IL-1β expression in the distal lung epithelium disrupts lung morphogenesis and epithelial cell differentiation in fetal mice

Abstract

Perinatal inflammation and the inflammatory cytokine IL-1 can modify lung morphogenesis. To examine the effects of antenatal expression of IL-1β in the distal airway epithelium on fetal lung morphogenesis, we studied lung development and surfactant expression in fetal mice expressing human IL-1β under the control of the surfactant protein (SP)-C promoter. IL-1β-expressing pups suffered respiratory failure and died shortly after birth. IL-1β caused fetal lung inflammation and enhanced the expression of keratinocyte-derived chemokine (KC/CXCL1) and monocyte chemoattractant protein 3 (MCP-3/CCL7), the calgranulins S100A8 and S100A9, the acute-phase protein serum amyloid A3, the chitinase-like proteins Ym1 and Ym2, and pendrin. IL-1β decreased the percentage of the total distal lung area made up of air saccules and the number of air saccules in the lungs of fetal mice. IL-1β inhibited the expression of VEGF-A and its receptors VEGFR-1 and VEGFR-2. The percentage of the cellular area of the distal lung made up of capillaries was decreased in IL-1β-expressing fetal mice. IL-1β suppressed the production of SP-B and pro-SP-C and decreased the amount of phosphatidylcholine and the percentage of palmitic acid in the phosphatidylcholine fraction of lung phospholipids, indicating that IL-1β prevented the differentiation of type II epithelial cells. The production of Clara cell secretory protein in the nonciliated bronchiolar (Clara) cells was likewise suppressed by IL-1β. In conclusion, expression of IL-1β in the epithelium of the distal airways disrupted the development of the airspaces and capillaries in the fetal lung and caused fatal respiratory failure at birth.

Cyp26b1 is required for proper airway epithelial differentiation during lung development

“…Although death in Cyp26b1 mutants was previously characterized as "respiratory distress" (Yashiro et al, 2004), RDS is characterized by decreased surfactant production from AT2 cells. In that regard, our work stands in contrast to other studies that have also identified similar defects in distal epithelial differentiation but found a decrease in surfactant production or proSP-C + AT2 cells (Compernolle et al, 2002;Hogmalm et al, 2014;Kersbergen et al, 2018;Rockich et al, 2013;Woik et al, 2014;Yang et al, 2002). Whereas the defects seen in these studies most likely arise from an inability of distal progenitor cells to first differentiate into AT2 cells, loss of Cyp26b1 appears to reduce the differentiation of distal progenitor into AT1.…”

Maternal high-fat diet is associated with impaired fetal lung development

“…Given the known association of placental inflammation and FGR with decreased fetal lung development, we evaluated the influence of maternal HFD on fetal maturation (13,17). FGR is an independent risk factor for the development of chronic lung disease in the postnatal period (4,26,27).…”

Interleukin-1β Promotes Epithelial-Derived Alveolar Elastogenesis via αvβ6 Integrin-Dependent TGF-β Activation

“…The conditional expression of -1 causes severe pulmonary in lammation, alveolar hypoplasia, and progressive lung ibrosis, whereas the in vivo bloc age or depletion of -1 alleviates in lammation and ibrosis and ultimately prevents murine bronchopulmonary dysplasia [14,15]. Regarding the direct effects of -1 on the regulation of extracellular matrix (ECM) expression and composition, con licting data exist regarding the contributions of -1 to the development of myo ibroblasts, which are critical for alveolar formation [16][17][18].…”