Date of Award
MS in Pharmaceutical Science
Lin L Mantell
Supraphysiological levels of oxygen (i.e. hyperoxia) are used to treat patients with respiratory distress. Prolonged exposure to hyperoxia can impair alveolar macrophage functions and increase susceptibility to ventilator-associated pneumonia (VAP). Hyperoxia-induced alveolar macrophage dysfunction is, in part, mediated by high airway levels of the pro-inflammatory mediator, high mobility group box-1 (HMGB1). An early generation glycosaminoglycan (GAG), 2-O, 3-O desulfated heparin (ODSH), attenuates hyperoxia-compromised innate immunity by preventing the binding of HMGB1 with receptors that activate pro-inflammatory pathways. In this study, we investigated whether the next generation GAG, GM-1111, can attenuate hyperoxia-compromised macrophage function. GM-1111 (100μM) prevented hyperoxia-induced (95% O2 for 24 h) dysfunction of phagocytosis in RAW 264.7 macrophages GM-1111 (0.1-100μM) had no significant effect on the extracellular accumulation of HMGB1 in cultured macrophages produced by hyperoxia. GM-1111 significantly decreased HMGB1-mediated phagocytic dysfunction in RAW 264.7 cells. Localized surface plasmon resonance data indicated that GM-1111 had a high binding affinity (KD = 3.77x10-8M) to HMGB1. GM-1111 also significantly decreased NF-κB/AP-1 activation and the extracellular accumulation of TNF-α from hyperoxia-compromised macrophages. Overall, our results indicate that GM-1111 attenuates hyperoxia-compromised macrophage function by inhibiting HMGB1-mediated impairment of macrophage phagocytosis and downstream pro-inflammatory responses. Thus, GM-1111 may serve as a potential novel treatment for VAP.
Daley, Leanne, "GM-1111 PRESERVES PHAGOCYTIC FUNCTION OF MACROPHAGES EXPOSED TO PROLONGED HYPEROXIA VIA INTERRUPTION OF HMGB1-MEDIATED SIGNALING" (2020). Theses and Dissertations. 62.