Am Surg. 2021 Feb 25:3134821998686. doi: 10.1177/0003134821998686. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) and gastroesophageal reflux disease (GERD) are undoubtedly related. Even though it is not clear yet which one is the primary disease, they certainly interact increasing each other's severity. Symptoms are unreliable to diagnose GERD in patients with IPF, and objective evaluation with pH monitoring and/or bronchoalveolar lavage analysis is mandatory. Pharmacological treatment with proton pump inhibitors (PPIs) may bring control of IPF in few patients, but PPIs do not control reflux but just change the pH of the gastric refluxate. Surgical therapy based on a fundoplication is safe and effective as it controls any type of reflux, independently from the pH of the gastric refluxate. In patients waiting for lung transplantation (if they can tolerate a laparoscopic operation under general anesthesia), a fundoplication before the operation might block the progression of IPF, while after transplantation it might prevent rejection by preventing the bronchiolitis obliterans syndrome.

PMID:33629881 | DOI:10.1177/0003134821998686

Eur Rev Med Pharmacol Sci. 2021 Feb;25(3):1399-1409. doi: 10.26355/eurrev_202102_24848.

ABSTRACT

Long noncoding RNAs (lncRNAs) are important participants in biological processes including cell proliferation, differentiation and death, as well as pathogenesis of various diseases. LncRNA differentiation antagonizing non-protein coding RNA (DANCR) is an emerging regulator in cell metabolism and many diseases besides cancers. DANCR is negative in epidermal, osteoblastic and endoderm differentiation, but positive in chondrogenic differentiation of progenitor cells. It is protective for calcification of the ligamentum flavum, stroke, acute myocardial infarction and arterial calcification, but a risk factor for bone loss, fracture healing and idiopathic pulmonary fibrosis. In addition, DANCR is a potential target for improving tissue regeneration. Mechanically, DANCR, a cytoplasmic lncRNA, sponges corresponding microRNAs or interacts with various proteins. This review aims to summarize the role of DANCR in progenitor cells and provide perspectives for further studies.

PMID:33629310 | DOI:10.26355/eurrev_202102_24848

Respir Res. 2021 Feb 24;22(1):66. doi: 10.1186/s12931-021-01643-w.

ABSTRACT

BACKGROUND: FIBRONET was an observational, multicentre, prospective cohort study investigating the baseline characteristics, clinical course of disease and use of antifibrotic treatment in Italian patients with idiopathic pulmonary fibrosis (IPF).

METHODS: Patients aged ≥ 40 years diagnosed with IPF within the previous 3 months at 20 Italian centres were consecutively enrolled and followed up for 12 months, with evaluations at 3, 6, 9 and 12 months. The primary objective was to describe the clinical course of IPF over 12 months of follow-up, including changes in lung function measured by % predicted forced vital capacity (FVC% predicted).

RESULTS: 209 patients (82.3% male, mean age 69.54 ± 7.43 years) were enrolled. Mean FVC% predicted was relatively preserved at baseline (80.01%). The mean time between IPF diagnosis and initiation of antifibrotic therapy was 6.38 weeks; 72.3% of patients received antifibrotic therapy within the first 3 months of follow-up, and 83.9% within 12 months of follow-up. Mean FVC% predicted was 80.0% at baseline and 82.2% at 12 months, and 47.4% of patients remained stable (i.e. had no disease progression) in terms of FVC% predicted during the study.

CONCLUSIONS: FIBRONET is the first prospective, real-life, observational study of patients with IPF in Italy. The short time between diagnosis and initiation of antifibrotic therapy, and the stable lung function between baseline and 12 months, suggest that early diagnosis and prompt initiation of antifibrotic therapy may preserve lung function in patients with IPF.

TRIAL REGISTRATION: NCT02803580.

PMID:33627105 | DOI:10.1186/s12931-021-01643-w

Stem Cells Transl Med. 2021 Feb 24. doi: 10.1002/sctm.20-0526. Online ahead of print.

ABSTRACT

Developing, regenerating, and repairing a lung all require interstitial resident fibroblasts (iReFs) to direct the behavior of the epithelial stem cell niche. During lung development, distal lung fibroblasts, in the form of matrix-, myo-, and lipofibroblasts, form the extra cellular matrix (ECM), create tensile strength, and support distal epithelial differentiation, respectively. During de novo septation in a murine pneumonectomy lung regeneration model, developmental processes are reactivated within the iReFs, indicating progenitor function well into adulthood. In contrast to the regenerative activation of fibroblasts upon acute injury, chronic injury results in fibrotic activation. In murine lung fibrosis models, fibroblasts can pathologically differentiate into lineages beyond their normal commitment during homeostasis. In lung injury, recently defined alveolar niche cells support the expansion of alveolar epithelial progenitors to regenerate the epithelium. In human fibrotic lung diseases like bronchopulmonary dysplasia (BPD), idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD), dynamic changes in matrix-, myo-, lipofibroblasts, and alveolar niche cells suggest differential requirements for injury pathogenesis and repair. In this review, we summarize the role of alveolar fibroblasts and their activation stage in alveolar septation and regeneration and incorporate them into the context of human lung disease, discussing fibroblast activation stages and how they contribute to BPD, IPF, and COPD.

PMID:33624948 | DOI:10.1002/sctm.20-0526

Magn Reson Med. 2021 Feb 23. doi: 10.1002/mrm.28703. Online ahead of print.

ABSTRACT

PURPOSE: This work assesses the accuracy of the stretched exponential (SEM) and cylinder models of lung microstructural length scales that can be derived from hyperpolarized gas DWI. This was achieved by simulating 3 He and 129 Xe DWI signals within two micro-CT-derived realistic acinar airspace meshes that represent healthy and idiopathic pulmonary fibrosis lungs.

METHODS: The healthy and idiopathic pulmonary fibrosis acinar airway meshes were derived from segmentations of 3D micro-CT images of excised human lungs and meshed for finite element simulations of the Bloch-Torrey equations. 3 He and 129 Xe multiple b value DWI experiments across a range of diffusion times (3 He Δ = 1.6 ms; 129 Xe Δ = 5 to 20 ms) were simulated in each mesh. Global SEM mean diffusive length scale and cylinder model mean chord length value was derived from each finite element simulation and compared against each mesh's mean linear intercept length, calculated from intercept length measurements within micro-CT segmentation masks.

RESULTS: The SEM-derived mean diffusive length scale was within ±10% of the mean linear intercept length for simulations with both 3 He (Δ = 1.6 ms) and 129 Xe (Δ = 7 to 13 ms) in the healthy mesh, and with 129 Xe (Δ = 13 to 20 ms) for the idiopathic pulmonary fibrosis mesh, whereas for the cylinder model-derived mean chord length the closest agreement with mean linear intercept length (11.7% and 22.6% difference) was at 129 Xe Δ = 20 ms for both healthy and IPF meshes, respectively.

CONCLUSION: This work validates the use of the SEM for accurate estimation of acinar dimensions and indicates that the SEM is relatively robust across a range of experimental conditions and acinar length scales.

PMID:33624325 | DOI:10.1002/mrm.28703

Thorax. 2021 Feb 23:thoraxjnl-2021-216863. doi: 10.1136/thoraxjnl-2021-216863. Online ahead of print.

NO ABSTRACT

PMID:33622980 | DOI:10.1136/thoraxjnl-2021-216863

Expectations about treatment of idiopathic pulmonary fibrosis: Comparative survey of patients, carers and physicians (the RESPIR French survey).

Respir Med Res. 2021 Jan 05;79:100811

Authors: Cottin V, Bergot E, Bourdin A, Nunes H, Prévot G, Wallaert B, Marchand-Adam S

Abstract
CONTEXT: Idiopathic pulmonary fibrosis (IPF) is a severe chronic disease during which anxiety and depression are frequent comorbidities. Better knowledge of patients' expectations is needed to inform an action plan to improve medical care.
AIM: To describe feelings and expectations of patients suffering from IPF and of their carers about antifibrotic therapy and compare them to what is perceived by their pulmonologist.
METHODS: National prospective study on practices and perceptions. Specific questionnaires were e-mailed to all 3276 pulmonologists in France who, in turn, invited patients and carers to participate in a survey.
RESULTS: 147 pulmonologists, 161 patients and 144 carers participated in the survey. The role of the carer was evaluated as "important" or "very important" by more than 90% of participants, i.e. pulmonologists, patients or carers. Inconsistencies between how patients felt and how pulmonologists perceived them were identified: 88% of patients responded that they understood quite well what IPF is (vs. 75% of patients according to pulmonologists); 85.5% of patients said they were determined to fight the disease (vs. 68.0%); 61.7% of patients wanted to be kept informed of potential complications before they occurred (vs. 69.6%) and 81.2% wanted to be involved in therapeutic decisions (vs. 43.1%). Globally, patients had a more positive view of antifibrotic therapies than expected by pulmonologists: 41.5% evaluated their advantages superior to what they had expected (vs. 29.1% of patients according to pulmonologists) and 76.5% had a positive image of the benefits/disadvantages ratio (vs. 62.4%). Although pulmonologists had the impression that they were keeping their patients well-informed about exacerbations, hospital stays and the possible negative evolution of the disease despite antifibrotic therapies, 34.0%, 42.0% and 22.0% of patients respectively declared not being aware of these aspects.
CONCLUSION: The feelings of patients suffering from IPF regarding their disease and treatment globally proved more positive compared with how pulmonologists perceived them. Taking into account the expectations and needs of patients may allow healthcare professionals to better address their needs and priorities.

PMID: 33618076 [PubMed - as supplied by publisher]

Gene therapy strategies for idiopathic pulmonary fibrosis: recent advances, current challenges, and future directions.

Mol Ther Methods Clin Dev. 2021 Mar 12;20:483-496

Authors: Ruigrok MJR, Frijlink HW, Melgert BN, Olinga P, Hinrichs WLJ

Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic disease in which the lungs become irreversibly scarred, leading to declining lung function. As currently available drugs do not cure IPF, there remains a great medical need for more effective treatments. Perhaps this need could be addressed by gene therapies, which offer powerful and versatile ways to attenuate a wide range of processes involved in fibrosis. Despite the potential benefits of gene therapy, no one has reviewed the current state of knowledge regarding its application for treating IPF. We therefore analyzed publications that reported the use of gene therapies to treat pulmonary fibrosis in animals, as clinical studies have not been published yet. In this review, we first provide an introduction on the pathophysiology of IPF and the most well-established gene therapy approaches. We then present a comprehensive evaluation of published animal studies, after which we provide recommendations for future research to address challenges with respect to the selection and use of animal models as well as the development of delivery vectors and dosage forms. Addressing these considerations will bring gene therapies one step closer to clinical testing and thus closer to patients.

PMID: 33614824 [PubMed]

Cryptogenic organising pneumonia: an unusual cause of pleuritic chest pain.

BMJ Case Rep. 2021 Jan 18;14(1):

Authors: Ceci Bonello R, Ceci Bonello E, Vassallo C, Bellia EG

Abstract
A 76-year-old woman presented with a 2-hour history of pleuritic chest pain with no other associated symptoms. Blood investigations revealed raised inflammatory markers and an elevated white cell count. On chest radiograph, an airspace shadow indicative of a consolidation was prominent. This was followed by a CT scan of her thorax which showed a spiculated lesion in the right upper lobe, a lesion in the posterior segment of the left lower lobe and mildly enlarged right hilar lymph nodes. She was started on dual antibiotic therapy; however, the patient's clinical status and inflammatory markers did not improve. A bronchoscopy was performed which excluded malignancy and atypical pathogens. CT-guided biopsy confirmed the presence of cryptogenic organising pneumonia. Prednisolone 50 mg daily was prescribed with quick resolution of symptoms.

PMID: 33462025 [PubMed - indexed for MEDLINE]

Disease-modifying antirheumatic drugs and organising pneumonia.

BMJ Case Rep. 2021 Jan 06;14(1):

Authors: Faisal M, Roslan A, Nik Abeed NN, Ban Yu-Lin A

Abstract
Organising pneumonia (OP) in rheumatoid arthritis (RA) may be part of pulmonary manifestation (disease related) or disease-modifying antirheumatic drugs (DMARDs) related. We report a case series of RA patients with DMARDs related OP. A 65-year-old woman developed OP 3 weeks after initiation of methotrexate (MTX). High-resolution CT (HRCT) scan of the thorax revealed bilateral consolidations in the lung bases. She had complete radiological resolution 6 months after corticosteroid therapy with cessation of MTX. The second case was of a 60-year-old woman on MTX with recent addition of leflunomide due to flare of RA. She developed worsening cough 4 months later and HRCT scan revealed consolidation in the left upper lobe with biopsy proven OP. She responded within 6 months of corticosteroid therapy with clinical and radiological resolution. This case series highlights that OP may developed with low-dose MTX (as early as 3 weeks) and leflunomide and the diagnosis requires a high index of suspicion.

PMID: 33408105 [PubMed - indexed for MEDLINE]

Br J Clin Pharmacol. 2021 Feb 23. doi: 10.1111/bcp.14793. Online ahead of print.

ABSTRACT

The intracellular tyrosine kinase inhibitor nintedanib has shown great efficacy for the treatment of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases. However, the incidence rate of myocardial infarction (MI) among participants in landmark IPF trials was remarkable, peaking at 3/100 patients-year. Although subjects with IPF often have a high cardiovascular (CV) risk profile, the occurrence of MI in nintedanib-treated patients may not be fully explained by clustering of CV risk factors. Nintedanib inhibits the vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor pathways, which play important roles in the biology of the atherosclerotic plaque and in the response of the heart to ischemia. Hence, unwanted CV effects may partly account for nintedanib-related MI. We review the evidence supporting this hypothesis and discuss possible actions for a safe implementation of nintedanib in clinical practice, building on the experience with tyrosine kinase inhibitors acquired in cardio-oncology.

PMID:33620103 | DOI:10.1111/bcp.14793

Respir Investig. 2021 Feb 19:S2212-5345(21)00022-8. doi: 10.1016/j.resinv.2021.01.002. Online ahead of print.

ABSTRACT

BACKGROUND: Pirfenidone is an anti-fibrotic agent approved for idiopathic pulmonary fibrosis (IPF), and long-term treatment data and the effect of continuation after disease progression have been reported. The efficacy and safety of pirfenidone in fibrosing interstitial lung disease (ILD) patients without IPF have been recently reported in clinical trials; therefore, the benefits of long-term treatment are also expected. This study aims to analyze the long-term treatment data of pirfenidone and clarify the predictive factors for long-term use of pirfenidone in non-IPF patients.

METHODS: We retrospectively reviewed the records of consecutive fibrosing ILD patients who started using pirfenidone between 2008 and 2014.

RESULTS: Of the 266 fibrosing ILD patients, 167 patients had IPF, and 99 had non-IPF. Despite the non-significant differences in body size and pulmonary function between IPF and non-IPF patients, the non-IPF patients had better overall survival than the IPF patients (median 4.06 years vs. 2.09 years, p < 0.0001). In addition, the non-IPF patients had a significantly longer time to treatment discontinuation than the IPF patients (median 2.20 years vs. 1.20 years, p = 0.002). Multivariate logistic regression analysis for ≥2 years of use of pirfenidone showed that the percent predicted forced vital capacity (%FVC) and age were predictive factors common to both IPF and non-IPF patients.

CONCLUSIONS: Our results indicate that non-IPF patients can continue using pirfenidone for longer durations than IPF patients. Initiation of pirfenidone for fibrosing ILD patients with higher %FVC and younger age would lead to long-term use of pirfenidone.

PMID:33618993 | DOI:10.1016/j.resinv.2021.01.002

BMC Pulm Med. 2021 Feb 22;21(1):63. doi: 10.1186/s12890-021-01428-3.

ABSTRACT

BACKGROUND: The precise classification of idiopathic interstitial pneumonia (IIP) is essential for selecting treatment as well as estimating clinical outcomes; however, this is sometimes difficult in clinical practice. Therefore, cluster analysis was used to identify the clinical phenotypes of IIPs, and its usefulness for predicting clinical outcomes was evaluated.

METHODS: Cluster analysis was performed using clinical features including patients' demographics; histories; pulmonary function test data; and laboratory, physical and radiological findings.

RESULTS: In 337 patients with IIPs, four clusters were identified: Cluster I, in which > 80% of the patients had autoimmune features; Cluster II, which had the lowest rate of smoking, the lowest percent predicted forced vital capacity (%FVC) and the lowest body mass index (BMI); Cluster III, which had the highest rate of smoking, the highest rate of dust exposure, the second lowest %FVC and normal BMI; and Cluster IV, which exhibited maintenance of %FVC and normal BMI. Cluster IV had significantly longer overall survival than Clusters II and III. Clusters I and III had significantly longer overall survival than Cluster II. Clusters II and III had a significantly higher cumulative incidence of acute exacerbation than Cluster IV.

CONCLUSION: Cluster analysis using clinical features identified four clinical phenotypes of IIPs, which may be useful for predicting the risk of acute exacerbation and overall survival.

PMID:33618682 | DOI:10.1186/s12890-021-01428-3

Cigarette smoke-inactivated SIRT1 promotes autophagy-dependent senescence of alveolar epithelial type 2 cells to induce pulmonary fibrosis.

Free Radic Biol Med. 2021 Feb 17;:

Authors: Zhang Y, Huang W, Zheng Z, Wang W, Yuan Y, Hong Q, Lin J, Li X, Meng Y

Abstract
AIMS: The senescence of alveolar epithelial type 2 (AT2) cells is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Cigarette smoke (CS) is a strong risk factor for IPF and it is also a pro-senescent factor. Here we aimed to investigate whether and how CS induces AT2 cells senescence via a SIRT1/autophagy dependent pathway. Our results showed that CS extract (CSE) reduced autophagy and mitophagy and increased mitochondrial reactive oxygen species (mitoROS) in MLE-12 cells, an AT2 cell line. The autophagy inducer rapamycin (RAPA) and the mitochondria-targeted antioxidant mitoquinone (mitoQ) inhibited CSE-related senescence and decreased mitoROS. Next, we found that CSE promoted DNA damage, downregulated the nicotinamide adenine dinucleotide (NAD+)/nicotinamide adenine dinucleotide (NADH) ratio and suppressed SIRT1 activity. Activating SIRT1 with its activator SRT1720 attenuated senescence through an autophagy-dependent pathway. The NAD+ precursor nicotinamide mononucleotide and the poly ADP-ribose polymerase (PARP1) inhibitor olaparib also exerted anti-senescent effects by activating SIRT1. Moreover, the results showed that mitoQ and RAPA, in turn, elevated SIRT1 activity by inhibiting DNA damage. Consistent with these results, SRT1720 and mitoQ mitigated CS-induced AT2 cells senescence and lung fibrosis in vivo. Moreover, autophagy in AT2 cells was rescued by SRT1720. Taken together, our results suggested that CS-induced senescence of AT2 cells was due to decreased autophagy mediated by SIRT1 inactivation, which was attributed to competitive consumption of NAD+ caused by DNA damage-induced PARP1 activation. The reduction in autophagy, in turn, decreased SIRT1 activity by promoting mitochondrial oxidative stress-related DNA damage, thereby establishing a positive feedback loop between SIRT1 and autophagy in CS-induced AT2 cells senescence. Consequently, CS-inactivated SIRT1 promoted autophagy-dependent senescence of AT2 cells to induce pulmonary fibrosis.

PMID: 33609723 [PubMed - as supplied by publisher]

Identification and Remediation of Environmental Exposures in Patients with Interstitial Lung Disease: Evidence Review and Practical Considerations.

Chest. 2021 Feb 17;:

Authors: Copeland CR, Collins BF, Salisbury ML

Abstract
A relationship between inhalational exposure to materials in the environment and development of interstitial lung disease (ILD) is long recognized. Hypersensitivity pneumonitis (HP) is an environmentally induced diffuse parenchymal lung disease. In addition to HP, domestic and occupational exposures have been shown to influence onset and progression of other ILDs, including idiopathic interstitial pneumonias such as idiopathic pulmonary fibrosis (IPF). A key component of the clinical evaluation of patients presenting with ILD includes elucidation of a complete exposure history, which may influence diagnostic classification of the ILD as well as its management. Currently, there is no standardized approach to environmental evaluation or remediation of potentially harmful exposures in home or workplace environments for patients with ILD. In this review, we discuss evidence for environmental contributions to ILD pathogenesis, and draw on asthma and occupational medicine literature to frame the potential utility of a professional evaluation for environmental factors contributing to development and progression of ILD. While several reports suggest benefits of environmental assessment to those with asthma or certain occupational exposures, lack of information about benefits in broader populations may limit application. Determining the feasibility, long term outcomes, and cost effectiveness of environmental evaluation and remediation in acute and chronic ILDs should be a focus of future research.

PMID: 33609518 [PubMed - as supplied by publisher]

A machine-learning based approach to quantify fine crackles in the diagnosis of interstitial pneumonia: A proof-of-concept study.

Medicine (Baltimore). 2021 Feb 19;100(7):e24738

Authors: Horimasu Y, Ohshimo S, Yamaguchi K, Sakamoto S, Masuda T, Nakashima T, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Sadamori T, Shime N, Hattori N

Abstract
ABSTRACT: Fine crackles are frequently heard in patients with interstitial lung diseases (ILDs) and are known as the sensitive indicator for ILDs, although the objective method for analyzing respiratory sounds including fine crackles is not clinically available. We have previously developed a machine-learning-based algorithm which can promptly analyze and quantify the respiratory sounds including fine crackles. In the present proof-of-concept study, we assessed the usefulness of fine crackles quantified by this algorithm in the diagnosis of ILDs.We evaluated the fine crackles quantitative values (FCQVs) in 60 participants who underwent high-resolution computed tomography (HRCT) and chest X-ray in our hospital. Right and left lung fields were evaluated separately.In sixty-seven lung fields with ILDs in HRCT, the mean FCQVs (0.121 ± 0.090) were significantly higher than those in the lung fields without ILDs (0.032 ± 0.023, P < .001). Among those with ILDs in HRCT, the mean FCQVs were significantly higher in those with idiopathic pulmonary fibrosis than in those with other types of ILDs (P = .002). In addition, the increased mean FCQV was associated with the presence of traction bronchiectasis (P = .003) and honeycombing (P = .004) in HRCT. Furthermore, in discriminating ILDs in HRCT, an FCQV-based determination of the presence or absence of fine crackles indicated a higher sensitivity compared to a chest X-ray-based determination of the presence or absence of ILDs.We herein report that the machine-learning-based quantification of fine crackles can predict the HRCT findings of lung fibrosis and can support the prompt and sensitive diagnosis of ILDs.

PMID: 33607819 [PubMed - as supplied by publisher]

High-Expressed Macrophage Scavenger Receptor 1 Predicts Severity Clinical Outcome in Transplant Patient in Idiopathic Pulmonary Fibrosis Disease.

J Immunol Res. 2021;2021:6690100

Authors: Zheng M, Tian T, Liang J, Ye S, Chen J, Ji Y

Abstract
Background: Lung transplantation has been performed worldwide and admitted as an effective treatment for patients with various end-stage lung diseases. However, limit reliable clinical indicators exist to identify patients at high risk for allograft failure in lung transplant recipients. The recent advances in the knowledge of immunological aspects of the pulmonary diseases, for that innate macrophage activation, are induced by pathogen or pathogen-derived molecules and widely accepted as the critical evidence among the pathogenesis of lung inflammation and fibrosis. This study was aimed at evaluating the clinical significance of CD86- and macrophage scavenger receptor 1- (MSR1-) positive cells during the development of idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH), and their potential roles in the prediction of the outcomes after lung transplantation were examined.
Methods: Tissues from lung transplantation for 37 IPF and 15 PAH patients from the Department of Cardiothoracic Surgery in Wuxi People's Hospital from December 2015 to December 2016 were analyzed by immunohistochemistry (IHC) for detecting the expression and CD86 and MSR1 and correlated with clinical events after lung transplantation.
Results: IHC results showed that the expression of MSR1, IL-13, and arginase-1 (Arg1) but not CD86 in the lung section of IPF patients was dramatically enhanced when compared with that of PAH patients. The expression of MSR1, IL-13, and Arg1 but not CD86 in the lung from IPF patients with smoking was significantly increased when compared with that from nonsmoking subjects. In addition, the expression of MSR1-positive cells in IPF subjects with Klebsiella pneumoniae infection was dramatically enhanced than that in noninfection subjects. MSR1-positive macrophages were negatively associated with FEV1 and with FVC but not associated with TLC and with TLCO. However, CD86-positive macrophages were not significantly associated with the above lung function-related factors. Furthermore, MSR1 had a higher area under the ROC curve (AUC) than CD86 for IPF diagnosis. Survival analysis indicated that high levels of MSR1-positive macrophages had a worse prognostic effect for IPF patients with lung transplantation.
Conclusion: Our study indicates the clinical significance of Klebsiella pneumoniae infection-related MSR1-positive cells in IPF progression, and it could be a prognostic marker in IPF after the lung transplant; development strategies to reduce the expression of MSR1-positive macrophages in IPF may be beneficial for the lung transplant.

PMID: 33604393 [PubMed - in process]

Role of the Microbiome in Interstitial Lung Diseases.

Front Med (Lausanne). 2021;8:595522

Authors: Chioma OS, Hesse LE, Chapman A, Drake WP

Abstract
There are trillions of microorganisms in the human body, consisting of bacteria, viruses, fungi, and archaea; these collectively make up the microbiome. Recent studies suggest that the microbiome may serve as a biomarker for disease, a therapeutic target, or provide an explanation for pathophysiology in lung diseases. Studies describing the impact of the microorganisms found in the respiratory tract on lung health have been published and are discussed here in the context of interstitial lung diseases. Additionally, epidemiological and experimental evidence highlights the importance of cross-talk between the gut microbiota and the lungs, called the gut-lung axis. The gut-lung axis postulates that alterations in gut microbial communities may have a profound effect on lung disease. Dysbiosis in the microbial community of the gut is linked with changes in immune responses, homeostasis in the airways, and inflammatory conditions in the gastrointestinal tract itself. In this review, we summarize studies describing the role of the microbiome in interstitial lung disease and discuss the implications of these findings on the diagnosis and treatment of these diseases. This paper describes the impact of the microbial communities on the pathogenesis of lung diseases by assessing recent original research and identifying remaining gaps in knowledge.

PMID: 33604346 [PubMed]

Comparison of CURB-65, PSI, and qSOFA for predicting pneumonia mortality in patients with idiopathic pulmonary fibrosis.

Sci Rep. 2021 Feb 16;11(1):3880

Authors: Yamazaki R, Nishiyama O, Yoshikawa K, Saeki S, Sano H, Iwanaga T, Tohda Y

Abstract
Some patients with idiopathic pulmonary fibrosis (IPF) require hospitalization due to pneumonia. Although predictive scoring tools have been developed and validated for community-acquired pneumonia (CAP), their usefulness in IPF is unknown. The Confusion, Urea, Respiratory Rate, Blood Pressure and Age (CURB-65) score and the Pneumonia Severity Index (PSI) are validated for CAP. The quick Sequential Organ Failure Assessment (qSOFA) is also reported to be useful. The aim of this study was to investigate the ability of these tools to predict pneumonia mortality among hospitalized patients with IPF. A total of 79 patients with IPF and pneumonia were hospitalized for the first time between January 2008 and December 2017. The hospital mortality rate was 15.1%. A univariate logistic regression analysis revealed that the CURB-65 (odds ratio 4.04, 95% confidence interval 1.60-10.2, p = 0.003), PSI (4.00, 1.48-10.7, 0.006), and qSOFA (5.00, 1.44-1.72, 0.01) scores were significantly associated with hospital mortality. There was no statistically significant difference between the three receiver operating characteristic curves (0.712, 0.736, and 0.692, respectively). The CURB-65, PSI, and qSOFA are useful tools for predicting pneumonia mortality among hospitalized patients with IPF. Because of its simplicity, the qSOFA may be most suitable for early assessment.

PMID: 33594102 [PubMed - in process]

Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation.

Nat Commun. 2021 02 16;12(1):1072

Authors: Dobersch S, Rubio K, Singh I, Günther S, Graumann J, Cordero J, Castillo-Negrete R, Huynh MB, Mehta A, Braubach P, Cabrera-Fuentes H, Bernhagen J, Chao CM, Bellusci S, Günther A, Preissner KT, Kugel S, Dobreva G, Wygrecka M, Braun T, Papy-Garcia D, Barreto G

Abstract
In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of high-mobility group proteins during transcription initiation remain unclear. Here we show that high-mobility group AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support the concept that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure genome integrity.

PMID: 33594057 [PubMed - in process]