Hydrogen Sulfide Delays LPS-Induced Preterm Birth in Mice via Anti-Inflammatory Pathways

PLOS ONE, Dec 2019

A major cause of preterm labor in pregnant women is intra-amniotic infection, which is mediated by an inflammatory process. Hydrogen sulfide (H2S), a gaseous transmitter, has been implicated to be involved in inflammatory responses. We sought to investigate whether H2S affects infectious preterm birth using the mouse model of lipopolysaccharides (LPS)-induced preterm birth. Administration of LPS at 0.4 mg/kg with two injections intraperitoneally (i.p.) on gestational day 14.5 induced preterm labor. LPS significantly increased leukocyte infiltration in uterus, stimulated the expression of pro-inflammatory cytokines interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), CCL2 and CXCL15 in myometrium. Administration of NaHS (i.p.) delayed the onset of labor induced by LPS in a dose-dependent manner. NaHS prevented leukocyte infiltration into intrauterine tissues and inhibited the production of pro-inflammatory cytokines in myometrium and decreased the levels of these cytokines in maternal circulation. H2S also decreased LPS-activated extracellular signal-regulated kinase (ERK) 1/2/ nuclear factor (NF)-κB signaling pathways in myometrium. This study provides new in vivo evidence for the roles of H2S in attenuating inflammation, and a potential novel therapeutic strategy for infection-related preterm labor.

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Hydrogen Sulfide Delays LPS-Induced Preterm Birth in Mice via Anti-Inflammatory Pathways

April Hydrogen Sulfide Delays LPS-Induced Preterm Birth in Mice via Anti-Inflammatory Pathways Weina Liu 0 2 3 4 Chen Xu 0 2 3 4 Xingji You 0 2 3 4 David M. Olson 0 2 4 Sylvain Chemtob 0 1 2 4 Lu Gao 0 2 3 4 Xin Ni 0 2 3 4 0 a Current address: The 413rd hospital of Chinese People's Liberation Army , Zhoushan, Zhejiang , China ¤b Current address: Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College , Shanghai , China 1 Departments of Pediatrics, Ophthalmology and Pharmacology, CHU Sainte-Justine Research Centre , Montréal , Canada 2 Natural Science Foundation of China No. 81170596 & 81270756 (to LG) , No. 81370734 (to XN) , and 81471479 (to XY); Science and Technology Commission of Shanghai Municipals No. 15PJ1410400 (to LG) and No. 13430722900 (to XN); and Global Alliance for the Prevention of Prematurity and Stillbirth (GAPPS): Preventing Preterm Birth Initiative, to DMO, SC & XN , USA 3 Department of Physiology, Second Military Medical University , Shanghai , China , 2 Departments of Obstetrics and Gynecology, Pediatrics and Physiology, University of Alberta , Edmonton , Canada 4 Editor: Yi Zhun Zhu, Fudan Univeristy School of Pharmacy , CHINA A major cause of preterm labor in pregnant women is intra-amniotic infection, which is mediated by an inflammatory process. Hydrogen sulfide (H2S), a gaseous transmitter, has been implicated to be involved in inflammatory responses. We sought to investigate whether H2S affects infectious preterm birth using the mouse model of lipopolysaccharides (LPS)induced preterm birth. Administration of LPS at 0.4 mg/kg with two injections intraperitoneally (i.p.) on gestational day 14.5 induced preterm labor. LPS significantly increased leukocyte infiltration in uterus, stimulated the expression of pro-inflammatory cytokines interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), CCL2 and CXCL15 in myometrium. Administration of NaHS (i.p.) delayed the onset of labor induced by LPS in a dosedependent manner. NaHS prevented leukocyte infiltration into intrauterine tissues and inhibited the production of pro-inflammatory cytokines in myometrium and decreased the levels of these cytokines in maternal circulation. H2S also decreased LPS-activated extracellular signal-regulated kinase (ERK) 1/2/ nuclear factor (NF)-κB signaling pathways in myometrium. This study provides new in vivo evidence for the roles of H2S in attenuating inflammation, and a potential novel therapeutic strategy for infection-related preterm labor. - Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Introduction Preterm birth (PTB) occurs in 5–15% of all pregnancies worldwide, and is the leading cause of infant morbidity and mortality [ 1, 2 ]. Of the survivors of PTB, 25% will have at least one developmental delay such as cerebral palsy and long term vision, hearing and respiratory problems [3]. Approximately half of PTB is of unknown aetiology, while maternal genito-urinary infections account for up to 30% to 40% of all PTB [ 4 ]. It has been demonstrated that uterine Competing Interests: The authors have declared that no competing interests exist. infection initiates a cascade of events such as induction of inflammatory responses, premature rupture of fetal membranes and myometrial contractions, all leading to preterm delivery of fetus [ 4 ]. There is increasing body of evidence indicating that the inflammatory state within uterus is a common element of both infection and idiopathic PTB [ 5, 6 ]. The expression of pro-inflammatory cytokines (including chemokines) in uterine tissues is increased prior to onset of term and preterm labor, and infiltration of myometrium, cervix, and fetal membranes by neutrophils and macrophages (Mϕ) [ 7–9 ] is found in both term and preterm labor. Many studies have demonstrated that inflammatory mediators such as IL-1β, IL-6 and TNF-α can stimulate the expression of contraction-associated proteins (CAPs), such as oxytocin receptor (OTR), connexin 43(CX43), prostaglandin H synthase (PGHS)-2 and prostaglandin receptors, in myometrium and production of uterotonic factors such as PGs, eventually leading to onset of labor. Thus, it has been implicated that these inflammatory pathways represent targets for the development of novel therapeutic agents to prevent PTB. Hydrogen sulfide (H2S) has recently been suggested to be “the third endogenous gaseous signaling transmitter” in addition to nitric oxide (NO) and carbon monoxide (CO) in mammalian tissues. H2S has been implicated in many physiologic and pathologic processes, in particular, the inflammatory responses. There are many studies demonstrating that H2S exerts the anti-inflammatory actions in various tissues [ 10–12 ]. However, controversies emerge from many studies, indicating that H2S may play dual roles in the inflammatory process. For instance, H2S in synovial fluid appears to act as a pro-inflammatory mediat (...truncated)


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Weina Liu, Chen Xu, Xingji You, David M. Olson, Sylvain Chemtob, Lu Gao, Xin Ni. Hydrogen Sulfide Delays LPS-Induced Preterm Birth in Mice via Anti-Inflammatory Pathways, PLOS ONE, 2016, Volume 11, Issue 4, DOI: 10.1371/journal.pone.0152838