Systemic interleukin-2 administration improves lung function and modulates chorioamnionitis-induced pulmonary inflammation in the ovine fetus

Abstract

Chorioamnionitis, an inflammatory reaction of the fetal membranes to microbes, is an important cause of preterm birth and associated with inflammation-driven lung injury. However, inflammation in utero overcomes immaturity of the premature lung by inducing surfactant lipids and lung gas volume. Previously, we found that lipopolysaccharide (LPS)-induced chorioamnionitis resulted in pulmonary inflammation with increased effector T cells and decreased regulatory T cell (Treg) numbers. Because Tregs are crucial for immune regulation, we assessed the effects of interleukin (IL)-2-driven selective Treg expansion on the fetal lung in an ovine chorioamnionitis model. Instrumented fetuses received systemic prophylactic IL-2 treatment [118 days gestational age (dGA)] with or without subsequent exposure to intra-amniotic LPS (122 dGA). Following delivery at 129 dGA (term 147 dGA), pulmonary and systemic inflammation, morphological changes, lung gas volume, and phospholipid concentration were assessed. IL-2 pretreatment increased the FoxP3(+)/CD3(+) ratio, which was associated with reduced CD3-positive cells in the fetal lungs of LPS-exposed animals. Prophylactic IL-2 treatment did not prevent pulmonary accumulation of myeloperoxidase- and PU.1-positive cells or elevation of bronchoalveolar lavage fluid IL-8 and systemic IL-6 concentrations in LPS-exposed animals. Unexpectedly, IL-2 treatment improved fetal lung function of control lambs as indicated by increased disaturated phospholipids and improved lung gas volume. In conclusion, systemic IL-2 treatment in utero preferentially expanded Tregs and improved lung gas volume and disaturated phospholipids. These beneficial effects on lung function were maintained despite the moderate immunomodulatory effects of prophylactic IL-2 in the course of chorioamnionitis.

Chorioamnionitis induces enteric nervous system injury: effects of timing and inflammation in the ovine fetus

“…Differences are considered statistically significant at p ≤ 0.05. Differences with a p < 0.10 are also taken into account because of the small study groups and because of potential biological relevance, and described as tendencies as previously described (Willems et al 2016 ). This assumption will decrease the chance of a type II error, but increases the chance of a type I error.…”

Pulmonary vascular changes in extremely preterm sheep after intra-amniotic exposure to Ureaplasma parvum and lipopolysaccharide

“…Paraffin-embedded RUL tissues were cut (4 μm) and stained for CD3 to identify T cells, for myeloperoxidase (MPO) to detect activated neutrophils and monocytes, and for α-smooth muscle actin (α-SMA) to visualize the tunica media of arterioles [20, 25]. Information about antibodies and protocols were published previously for MPO [26] and CD3 [19].…”

Regulatory T Cells and Acute Lung Injury: Cytokines, Uncontrolled Inflammation, and Therapeutic Implications

“…The levels of IL-2 and Treg-related cytokines in BALF and serum gradually decreased in ALI over time ( 80 ). Animal studies have shown that in chorioamnionitis, systemic treatment with IL-2 expanded Tregs preferentially by increasing the ratio of FoxP3 + /CD3 + in fetal lungs, thus improving lung function and modulating pulmonary inflammation ( 81 ). However, there is little evidence of ARDS/ALI induced by other causes.…”

“…There has also been some indirect evidence that Tregs have an impact on TNF-α ( 60 , 61 ), IL-2 ( 81 , 101 ), and IL-8 ( 87 ). In addition, some immunosuppressive molecules [BLT1 ( 20 , 101 ), PD-1 ( 106 ), and CD73 ( 107 )] have also been shown to play an important role in Treg immune function in ALI.…”