Telomere Length and Use of Immunosuppressive Medications in Idiopathic Pulmonary Fibrosis

Newton, Chad A.; Zhang, David; Oldham, Justin M.; Kozlitina, Julia; Fan, Shwu; Martínez, Fernando J.; Raghu, Ganesh; Noth, Imre; Garcia, Christine Kim

doi:10.1164/rccm.201809-1646oc

Cited by 111 publications

(73 citation statements)

References 49 publications

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“…In the PANTHER trial, a regimen involving prednisone, azathioprine and NAC increased the rates of mortality, hospitalization and serious adverse events, while the result of the follow-up study showed that there were no significant differences between NAC and placebo in terms of mortality and acute exacerbation (45). A recent study indicated that an immunosuppressive agent affecting the telomere length in leukocytes resulted in adverse events in the patients with IPF in the PANTHER trial (46). This suggests that the safety of NAC therapy for IPF may be severely limited by the addition of azathioprine.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of N‑acetylcysteine therapy for idiopathic pulmonary fibrosis: An updated systematic review and meta‑analysis

et al. 2019

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Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal lung disease with poor prognosis and limited treatment options. N -acetylcysteine (NAC), an anti-oxidant drug, has promising potential in the treatment of IPF. In the present systematic review and meta-analysis, the efficacy and safety of NAC for IPF were investigated. The following databases were comprehensively searched for relevant studies published until August 2018: Pubmed, Embase, Cochrane library, Chinese National Knowledge Infrastructure, Wangfang Database, VIP and the Chinese Biology Medical Database. A total of 21 controlled trials assessing the efficacy and safety of NAC therapy for IPF were identified and primary outcomes [forced vital capacity (FVC), adverse side effects] and secondary outcomes [diffusing capacity for carbon monoxide (DLCO) and its percentage predicted value (DLCO%), vital capacity (VC), partial arterial oxygen pressure (PaO 2 ), 6-min walking distance test and mortality] were extracted for the meta-analysis. The risk ratio and mean difference or standardized mean difference with 95% confidence interval were calculated using RevMan 5.3 software. Analysis of the pooled data revealed that, compared with control treatments (routine treatment or drugs other than anti-oxidants), NAC therapy reduced the decline in lung function, as indicated by the FVC and DLCO, and slowed the progression of the disease, as indicated by the PaO 2 , while complications and mortality were similar. These results suggest good efficacy, tolerability and safety of the treatment. Furthermore, subgroup analysis revealed that combined therapy including NAC for IPF might be more effective than NAC monotherapy, while oral administration of NAC was safer than inhalation. In conclusion, the results of the present review and meta-analysis provide important information that may serve as a guide regarding NAC therapy for IPF in clinical practice.

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Section: Discussionmentioning

confidence: 99%

Efficacy and safety of N‑acetylcysteine therapy for idiopathic pulmonary fibrosis: An updated systematic review and meta‑analysis

et al. 2019

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“…The PANTHER trial demonstrated increased risks of death and hospitalization in patients with idiopathic pulmonary fibrosis who were treated with a combination of prednisone, azathioprine and N acetyl cysteine as compared with a placebo [62]. Newton et al described a strong correlation between the presence of reduced telomere length below the 10th percentile and the harmful effect of immunosuppressive medication in patients from the PANTHER clinical trial [63]. The effects of immunosuppressive therapy in other forms of ILDs with a telomerase-related gene mutation are as yet unknown.…”

Section: Discussionmentioning

confidence: 99%

The Role of Telomerase and Telomeres in Interstitial Lung Diseases: From Molecules to Clinical Implications

Petukhov

Wallach-Dayan

2019

IJMS

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Telomeres are distal chromosome regions associated with specific protein complexes that protect the chromosome against degradation and aberrations. Telomere maintenance capacity is an essential indication of healthy cell populations, and telomere damage is observed in processes such as malignant transformation, apoptosis, or cell senescence. At a cellular level, telomere damage may result from genotoxic stress, decreased activity of telomerase enzyme complex, dysfunction of shelterin proteins, or changes in expression of telomere-associated RNA such as TERRA. Clinical evidence suggests that mutation of telomerase genes (Tert/Terc) are associated with increased risk of congenital as well as age-related diseases (e.g., pneumonitis, idiopathic pulmonary fibrosis (IPF), dyskeratosis congenita, emphysema, nonspecific interstitial pneumonia, etc.). Thus, telomere length and maintenance can serve as an important prognostic factor as well as a potential target for new strategies of treatment for interstitial lung diseases (ILDs) and associated pulmonary pathologies.

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“…Pulmonary fibrosis (PF) is a chronic disease characterized by respiratory architecture injury and remodeling as well as heterogeneous fibroblast replacement [ 1 , 2 ]. The prevalence of PF is over 60 per 100 000 persons and has had a dramatic upward trend in recent years [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Ginkgo biloba Extract EGb761 Attenuates Bleomycin-Induced Experimental Pulmonary Fibrosis in Mice by Regulating the Balance of M1/M2 Macrophages and Nuclear Factor Kappa B (NF-κB)-Mediated Cellular Apoptosis

Pan

et al. 2020

Med Sci Monit

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Background The aim of this study was to show whether the standardized Ginkgo biloba extract EGb761, a traditional Chinese medicine, has a therapeutic effect on pulmonary fibrosis (PF). Material/Methods Bleomycin (BLM) was used for establishing the PF mouse model. The mice were treated with a gradient of EGb761 for 28 days to determine an appropriate drug dose. On day 28, the effect of EGb761 on lung injury and inflammation was confirmed by hematoxylin and eosin and Masson staining and evaluated by pulmonary alveolitis and Ashcroft score. The balance of M1/M2 macrophages was evaluated with the respective markers inducible nitric oxide synthase and and interleukin-10 by real-time polymerase chain reaction. Furthermore, the expressions of fibrosis-associated protein α-smooth muscle actin (SMA), related inflammatory protein transforming growth factor (TGF)-β1, the apoptosis-related proteins B-cell lymphoma-associated X protein (Bax), B-cell lymphoma (Bcl)-2, caspase-3, caspase-9, and phosphorylated nuclear factor (NF)-κB (p65) were assessed by western blot. Results On day 28, PF was induced by treating with BLM, whereas EGb761 suppressed the PF of lung tissue. The BLM-induced imbalance of M1/M2 macrophages was reduced by EGb761. Furthermore, the increasing amounts of α-SMA and TGF-β1 induced by BLM were suppressed by EGb761. In addition, the protein or messenger ribonucleic acid expression levels of phosphorylated NF-κB (p65), caspase-3, and caspase-9 were upregulated, whereas Bax and Bcl-2 were downregulated. Treatment with EGb761 restored the levels of these proteins except for caspase-9. Conclusions This study illustrated the protective effect of EGb761 on BLM-induced PF by regulating the balance of M1/M2 macrophages and NF-κB (p65)-mediated apoptosis. The results demonstrated the potential clinical therapeutic effect of EGb761, providing a novel possibility for curing PF.

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Telomere Length and Use of Immunosuppressive Medications in Idiopathic Pulmonary Fibrosis

Cited by 111 publications

References 49 publications

Efficacy and safety of N‑acetylcysteine therapy for idiopathic pulmonary fibrosis: An updated systematic review and meta‑analysis

Efficacy and safety of N‑acetylcysteine therapy for idiopathic pulmonary fibrosis: An updated systematic review and meta‑analysis

The Role of Telomerase and Telomeres in Interstitial Lung Diseases: From Molecules to Clinical Implications

Ginkgo biloba Extract EGb761 Attenuates Bleomycin-Induced Experimental Pulmonary Fibrosis in Mice by Regulating the Balance of M1/M2 Macrophages and Nuclear Factor Kappa B (NF-κB)-Mediated Cellular Apoptosis

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