# Mechanism and prevention of lipopolysaccharide-induced early pregnancy complications

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $424,314

## Abstract

PROJECT SUMMARY
The available evidence suggests that intrauterine and/or maternal bacterial infection is a major cause of early
and late pregnancy complications. Current antibacterial and anti-inflammatory drugs used to treat bacterial
infection during pregnancy are considered harmful to maternal and fetal health. Thus, continued research to
look for better treatment options to avoid bacterial infection-induced pregnancy complications is alluring.
The decidua and placenta are uniquely positioned at the maternal-embryonic interface to serve as a first line of
defense against bacterial toxins, but their defensive mechanisms against bacterial toxins are poorly
understood. Lipopolysaccharide (LPS) is an endotoxin of Gram-negative E. coli that is associated with
infection-induced pregnancy defects. LPS recognition by cell surface proteins is an important step required for
the initiation of its inflammatory signaling or inactivation by cell surface molecules. Our preliminary results
establish that: 1) the uterine luminal epithelium, decidua and placenta express the LPS sensing and signaling
TLR4/CD14/MD2 complex; 2) LPS injection on day 5 of pregnancy terminates pregnancy by day 8 via
selective-activation of the MyD88-dependent TLR4 signaling pathway at the embryo implantation site (EIS); 3)
LPS induces expression of proinflammatory cytokine genes such as Tnf-α & Il-1β, chemokine genes such as
Cxcl1&2, and neutrophil recruitment to the EIS; 4) cell surfaces of the decidua and placenta express tissue-
nonspecific alkaline phosphatase (TNAP) isozyme that is capable of dephosphorylating LPS; 5)
dephosphorylated LPS is non-inflammatory and non-toxic to murine pregnancy; and 6) AP isozyme treatment
alleviates LPS-induced early pregnancy loss in mice. These preliminary findings have led to the hypothesis
that LPS-induced microenvironment disruption at the early EIS is a result of concerted action of
resident decidual cells and recruited neutrophils, and LPS detoxification by supplementation and/or
induction of TNAP production/activity may abrogate LPS-mediated early pregnancy defects/loss.
To test our hypothesis, we have proposed three mechanistic aims. In Aim 1, we will use Cre-lox and antibody-
mediated neutralization technologies to establish that an important step in the development of LPS-induced
unwanted inflammation at the early EIS is decidual cell-type-dependent recruitment of inflammatory
neutrophils. In Aim 2, we will generate novel female mice with uterine deletion of TNAP gene Alpl to determine
whether endogenous TNAP deficiency in the uterus augments the response to LPS. In Aim 3, we will examine
the potential of TNAP and its activator or inducer in mitigating LPS- or E. coli-induced early pregnancy
defects/loss.
Upon completion of these aims, we hope to gain: 1) insights into the mechanisms of infection-induced
inflammation at the early EIS; and 2) develop a novel LPS-detoxification therapeutic strategy to avoid bacteria-
induced early pregnan...

## Key facts

- **NIH application ID:** 9963331
- **Project number:** 5R01HD094946-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Bibhash Chandra Paria
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $424,314
- **Award type:** 5
- **Project period:** 2018-09-04 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963331

## Citation

> US National Institutes of Health, RePORTER application 9963331, Mechanism and prevention of lipopolysaccharide-induced early pregnancy complications (5R01HD094946-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9963331. Licensed CC0.

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