Extracellular matrix and the regulation of lung development and repair ¹

Abstract

During lung development the extracellular matrix regulates cellular growth, migration, and differentiation. Pulmonary cells reciprocate and regulate extracellular matrix formation by elaborating a variety of peptides that affect gene transcription, RNA processing, translation, and posttranslational modifications of proteins. This regulation involves prenatal events such as the branching of airways and postnatal events such as alveolar septal formation. Normal airway branching requires multiple extracellular matrix proteins, proteoglycans, and the expression of cellular receptors for these molecules. Alveolar septal formation exemplifies how cells regulate the production, export, and deposition of an important structural protein, elastin, which is essential for the development of normal gas exchange units. Repair after injury to the adult lung engages some of the same factors that regulate lung development. However, in this case, inflammatory cells that enter the lung after injury elaborate many of these regulatory peptides. The effects of these peptides on the resident cells, which produce extracellular matrix, are a major determinant of whether the repair restores normal pulmonary architecture or progresses to fibrosis and additional impairment of gas exchange.

Reconstructing dynamic microRNA-regulated interaction networks

“…2, we labeled the nine different paths in the model with the letters A to I and computed significantly enriched gene ontology (GO) terms for these paths (SI Appendix, Table S1). For example, path A (up-regulated genes) contains genes involved in remodeling extracellular structures, which is an important process during lung development (27). In contrast, genes on path I, which is down-regulated in the week 1 to week 2 transition, are enriched for the GO terms cell-cycle regulation and cell differentiation.…”

Gene encoding a novel murine tissue inhibitor of metalloproteinases (TIMP), TIMP‐3, is expressed in developing mouse epithelia, cartilage, and muscle, and is located on mouse chromosome 10

“…Branching involves ECM degradation a t the apex of the branches and sparing of ECM in the clefts between the branches (Matrisian et al, 1992). Matrix degrading enzymes, especially collagenases, play a role in epithelial branching (Nakanishi et al, 1986;Fukuda et al, 1988;McGowan, 1992). Expression of Timp-3 in the developing epithelia during critical morphogenetic periods, e.g., invagination of surface epithelium or branching in bronchial epithelium, may protect the basement membrane or cell-cell adhesions from the matrix degrading enzymes occurring in the immediate vicinity (Smith and Bernfield, 1982;Reponen et al, 1992), and permit these epithelia some autonomy of development.…”

Respiratory Tissue Engineering: Current Status and Opportunities for the Future

“…Smooth muscle cells, fibroblasts, chondrocytes, and inflammatory cells constitute the cellular content, mediating muscle contraction, matrix composition, and signalling processes. Noncellular molecules such as collagen, elastin and various glycosaminoglycans (GAGs) modulate structural support and morphogenesis in tandem with growth factors and morphogens such as epidermal growth factor, bone morphogenetic proteins and fibroblast growth factors (19)(20)(21)(22), which can dictate cell differentiation when engineering an in vitro tissue engineered tracheobronchial model. A continuous network of fibrillar collagen I and III supports the epithelium and airway smooth muscle (20),reinforced by a series of C-shaped cartilage rings located along the outside of the upper respiratory tract.…”

“…A continuous network of fibrillar collagen I and III supports the epithelium and airway smooth muscle (20),reinforced by a series of C-shaped cartilage rings located along the outside of the upper respiratory tract. This cartilage is hyaline in nature, composed predominantly of type II collagen and proteoglycans including aggregans, decorin, biglycan and fibromodulin (23,24); it conveys increased structural integrity to the trachea and bronchi, preventing airway collapse and ensuring transit of inhaled air to the alveoli (19). The ECM architectural design in the conducting region allows for longitudinal flexibility but lateral rigidity (25), a combination that must be incorporated into any engineered construct that is implanted for tracheobronchial regeneration in order to preserve large airway patency and functionality.…”