Inhibition of Dimethylarginine Dimethylaminohydrolase 1 Improves the Outcome of Sepsis in Pregnant Mice

Abstract

Sepsis is one of the most important causes of maternal mortality. In our previous work, we established a polymicrobial sepsis (cecal ligation and puncture [CLP]) model in murine pregnancy and found that pregnant mice had a greater susceptibility to septic shock. In this model, mortality seemed to be associated with the development of early hemodynamic dysfunction and although circulating cytokine levels were similar, “off target” lung inflammatory cell numbers were greater in pregnant mice. Here, we have used the same CLP model to test the hypothesis that inhibiting the metabolism of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine would improve the outcome of sepsis in pregnancy. We used a dimethylarginine dimethylaminohydrolase 1-selective inhibitor (L-257), which reduces vascular nitric oxide synthesis without impairing immune cell function, in combination with a broad-spectrum antibiotic (Imipenem) and studied the outcome of septic shock in pregnant mice. Treatments were administered 3 h after CLP and samples were taken 3 h later. Both Imipenem and L-257 treatment alone slightly improved mortality rates from 13% (NaCl) to 20% (Imipenem) and 33% (L-257), whereas the combination of Imipenem and L-257 significantly improved survival to 50%. Imipenem and L-257 together prevented cardiovascular collapse and improved both organ function and bacterial killing, but did not reduce lung inflammatory cell numbers and actually increased lung cytokine levels. These data suggest that conventional management in combination with selective inhibition of DDAH1 may have therapeutic potential in the management of sepsis in pregnancy.

Antimicrobial stewardship and targeted therapies in the changing landscape of maternal sepsis

“…[ 25 ] Interestingly, the use of broad-spectrum antibiotics and a vascular smooth muscle specific inhibitor of nitric oxide synthesis was associated with better outcomes. [ 26 ] This suggests that identification and treatment are important tools to improve poor outcomes. In humans, certain pathogens predominate.…”

An Update Review of the Pathogenesis Hypothesis in Preeclampsia

“…Blocking NO synthesis with NOS inhibitors in pregnant rats would cause preeclampsia-like symptoms, including hypertension, proteinuria, FGR, even stillbirths and malformations [100,101]. In pregnant mice with NOS knockout, the uterine blood flow were reduced and spiral arteries were shortened, leading placenta oxygen supply insufficient [102,103]. The reduction of NO may cause an imbalance of vascular factors, followed by arteriole spasm and increased peripheral resistance, especially in kidney, uterus and placenta, which promotes the development of hypertension and preeclampsia [104].…”

Adipose-derived stem cells ameliorate radiation-induced lung injury by activating the DDAH1/ADMA/eNOS signaling pathway

“…Selective DDAH1 inhibitors upregulate ADMA levels in a tissue-specific manner. For example, selective DDAH1 inhibitor L-257 competitively binds to the active site of DDAH1 for isomer-specific competitive inhibition [ 11 ]. eNOS is essential to maintain the functions and homeostasis of endothelial cells and regulates pulmonary arterial hypertension [ 12 ].…”