Azithromycin for idiopathic acute exacerbation of idiopathic pulmonary fibrosis: a retrospective single-center study

Kawamura, Kodai; Ichikado, Kazuya; Yasuda, Yuko; Anan, Keisuke; Suga, Moritaka

doi:10.1186/s12890-017-0437-z

Cited by 63 publications

(52 citation statements)

References 24 publications

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“…An international working group in 2016 proposed to classify this complication into triggered (identified event: post-procedure, drug toxicity, infection, aspiration) or idiopathic (unidentified inciting event) acute exacerbation 36 . Recent data associating acute exacerbation with the lung microbiome and with the host immunosuppressive states, and retrospective studies showing the preventive effect of antibiotic therapy suggest the role of infection in the pathogenesis of acute exacerbation and progression of pulmonary fibrosis 7,[42][43][44][45] . Further, a double-blind, randomized, placebo-controlled study showing improvement of symptoms and exercise capacity in progressive IPF patients treated with co-trimoxazole, and a subsequent double-blind follow-up and multicenter study showing significant reduction of mortality with better quality of life and less respiratory tract infections in IPF patients treated with co-trimoxazole also support the pathogenic role of bacteria in lung fibrosis 46,47 .…”

Section: Discussionmentioning

confidence: 99%

A Staphylococcus pro-apoptotic peptide induces acute exacerbation of pulmonary fibrosis

et al. 2020

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Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown etiology; however, apoptosis of lung alveolar epithelial cells plays a role in disease progression. This intractable disease is associated with increased abundance of Staphylococcus and Streptococcus in the lungs, yet their roles in disease pathogenesis remain elusive. Here, we report that Staphylococcus nepalensis releases corisin, a peptide conserved in diverse staphylococci, to induce apoptosis of lung epithelial cells. The disease in mice exhibits acute exacerbation after intrapulmonary instillation of corisin or after lung infection with corisin-harboring S. nepalensis compared to untreated mice or mice infected with bacteria lacking corisin. Correspondingly, the lung corisin levels are significantly increased in human IPF patients with acute exacerbation compared to patients without disease exacerbation. Our results suggest that bacteria shedding corisin are involved in acute exacerbation of IPF, yielding insights to the molecular basis for the elevation of staphylococci in pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

A Staphylococcus pro-apoptotic peptide induces acute exacerbation of pulmonary fibrosis

et al. 2020

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“…Inflammation also contributes to acute exacerbations in IPF [21]. In recent retrospective clinical observations, AZT reduced mortality in acute exacerbations and hospitalization rates of IPF patients [22,23]. In addition to antimicrobial effects, AZT might act on inflammation and thus reduce severity of acute exacerbation.…”

Section: Introductionmentioning

confidence: 99%

Azithromycin has enhanced effects on lung fibroblasts from idiopathic pulmonary fibrosis (IPF) patients compared to controls

et al. 2020

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Background: Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease without a cure and new drug strategies are urgently needed. Differences in behavior between diseased and healthy cells are well known and drug response can be different between cells isolated from IPF patients and controls. The macrolide Azithromycin (AZT) has anti-inflammatory and immunomodulatory properties. Recently anti-fibrotic effects have been described. However, the anti-fibrotic effects on primary IPF-fibroblasts (FB) directly compared to control-FB are unknown. We hypothesized that IPF-FB react differently to AZT in terms of anti-fibrotic effects. Methods: Primary normal human lung and IPF-FB were exposed to TGF-β (5 ng/ml), Azithromycin (50 μM) alone or in combination prior to gene expression analysis. Pro-collagen Iα1 secretion was assessed by ELISA and protein expression by western blot (αSMA, Fibronectin, ATP6V1B2, LC3 AB (II/I), p62, Bcl-xL). Microarray analysis was performed to screen involved genes and pathways after Azithromycin treatment in control-FB. Apoptosis and intraluminal lysosomal pH were analyzed by flow cytometry. Results: AZT significantly reduced collagen secretion in TGF-β treated IPF-FB compared to TGF-β treatment alone, but not in control-FB. Pro-fibrotic gene expression was similarly reduced after AZT treatment in IPF and control-FB. P62 and LC3II/I western blot revealed impaired autophagic flux after AZT in both control and IPF-FB with significant increase of LC3II/I after AZT in control and IPF-FB, indicating enhanced autophagy inhibition. Early apoptosis was significantly higher in TGF-β treated IPF-FB compared to controls after AZT. Microarray analysis of control-FB treated with AZT revealed impaired lysosomal pathways. The ATPase and lysosomal pH regulator ATP6V0D2 was significantly less increased after additional AZT in IPF-FB compared to controls. Lysosomal function was impaired in both IPF and control FB, but pH was significantly more increased in TGF-β treated IPF-FB. Conclusion: We report different treatment responses after AZT with enhanced anti-fibrotic and pro-apoptotic effects in IPF compared to control-FB. Possibly impaired lysosomal function contributes towards these effects. In summary, different baseline cell phenotype and behavior of IPF and control cells contribute to enhanced anti-fibrotic and proapoptotic effects in IPF-FB after AZT treatment and strengthen its role as a new potential anti-fibrotic compound, that should further be evaluated in clinical studies.

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“…Moreover, it has been observed that augmented concentrations of certain strains of Streptococcus, in BAL samples from IPF patients, associate with increased NOD receptor signaling and poor outcomes [69]. The potential contribution of bacteria in IPF pathogenesis is also an attractive area of investigation for novel treatment approaches [70]. It should be mentioned that, in our analysis, "NOD-like receptor signaling pathway" is linked with "MAPK signaling pathway", a central molecular pathway of IPF.…”

Section: Discussionmentioning

confidence: 77%

PathWalks: Identifying pathway communities using a disease-related map of integrated information

Karatzas¹,

Zachariou

Bourdakou

et al. 2020

Preprint

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AbstractUnderstanding disease underlying biological mechanisms and respective interactions remains an elusive, time consuming and costly task. The realization of computational methodologies that can propose pathway/mechanism communities and reveal respective relationships can be of great value as it can help expedite the process of identifying how perturbations in a single pathway can affect other pathways.Random walks is a stochastic approach that can be used for both efficient discovery of strong connections and identification of communities formed in networks. The approach has grown in popularity as it efficiently exposes key network components and reveals strong interactions among genes, proteins, metabolites, pathways and drugs. Using random walks in biology, we need to overcome two key challenges: 1) construct disease-specific biological networks by integrating information from available data sources as they become available, and 2) provide guidance to the walker so as it can follow plausible trajectories that comply with inherent biological constraints.In this work, we present a methodology called PathWalks, where a random walker crosses a pathway-to-pathway network under the guidance of a disease-related map. The latter is a gene network that we construct by integrating multi-source information regarding a specific disease. The most frequent trajectories highlight communities of pathways that are expected to be strongly related to the disease under study. We present maps for Alzheimer’s Disease and Idiopathic Pulmonary Fibrosis and we use them as case-studies for identifying pathway communities through the application of PathWalks.In the case of Alzheimer’s Disease, the most visited pathways are the “Alzheimer’s disease” and the “Calcium signaling” pathways which have indeed the strongest association with Alzheimer’s Disease. Interestingly however, in the top-20 visited pathways we identify the “Kaposi sarcoma-associated herpesvirus infection” (HHV-8) and the “Human papillomavirus infection” (HPV) pathways suggesting that viruses may be involved in the development and progression of Alzheimer’s. Similarly, most of the highlighted pathways in Idiopathic Pulmonary Fibrosis are backed by the bibliography. We establish that “MAPK signaling” and “Cytokine-cytokine receptor interaction” pathways are the most visited. However, the “NOD receptor signaling” pathway is also in the top-40 edges. In Idiopathic Pulmonary Fibrosis samples, increased NOD receptor signaling has been associated with augmented concentrations of certain strains of Streptococcus. Additional experimental evidence is required however to further explore and ascertain the above indications.

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Azithromycin for idiopathic acute exacerbation of idiopathic pulmonary fibrosis: a retrospective single-center study

Cited by 63 publications

References 24 publications

A Staphylococcus pro-apoptotic peptide induces acute exacerbation of pulmonary fibrosis

A Staphylococcus pro-apoptotic peptide induces acute exacerbation of pulmonary fibrosis

Azithromycin has enhanced effects on lung fibroblasts from idiopathic pulmonary fibrosis (IPF) patients compared to controls

PathWalks: Identifying pathway communities using a disease-related map of integrated information

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