Proliferative activity of liver growth factor is associated with an improvement of cigarette smoke-induced emphysema in mice.

Álvaro Girón-Martínez,Juan José Díaz-Gil,Raúl Terrón-Expósito,Nicolás González-Mangado,Sandra Pérez-Rial,Germán Peces-Barba,Carolyn J Baglole

doi:10.1371/journal.pone.0112995

Abstract

Cigarette smoke (CS)-induced emphysema is a major component of chronic obstructive pulmonary disease (COPD). COPD treatment is based on the administration of bronchodilators and corticosteroids to control symptoms and exacerbations, however, to date, there are no effective therapies to reverse disease progression. Liver growth factor (LGF) is an albumin-bilirubin complex with mitogenic properties, whose therapeutic effects have previously been reported in a model of emphysema and several rodent models of human disease. To approach the therapeutic effect of LGF in a model of previously established emphysema, morphometric and lung function parameters, matrix metalloproteinase (MMP) activity and the expression of several markers, such as VEGF, PCNA, 3NT and Nrf2, were assessed in air-exposed and CS-exposed C57BL/6J male mice with and without intraperitoneal (i.p.) injection of LGF. CS-exposed mice presented a significant enlargement of alveolar spaces, higher alveolar internal area and loss of lung function that correlated with higher MMP activity, higher expression of 3NT and lower expression of VEGF. CS-exposed mice injected with LGF, showed an amelioration of emphysema and improved lung function, which correlated with lower MMP activity and 3NT expression and higher levels of VEGF, PCNA and Nrf2. Taken together, this study suggests that LGF administration ameliorates CS-induced emphysema, highlights the ability of LGF to promote alveolar cell proliferation and may be a promising strategy to revert COPD progression.

Highlights

Chronic obstructive pulmonary disease (COPD) is a major disease affecting millions of people worldwide
The morphology of alveolar spaces in lungs from mice exposed to cigarette smoke (CS) and treated with Liver growth factor (LGF) was similar to that observed in normal lungs (Fig. 2A)
The shape of the density curve corresponding to the distribution of the intercept lengths in lungs from mice exposed to CS and treated with LGF was more similar to that observed in normal lungs, suggesting that LGF was promoting tissue repair

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a major disease affecting millions of people worldwide. The toxic compounds present in CS are partly responsible for the disruption of the alveolar and capillary network in the lung. It has been reported that there are greater numbers of apoptotic alveolar epithelial and endothelial cells in lung tissues of COPD patient than in control patients, which in turn can lead to the development of emphysema [2]. Inflammatory cells release reactive oxygen/nitrogen species, which contribute to the sustained oxidative/ nitrosative burden in the lungs [6]. In the context of the inflammatory milieu as it occurs in COPD, nitric oxide reacts with reactive nitrogen species resulting in the formation of 3nitrotyrosine (3NT), which is considered a marker of nitrosative stress and inflammation [7]. Nrf2-deficient mice have early-onset and more extensive CS-induced emphysema compared with wild-type littermates, suggesting that Nrf protects against the development of emphysema [8]

Methods

Results

Conclusion