Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development

Abstract

The highly orchestrated interactions between the epithelium and mesenchyme required for normal lung development can be disrupted by perinatal inflammation in preterm infants, although the mechanisms are incompletely understood. We used transgenic (inhibitory kB kinase b transactivated) mice that conditionally express an activator of the NF-kB pathway in airway epithelium to investigate the impact of epithelial-derived inflammation during lung development. Epithelial NF-kB activation selectively impaired saccular stage lung development, with a phenotype comprising rapidly progressive distal airspace dilation, impaired gas exchange, and perinatal lethality. Epithelial-derived inflammation resulted in disrupted elastic fiber organization and down-regulation of elastin assembly components, including fibulins 4 and 5, lysyl oxidase likee1, and fibrillin-1. Fibulin-5 expression by saccular stage lung fibroblasts was consistently inhibited by treatment with bronchoalveolar lavage fluid from inhibitory kB kinase b transactivated mice, Escherichia coli lipopolysaccharide, or tracheal aspirates from preterm infants exposed to chorioamnionitis. Expression of a dominant NF-kB inhibitor in fibroblasts restored fibulin-5 expression after lipopolysaccharide treatment, whereas reconstitution of fibulin-5 rescued extracellular elastin assembly by saccular stage lung fibroblasts. Elastin organization was disrupted in saccular stage lungs of preterm infants exposed to systemic inflammation. Our study reveals a critical window for elastin assembly during the saccular stage that is disrupted by inflammatory signaling and could be amenable to interventions that restore elastic fiber assembly in the developing lung.

Yap/Taz regulate alveolar regeneration and resolution of lung inflammation

“…During development, epithelial NF-κB signaling is known to regulate lung inflammation and alveolar development in both humans and mice (45)(46)(47). In adulthood, correlations between persistent lung inflammation and decreased lung regeneration have been observed in both various animal injury models and human patients (8,10), but it has not been clear whether higher inflammatory burdens in the lung precede loss of lung regeneration or are an effect of respiratory disease.…”

Prevention of Oxygen-Induced Inflammatory Lung Injury by Caffeine in Neonatal Rats

“…It is acknowledged that NF κ B regulates the transcription of several genes related to the immune response to exogenous and endogenous noxae and thus plays an important role in inflammatory processes, cell survival, and developmental functions in the newborn lung [ 53 ]. Further, NF κ B transcription can be activated by hyperoxia followed by amplification of inflammatory response [ 84 ], and during the saccular stage, overexpressing NF κ B in the airway epithelium induces inflammation and disrupts lung development [ 95 ]. Oxidative stress rapidly activated the cellular pool of GCLC, which is important for the rate-limiting step in the formation of the antioxidant glutathione [ 96 ].…”

Lung development and emerging roles for type 2 immunity

“…NF‐κB signalling is also beneficial in hyperoxia‐induced lung injury , compensatory lung growth after pneumonectomy , and has roles in alveolarisation and angiogenesis . However, during the saccular stage, overexpressing NF‐κB in the airway epithelium induces inflammation and disrupts lung development , and its activation in macrophages causes aberrant lung morphogenesis upon LPS exposure . Such differences may be caused by NF‐κB activation in different cell types and developmental stages, and through the action of different pathways and NF‐κB subunits .…”