Rev Mal Respir. 2022 Mar 14:S0761-8425(22)00026-2. doi: 10.1016/j.rmr.2022.01.005. Online ahead of print.

ABSTRACT

BACKGROUND: Since the previous French guidelines were published in 2017, substantial additional knowledge about idiopathic pulmonary fibrosis has accumulated.

METHODS: Under the auspices of the French-speaking Learned Society of Pulmonology and at the initiative of the coordinating reference center, practical guidelines for treatment of rare pulmonary diseases have been established. They were elaborated by groups of writers, reviewers and coordinators with the help of the OrphaLung network, as well as pulmonologists with varying practice modalities, radiologists, pathologists, a general practitioner, a head nurse, and a patients' association. The method was developed according to rules entitled "Good clinical practice" in the overall framework of the "Guidelines for clinical practice" of the official French health authority (HAS), taking into account the results of an online vote using a Likert scale.

RESULTS: After analysis of the literature, 54 recommendations were formulated, improved, and validated by the working groups. The recommendations covered a wide-ranging aspects of the disease and its treatment: epidemiology, diagnostic modalities, quality criteria and interpretation of chest CT, indication and modalities of lung biopsy, etiologic workup, approach to familial disease entailing indications and modalities of genetic testing, evaluation of possible functional impairments and prognosis, indications for and use of antifibrotic therapy, lung transplantation, symptom management, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis.

CONCLUSION: These evidence-based guidelines are aimed at guiding the diagnosis and the management in clinical practice of idiopathic pulmonary fibrosis.

PMID:35304014 | DOI:10.1016/j.rmr.2022.01.005

Respir Res. 2022 Mar 18;23(1):61. doi: 10.1186/s12931-022-01980-4.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease with limited treatment options. A phase 2 trial (NCT01766817) showed that twice-daily treatment with BMS-986020, a lysophosphatidic acid receptor 1 (LPA1) antagonist, significantly decreased the slope of forced vital capacity (FVC) decline over 26 weeks compared with placebo in patients with IPF. This analysis aimed to better understand the impact of LPA1 antagonism on extracellular matrix (ECM)-neoepitope biomarkers and lung function through a post hoc analysis of the phase 2 study, along with an in vitro fibrogenesis model.

METHODS: Serum levels of nine ECM-neoepitope biomarkers were measured in patients with IPF. The association of biomarkers with baseline and change from baseline FVC and quantitative lung fibrosis as measured with high-resolution computed tomography, and differences between treatment arms using linear mixed models, were assessed. The Scar-in-a-Jar in vitro fibrogenesis model was used to further elucidate the antifibrotic mechanism of BMS-986020.

RESULTS: In 140 patients with IPF, baseline ECM-neoepitope biomarker levels did not predict FVC progression but was significantly correlated with baseline FVC and lung fibrosis measurements. Most serum ECM-neoepitope biomarker levels were significantly reduced following BMS-986020 treatment compared with placebo, and several of the reductions correlated with FVC and/or lung fibrosis improvement. In the Scar-in-a-Jar in vitro model, BMS-986020 potently inhibited LPA1-induced fibrogenesis.

CONCLUSIONS: BMS-986020 reduced serum ECM-neoepitope biomarkers, which were previously associated with IPF prognosis. In vitro, LPA promoted fibrogenesis, which was LPA1 dependent and inhibited by BMS-986020. Together these data elucidate a novel antifibrotic mechanism of action for pharmacological LPA1 blockade. Trial registration ClinicalTrials.gov identifier: NCT01766817; First posted: January 11, 2013; https://clinicaltrials.gov/ct2/show/NCT01766817 .

PMID:35303880 | DOI:10.1186/s12931-022-01980-4

Rheumatology (Oxford). 2022 Mar 18:keac184. doi: 10.1093/rheumatology/keac184. Online ahead of print.

ABSTRACT

OBJECTIVE: The prognosis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is difficult to predict because of the variable clinical course. This study aimed to determine the prognostic value of an automated quantification system (AQS) in RA-ILD.

METHODS: We retrospectively analysed the clinical data and high-resolution computed tomography (HRCT) images of 144 patients with RA-ILD. Quantitative lung fibrosis (QLF, sum of reticulation and traction bronchiectasis) and ILD (QILD; sum of QLF, honeycombing [QHC], and ground-glass opacity [QGG]) scores were measured using the AQS.

RESULTS: The mean age was 61.2 years, 43.8% of the patients were male, and the 5-year mortality rate was 30.5% (median follow-up, 52.2 months). Non-survivors showed older age, higher erythrocyte sedimentation rate (ESR), and greater AQS scores than survivors. In multivariable Cox analysis, higher QLF, QHC, and QILD scores were independent prognostic factors along with older age and higher ESR. In receiver-operating characteristic curve analysis, the QLF score showed better performance in predicting 5-year mortality than the QHC and QGG scores but was similar to the QILD score. Patients with high QLF scores (≥12% of total lung volume) showed higher 5-year mortality (50% vs. 17.4%, P<0.001) than those with low QLF scores and similar survival outcome to patients with idiopathic pulmonary fibrosis (IPF). Combining with clinical variables (age, ESR) further improved the performance of QLF score in predicting 5-year mortality.

CONCLUSION: QLF scores might be useful for predicting prognosis in patients with RA-ILD. High QLF scores differentiate a poor prognostic phenotype similar to IPF.

PMID:35302602 | DOI:10.1093/rheumatology/keac184

Eur J Ophthalmol. 2022 Mar 18:11206721221088259. doi: 10.1177/11206721221088259. Online ahead of print.

ABSTRACT

OBJECTIVES: Dry eye disease (DED) is arguably the most frequent ocular disease encountered in ophthalmic clinical practice. DED is frequently an underestimated condition causing a significant impact on visual function and quality of life. Many systemic autoimmune diseases (SAIDs) are related to moderate to severe DED. The main objective of this review is to enhance the awareness among ophthalmologists of the potential association of an underlying SAID in a high-risk patient with DED.

METHODS: An exhaustive literature search was performed in the National Library of Medicine's Pubmed, Scopus, Web of Science, and Google Scholar databases for all English language articles published until November 2021. The main keywords included "dry eye disease" associated with autoimmune, connective tissue, endocrine, gastrointestinal, hematopoietic, vascular, and pulmonary diseases. Case reports, series, letters to the editor, reviews, and original articles were included.

RESULTS: Although DED is frequently associated with SAIDs, its diagnosis is commonly delayed or missed, producing significant complications, including corneal ulceration, melting, scleritis, uveitis, and optic neuritis resulting in severe complications detrimental to visual function and quality of life. SAID should be suspected in a woman, 30 to 60 years old with a family history of autoimmunity, presenting with DED symptoms and extraocular manifestations including arthralgias, dry mouth, unexplained weight and hair loss, chronic fatigue, heat or cold intolerance, insomnia, and mood disorders.

CONCLUSIONS: Establishing the correct diagnosis and treatment of DED associated with SAIDs is crucial to avoid its significant burden and severe ocular complications.

PMID:35300528 | DOI:10.1177/11206721221088259

ERJ Open Res. 2022 Mar 14;8(1):00541-2021. doi: 10.1183/23120541.00541-2021. eCollection 2022 Jan.

ABSTRACT

BACKGROUND: Physical activity contributes to improving respiratory symptoms. However, validated end-points are few, and there is limited consensus about what is a clinically meaningful improvement for patients. This review summarises the evidence to date on the range of physical activity end-points used in COPD, asthma and idiopathic pulmonary fibrosis (IPF) whilst evaluating their appropriateness as end-points in trials and their relation to patients' everyday life.

METHODS: Trials reporting physical activity end-points were collected using Citeline's database Trialtrove; this was supplemented by searches in PubMed.

RESULTS: The daily-patient-reported outcome (PRO)active and clinical visit-PROactive physical activity composite end-points appeared superior at capturing the full experience of physical activity in patients with COPD and were responsive to bronchodilator intervention. Time spent in moderate-to-vigorous physical activity is a recently validated end-point for IPF that correlates with exercise capacity and quality of life. Step count appears the best available physical activity measure for asthma, which consistently declines with worse disease status. However, evidence suggests a time lag before significant improvement in step count is seen which may reflect the impact of human behaviour on physical activity.

CONCLUSIONS: Physical activity represents a challenging domain to accurately measure. This is the first review evaluating physical activity measures used specifically within the respiratory field. Whilst physical activity can be effectively captured using PROactive in patients with COPD, this review highlights the unmet need for novel patient-focused end-points in asthma and IPF which would offer opportunities to develop efficacious medicines with impact on patients' therapeutic care and quality of life.

PMID:35295234 | PMC:PMC8918933 | DOI:10.1183/23120541.00541-2021

ERJ Open Res. 2022 Mar 14;8(1):00591-2021. doi: 10.1183/23120541.00591-2021. eCollection 2022 Jan.

ABSTRACT

BACKGROUND: There are substantial advances in diagnosis and treatment for idiopathic pulmonary fibrosis (IPF), but without much evidence available on recent mortality and survival trends.

METHODS: A narrative synthesis approach was used to investigate the mortality trends, then meta-analyses for survival trends were carried out based on various time periods.

RESULTS: Six studies reported the mortality data for IPF in 22 countries, and 62 studies (covering 63 307 patients from 20 countries) reported survival data for IPF. Age-standardised mortality for IPF varied from ∼0.5 to ∼12 per 100 000 population per year after year 2000. There were increased mortality trends for IPF in Australia, Brazil, Belgium, Canada, Czech Republic, Finland, France, Germany, Hungary, Italy, Lithuania, the Netherlands, Poland, Portugal, Spain, Sweden and UK, while Austria, Croatia, Denmark, Romania and the USA showed decreased mortality trends. The overall 3-year and 5-year cumulative survival rates (CSRs) were 61.8% (95% CI 58.7-64.9; I2=97.1%) and 45.6% (95% CI 41.5-49.7; I2=97.7%), respectively. Prior to 2010, the pooled 3-year CSR was 59.9% (95% CI 55.8-64.1; I2=95.8%), then not significantly (p=0.067) increased to 66.2% (95% CI 62.9-69.5; I2=92.6%) in the 2010s decade. After excluding three studies in which no patients received antifibrotics after year 2010, the pooled 3-year CSRs significantly (p=0.039) increased to 67.4% (95% CI 63.9-70.9; I2=93.1%) in the 2010s decade.

DISCUSSION: IPF is a diagnosis associated with high mortality. There was no observed increasing survival trend for patients with IPF before year 2010, with then a switch to an improvement, which is probably multifactorial.

PMID:35295232 | PMC:PMC8918939 | DOI:10.1183/23120541.00591-2021

N Engl J Med. 2022 Mar 17;386(11):1058-1069. doi: 10.1056/NEJMra2116777.

NO ABSTRACT

PMID:35294814 | DOI:10.1056/NEJMra2116777

Respirology. 2022 Mar 15. doi: 10.1111/resp.14245. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: The development of clinically progressive fibrosis complicates a wide array of interstitial lung diseases (ILDs). However, there are limited data regarding its prevalence and prognosis.

METHODS: We analysed consecutive patients seen for initial evaluation of a fibrosing form of ILD (FILD). Patients were evaluated for evidence of progressive fibrosis over the first 24 months of follow-up. We defined a progressive phenotype as the presence of at least one of the following: a relative decline in forced vital capacity (FVC) of ≥10%; a relative decline in FVC of ≥5%-<10% with a relative decline in diffusing capacity of the lung for carbon monoxide of ≥15%, increased fibrosis on HRCT or progressive symptoms.

RESULTS: Eight hundred and forty-four patients (397 with idiopathic pulmonary fibrosis [IPF] and 447 non-IPF FILD) made up the final analysis cohort. Three hundred and fifty-five patients (42.1%) met the progressive phenotype criteria (59.4% of IPF patients and 26.6% of non-IPF FILD patients, p <0.01). In both IPF and non-IPF FILD, transplantation-free survival differed between patients with a progressive phenotype and those without (p <0.01). Multivariable analysis showed that a progressive phenotype was an independent predictor of transplantation-free survival (hazard ratio [HR]: 3.36, 95% CI: 2.68-4.23, p <0.01). Transplantation-free survival did not differ between non-IPF FILD with a progressive phenotype and IPF (HR: 1.12, 95% CI: 0.85-1.48, p = 0.42).

CONCLUSION: Over one-fourth of non-IPF FILD patients develop a progressive phenotype compared to approximately 60% of IPF patients. The survival of non-IPF FILD patients with a progressive phenotype is similar to IPF.

PMID:35293077 | DOI:10.1111/resp.14245

J Biomech Eng. 2022 Mar 16. doi: 10.1115/1.4054106. Online ahead of print.

ABSTRACT

Pulmonary function is tightly linked to the lung mechanical behavior, especially large deformation during breathing. Interstitial lung diseases, such as Idiopathic Pulmonary Fibrosis (IPF), have an impact on the pulmonary mechanics and consequently alter lung function. However, IPF remains poorly understood, poorly diagnosed and poorly treated. Currently, the mechanical impact of such diseases is assessed by pressure-volume curves, giving only global information. We developed a poromechanical model of the lung that can be personalized to a patient based on routine clinical data. The personalization pipeline uses clinical data, mainly CT-images at two time steps and involves the formulation of an inverse problem to estimate regional compliances. The estimation problem can be formulated both in terms of "effective", i.e., without considering the mixture porosity, or "rescaled", i.e., where the first-order effect of the porosity has been taken into account, compliances. Regional compliances are estimated for one control subject and three IPF patients, allowing to quantify the IPF-induced tissue stiffening. This personalized model could be used in the clinic as an objective and quantitative tool for IPF diagnosis.

PMID:35292805 | DOI:10.1115/1.4054106

EBioMedicine. 2022 Mar 12:103912. doi: 10.1016/j.ebiom.2022.103912. Online ahead of print.

ABSTRACT

BACKGROUND: α-Klotho is a geroprotective protein that can attenuate or alleviate deleterious changes with ageing and disease. Declines in α-Klotho play a role in the pathophysiology of multiple diseases and age-related phenotypes. Pre-clinical evidence suggests that boosting α-Klotho holds therapeutic potential. However, readily clinically-translatable, practical strategies for increasing α-Klotho are not at hand. Here, we report that orally-active, clinically-translatable senolytics can increase α-Klotho in mice and humans.

METHODS: We examined α-Klotho expression in three different human primary cell types co-cultured with conditioned medium (CM) from senescent or non-senescent cells with or without neutralizing antibodies. We assessed α-Klotho expression in aged, obese, and senescent cell-transplanted mice treated with vehicle or senolytics. We assayed urinary α-Klotho in patients with idiopathic pulmonary fibrosis (IPF) who were treated with the senolytic drug combination, Dasatinib plus Quercetin (D+Q).

FINDINGS: We found exposure to the senescent cell secretome reduces α-Klotho in multiple nonsenescent human cell types. This was partially prevented by neutralizing antibodies against the senescence-associated secretory phenotype (SASP) factors, activin A and Interleukin 1α (IL-1α). Consistent with senescent cells' being a cause of decreased α-Klotho, transplanting senescent cells into younger mice reduced brain and urine α-Klotho. Selectively removing senescent cells genetically or pharmacologically increased α-Klotho in urine, kidney, and brain of mice with increased senescent cell burden, including naturally-aged, diet-induced obese (DIO), or senescent cell-transplanted mice. D+Q increased α-Klotho in urine of patients with IPF, a disease linked to cellular senescence.

INTERPRETATION: Senescent cells cause reduced α-Klotho, partially due to their production of activin A and IL-1α. Targeting senescent cells boosts α-Klotho in mice and humans. Thus, clearing senescent cells restores α-Klotho, potentially opening a novel, translationally-feasible avenue for developing orally-active small molecule, α-Klotho-enhancing clinical interventions. Furthermore, urinary α-Klotho may prove to be a useful test for following treatments in senolytic clinical trials.

FUNDING: This work was supported by National Institute of Health grants AG013925 (J.L.K.), AG062413 (J.L.K., S.K.), AG044271 (N.M.), AG013319 (N.M.), and the Translational Geroscience Network (AG061456: J.L.K., T.T., N.M., S.B.K., S.K.), Robert and Arlene Kogod (J.L.K.), the Connor Group (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K.), and the Noaber Foundation (J.L.K.). The previous IPF clinical trial was supported by the Claude D. Pepper Older Americans Independence Centers at WFSM (AG021332: J.N.J., S.B.K.), UTHSCA (AG044271: A.M.N.), and the Translational Geroscience Network.

PMID:35292270 | DOI:10.1016/j.ebiom.2022.103912

Bioengineered. 2022 Mar;13(3):7746-7759. doi: 10.1080/21655979.2022.2044252.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an idiopathic interstitial lung disease. At present, the pathogenesis of IPF has not been fully elucidated, which has affected the development of effective treatment methods. Here, we explored the function and potential mechanism of long noncoding RNA (lncRNA) CDKN2B antisense RNA 1 (CDKN2B-AS1) in IPF.Transforming growth factor-β (TGF-β) and bleomycin (BLM) were used to induce IPF in cells and animal models. Real Time quantitative Polymerase Chain Reaction (RT-qPCR) showed the expression of CDKN2B-AS1, miR-199a-5p and Sestrin-2 (SESN2) in cells and tissues. The double luciferase reporter gene assay confirmed the targeting relationship among CDKN2B-AS1, miR-199a-5p, and SESN2. Related protein levels were detected by Western blot combined with Cell Counting Kit-8 (CCK-8), wound healing, and flow cytometry to analyze cell proliferation, migration, and apoptosis. The pathological characteristics of mouse lung tissue were determined by Hematoxylin-eosin (HE) and Masson staining. We found that the expression of CDKN2B-AS1 was decreased in TGF-β-treated cells and BLM-treated mice. Overexpression of CDKN2B-AS1 inhibited cell proliferation and migration, promoted apoptosis, decreased the expression of fibrosis-related proteins and promoted autophagy. In addition, overexpression of CDKN2B-AS1 alleviated pulmonary fibrosis in BLM-treated mice. Mechanistically, CDKN2B-AS1 acts as a miR-199a-5p sponge to regulate SESN2 expression. Our results indicate the importance of the CDKN2B-AS1/miR-199a-5p/SESN2 axis.

PMID:35291918 | DOI:10.1080/21655979.2022.2044252

Mol Pharm. 2022 Mar 15. doi: 10.1021/acs.molpharmaceut.2c00052. Online ahead of print.

ABSTRACT

Pirfenidone (PFD) is the first pharmacological agent approved by the US Food and Drug Administration (FDA) in 2014 for the treatment of idiopathic pulmonary fibrosis (IPF). The recommended daily dosage of PFD in patients with IPF is very high (2403 mg/day) and must be mitigated through additives. In the present work, sustained-release (SR) formulations of the PFD-FA cocrystal of two different strengths such as 200 and 600 mg were prepared and its comparative bioavailability in healthy human volunteers was studied against the reference formulation PIRFENEX (200 mg). A single-dose pharmacokinetic study (200 mg IR vs 200 mg SR) demonstrated that the test formulation exhibited lower Cmax and Tmax in comparison to the reference formulation, which showed that the cocrystal behaved like an SR formulation. Further in the multiple-dose comparative bioavailability study (200 mg IR thrice daily vs 600 mg SR once daily), the test formulation was found bioequivalent to the reference formulation. In conclusion, the present study suggests that cocrystallization offers a promising strategy to reduce the solubility of PFD and opens the door for potential new dosage forms of this important pharmaceutical.

PMID:35290064 | DOI:10.1021/acs.molpharmaceut.2c00052

Ann Am Thorac Soc. 2022 Mar 15. doi: 10.1513/AnnalsATS.202203-196LE. Online ahead of print.

NO ABSTRACT

PMID:35289737 | DOI:10.1513/AnnalsATS.202203-196LE

Ann Am Thorac Soc. 2022 Mar 15. doi: 10.1513/AnnalsATS.202202-139LE. Online ahead of print.

NO ABSTRACT

PMID:35289726 | DOI:10.1513/AnnalsATS.202202-139LE

Mediators Inflamm. 2022 Mar 3;2022:6755407. doi: 10.1155/2022/6755407. eCollection 2022.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial pneumonia disease with no cure. Communication between injured cells is triggered and maintained by a complicated network of cytokines and their receptors. IL-19 is supported by increasing evidences for a deleterious role in respiratory diseases. However, its potential role in lung fibrosis has never been explored.

METHODS: Bioinformatic, immunohistochemistry and western blot analysis were used to assess the expression of IL-19 in human and mouse fibrosis lung tissues. CCK-8, transwell and flow cytometry assay were utilized to analyze the effect of IL-19 on biological behaviors of lung fibroblasts. Histopathology was used to elucidate profibrotic effect of IL-19 in vivo.

RESULTS: IL-19 was upregulated in fibrosis lung tissues. IL-19 promoted lung fibroblasts proliferation and invasion, inhibited cell apoptosis, and induced differentiation of fibroblasts to the myofibroblast phenotype, which could be revised by LY2109761, a TGF-β/Smad signaling pathway inhibitor. Furthermore, we found that IL-19 aggravated lung fibrosis in murine bleomycin-induced lung fibrosis.

CONCLUSIONS: Our results imply the profibrotic role for IL-19 through direct effects on lung fibroblasts and the potential of targeting IL-19 for therapeutic intervention in pulmonary fibrosis.

PMID:35281428 | PMC:PMC8913154 | DOI:10.1155/2022/6755407

J Thorac Dis. 2022 Feb;14(2):278-294. doi: 10.21037/jtd-21-1418.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis is a fibrotic disease of unknown aetiology and has a poor prognosis. Some patients experience episodes of rapid deterioration known as acute exacerbations (AEs), which are often fatal. This study aimed to clarify whether serum cytokine levels can predict the outcome of idiopathic pulmonary fibrosis.

METHODS: This retrospective study included 69 patients with idiopathic pulmonary fibrosis diagnosed according to the 2018 guideline. AE of idiopathic pulmonary fibrosis was diagnosed using the Japanese Respiratory Society criteria. Serum levels of 27 cytokines were measured using the Bio-Plex method. Cytokine production was estimated per lung volume using the serum cytokine level/percent predicted forced vital capacity (%FVC) value. The ability of the serum cytokine level and serum cytokine level/%FVC value to predict the prognosis and AE was examined in a univariate Cox proportional hazards regression model; significant factors were subjected to multivariate analysis with adjustment for significant clinical parameters, including the modified Medical Research Council score.

RESULTS: The study included 57 men and 12 women (median age, 67 years). The modified Medical Research Council score was ≤1 in 47 patients and ≥2 in 22. None of the serum cytokine levels measured could predict survival or AE; however, the serum platelet-derived growth factor/%FVC and interleukin-9/%FVC values were significant prognostic factors and the serum platelet-derived growth factor/%FVC and interleukin-13/%FVC values were significant predictors of AE. Serum platelet-derived growth factor/%FVC alone was a significant predictor of the prognosis and AE after adjustment for clinical parameters.

CONCLUSIONS: The prognosis of idiopathic pulmonary fibrosis and AEs of the disease could be predicted by the serum platelet-derived growth factor/%FVC value.

PMID:35280478 | PMC:PMC8902107 | DOI:10.21037/jtd-21-1418

Mol Ther. 2022 Mar 9:S1525-0016(22)00159-9. doi: 10.1016/j.ymthe.2022.01.045. Online ahead of print.

ABSTRACT

Increasing circular RNAs (circRNAs) are involved in the progression of idiopathic pulmonary fibrosis (IPF). However, circRNA biogenesis and circRNA-mediated crosstalk between mechanical stiffness and biochemical signals in IPF remain obscure. In this study, a novel circRNA-ANKRD42 from peripheral blood of patients with IPF, which participated in pulmonary fibrosis through the close communication of mechanical stiffness and biochemical signals, was identified. Mechanistic studies revealed that the heterogeneous nuclear ribonucleoprotein L (hnRNP L) activated the circANKRD42 reverse splicing biogenesis. The biogenetic circANKRD42 sponged miR-324-5p to promote the AJUBA expression, which blocked the binding between phosphorylated yes-associated protein 1 (YAP1) and large tumor suppressor kinase 1/2 (LATS1/2), leading to increased YAP1 entering the nucleus. circANKRD42 also sponged miR-136-5p to promote the YAP1 translation. Accumulating YAP1 in nucleus bound to TEAD, which initiated the transcription of genes related to mechanical stiffness. Finally, the therapeutic effect of circANKRD42 was evaluated in mice and the association between circANKRD42 and clinicopathological features was analyzed in IPF patients. Our findings supported that circANKRD42 is a promising biomarker and a potential therapeutic target related to cytoskeleton tension for IPF treatment.

PMID:35278674 | DOI:10.1016/j.ymthe.2022.01.045

Respir Res. 2022 Mar 11;23(1):57. doi: 10.1186/s12931-022-01978-y.

ABSTRACT

BACKGROUND: Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD), like those with idiopathic pulmonary fibrosis (IPF), might develop an unexpected acute exacerbation (AE)-a rapidly progressing and deadly respiratory decline. Although AE incidence and risk factors in RA-ILD patients are known, their post-AE clinical course remains unknown owing to the rarity of AE-RA-ILD. This multicentre retrospective study evaluated post-AE mortality and prognostic variables in AE-RA-ILD patients and created a mortality prediction model for AE-RA-ILD.

METHODS: This research comprised 58 patients with AE-RA-ILD and 96 with AE-IPF (a control disease). Multivariate Cox regression analysis was performed to identify prognostic variables. A prediction model was created with recursive partitioning (decision tree).

RESULTS: The post-AE 90-day mortality rate in the overall AE-RA-ILD group was 48.3%; percent predicted forced vital capacity within 12 months before AE onset (baseline %FVC) and PaO2/FiO2 ratio at AE onset (P/F at AE) were independent predictors of mortality. Post-AE 90-day mortality rates were 40.6% and 43.8%, respectively, in AE-RA-ILD and AE-IPF patients propensity score-matched for age, sex, baseline %FVC and P/F at AE (P = 1.0000). In AE-RA-ILD patients, C-indices of baseline %FVC and P/F at AE to predict post-AE 90-day mortality were 0.604 and 0.623, respectively. A decision tree model based on these prognostic factors classified AE-RA-ILD patients into mild, moderate and severe groups (post-AE 90-day mortality rates: 20.8%, 64.0% and 88.9%, respectively; P = 0.0002); the C-index improved to 0.775.

CONCLUSIONS: Post-AE mortality was high in AE-RA-ILD patients similar to AE-IPF patients. The discovered prognostic factors and our mortality prediction model may aid in the management of AE-RA-ILD patients.

PMID:35277175 | DOI:10.1186/s12931-022-01978-y

Physiol Res. 2022 Apr 11. Online ahead of print.

ABSTRACT

Exercise tolerance in patients with idiopathic pulmonary fibrosis IPF is mainly limited by mechanical constrain of ventilation and high physiologic dead space. Oxygen enriched gas inhalation seems to increase ventilatory efficiency by reduction of dead space to tidal volume ratio (VD/VT) which probably mirrors improved pulmonary capillary flow and leads to longer physical tolerance at lower level of minute ventilation. The effect is noticeable at FIO2 that can be delivered in rehabilitation purposes or daily living activities.

PMID:35275694

Eur Respir J. 2022 Mar 10:2102058. doi: 10.1183/13993003.02058-2021. Online ahead of print.

ABSTRACT

OBJECTIVES: The objective of this work was to apply quantitative and semi-quantitative dynamic contrast enhanced MRI (DCE-MRI) methods to evaluate lung perfusion in idiopathic pulmonary fibrosis (IPF).

MATERIALS AND METHODS: In this prospective trial 41 subjects, including healthy control (control) and IPF subjects, were studied using DCE-MRI at baseline. IPF subjects were then followed for 1 year, progressive IPF (IPFprog) were distinguished from stable IPF (IPFstable) subjects based on a decline in percent predicted FVC (FVC%p) or DLCO (DLCO%p) measured during followup visits. 35/41 subjects were retained for final baseline analysis at (control: N=15; IPFstable: N=14; IPFprog: N=6). Seven measures and their coefficients of variation (CV) were derived using temporally resolved DCE-MRI. Two sets of global and regional comparisons were made: control versus IPF groups, and control versus IPFstable versus IPFprog groups, using linear regression analysis. Each measure was compared to FVC%p, DLCO%p, and the lung clearance index (LCI%p) using a Spearman rank correlation.

RESULTS: DCE-MRI identified regional perfusion differences between control and IPF subjects using first moment transit time (FMTT), contrast uptake slope (SLOPE), and pulmonary blood flow (PBF) (p≤0.05), while global averages did not. FMTT was shorter for IPFprog compared to both IPFstable (p=0.004) and control groups (p=0.023). Correlations were observed between PBF CV and DLCO%p (rs=-0.48, p=0.022) and %LCI (rs=+0.47, p=0.015). Significant group differences were detected in age (p<0.001), DLCO%p (p<0.001), FVC%p (p=0.001), and LCI%p (p=0.007).

CONCLUSIONS: Global analysis obscures regional changes in pulmonary hemodynamics in IPF using DCE-MRI in IPF. Decreased FMTT may be a candidate marker for IPF progression.

PMID:35273033 | DOI:10.1183/13993003.02058-2021