Comparative study of two models of combined pulmonary fibrosis and emphysema in mice

Zhang, Wanguang; Wu, Sisi; He, Li; Yang, Qun; Feng, Yun‐Zhi; Chen, Yuetao; Zhen, Guohua; Xu, Yu; Zhang, Zhenxiang; Zhao, Jianping; Zhang, Huilan

doi:10.1016/j.acthis.2017.01.007

Cited by 6 publications

(9 citation statements)

References 30 publications

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“…Features of CPFE have been modeled by treating mice with both the fibrotic agent bleomycin and elastase to induce airspace enlargement (Cattani-Cavalieri et al, 2017; Trajano et al, 2016). Experiments have also been performed treating cigarette-smoke exposed mice with bleomycin or herpesvirus, leading to airspace enlargement and fibrotic matrix deposition (Zhang et al, 2017). In addition, exposure to the halogen gas bromine has also been shown to induce combined airway fibrosis and emphysema (Aggarwal et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Adenosine and hyaluronan promote lung fibrosis and pulmonary hypertension in combined pulmonary fibrosis and emphysema

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Molina

Hanmandlu

et al. 2019

Disease Models &Amp; Mechanisms

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Combined pulmonary fibrosis and emphysema (CPFE) is a syndrome that predominantly affects male smokers or ex-smokers and it has a mortality rate of 55% and a median survival of 5 years. Pulmonary hypertension (PH) is a frequently fatal complication of CPFE. Despite this dismal prognosis, no curative therapies exist for patients with CPFE outside of lung transplantation and no therapies are recommended to treat PH. This highlights the need to develop novel treatment approaches for CPFE. Studies from our group have demonstrated that both adenosine and its receptor ADORA2B are elevated in chronic lung diseases. Activation of ADORA2B leads to elevated levels of hyaluronan synthases (HAS) and increased hyaluronan, a glycosaminoglycan that contributes to chronic lung injury. We hypothesize that ADORA2B and hyaluronan contribute to CPFE. Using isolated CPFE lung tissue, we characterized expression levels of ADORA2B and HAS. Next, using a unique mouse model of experimental lung injury that replicates features of CPFE, namely airspace enlargement, PH and fibrotic deposition, we investigated whether 4MU, a HAS inhibitor, was able to inhibit features of CPFE. Increased protein levels of ADORA2B and HAS3 were detected in CPFE and in our experimental model of CPFE. Treatment with 4MU was able to attenuate PH and fibrosis but not airspace enlargement. This was accompanied by a reduction of HAS3-positive macrophages. We have generated pre-clinical data demonstrating the capacity of 4MU, an FDA-approved drug, to attenuate features of CPFE in an experimental model of chronic lung injury. .

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Section: Discussionmentioning

confidence: 99%

Adenosine and hyaluronan promote lung fibrosis and pulmonary hypertension in combined pulmonary fibrosis and emphysema

Collum

Molina

Hanmandlu

et al. 2019

Disease Models &Amp; Mechanisms

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“…Five‐micrometer sections were stained with hematoxylin and eosin or Masson's trichrome stain to assess histology, and periodic acid‐Schiff (PAS) reagent was used to detect goblet cells. Emphysematous changes were assessed by measuring both the mean linear intercept and destructive index, as described previously 10,12 . For each animal, eight fields at a magnification of ×100 were captured randomly from the three different zones of the left lung.…”

Section: Methodsmentioning

confidence: 99%

“…Collagen area of the basal membrane of the airways was analyzed in 3 to 5 bronchioles on each slide. The result was expressed as collagen‐stained areas per micrometer length of basement membrane of bronchioles, as described previously 10 . The number of PAS‐positive cells per 100 μM basement membrane length was counted in random fields.…”

Section: Methodsmentioning

confidence: 99%

“…It is known that murine gammaherpesvirus 68 (MHV‐68) infection in aging mice may result in severe pneumonitis and fibrosis 9 . We have previously proved that MHV‐68 infection could induce emphysema in mice, which later developed into CPFE in the infected mice 10 . In this study, a mouse model that overexpresses MUC5AC was constructed to explore whether increased MUC5AC secretion could provide benefits against fibrosis induced by MHV‐68.…”

Section: Introductionmentioning

confidence: 99%

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Protective role of overexpressed MUC5AC against fibrosis in MHV‐68‐induced combined pulmonary fibrosis and emphysema mouse model

Feng

Zhang

et al. 2020

Journal of Medical Virology

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Mucins have long been regarded to play a role as a barrier to prevent mucosal infections; however, some studies report that overexpression of mucins induces obstruction and inflammation of airways. We investigated whether the secretion of overexpressed mucin, mucin5ac (MUC5AC), could improve protection against pathogens. To examine the possible roles of mucin hypersecretion in augmenting host defense against disease‐promoting muco‐obstructive lung disease, a mouse model that overexpressed MUC5AC was generated. We had previously proved that murine gammaherpesvirus‐68 (MHV‐68) infection could induce emphysema in mice, which later developed into combined pulmonary fibrosis and emphysema (CPFE). We further explored whether increased MUC5AC secretion could provide benefits against MHV‐68 induced fibrosis. We initially developed a pcDNA3.1‐MUC5AC mouse model. Next, the experimental mice were randomly divided into five groups: normal control, pcDNA3.1 control, pcDNA3.1‐MUC5AC, CPFE, and pcDNA3.1‐ MUC5AC + CPFE. Morphometric analysis of each group was performed by hematoxylin and eosin staining and Masson trichrome staining. MUC5AC levels in lung tissues were analyzed by immunohistochemical staining, real‐time polymerase chain reaction, and Western blot analysis. The airway inflammation was determined by differential cell counts of bronchoalveolar lavage fluid (BALF) and measurement of cytokines and chemokines in BALF by enzyme‐linked immunosorbent assay. MUC5AC hypersecretion alone was not sufficient to drive goblet cell metaplasia to induce obvious mucus plugging and airway inflammation. However, MUC5AC overexpression served as a protective barrier against MHV‐68 virus infection in vivo. Infectivity of MHV‐68 was decreased in the pcDNA3.1‐MUC5AC + CPFE group compared with that in CPFE group. Meanwhile, a reduction of MHV‐68 virus attenuated the expressions of chemokine (C‐C motif) ligand 2 (CCL2), chemokine (C‐X‐C motif) ligand 5 (CXCL5), interleukin‐13 (IL‐13), and transforming growth factor‐β1 (TGF‐β1), and weakened airway inflammation and fibrosis in the pcDNA3.1‐MUC5AC + CPFE group. Overexpression of MUC5AC appears to exhibit a protective role against MHV‐68 infection in mice with emphysema that subsequently developed into CPFE and to further decrease airway inflammation and fibrosis induced by MHV‐68 by decreasing the expressions of CCL2, CXCL5, IL‐13, and TGF‐β1.

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“…An immunosuppressed mouse model of lethal MHV-68 infection is useful for studying potential treatment of EBV infection in man (Smee et al, 1997). The MHV-68 mouse model can help clarify the pathogenesis and immunology of the pulmonary granuloma formation and pulmonary fibrosis and emphysema (Coelho et al, 2006;Zhang et al, 2017). The model of MHV-68 experimental transmission in laboratory mice could help us to better understand the biology of gammaherpesviruses and could also allow the development of strategies that could prevent the spread of gammaherpesviruses in natural populations (François et al, 2013).…”

Section: Genome Of Mhv-68mentioning

confidence: 99%

Murid herpesvirus 4 (MuHV-4, prototype strain MHV-68) as an important model in global research of human oncogenic gammaherpesviruses

Mistríková¹,

Briestenská²

2020

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The aim of this work was to give an overview of murid herpesvirus 4 (MuHV-4) (synonyms: murine gammaherpesvirus 68, mouse herpesvirus strain 68), the first model for the study of human and animal oncogenic gammaherpesviruses. Based on our results confirming similarity of murine gammaherpesvirus 68 (MHV-68) to another gammaherpesvirus, human oncogenic Epstein-Barr virus (EBV), we were able to interpret some processes observed in the course of MHV-68 infection in analogy to EBV infection. In particular, that were the processes occurring during MHV-68-induced persistent infection in mice accompanied by tumor formation and leukemia following immunosuppression. Since EBV is a highly species specific virus, infecting humans only, these processes cannot be experimentally examined at the molecular, cellular, and tissue levels in natural host. However, they can be investigated in BALB/c mice infected with MHV-68, which is nowadays generally accepted model mainly thanks to experimental results achieved by our research team. The important mouse model MHV-68 is a prototype strain of MuHV-4 species and is classified as a member of the order Herpesvirales, family Herpesviridae, subfamily Gammaherpesvirinae and genus Rhadinovirus. During 40 years since its isolation from wild rodents, the virus was distributed into many virological laboratories in Europe (such as England,

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Comparative study of two models of combined pulmonary fibrosis and emphysema in mice

Cited by 6 publications

References 30 publications

Adenosine and hyaluronan promote lung fibrosis and pulmonary hypertension in combined pulmonary fibrosis and emphysema

Adenosine and hyaluronan promote lung fibrosis and pulmonary hypertension in combined pulmonary fibrosis and emphysema

Protective role of overexpressed MUC5AC against fibrosis in MHV‐68‐induced combined pulmonary fibrosis and emphysema mouse model

Murid herpesvirus 4 (MuHV-4, prototype strain MHV-68) as an important model in global research of human oncogenic gammaherpesviruses

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