Comparative study of two models of combined pulmonary fibrosis and emphysema in mice
Introduction
Pulmonary fibrosis (PF) is characterized by accumulation of inflammatory cells, a complex network of immunomodulatory cytokines and growth factors, and expansion of the population of mesenchymal cells. These events result in deposition of proteins from the extracellular matrix. In contrast, emphysema results in reduced elastic recoil in the lungs and premature closure of the airways. Consequently, emphysema is characterized by reductions in the indices of forced expiratory flow, with a reduction in the ratio of forced expiratory volume in one second to forced vital capacity.
Emphysema and PF are defined by distinct clinical, functional, imaging and pathologic characteristics. However, a growing body of evidence supports the existence of “combined pulmonary fibrosis and emphysema” (CPFE). Lung volumes and spirometry are relatively preserved in patients with CPFE, but they can experience marked reductions in diffusing capacity. In patients with CPFE, a common factor that has been described is a history of current or past use of tobacco (Cottin, 2013, Portillo and Morera, 2012, He et al., 2014, Papiris et al., 2013, Jankowich and Rounds, 2012). Clinical features of CPFE are well known, but the mechanisms leading to CPFE are not clear. Therefore, an animal model of CPFE must be established to study CPFE pathogenesis.
Several clinical studies have demonstrated the relationship between infection with the Epstein–Barr virus (EBV), inflammation, and PF (Bossink et al., 2008, McManus et al., 2008, Stewart et al., 1999, Williams, 2014). In the present study, we sought to develop a murine model of CPFE by tracheal instillation of murine gammaherpesvirus 68 (MHV-68), a virus closely related to the EBV. We also used another method to create a CPFE model in mice by employing bleomycin (BLM). Then, we compared the results elicited using these two models.
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Experimental animals and design
The Ethics Committee of Tongji Medical College within the Huazhong University of Science and Technology (Wuhan, China) approved the study protocol, which was in accordance with the Helsinki Declaration.
Forty-two male, specific pathogen-free C57BL/6 mice (6–8 weeks) were purchased from the Center of Experimental Animals (Tongji Medical College) Mice were divided randomly into four groups: A (normal control; n = 6); B (emphysema; passive cigarette smoking for 1 h twice a day for 13 months; 0.1 mL
Emphysematous changes in lung tissues
H&E staining of lung tissues showed no evident pathological changes in the normal control group. However, conspicuous alveolar walls were broken and merged, and alveolar cavities were enlarged in the emphysema group, emphysema + MHV-68 group, and emphysema + BLM group (Fig. 1).
Airway inflammation and fibrotic changes
In the emphysema + MHV-68 group, inflammation and fibrosis were detectable in the day-7 subgroup and reached a peak in the day-28 subgroup. Morphometric changes were different in the emphysema + MHV-68 group compared with those
Discussion
CPFE is associated with several pathologic processes: chronic obstructive pulmonary disease, PF, and lung cancer. CPFE is regarded to be a complex syndrome instead of a standalone disease. A model of BLM-induced PF in mice has been used extensively for investigation of PF pathogenesis in humans (Fridlender et al., 2007). Therefore, BLM can be used to induce CPFE in mice suffering from emphysema. Another mouse model of CPFE induced by MHV-68 that is more similar to CPFE observed in humans needs
Conclusions
We analyzed two CPFE models in mice. Different changes in pathology between the BLM model and MHV-68 model demonstrated the different pathologic subtypes of CPFE: macrophage infiltration and T2LEC apoptosis increased with increasing pathology score for PF.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
Conceived and designed the study: WGZ and HLZ. Performed the animal experiments: SSW, QY, YKF, and YTC. Analyzed the data and prepared results: HLZ, LH, and WGZ. Wrote the manuscript: HLZ and LH. Study supervised and coordinated: GHZ, YJX, ZXZ, and JPZ. All authors read and approved the final manuscript.
Acknowledgements
We thank the staff at the Key Laboratory of Respiratory Diseases in Tongji Hospital, Ministry of Health, China. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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These authors contributed equally to this work.