloproteinase 2, 7, and 9 expression in human airway epithelial cells. Am Perinatol. Aug 21, 2008, Epub ahead of print.
    Zhu Y, Miller TL, Singhaus CJ, Shaffer TH, Chidekel A: Effects of oxygen concentration and exposure time on cultured human airway epithelial cells. Pediatr Crit Care Med, Mar; 9(2):224-229, 2008.
    Zhu Y, Miller TL, Chidekel A, Shaffer TH: KL4-surfactant (Lucinactant) protects human airway epithelium from hyperoxia. Pediatr Research, March 26, 2008, Epub ahead of print.