Postnatal inflammation following intrauterine inflammation exacerbates the development of atherosclerosis in ApoE−/− mice

Abstract

Atherosclerosis is a chronic inflammatory disease that has its origins in early life. Postnatal inflammation exacerbates atherosclerosis, but the possible effect of intrauterine inflammation is largely unexplored. Exposure to inflammation in utero is common, especially in infants born preterm, who have increased cardiovascular risk in adulthood. We hypothesised that exposure to inflammation before birth would accelerate the development of atherosclerosis, with the most severe atherosclerosis following exposure to both pre- and postnatal inflammation. Here we studied the effect of prenatal and postnatal inflammation on the development of atherosclerosis by combining established techniques for modelling histological chorioamnionitis and atherosclerosis using apolipoprotein E (ApoE) knockout mice. A single intra-amniotic (IA) injection of lipopolysaccharide (LPS) caused intrauterine inflammation, and increased atherosclerosis at 13 weeks of postnatal age. In mice exposed to postnatal LPS, chorioamnionitis modulated subsequent responses; atherosclerotic lesion size, number and severity were greatest for mice exposed to both intrauterine and postnatal inflammation, with a concomitant decrease in collagen content and increased inflammation of the atherosclerotic plaque. In conclusion, pre- and postnatal inflammation have additive and deleterious effects on the development of atherosclerosis in ApoE knockout mice. The findings are particularly relevant to preterm human infants, whose gestations are frequently complicated by chorioamnionitis and who are particularly susceptible to repeated postnatal infections. Human and mechanistic studies are warranted to guide preventative strategies.

Pulmonary Consequences of Prenatal Inflammatory Exposures: Clinical Perspective and Review of Basic Immunological Mechanisms

“…The effect of double hits, namely chorioamnionitis and hyperoxia, has also been explored in rodents. Interestingly, moderate hyperoxia improved lung function in rats exposed to intra-amniotic LPS, whereas severe hyperoxia further reduced it, highlighting the concept that the type of post-natal care, notably of post-natal ventilation, will also influence the overall outcome (163).…”

“…Despite these differences, the rodent model has provided important clues on how inflammation impacts fetal and neonatal lung development. IA injections of LPS and IL-1β in mice (162,163) and rat (164) as well as endocervical injection of E. coli (165) have been used to induce chorioamnionitis in mice. Several characteristic features of human chorioamnionitis are recapitulated in these models, including neutrophilic infiltration in the placental membranes (163)(164)(165) and elevated IL-1β and TNFα in the amniotic fluid (162).…”

“…IA injections of LPS and IL-1β in mice (162,163) and rat (164) as well as endocervical injection of E. coli (165) have been used to induce chorioamnionitis in mice. Several characteristic features of human chorioamnionitis are recapitulated in these models, including neutrophilic infiltration in the placental membranes (163)(164)(165) and elevated IL-1β and TNFα in the amniotic fluid (162). There were also alterations to the fetal lung including neutrophil invasion, increased cytokine expression, decreased alveolarization (in those sacrificed post birth) with increased number of alveolar type II cells, the main source of surfactant proteins required for alveolar function (162,(165)(166)(167)(168).…”

Postnatal inflammation inApoe−/−mice is associated with immune training and atherosclerosis

“…Given that the combination of prenatal and postnatal inflammation induced greater atherosclerosis compared to either treatment alone [24], we next sought to determine if this was due to heightened immune training compared to either treatment alone. Peritoneal macrophages derived from mice treated only prenatally with LPS exhibited no increase in cytokine expression relative to controls following 24hour ex vivo stimulation with Pam3Cys (Figure 3).…”

“…This heightened risk may reflect the increased inflammatory exposures that characterise pregnancies that culminate in preterm birth, including prenatal inflammation (chorioamnionitis) and that arising from early life infections, which are highly prevalent in preterm infants [8]. We have previously reported that experimental prenatal and postnatal inflammation both result in additive, deleterious effects on the development of atherosclerosis in Apoe -/mice [9], but the underlying immunological mechanisms are unknown.…”