Comparative gene expression profiling of post-natal and post-pneumonectomy lung growth

Abstract

Although increasing numbers of patients suffer from chronic destructive lung diseases, there are no effective therapeutic options apart from transplantation. Understanding the mechanisms of physiological and regenerative alveolar septation is prerequisite for the development of regenerative therapies for the lung. We compared lung gene expression in the phase of induction of post-natal and post-pneumonectomy alveolarisation to identify regulatory genes involved in both processes.We performed genome-wide microarray screenings of newborn and pneumonectomised mouse lungs 1 and 3 days after birth or surgery. Selected candidates were validated by real-time PCR, Western blot and in situ hybridisation.We found 58 genes to be regulated in both models with 40 candidates being changed likewise. Many of these genes participated in growth and differentiation processes. Additionally, immune system, structural molecules, respiratory chain, signal transduction and metabolism were involved. Some candidates were not yet linked to specific functions. The highest regulatory concordance was observed for various isoforms of (pro-)collagen molecules, elastin and the elastin-associated protein fibrillin1 being corporately upregulated.Our findings do not definitively support a common regulating mechanism for induction of postnatal and adult alveolarisation, but some candidates in the intersection of both models are promising for further investigations.

Profiling target genes of FGF18 in the postnatal mouse lung: possible relevance for alveolar development

“…Conversely, FGF18 downregulated a number of P450 cytochrome oxidases and other genes involved in xenobiotic metabolism. Numerous cytochrome oxidases with FGF18-decreased expression, including Cyp2b10, Cyp2b20, Cyp2f2, and Cyp4b1, were recently found to be downregulated in the alveolarizing postnatal lung (54). It was suggested that these changes could be related to expansion of the epithelial precursor cell pool through a balance between proliferation and differentiation of epithelial cells (54).…”

“…FGF18 conversely decreased the expression of a variety of other ECM components. Previous investigations (4,31,54) have shown clusters of ECM-component genes upregulated either early during the phase of secondary septation or later during maturation of septa. FGF18 appears as an inducer of genes belonging to the former group.…”

“…Numerous cytochrome oxidases with FGF18-decreased expression, including Cyp2b10, Cyp2b20, Cyp2f2, and Cyp4b1, were recently found to be downregulated in the alveolarizing postnatal lung (54). It was suggested that these changes could be related to expansion of the epithelial precursor cell pool through a balance between proliferation and differentiation of epithelial cells (54). Consistent with this assumption is the FGF18-diminished expression of a number of genes expressed selectively in lung epithelial cell subsets, including Ca 2ϩ -sensitive chloride channel 2, Abca3, Cyp1b1, Cyp2f2, stearoyl coenzyme A dehydrogenase (Scd1), aquaporins 3 and 4, uteroglobin-related protein 1a, and aldehyde oxidase 3.…”

Lung Regeneration Therapy for Chronic Obstructive Pulmonary Disease

“…In addition, Kho et al8 revealed that the expression levels of genes related to extracellular matrixes such as collagen and elastin, which are vital to the repair of damaged pulmonary structures, were increased in pneumonectomy-treated mice, suggesting reinforced regenerative processes after a pulmonary insult. In contrast, the genes related to growth inhibition and cell cycle arrest, such as phospholipase A2 group XVI (Pla2g16), were downregulated after pneumonectomy9. Accordingly, the lung is currently considered an active organ that has regenerative capacity through various mediators and signaling pathways that promote cell proliferation and differentiation.…”

Laser Microdissection of the Alveolar Duct Enables Single-Cell Genomic Analysis

“…Recent evidence indicates that these structures reflect not only mechanical relationships, but also functional units that selectively participate in integrated processes such as tissue regeneration (2) and the development of bronchioalveolar carcinoma (3). Because bulk analyses of cells and gene expression – ignoring these regenerative units – have failed to illuminate the interactions between cells participating in these processes (4, 5), there is growing interest in the spatial sampling of the cells within regenerative units.…”