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      Idiopathic Pulmonary Fibrosis: A Systemic Disease?

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          Abstract

          INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is a specific type of chronic progressive fibrosing interstitial pneumonia associated with a histopathologic pattern of usual interstitial pneumonia. IPF is typically considered to be a lung-limited disorder. Although the primary manifestations of IPF are pulmonary in nature, IPF is increasingly recognized as a systemic disease due to its strong association with comorbidities and complications. GENETICS OF IDIOPATHIC PULMONARY FIBROSIS The genetic etiology of IPF is in favor of considering the disease as a systemic syndrome. Early reports of cases of pulmonary fibrosis occurring in families suggested a genetic predisposition to some forms of the disease.[1] Wang et al.[2] identified chromosome 10q22 as an IPF-related region. Genes residing in this region include surfactant proteins A1, A2, and D. These have been identified as candidate genes. Mutations in TERT or TERC and surfactant protein C have been identified in sporadic IPF individuals.[3 4 5] A significantly higher proportion of patients with IPF display shorter telomeres in peripheral blood and in alveolar epithelial cells, as compared to controls.[3 4] A meta-analysis shows that the MUC5B promoter rs35705950 polymorphism is strongly associated with the risk of IPF,[6] the result has been confirmed by an independent analysis in two cohorts with sporadic IPF.[7] GASTROESOPHAGEAL REFLUX DISEASE There are so many pulmonary or extrapulmonary comorbidities and complications of IPF, which further support that IPF is a systemic disease. Architectural distortion and increased traction on mediastinal structures may lead to weakening of the lower esophageal sphincter and increased gastroesophageal reflux disease (GERD). GERD is associated with several pulmonary disorders, while IPF shows the strongest association. The incidence of GERD in patients with IPF is higher than that in the general population, and it has been reported to be 62.3%.[8] GERD also plays an important role in the development and progression of IPF, including acute exacerbations.[9] Long-term chronic suction of gastric contents, including gastric acid, pepsin, and bile acid, could damage pulmonary alveolar epithelium, resulting in abnormal tissue repair and eventually pulmonary fibrosis. Interestingly, three randomized controlled trials have shown patients with IPF taking a proton pump inhibitor/H2 blocker (PPI/H2B) had a significantly smaller decline in forced vital capacity at 30 weeks and fewer acute exacerbations,[10] suggesting that treating GERD may benefit IPF patients. CORONARY ARTERY DISEASE AND PULMONARY HYPERTENSION Patients with IPF have been reported to be more vulnerable to vascular diseases. It has been reported that increased risks of acute coronary syndrome, angina, and deep-vein thrombosis proceed the diagnosis of IPF.[11] A study[12] with 460 IPF patients and 1925 controls showed that the incidence of newly diagnosed coronary artery disease (CAD) was higher in patients with IPF (6.8%) compared to controls (2.8%), leading to the conclusion that IPF itself is an independent risk factor for CAD after adjusting for age, hypertension, diabetes, and hypercholesterolemia. Multiple studies have reported an increased incidence of venous thromboembolism in patients with IPF compared with the general population.[11] A study of Danish population from 1980 to 2007 revealed that the incidence of IPF was higher among individuals with a history of venous thromboembolism than those without. The incidence of pulmonary hypertension (PH) in IPF patients has been reported to be 23.5% at a tertiary referral center in China.[13] IPF patients with higher systolic pulmonary artery pressure may have poorer right ventricular function. PH may worsen dyspnea, right heart dysfunction, and decrease the life quality of the patients with IPF. DYSPNEA AND DEPRESSION AND LUNG CANCER Dyspnea and depression influence one another: dyspnea is a primary cause of depressive symptoms, and conversely, depression exacerbates the perception of respiratory symptoms. Patients with IPF often report extremely poor sleep quality and with sleep-related breathing disorders (SRBDs). In 2001, Clark et al.[14] studied 48 patients with IPF through overnight oximetry and noted that nocturnal hypoxia was common and affected the quality of life. Some studies[15] suggested that patients with IPF presented poorer sleep quality and daytime sleepiness and higher apnea-hypopnea index. Patients with IPF present alterations in sleep architecture, including decreased sleep efficiency, slow wave sleep and rapid eye movement (REM) sleep, and increased sleep fragmentation. Moreover, sleep-related hypoventilation during the vulnerable REM sleep period and obstructive sleep apnea-hypopnea syndrome are frequent, but remain usually underdiagnosed. These SRBDs in IPF are associated with alterations of the sleep structure, reduction of quality of life, and increased risk of mortality. Besides, lung cancer was also identified as one of the comorbidities of IPF and the two diseases share several risk factors and pathogenic pathways and also show a similar anatomic distribution. From what has been discussed above, we come up with the standpoint that IPF is a kind of systemic disease. Financial support and sponsorship The study was supported by grants from the National Natural Science Foundation of China (No. 30800503, No. 81170036, and No. 81370164), the Natural Science Foundation of Hunan Province (No. 2015JJ4087), and the National Key Clinical Specialty Construction Projects. Conflicts of interest There are no conflicts of interest.

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          Most cited references 15

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          Short telomeres are a risk factor for idiopathic pulmonary fibrosis.

          Idiopathic interstitial pneumonias (IIPs) have a progressive and often fatal course, and their enigmatic etiology has complicated approaches to effective therapies. Idiopathic pulmonary fibrosis (IPF) is the most common of IIPs and shares with IIPs an increased incidence with age and unexplained scarring in the lung. Short telomeres limit tissue renewal capacity in the lung and germ-line mutations in telomerase components, hTERT and hTR, underlie inheritance in a subset of families with IPF. To examine the hypothesis that short telomeres contribute to disease risk in sporadic IIPs, we recruited patients who have no family history and examined telomere length in leukocytes and in alveolar cells. To screen for mutations, we sequenced hTERT and hTR. We also reviewed the cases for features of a telomere syndrome. IIP patients had shorter leukocyte telomeres than age-matched controls (P < 0.0001). In a subset (10%), IIP patients had telomere lengths below the first percentile for their age. Similar to familial cases with mutations, IPF patients had short telomeres in alveolar epithelial cells (P < 0.0001). Although telomerase mutations were rare, detected in 1 of 100 patients, we identified a cluster of individuals (3%) with IPF and cryptogenic liver cirrhosis, another feature of a telomere syndrome. Short telomeres are thus a signature in IIPs and likely play a role in their age-related onset. The clustering of cryptogenic liver cirrhosis with IPF suggests that the telomere shortening we identify has consequences and can contribute to what appears clinically as idiopathic progressive organ failure in the lung and the liver.
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            Telomere shortening in familial and sporadic pulmonary fibrosis.

            Heterozygous mutations in the coding regions of the telomerase genes, TERT and TERC, have been found in familial and sporadic cases of idiopathic interstitial pneumonia. All affected patients with mutations have short telomeres. To test whether telomere shortening is a frequent mechanism underlying pulmonary fibrosis, we have characterized telomere lengths in subjects with familial or sporadic disease who do not have coding mutations in TERT or TERC. Using a modified Southern blot assay, the telomerase restriction fragment length method, and a quantitative polymerase chain reaction assay we have measured telomere lengths of genomic DNA isolated from circulating leukocytes from normal control subjects and subjects with pulmonary fibrosis. All affected patients with telomerase mutations, including case subjects heterozygous for newly reported mutations in TERT, have short telomere lengths. A significantly higher proportion of probands with familial pulmonary fibrosis (24%) and sporadic case subjects (23%) in which no coding mutation in TERT or TERC was found had telomere lengths less than the 10th percentile when compared with control subjects (P = 2.6 x 10(-8)). Pulmonary fibrosis affectation status was significantly associated with telomerase restriction fragment lengths, even after controlling for age, sex, and ethnicity (P = 6.1 x 10(-11)). Overall, 25% of sporadic cases and 37% of familial cases of pulmonary fibrosis had telomere lengths less than the 10th percentile. A significant fraction of individuals with pulmonary fibrosis have short telomere lengths that cannot be explained by coding mutations in telomerase. Telomere shortening of circulating leukocytes may be a marker for an increased predisposition toward the development of this age-associated disease.
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              Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials.

              Abnormal acid gastro-oesophageal reflux is common in patients with idiopathic pulmonary fibrosis (IPF) and is considered a risk factor for development of IPF. Retrospective studies have shown improved outcomes in patients given anti-acid treatment. The aim of this study was to investigate the association between anti-acid treatment and disease progression in IPF. In an analysis of data from three randomised controlled trials, we identified patients with IPF assigned to receive placebo. Case report forms had been designed to prospectively obtain data about diagnosis and treatment of abnormal acid gastro-oesophageal reflux in each trial. The primary outcome was estimated change in forced vital capacity (FVC) at 30 weeks (mean follow-up) in patients who were and were not using a proton-pump inhibitor or histamine-receptor-2 (H2) blocker. Of the 242 patients randomly assigned to the placebo groups of the three trials, 124 (51%) were taking a proton-pump inhibitor or H2 blocker at enrolment. After adjustment for sex, baseline FVC as a percentage of predicted, and baseline diffusing capacity of the lung for carbon monoxide as a percentage of predicted, patients taking anti-acid treatment at baseline had a smaller decrease in FVC at 30 weeks (-0·06 L, 95% CI -0·11 to -0·01) than did those not taking anti-acid treatment (-0·12 L, -0·17 to -0·08; difference 0·07 L, 95% CI 0-0·14; p=0·05). Anti-acid treatment could be beneficial in patients with IPF, and abnormal acid gastro-oesophageal reflux seems to contribute to disease progression. Controlled clinical trials of anti-acid treatments are now needed. National Institutes of Health. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Chin Med J (Engl)
                Chin. Med. J
                CMJ
                Chinese Medical Journal
                Medknow Publications & Media Pvt Ltd (India )
                0366-6999
                05 September 2017
                : 130
                : 17
                : 2140-2141
                Affiliations
                [1 ]Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
                [2 ]Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, China
                [3 ]Diagnosis and Treatment Central of Respiratory Disease, Central South University, Changsha, Hunan 410011, China
                Author notes
                Address for correspondence: Prof. Peng Hong, Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China E-Mail: phdiana@ 123456126.com
                Article
                CMJ-130-2140
                10.4103/0366-6999.213423
                5586194
                28836568
                Copyright: © 2017 Chinese Medical Journal

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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