Date of Award

2020

Document Type

Thesis

Degree Name

MS in Pharmaceutical Science

Department

Pharmaceutical Sciences

First Advisor

Lin L Mantell

Second Advisor

Francis Schanne

Third Advisor

Vivek Gupta

Abstract

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.

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