Gastro-oesophageal reflux and idiopathic pulmonary fibrosis: the heart burn in patients with IPF can no longer be silent

Kreuter, Michael; Raghu, Ganesh

doi:10.1183/13993003.00921-2018

Cited by 18 publications

(14 citation statements)

References 15 publications

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“…The role of gastroesophageal reflux in the pathogenesis and progression of IPF remains controversial. 90,91 Similarly, conflicting results are observed in SSc where esophageal involvement affects up to 90% of those with both lcSSc and dcSSc. [92][93][94][95][96] In a recently published study of 145 patients with SSc, esophageal dilatation and hiatus hernia were associated with greater degrees of fibrosis on CT and lower baseline FVC, but not disease progression, after correction for these baseline measures.…”

Section: The Role Of Reflux In Ssc-ildmentioning

confidence: 99%

Systemic Sclerosis Associated Interstitial Lung Disease: A Comprehensive Overview

Mackintosh

Stainer

Barnett

et al. 2019

Semin Respir Crit Care Med

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Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). SSc-ILD adversely impacts quality of life and is currently the leading cause of death in this multisystem disease. Identifying clinically significant SSc-ILD is critically important. Accurate staging and prognostication remain difficult; however, significant advances have been made in the last decade. Evidence supports the need to treat patients with extensive and/or progressive SSc-ILD, while only a subset of patients with limited ILD may require treatment. Research is urgently required to allow improved prediction of patients at risk of ILD progression at an early point in the disease, and ideally prior to its onset, to allow prevention. The last decade has seen the publication of landmark clinical trials for SSc-ILD. More effective strategies with less toxicity are under investigation. For those with refractory or very advanced disease, studies into disease-specific palliative approaches are in their infancy. Lung transplantation as an option for SSc-ILD remains patient- and center-specific, with data to suggest equivalent outcomes to other fibrotic lung diseases, in carefully selected cases. This review aims to provide a comprehensive overview of all key aspects of SSc-ILD.

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Section: The Role Of Reflux In Ssc-ildmentioning

confidence: 99%

Systemic Sclerosis Associated Interstitial Lung Disease: A Comprehensive Overview

Mackintosh

Stainer

Barnett

et al. 2019

Semin Respir Crit Care Med

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“…Next to antimicrobial properties, AZT is known to reduce gastrointestinal reflux and aspiration [42]. Reflux is thought to contribute to IPF pathogenesis [43]. The acidic material of the reflux increases epithelial permeability and as a consequence promotes fibrogenesis [43].…”

Section: Discussionmentioning

confidence: 99%

“…Reflux is thought to contribute to IPF pathogenesis [43]. The acidic material of the reflux increases epithelial permeability and as a consequence promotes fibrogenesis [43]. Moreover, direct anti-fibrotic effects of AZT have been previously described in the bleomycin mouse model of lung fibrosis.…”

Section: Discussionmentioning

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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“…Presently, rational treatment options may include the following local or global guidelines or personal expertise, with individualization and full consideration of the patients’ willingness and the available treatment options in the respective country. As the current data are insufficient for drawing precise algorithms or flow charts for the diagnosis and management of GERD in patients with IPF, resolution of this problem requires data from further experimental and clinical trials [76]. For instance, the long-term effects and safety of antacids on patients with IPF are to be elucidated in prospective blinded randomized trials.…”

Section: Open Questionsmentioning

confidence: 99%

“…Owing to the need for critical evaluation of the current low-quality evidence from only exploratory, retrospective, and post hoc analysis, an appeal for prospective, randomized trials to determine the safety and efficacy of antacid drugs as a potential treatment of IPF was published [76]. …”

Section: Treatment Of Gerd In Ipfmentioning

confidence: 99%

Gastroesophageal Reflux Disease in Idiopathic Pulmonary Fibrosis: Uncertainties and Controversies

Wang

Bonella

et al. 2018

Respiration

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The mechanisms of idiopathic pulmonary fibrosis (IPF), a rare, devastating disease with a median survival of 3–5 years, are not fully understood. Gastroesophageal reflux disease (GERD) is a frequent comorbidity encountered in IPF. Hypothetically, GERD-associated microaspiration may lead to persistent inflammation impairing lung infrastructure, thereby possibly accelerating the progression of IPF. IPF may increase intrathoracic pressure, which can aggravate GERD and vice versa. On the basis of the possible beneficial effects of antireflux or antacid therapy on lung function, acute exacerbation, and survival, the recent international IPF guideline recommends antacid therapies for patients with IPF, regardless of symptomatic GERD. However, due to newer conflicting data, several national guidelines do not support this recommendation. Elucidation of these questions by further clinical and bench-to-bedside research may provide us with rational clinical diagnostic and therapeutic approaches concerning GERD in IPF. The present review aims to discuss the latest data on the controversial association of IPF and GERD.

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Gastro-oesophageal reflux and idiopathic pulmonary fibrosis: the heart burn in patients with IPF can no longer be silent

Cited by 18 publications

References 15 publications

Systemic Sclerosis Associated Interstitial Lung Disease: A Comprehensive Overview

Systemic Sclerosis Associated Interstitial Lung Disease: A Comprehensive Overview

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

Gastroesophageal Reflux Disease in Idiopathic Pulmonary Fibrosis: Uncertainties and Controversies

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