Lung matrix and vascular remodeling in mechanically ventilated elastin haploinsufficient newborn mice

Abstract

Elastin plays a pivotal role in lung development. We therefore queried if elastin haploinsufficient newborn mice ( Eln+/−) would exhibit abnormal lung structure and function related to modified extracellular matrix (ECM) composition. Because mechanical ventilation (MV) has been linked to dysregulated elastic fiber formation in the newborn lung, we also asked if elastin haploinsufficiency would accentuate lung growth arrest seen after prolonged MV of neonatal mice. We studied 5-day-old wild-type ( Eln+/+) and Eln+/− littermates at baseline and after MV with air for 8–24 h. Lungs of unventilated Eln+/− mice contained ∼50% less elastin and ∼100% more collagen-1 and lysyl oxidase compared with Eln+/+ pups. Eln+/− lungs contained fewer capillaries than Eln+/+ lungs, without discernible differences in alveolar structure. In response to MV, lung tropoelastin and elastase activity increased in Eln+/+ neonates, whereas tropoelastin decreased and elastase activity was unchanged in Eln+/− mice. Fibrillin-1 protein increased in lungs of both groups during MV, more in Eln+/− than in Eln+/+ pups. In both groups, MV caused capillary loss, with larger and fewer alveoli compared with unventilated controls. Respiratory system elastance, which was less in unventilated Eln+/− compared with Eln+/+ mice, was similar in both groups after MV. These results suggest that elastin haploinsufficiency adversely impacts pulmonary angiogenesis and that MV dysregulates elastic fiber integrity, with further loss of lung capillaries, lung growth arrest, and impaired respiratory function in both Eln+/+ and Eln+/− mice. Paucity of lung capillaries in Eln+/− newborns might help explain subsequent development of pulmonary hypertension previously reported in adult Eln+/− mice.

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia

“…The expression of lysyl oxidases is elevated in the lung in clinical BPD (33), in clinical and experimental pulmonary arterial hypertension (48), and in clinical and experimental lung fibrosis (16). In a mouse model of ventilator-induced disturbances to alveolarization in mice, changes in lysyl oxidase expression have also been noted (7,9,23). In the present study, in a hyperoxia-based mouse model of BPD, the abundance of multiple lysyl oxidases was elevated in the lungs of mice exposed to elevated inspired oxygen levels.…”

“…The collagento-elastin ratio of affected lungs was threefold increased, which would likely lead to a marked stiffening of the lung parenchyma. Given the importance of breathing motions and physical forces in driving alveolar development (41), the decreased lung compliance resulting from a shift in the collagen-toelastin ratio almost certainly directly impacts the ability of the immature lung to develop properly (23).…”

“…Excessive elastase activity has been considered as a mediator of pathological elastin degradation, which might underlie the paucity of elastin and bizarre elastin fiber patterns seen in affected lungs (21)(22)(23)36). Additionally, the altered expression of proteins required for proper elastin fiber assembly has also been suggested to uncouple elastin synthesis and the assembly of elastin fibers (7)(8)(9).…”

Targeting transglutaminase 2 partially restores extracellular matrix structure but not alveolar architecture in experimental bronchopulmonary dysplasia

“…The FEBS Journal 285 (2018) 3056-3076 ª 2018 Federation of European Biochemical Societies increased expression and activity of protein cross-linking enzymes noted in aberrantly developing lungs. The expression of several lysyl oxidases is reported to be elevated in both clinical and experimental BPD [10][11][12][13][14][15][16]52]. Furthermore, expression of both the lysyl hydroxylase PLOD2 [17], as well as TGM2 [18], is increased in clinical and experimental BPD.…”

Update on novel targets and potential treatment avenues in pulmonary hypertension

“…The extracellular matrix (ECM) is clearly important in the development of the pulmonary vasculature, as neonatal mice haploinsufficient for elastin are known to develop PH as adults (73,217,256). When challenged with a course of mechanical ventilation, these mice developed increased collagen and fibrillin deposition, which was associated with decreased respiratory system elastance (111). While the number of alveoli remained stable, the number of pulmonary microvessels was significantly decreased, providing important insight into how changes in neonatal anatomic development, lung growth arrest, and impaired respiration may impact long-term outcomes (Fig.…”