Characterisation of post-pneumonectomy lung growth in adult mice

Abstract

A model of inducible expansion of the gas exchange area in adult mice would be ideal for the investigation of molecular determinants of airspace regeneration in vivo. Therefore, the post-pneumonectomy (post-PNX) compensatory lung growth in adult C57BL/6 mice was characterised in this study.Mice underwent left-sided PNX. Right lung volume was assessed on days 1, 3, 5, 7, 10 and 21 after PNX, and total DNA and cellular proliferation of the right lung were determined. Lung histology was studied using immunohistochemistry and quantitatively characterised by detailed stereological investigations. Pulmonary function was assessed using a mouse body-plethysmograph.Following PNX, right-lung volume rapidly restored the initial volume of left and right lung. Total DNA increased significantly over 21 days and equalled the total DNA amount of both lungs in the control mice. Septal cell proliferation significantly increased after PNX, and included endothelial cells, epithelial cells, smooth muscle cells and fibroblasts. Stereological investigations of left and right control lungs versus right lungs 21 days after PNX indicated complete restoration of body mass-specific alveolar surface area. Pulmonary function testing showed marked alteration at 3 days and normalisation at 21 days post-PNX.In conclusion, well reproducible reconstitution of alveolar gas-exchange surface based on septal tissue expansion may be provoked by pneumonectomy in adult mice. Eur Respir J 2004; 24: 524-532. Several pulmonary diseases originate from or are deteriorated by the loss of alveolar septae or, alternatively, remodelling processes of the septal walls, which result in severely compromised gas exchange within the alveoli. The principal ability of mammals to completely restore lung function after major losses of lung tissue by compensatory development of additional gas-exchange surface areas provides a rationale for identifying intrinsic regenerative programmes of the lung that may be employed for therapeutic purposes.The molecular basis of alveolar generation and alveolar remodelling is presently not well understood [1]. Furthermore, the cellular components which contribute to repair and remodelling of pulmonary tissue still await ultimate elucidation. Solutions to the problems concerning repair and regeneration of lung tissue for restoration of functional alveoli are at the cutting edge of identifying novel therapeutic options for lung diseases like chronic obstructive pulmonary disease (COPD) and fibrosis.It has been previously reported that partial resection of the lung results in a rapid compensatory growth process of the remaining lung tissue, restoring normal lung volume, cell mass and organ function, in a variety of mammalian species [2][3][4][5][6]. Compensatory lung growth following unilateral pneumonectomy (PNX) has been documented for dogs, rabbits, ferrets, rats and mice. However, it has been most extensively studied in rats, and the time course, volumetric and morphological changes are well characterised in this species [7,8]...

Quantitative morphology of compensatory lung growth

“…These data broadly outline the sequence of events spanning several months during post-pneumonectomy compensation in large animal species. In comparison, in rodents, the time course of post-pneumonectomy lung growth is considerably shorter [23] and the intense cellular response heightens susceptibility to tumourigenesis as well as metastasis [24,25]. It is probable that similar biochemical and molecular pathways are re-deployed during post-pneumonectomy alveolar growth as occurs during development, although in analysis by the present author's group of selected molecular pathways in the dog, compensatory growth does not exactly replicate developmental patterns of expression [26][27][28].…”

The building blocks of mammalian lung development

“…If the entire left lobe of a mouse lung is removed, total lung volume is restored within 3 weeks by compensatory growth of the right lung. Detailed stereological analysis has shown that this compensatory growth involves both expansion of remaining alveoli and the formation of new alveolar units (neoalveolarization; Voswinckel et al, 2004;Fehrenbach et al, 2008). In contrast, many chronic injuries are not repairable and can lead to lung conditions, such as emphysema in which alveolar units are lost.…”

Lung development: orchestrating the generation and regeneration of a complex organ

“…Indeed, pneumonectomy-induced injury, in which ~50% of the lung is removed, leads to a global increase in cell proliferation and re-establishment of overall respiratory capacity. Evidence exists for both expansion of certain stem/progenitor populations and coordinated proliferation of cell Development (2014Development ( ) doi:10.1242 lineages to expand existing lung tissue (Voswinckel et al, 2004;Hoffman et al, 2010;Eisenhauer et al, 2013). However, the underlying mechanisms related to such a dramatic increase in lung size and capacity still remain unclear.…”