The Extracellular Matrix in Bronchopulmonary Dysplasia: Target and Source

Abstract

Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth that contributes significantly to morbidity and mortality in neonatal intensive care units. BPD results from life-saving interventions, such as mechanical ventilation and oxygen supplementation used to manage preterm infants with acute respiratory failure, which may be complicated by pulmonary infection. The pathogenic pathways driving BPD are not well-delineated but include disturbances to the coordinated action of gene expression, cell–cell communication, physical forces, and cell interactions with the extracellular matrix (ECM), which together guide normal lung development. Efforts to further delineate these pathways have been assisted by the use of animal models of BPD, which rely on infection, injurious mechanical ventilation, or oxygen supplementation, where histopathological features of BPD can be mimicked. Notable among these are perturbations to ECM structures, namely, the organization of the elastin and collagen networks in the developing lung. Dysregulated collagen deposition and disturbed elastin fiber organization are pathological hallmarks of clinical and experimental BPD. Strides have been made in understanding the disturbances to ECM production in the developing lung, but much still remains to be discovered about how ECM maturation and turnover are dysregulated in aberrantly developing lungs. This review aims to inform the reader about the state-of-the-art concerning the ECM in BPD, to highlight the gaps in our knowledge and current controversies, and to suggest directions for future work in this exciting and complex area of lung development (patho)biology.

Can We Understand the Pathobiology of Bronchopulmonary Dysplasia?

“…Dynamic changes in the expression of a large spectrum of ECM molecules, including collagens and elastin, matrix processing enzymes such as metalloproteinases 149 and neutrophil elastase 150, 151 , and ECM cross-linking enzymes (lysyl oxidases, transglutaminases, and lysyl hydroxylases) occur during lung development. The expression of many of these molecules is dysregulated during aberrant lung development 152 . In general, the overall abundance of elastin is reduced, and elastin fibers in the developing septa are disorganized; although the general abundance of collagen and collagen cross-links is increased 153 , and collagen fibers also take on an abnormal structure 154 .…”

sRAGE Is Elevated in the Lungs of Premature Infants Receiving Mechanical Ventilation

“…26 Since sRAGE can also bind to extracellular membrane proteins, especially collagen, which peaks during the alveolar phase of development, 27 it is possible that excess sRAGE as seen in our study might interfere with normal migration and adherence of alveolar cells, contributing to the alveolar simplification seen in established BPD. 27,28 Our study only indicates that sRAGE is likely to be present in the lung in subjects at risk for developing for BPD. Further investigation will be needed to determine its role and whether manipulation of sRAGE levels may be therapeutically beneficial.…”

Tenascin-C inactivation impacts lung structure and function beyond lung development

“…Collagen represents 50% of lung ECM and is principally composed of fibrillar collagen (collagen I and III). Elastin represents 18% of lung ECM and is made essentially of crosslinked elastin surrounded by fibrillin microfibrils 28 . No difference in elastin or collagen staining was observed between TNC KO and WT newborn lungs.…”