ORCID

https://orcid.org/0000-0003-2295-5863

Date of Award

2024

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Sandra E. Reznik

Abstract

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. According to the CDC, at least 1.7 million adults in the US develop sepsis in a typical year. N,N-Dimethylacetamide (DMA) is a commonly used drug excipient. Previously, our lab has revealed the anti-inflammatory role of DMA both in vivo and in vitro. Therefore, we propose that 1) DMA improves animal survival from “sepsis”-like syndrome, 2) DMA alleviates systemic inflammation, and 3) DMA attenuates inflammation-induced organ damage. To study the effects of DMA on “sepsis”-like syndrome, we used a lipopolysaccharide (LPS)-induced endotoxemia murine model. In this study, DMA eliminated mortality in acute (24 h) moderate endotoxemia and significantly improved survival from 33.3% to 77.8% in severe endotoxemia. Serum interleukin (IL)-6 and tumor necrosis factor (TNF)-α were significantly attenuated in DMA-treated animals with severe endotoxemia as compared to the LPS only group suggesting that DMA alleviated systemic inflammation. In long-term (96 h) moderate endotoxemia, DMA- treated animals exhibited significantly improved vital signs, including mobility, heart rate, and respiratory rate. In the liver, DMA suppressed LPS-induced expression of pro- inflammatory cytokines and acute phase proteins, enhanced expression of anti- inflammatory IL-10, attenuated inflammasome NLRP3 activation, and regulated leukocyte infiltration. To further elucidate the effect of DMA on leukocytes, namely neutrophils and macrophages, we stimulated primary neutrophil and human U937- macrophages with LPS with or without the presence of DMA. DMA suppressed release of TNFα but increased IL-6 level, suggesting that neutrophil may not be the key player in LPS-induced endotoxemia. In U937-macrophages, DMA inhibited LPS-induced release of IL-6 and TNFα. And interestingly, U937-monocytes were differentiated with and without the addition of DMA, the presence of DMA exhibited attenuated response to LPS stimulation, suggesting that DMA regulated macrophage differentiation toward a less inflammatory phenotype. In conclusion, DMA significantly reduced the animal mortality against acute endotoxemia and improved survival outcomes in long-term endotoxemia through attenuating systemic and liver inflammation, enhancing expression of anti-inflammatory cytokine IL-10, reducing inflammation-induced organ damage, regulating leukocyte infiltration, and alleviating potential sepsis-induced coagulopathy.

Download

Available for download on Sunday, November 08, 2026

Share

COinS