The main objective of this research is to determine whether the innate immune response to intra-amniotic infection is a critical event in the pathogenesis of infection-induced preterm labor and fetal acute lung injury (ALI). Intra-amniotic infection causes the majority of early preterm births, which represent a significant economic and public health burden. Immune responses to bacteria are thought to drive infection-induced pre-term labor and no therapy exists to prevent preterm birth. The proposed study will determine the efficacy of a novel immunomodulator to prevent infection-induced preterm birth and fetal ALI by blocking the earliest immune response and may result in an effective treatment for preterm labor. Investigation of a novel drug targeting intra-amniotic infection is directly related to the NIAID mission to support research aimed at the treatment of infectious disease. The unifying hypothesis is that blockade of innate immune responses by intra-amniotic infusion of a toll-like receptor 4 (TLR4) antagonist will inhibit uterine activity and fetal ALI due to lipopolysaccharide (LPS) in our chronically catheterized nonhuman primate (NHP) model. LPS is a gram-negative bacterial product recognized by TLR4, an innate immune receptor. Antagonism of TLR4 in an LPS model allows investigation of the specific effect of innate immune response blockade on preterm labor and fetal ALI. We propose to inhibit preterm labor and ameliorate fetal ALI by blocking initial immune responses with a TLR4 antagonist (TLR4A) and decreasing active inflammation with dexamethasone (DEX) and indomethacin (INDO).
Specific aims of the research plan are to: 1) characterize the amniotic fluid pharmacokinetics of a TLR4A and determine potential side effects ex vivo and in vivo, 2) determine the ability of a TLR4A to inhibit uterine activity and cytokine/prostaglandin pathways in a chronically catheterized NHP model of LPS-induced preterm birth, and 3) determine the ability of a TLR4A to prevent in utero fetal ALI. To meet these aims, 24 chronically catheterized rhesus monkeys will be studied in one control and three interventional groups. After the onset of preterm labor induced by intra-amniotic LPS, animals will receive either: 1) no therapy (Group 1, n=6), 2) an intra-amniotic TLR4A (Group 2, n=6), 3) DEX and INDO (Group 3, n=6), or 4) an intra-amniotic TLR4A, DEX, and INDO (Group 4, n=6). The primary endpoint will be time from LPS infusion to delivery. Pharmacokinetics and adverse events associated with an intra-amniotic TLR4 antagonist will be studied and fetal pulmonary apoptosis and morphometry quantified and compared between groups. Investigating a new drug targeting infection-induced preterm birth and fetal ALI based on well-defined immunologic mechanisms may result in an effective treatment for preterm labor. Completion of these studies in conjunction with the training plan will enable the principal investigator to become an independent researcher of immune responses in infection-induced preterm birth. ? ? ? ?
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