17β-Estradiol Replacement Reverses Age-Related Lung Disease in Estrogen-Deficient C57BL/6J Mice

Glassberg, Marilyn K.; Choi, Rhea; Manzoli, Vita; Shahzeidi, Shahriar; Rauschkolb, Peter; Voswinckel, Robert; Aliniazee, Muddassir; Xia, Xiaomei; Elliot, Sharon J.

doi:10.1210/en.2013-1345

Cited by 30 publications

(27 citation statements)

References 43 publications

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“…are found to ameliorate the symptoms and protect against lung injury, 48 Implying diethylstilbestrol could be a novel finding of this analysis. 49 Similarly, dinoprostone (prostaglandin E2), ranked 16th in the list, significantly disrupted the DILD network, which is in good accordance with finding of prostaglandin-endoperoxide synthase 2 (also known as COX-2) being consistently downregulated in lung injury.…”

Section: Identification Of Candidate Drugs For Treating Dildmentioning

confidence: 88%

Identification of drug-specific pathways based on gene expression data: application to drug induced lung injury

et al. 2015

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Identification of signaling pathways that are functional in a specific biological context is a major challenge in systems biology, and could be instrumental to the study of complex diseases and various aspects of drug discovery. Recent approaches have attempted to combine gene expression data with prior knowledge of protein connectivity in the form of a PPI network, and employ computational methods to identify subsets of the protein-protein-interaction (PPI) network that are functional, based on the data at hand. However, the use of undirected networks limits the mechanistic insight that can be drawn, since it does not allow for following mechanistically signal transduction from one node to the next. To address this important issue, we used a directed, signaling network as a scaffold to represent protein connectivity, and implemented an Integer Linear Programming (ILP) formulation to model the rules of signal transduction from one node to the next in the network. We then optimized the structure of the network to best fit the gene expression data at hand. We illustrated the utility of ILP modeling with a case study of drug induced lung injury. We identified the modes of action of 200 lung toxic drugs based on their gene expression profiles and, subsequently, merged the drug specific pathways to construct a signaling network that captured the mechanisms underlying Drug Induced Lung Disease (DILD). We further demonstrated the predictive power and biological relevance of the DILD network by applying it to identify drugs with relevant pharmacological mechanisms for treating lung injury. Insight, innovation, integrationIn this manuscript we introduce a novel approach for the identification of signaling pathways that are functional in a specific biological context, by leveraging gene expression data and prior knowledge of protein connectivity. In more detail, we introduce a linear programming formulation to model signal transduction from one node to the next in a Prior Knowledge Network (PKN), and by minimizing the mismatch between model predictions and experimental data, we are able to identify subsets of the PKN that are most probably functional in the specific biological context. More specifically, we address the problem of identifying the modes of action of drugs that have been reported to induce respiratory side effects, based on their gene expression profiles, and subsequently, merge the drug specific pathways together to construct a signaling network that captures the signaling mechanisms underlying Drug Induced Lung Disease (DILD). Moreover, to demonstrate the predictive power and biological relevance of the DILD network, we use it to suggest potential drug repositioning for treating lung injury.

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Section: Identification Of Candidate Drugs For Treating Dildmentioning

confidence: 88%

Identification of drug-specific pathways based on gene expression data: application to drug induced lung injury

et al. 2015

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“…[35] For Caspase-9, pAKT, AKT, and β-actin, 5 to 25 μg of protein lysate was fractionated on 10% polyacrylamide gels. For TGFβ analysis, 60 μg of protein lysate was fractioned on a 12.5% gel.…”

Section: Methodsmentioning

confidence: 99%

“…[35] Briefly, Novex® 10% zymogram gels (Life Technologies) were incubated for 24 hours in a gelatinase solution, which allows the determination of total proteolytic MMP activities without interference from associated tissue inhibitors. Relative MMP activity was determined by densitometry using Image J (NIH).…”

Section: Methodsmentioning

confidence: 99%

Therapeutic benefits of young, but not old, adipose-derived mesenchymal stem cells in a chronic mouse model of bleomycin-induced pulmonary fibrosis

Tashiro

Elliot

Gerth

et al. 2015

Translational Research

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The observation that pulmonary inflammatory lesions and bleomycin (BLM)-induced pulmonary fibrosis spontaneously resolve in young mice, while remaining irreversible in aged mice, suggests that impairment of pulmonary regeneration and repair is associated with aging. Since mesenchymal stem cells (MSCs) may promote repair following injury, we postulated that differences in MSCs from aged mice may underlie post-injury fibrosis in aging. The potential for young-donor MSCs to inhibit BLM-induced pulmonary fibrosis in aged male mice (>22 months) has not been studied. Adipose-derived MSCs (ASCs) from young (4-month) and old (22-month) male mice were infused 1-day following intratracheal BLM administration. At 21-day sacrifice, aged BLM mice demonstrated lung fibrosis by Ashcroft score, collagen content, and αv-integrin mRNA expression. Lung tissue from aged BLM mice receiving young ASCs exhibited decreased fibrosis, matrix metalloproteinase (MMP)-2 activity, oxidative stress, and markers of apoptosis vs. BLM controls. Lung mRNA expression of TNFα was also decreased in aged BLM mice receiving young-donor ASCs vs. BLM controls. In contrast, old-donor ASC treatment in aged BLM mice did not reduce fibrosis and related markers. On examination of the cells, young-donor ASCs had decreased mRNA expression of MMP-2, insulin-like growth factor receptor, and AKT activation compared to old-donor ASCs. These results show that the BLM-induced pulmonary fibrosis in aged mice could be blocked by young-donor ASCs and that the mechanisms involve changes in collagen turnover and markers of inflammation.

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“…The higher lung expression of caspase‐3 and BCL‐2 in BD OVx rats compared to other groups points to an important estradiol regulation on cell death after BD. The increase in lung apoptotic markers such as caspase‐3 due to estrogen deficiency has been previously described in aging female mice that was accompanied by increased number of apoptotic cells in the lung .…”

Section: Discussionmentioning

confidence: 69%

The influence of female sex hormones on lung inflammation after brain death ‐ an experimental study

et al. 2019

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Summary Organ donor's age negatively influences graft survival of organs, increasing risk of complications. Aging occurs in both men and women; however, the menopause marks a decrease in sex hormones and a sudden increase in the process of vascular aging. We investigated sex hormones' influence on the lung inflammatory process induced by BD in female rats. Wistar rats were grouped as: female rats from high estradiol to heat period (non‐OVx) and ovariectomized (OVx) female rats. Ovariectomy was carried out 10 days before BD. BD was induced using intracranial balloon rapid inflation. Serum hormones and inflammatory mediators were quantified, leukocytes and platelets counted and lung samples were collected for RT‐PCR, immunohistochemical, and histological analysis. Female sex hormones and corticosterone were reduced 6 h after BD in non‐OVx group. The infiltration of leukocytes in female non‐OVx lungs was higher compared to OVx. G‐CSF, VEGF, and CINC‐1 were found increased in non‐OVx group serum in comparison to OVx. Lung mediators were increased in non‐OVx rats compared to controls. The acute reduction of sex hormones induced by BD appears to have a worse effect on lung inflammation than a reduction that has happened over a prolonged period of time, allowing a physiological adaptation prior to BD.

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17β-Estradiol Replacement Reverses Age-Related Lung Disease in Estrogen-Deficient C57BL/6J Mice

Cited by 30 publications

References 43 publications

Identification of drug-specific pathways based on gene expression data: application to drug induced lung injury

Identification of drug-specific pathways based on gene expression data: application to drug induced lung injury

Therapeutic benefits of young, but not old, adipose-derived mesenchymal stem cells in a chronic mouse model of bleomycin-induced pulmonary fibrosis

The influence of female sex hormones on lung inflammation after brain death ‐ an experimental study

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