TY - JOUR
T1 - N,N-dimethylacetamide regulates the proinflammatory response associated with endotoxin and prevents preterm birth
AU - Sundaram, Sruthi
AU - Ashby, Charles R.
AU - Pekson, Ryan
AU - Sampat, Vaishali
AU - Sitapara, Ravikumar
AU - Mantell, Lin
AU - Chen, Chih Hung
AU - Yen, Haoting
AU - Abhichandani, Khushboo
AU - Munnangi, Swapna
AU - Khadtare, Nikhil
AU - Stephani, Ralph A.
AU - Reznik, Sandra E.
N1 - Funding Information:
Supported by NIH grants 1 K08 HD1209 (S.E.R.) and 1 R01 NS069577 (S.E.R. and R.A.S.).
PY - 2013/8
Y1 - 2013/8
N2 - The proinflammatory response leads to various types of pathologic pathways, including the development of preterm birth. Preterm birth occurs in 12% of deliveries in the United States and causes more than 70% of perinatal morbidity and mortality. The most common cause of spontaneous preterm birth is intrauterine infection in the mother. There is accumulating evidence indicating that the release of proinflammatory cytokines plays a critical role in the pathogenesis of inflammation-associated premature delivery. We found that the common organic solvent, N,N-dimethylacetamide (DMA), prevents endotoxin-induced preterm birth in timed pregnant C57BL/6 embryonic day (E)15.5 mice and rescues their pups from spontaneous abortion at doses many-fold lower than those currently used clinically and in a dose-dependent fashion. We also provide histologic evidence that DMA suppresses the endotoxin-triggered proinflammatory response by significantly attenuating inflammatory cell infiltration of placental tissue. Furthermore, immunoblotting analysis of placental tissue harvested from our murine models revealed DMA-mediated regulation of expression of the proinflammatory cytokines IL-1β, tumor necrosis factor α, and IL-6, and increased expression of the regulatory inflammatory cytokine IL-10. By using in vitro studies, we provide evidence that DMA suppresses macrophage function and that this small molecule prevents nuclear translocation of nuclear factor-kB. These results suggest that DMA represents a newly discovered, nontoxic therapy for a broad range of inflammatory disorders.
AB - The proinflammatory response leads to various types of pathologic pathways, including the development of preterm birth. Preterm birth occurs in 12% of deliveries in the United States and causes more than 70% of perinatal morbidity and mortality. The most common cause of spontaneous preterm birth is intrauterine infection in the mother. There is accumulating evidence indicating that the release of proinflammatory cytokines plays a critical role in the pathogenesis of inflammation-associated premature delivery. We found that the common organic solvent, N,N-dimethylacetamide (DMA), prevents endotoxin-induced preterm birth in timed pregnant C57BL/6 embryonic day (E)15.5 mice and rescues their pups from spontaneous abortion at doses many-fold lower than those currently used clinically and in a dose-dependent fashion. We also provide histologic evidence that DMA suppresses the endotoxin-triggered proinflammatory response by significantly attenuating inflammatory cell infiltration of placental tissue. Furthermore, immunoblotting analysis of placental tissue harvested from our murine models revealed DMA-mediated regulation of expression of the proinflammatory cytokines IL-1β, tumor necrosis factor α, and IL-6, and increased expression of the regulatory inflammatory cytokine IL-10. By using in vitro studies, we provide evidence that DMA suppresses macrophage function and that this small molecule prevents nuclear translocation of nuclear factor-kB. These results suggest that DMA represents a newly discovered, nontoxic therapy for a broad range of inflammatory disorders.
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U2 - 10.1016/j.ajpath.2013.05.006
DO - 10.1016/j.ajpath.2013.05.006
M3 - Article
C2 - 23770347
AN - SCOPUS:84880626261
SN - 0002-9440
VL - 183
SP - 422
EP - 430
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 2
ER -