Respir Res. 2022 Jun 17;23(1):157. doi: 10.1186/s12931-022-02077-8.

ABSTRACT

BACKGROUND: Interstitial lung abnormalities (ILA) are radiologic findings that may progress to idiopathic pulmonary fibrosis (IPF). Blood gene expression profiles can predict IPF mortality, but whether these same genes associate with ILA and ILA outcomes is unknown. This study evaluated if a previously described blood gene expression profile associated with IPF mortality is associated with ILA and all-cause mortality.

METHODS: In COPDGene and ECLIPSE study participants with visual scoring of ILA and gene expression data, we evaluated the association of a previously described IPF mortality score with ILA and mortality. We also trained a new ILA score, derived using genes from the IPF score, in a subset of COPDGene. We tested the association with ILA and mortality on the remainder of COPDGene and ECLIPSE.

RESULTS: In 1469 COPDGene (training n = 734; testing n = 735) and 571 ECLIPSE participants, the IPF score was not associated with ILA or mortality. However, an ILA score derived from IPF score genes was associated with ILA (meta-analysis of test datasets OR 1.4 [95% CI: 1.2-1.6]) and mortality (HR 1.25 [95% CI: 1.12-1.41]). Six of the 11 genes in the ILA score had discordant directions of effects compared to the IPF score. The ILA score partially mediated the effects of age on mortality (11.8% proportion mediated).

CONCLUSIONS: An ILA gene expression score, derived from IPF mortality-associated genes, identified genes with concordant and discordant effects on IPF mortality and ILA. These results suggest shared, and unique biologic processes, amongst those with ILA, IPF, aging, and death.

PMID:35715807 | DOI:10.1186/s12931-022-02077-8

Sci Rep. 2022 Jun 17;12(1):10275. doi: 10.1038/s41598-022-14491-5.

ABSTRACT

Chronic inflammation of the human intestine in Crohn's disease (CD) causes bowel wall thickening, which typically progresses to stricturing and a recurrent need for surgery. Current therapies have limited success and CD remains idiopathic and incurable. Recent evidence shows a key role of intestinal smooth muscle cell (ISMC) hyperplasia in stricturing, which is not targeted by current anti-inflammatory therapeutics. However, progression of idiopathic pulmonary fibrosis, resembling CD in pathophysiology, is controlled by the tyrosine kinase inhibitors nintedanib (NIN) or pirfenidone, and we investigated these drugs for their effect on ISMC. In a culture model of rat ISMC, NIN inhibited serum- and PDGF-BB-stimulated growth and cell migration, and promoted the differentiated phenotype, while increasing secreted collagen. NIN did not affect signaling through PDGF-Rβ or NFκB but did inhibit cytokine-induced expression of the pro-inflammatory cytokines IL-1β and TNFα, supporting a transcriptional level of control. In TNBS-induced colitis in mice, which resembles CD, NIN decreased ISMC hyperplasia as well as expression of TNFα and IL-1β, without effect in control animals. NIN also inhibited growth of human ISMC in response to human serum or PDGF-BB, which further establishes a broad range of actions of NIN that support further trial in human IBD.

PMID:35715562 | DOI:10.1038/s41598-022-14491-5

Rev Mal Respir. 2022 Jun 14:S0761-8425(22)00161-9. doi: 10.1016/j.rmr.2022.03.011. Online ahead of print.

ABSTRACT

Genetic studies of familial forms of interstitial lung disease (ILD) have led to the discovery of telomere-related gene (TRG) mutations (TERT, TERC, RTEL1, PARN, DKC1, TINF2, NAF1, NOP10, NHP2, ACD, ZCCH8) in approximately 30% of familial ILD forms. ILD patients with TRG mutation are also subject to extra-pulmonary (immune-hematological, hepatic and/or mucosal-cutaneous) manifestations. TRG mutations may be associated not only with idiopathic pulmonary fibrosis (IPF), but also with non-IPF ILDs, including idiopathic and secondary ILDs, such as hypersensitivity pneumonitis (HP). The presence of TRG mutation may also be associated with an accelerated decline of forced vital capacity (FVC) or poorer prognosis after lung transplantation, notwithstanding which, usual ILD treatments may be proposed. Lastly, patients and their relatives are called upon to reduce their exposure to environmental lung toxicity, and are likely to derive benefit from specific genetic counseling and pre-symptomatic genetic testing.

PMID:35715316 | DOI:10.1016/j.rmr.2022.03.011

BMJ Open Respir Res. 2022 Jun;9(1):e001202. doi: 10.1136/bmjresp-2022-001202.

ABSTRACT

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease. Patients present at different stages and disease course is varied. Blood monocytes have been linked to all-cause mortality, and neutrophils to progression to IPF in patients with the indeterminate for usual interstitial pneumonia CT pattern.

OBJECTIVE: To determine association between blood monocytes, neutrophils and lymphocytes levels (and their derived indexes), with lung function decline and mortality in IPF.

METHODS: We performed a retrospective analysis of an IPF cohort (n=128) who had their first clinical visit at the Oxford Interstitial Lung Disease Service between 2013 and 2017. Association between blood monocytes, neutrophils, lymphocytes and derived indexes (within 4 months of visit) and decline in forced vital capacity (FVC) and all-cause mortality were assessed using Cox proportional hazard regression analysis. Kaplan-Meier analysis was used to assess time-to-event for 10% FVC decline and mortality for patients dichotomised to high and low leucocyte counts.

RESULTS: Median length of follow-up was 31.0 months (IQR 16.2-42.4); 41.4% demonstrated FVC decline >10% per year and 43.8% died. In multivariate models (incorporating age, gender and initial FVC%), raised neutrophils, lymphopaenia and neutrophil:lymphocyte ratio were associated with FVC decline (p≤0.01); while both monocytes and neutrophil levels (and their derived indexes) were associated with all-cause mortality (p≤0.01). Kaplan-Meier analysis also showed association between neutrophils and its derived indexes but not monocyte, with FVC decline.

CONCLUSION: Blood neutrophil and lymphopaenia are more sensitive than monocytes as prognostic indicators of disease progression in those with established IPF.

PMID:35715193 | DOI:10.1136/bmjresp-2022-001202

Front Med (Lausanne). 2022 May 31;9:941008. doi: 10.3389/fmed.2022.941008. eCollection 2022.

NO ABSTRACT

PMID:35712108 | PMC:PMC9195006 | DOI:10.3389/fmed.2022.941008

Eur J Pharm Sci. 2022 Jun 13:106236. doi: 10.1016/j.ejps.2022.106236. Online ahead of print.

ABSTRACT

Current pathophysiological findings indicate that damage to the alveolar epithelium plays a decisive role in the development of idiopathic pulmonary fibrosis (IPF). The available pharmacological interventions (i.e., oral pirfenidone and nintedanib) only slow down progression of the disease, but do not offer a cure. In order to develop new drug candidates, the pathophysiology of IPF needs to be better understood on a molecular level. It has previously been reported that a loss of caveolin-1 (Cav-1) contributes to profibrotic processes by causing reduced alveolar barrier function and fibrosis-like alterations of the lung-parenchyma. Conversely, overexpression of caveolin-1 appears to counteract the development of fibrosis by inhibiting the inflammasome NLRP3 and the associated expression of interleukin-1β. In this study, the interaction between Fyn-kinase and caveolin-1 in the alveolar epithelium of various bleomycin (BLM)/TGF-β damage models using precision-cut lung slices (PCLS), wildtype (WT) and caveolin-1 knockout (KO) mice as well as the human NCI-H441 cell line, were investigated. In WT mouse lung tissues, strong signals for Fyn-kinase were detected in alveolar epithelial type I cells, whereas in caveolin-1 KO animals, expression shifted to alveolar epithelial type II cells. Caveolin-1 and Fyn-kinase were found to be co-localized in isolated lipid rafts of NCI-H441 cell membrane fractions. These findings were corroborated by co-immunoprecipitation studies in which a co-localization of Cav-1 and Fyn-kinase was detected in the cell membrane of the alveolar epithelium. After TGF-β and BLM-induced damage to the alveolar epithelium both in PCLS and cell culture experiments, a decrease in caveolin-1 and Fyn-kinase was found. Furthermore, TEER (transepithelial electrical resistance) measurements indicated that TGF-β and BLM have a damaging effect on cell-cell contacts and thus impair the barrier function in NCI-H441 cell monolayers. This effect was attenuated after co-incubation with the Fyn-kinase inhibitor, PP-2. Our data suggest an involvement of Fyn-kinase and caveolin-1 in TGF-β/bleomycin-induced impairment of alveolar barrier function and thus a possible role in the early stages of pulmonary fibrosis. Fyn-kinase and/or its complex with caveolin-1 might, therefore, be novel therapeutic targets in IPF.

PMID:35710078 | DOI:10.1016/j.ejps.2022.106236

Oxid Med Cell Longev. 2022 Jun 6;2022:8002566. doi: 10.1155/2022/8002566. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a refractory chronic respiratory disease with progressively exacerbating symptoms and a high mortality rate. There are currently only two effective drugs for IPF; thus, there is an urgent need to develop new therapeutics. Previous experiments have shown that ginkgolic acid (GA), as a SUMO-1 inhibitor, exerted an inhibitory effect on cardiac fibrosis induced by myocardial infarction. Regarding the pathogenesis of PF, previous studies have concluded that small ubiquitin-like modifier (SUMO) polypeptides bind multiple target proteins and participate in fibrosis of multiple organs, including PF. In this study, we found altered expression of SUMO family members in lung tissues from IPF patients. GA mediated the reduced expression of SUMO1/2/3 and the overexpression of SENP1 in a PF mouse model, which improved PF phenotypes. At the same time, the protective effect of GA on PF was also confirmed in the SENP1-KO transgenic mice model. Subsequent experiments showed that SUMOylation of SMAD4 was involved in PF. It was inhibited by TGF-β1, but GA could reverse the effects of TGF-β1. SENP1 also inhibited the SUMOylation of SMAD4 and then participated in epithelial-mesenchymal transition (EMT) downstream of TGF-β1. We also found that SENP1 regulation of SMAD4 SUMOylation affected reactive oxygen species (ROS) production during TGF-β1-induced EMT and that GA prevented this oxidative stress through SENP1. Therefore, GA may inhibit the SUMOylation of SMAD4 through SENP1 and participate in TGF-β1-mediated pulmonary EMT, all of which reduce the degree of PF. This study provided potential novel targets and a new alternative for the future clinical testing in PF.

PMID:35707278 | PMC:PMC9192210 | DOI:10.1155/2022/8002566

BMJ Open. 2022 Jun 15;12(6):e055077. doi: 10.1136/bmjopen-2021-055077.

ABSTRACT

OBJECTIVES: To describe 6-min walk test (6MWT) outcomes, and to investigate their correlations with cardiopulmonary and lung function among patients with interstitial lung disease (ILD) which was not limited to idiopathic pulmonary fibrosis.

METHODS: We collected patients' demographic data and obtained minute-by-minute 6MWT outcomes. Modified Borg scale was employed to assess patients' dyspnoea, whereas New York Heart Association (NYHA) classification and pulmonary function test were used to evaluate patients' cardiopulmonary functions.

RESULTS: Heart rate (HR) exhibited a continuous upward trend, while SpO2 exhibited an overall downward with a slight increase at the fifth minute. The SpO2 nadir for 70 patients (9.3%) was lower than 80%. Further, the SpO2 nadir for 78.27% of the participants appeared at the end of the fourth minute. The 6-min walk distance (6MWD) had the strongest correlation with NYHA classification (r=0.82, p<0.01). The ratio of 6MWD to predicted 6MWD was most correlated to forced expiratory volume in the first second (r=0.30, p<0.01) and forced vital capacity (r=0.30, p<0.01). SpO2 at 3 min had the strongest correlation to patients' diffusing capacity of the lungs for carbon monoxide (r=0.41, p<0.01). We found significant differences in 6MWD (F=2.44, p=0.033), SpO2 change (F=2.58, p=0.025), HR at 0 min (F=2.87, p=0.014), HR at end of 6 min (F=2.58, p=0.025) and HR zenith (F=2.64, p=0.022) between the subtypes of ILD.

CONCLUSION: This observation provided an important evidence regarding oxygen titration. It is better to maintain SpO2 above 88% for 4 min instead of 3 min. SpO2 at the third minute was the most valuable predictor of patients' lung function. 6MWD and SpO2 changes were more discriminative in subtypes.

PMID:35705338 | DOI:10.1136/bmjopen-2021-055077

PLoS One. 2022 Jun 15;17(6):e0270005. doi: 10.1371/journal.pone.0270005. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with no curative pharmacological treatment. The most used animal model of IPF for anti-fibrotic drug screening is bleomycin (BLM)-induced lung fibrosis. However, several issues have been reported: the balance among disease resolution, an appropriate time window for therapeutic intervention and animal welfare remain critical aspects yet to be fully elucidated. In this study, C57Bl/6 male mice were treated with BLM via oropharyngeal aspiration (OA) following either double or triple administration. The fibrosis progression was longitudinally assessed by micro-CT every 7 days for 4 weeks after BLM administration. Quantitative micro-CT measurements highlighted that triple BLM administration was the ideal dose regimen to provoke sustained lung fibrosis up to 28 days. These results were corroborated with lung histology and Bronchoalveolar Lavage Fluid cells. We have developed a mouse model with prolonged lung fibrosis enabling three weeks of a curative therapeutic window for the screening of putative anti-fibrotic drugs. Moreover, we have demonstrated the pivotal role of longitudinal micro-CT imaging in reducing the number of animals required per experiment in which each animal can be its own control. This approach permits a valuable decrease in costs and time to develop disease animal models.

PMID:35704641 | DOI:10.1371/journal.pone.0270005

Risk Manag Healthc Policy. 2022 Jun 8;15:1189-1201. doi: 10.2147/RMHP.S357606. eCollection 2022.

ABSTRACT

OBJECTIVE: This study aims to evaluate the risk of bias (ROB) and reporting quality of idiopathic pulmonary fibrosis (IPF) prediction models by assessing characteristics of these models.

METHODS: The development and/or validation of IPF prognostic models were identified via an electronic search of PubMed, Embase, and Web of Science (from inception to 12 August, 2021). Two researchers independently assessed the risk of bias (ROB) and reporting quality of IPF prediction models based on the Prediction model Risk Of Bias Assessment Tool (PROBAST) and Transparent Reporting of a multivariable prognostic model for Individual Prognosis or Diagnosis (TRIPOD) checklist.

RESULTS: Twenty prognostic model studies for IPF were included, including 7 (35%) model development and external validation studies, 8 (40%) development studies, and 5 (25%) external validation studies. According to PROBAST, all studies were appraised with high ROB, because of deficient reporting in the domains of participants (45.0%) and analysis (67.3%), and at least 55% studies were susceptible to 4 of 20 sources of bias. For the reporting quality, none of them completely adhered to the TRIPOD checklist, with the lowest mean reporting score for the methods and results domains (46.6% and 44.7%). For specific items, eight sub-items had a reporting rate ≥80% and adhered to the TRIPOD checklist, and nine sub-items had a very poor reporting rate, less than 30%.

CONCLUSION: Studies adhering to PROBAST and TRIPOD checklists are recommended in the future. The reproducibility and transparency can be improved when studies completely adhere to PROBAST and TRIPOD checklists.

PMID:35702399 | PMC:PMC9188804 | DOI:10.2147/RMHP.S357606

Hum Genomics. 2022 Jun 13;16(1):20. doi: 10.1186/s40246-022-00393-0.

ABSTRACT

The increased resolution of single-cell RNA-sequencing technologies has led to major breakthroughs and improved our understanding of the normal and pathologic conditions of multiple tissues and organs. In the study of parenchymal lung disease, single-cell RNA-sequencing has better delineated known cell populations and identified novel cells and changes in cellular phenotypes and gene expression patterns associated with disease. In this review, we aim to highlight the advances and insights that have been made possible by applying these technologies to two seemingly very different lung diseases: fibrotic interstitial lung diseases, a group of relentlessly progressive lung diseases leading to pulmonary fibrosis, and COVID-19 pneumonia, an acute viral disease with life-threatening complications, including pulmonary fibrosis. We discuss changes in cell populations and gene expression, highlighting potential common features, such as alveolar cell epithelial injury and aberrant repair and monocyte-derived macrophage populations, as well as relevance and implications to mechanisms of disease and future directions.

PMID:35698166 | DOI:10.1186/s40246-022-00393-0

Arch Bronconeumol. 2022 May 26:S0300-2896(22)00389-1. doi: 10.1016/j.arbres.2022.05.005. Online ahead of print.

ABSTRACT

We present the case of a patient diagnosed with Idiopathic Pulmonary Fibrosis who experienced a hypersensitivity reaction to both pirfenidone and nintedanib. Given the lack of alternative treatment for the patient's condition and of standard antifibrotic desensitization protocols, we designed a protocol for desensitization to pirfenidone. The patient now tolerates pirfenidone, with functional and radiologic stability of the disease.

PMID:35697567 | DOI:10.1016/j.arbres.2022.05.005

Respirology. 2022 Jun 13. doi: 10.1111/resp.14310. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) has poor prognosis, and the multidisciplinary diagnostic agreement is low. Moreover, surgical lung biopsies pose comorbidity risks. Therefore, using data from non-invasive tests usually employed to assess interstitial lung diseases (ILDs), we aimed to develop an automated algorithm combining deep learning and machine learning that would be capable of detecting and differentiating IPF from other ILDs.

METHODS: We retrospectively analysed consecutive patients presenting with ILD between April 2007 and July 2017. Deep learning was used for semantic image segmentation of HRCT based on the corresponding labelled images. A diagnostic algorithm was then trained using the semantic results and non-invasive findings. Diagnostic accuracy was assessed using five-fold cross-validation.

RESULTS: In total, 646,800 HRCT images and the corresponding labelled images were acquired from 1068 patients with ILD, of whom 42.7% had IPF. The average segmentation accuracy was 96.1%. The machine learning algorithm had an average diagnostic accuracy of 83.6%, with high sensitivity, specificity and kappa coefficient values (80.7%, 85.8% and 0.665, respectively). Using Cox hazard analysis, IPF diagnosed using this algorithm was a significant prognostic factor (hazard ratio, 2.593; 95% CI, 2.069-3.250; p < 0.001). Diagnostic accuracy was good even in patients with usual interstitial pneumonia patterns on HRCT and those with surgical lung biopsies.

CONCLUSION: Using data from non-invasive examinations, the combined deep learning and machine learning algorithm accurately, easily and quickly diagnosed IPF in a population with various ILDs.

PMID:35697345 | DOI:10.1111/resp.14310

J Clin Rheumatol. 2022 Jun 13. doi: 10.1097/RHU.0000000000001847. Online ahead of print.

ABSTRACT

BACKGROUND/OBJECTIVE: Patients classified as interstitial pneumonia with autoimmune features (IPAF) have interstitial lung disease (ILD) and features of autoimmunity but do not fulfill criteria for connective tissue diseases (CTDs). Our goal was to identify patients classifiable as IPAF, CTD-ILD, and idiopathic pulmonary fibrosis (IPF) from a preexisting pulmonary cohort and evaluate the prognosis of patients with IPAF.

METHODS: We reviewed the medical records of 456 patients from a single-center pulmonary ILD cohort whose diagnoses were previously established by a multidisciplinary panel that did not include rheumatologists. We reclassified patients as IPAF, CTD-ILD, or IPF. We compared transplant-free survival using Kaplan-Meier methods and identified prognostic factors using Cox models.

RESULTS: We identified 60 patients with IPAF, 113 with CTD-ILD, and 126 with IPF. Transplant-free survival of IPAF was not statistically significantly different from that of CTD-ILD or IPF. Among IPAF patients, male sex (hazard ratio, 4.58 [1.77-11.87]) was independently associated with worse transplant-free survival. During follow-up, only 10% of IPAF patients were diagnosed with CTD-ILD, most commonly antisynthetase syndrome.

CONCLUSION: Despite similar clinical characteristics, most patients with IPAF did not progress to CTD-ILD; those who did often developed antisynthetase syndrome, highlighting the critical importance of comprehensive myositis autoantibody testing in this population. As in other types of ILD, male sex may portend a worse prognosis in IPAF. The routine engagement of rheumatologists in the multidisciplinary evaluation of ILD will help ensure the accurate classification of these patients and help clarify prognostic factors.

PMID:35697042 | DOI:10.1097/RHU.0000000000001847

Respir Med. 2022 Jun 4;200:106898. doi: 10.1016/j.rmed.2022.106898. Online ahead of print.

ABSTRACT

BACKGROUND: Several studies have reported that acute exacerbation (AE), which occurs during the clinical course of idiopathic pulmonary fibrosis (IPF), also occurs in rheumatoid arthritis-associated interstitial lung disease (RA-ILD). However, the incidence, clinical features, and risk factors for AE, a major cause of death of RA-ILD patients, and the differences in clinical aspects of AE between RA-ILD and IPF have yet to be fully understood.

METHODS: We retrospectively reviewed data on 149 RA-ILD patients and 305 IPF patients. We investigated the frequency of AE and compared the clinical data between RA-ILD with and without AE to clarify the risk factor for AE. We also compared the post-AE prognosis and cause of death between RA-ILD and IPF patients.

RESULTS: Twenty-seven (18.1%) RA-ILD patients and 84 (27.5%) IPF patients developed AE. The median survival time (MST) after AE of RA-ILD and IPF was 277 days and 60 days, respectively (log rank, p = 0.038). In a multivariate analysis, hypoalbuminemia [odds ratio (O.R.) 0.090 (95%CI 0.011-0.733), p = 0.012] and % carbon monoxide diffusion capacity (%DLCO) [O.R. 0.810 (95%CI 0.814-0.964), p < 0.01] were independent risk factors for AE. AE was the most frequent cause of death of RA-ILD and IPF.

CONCLUSION: RA-ILD patients could develop AE, and AE was not uncommon in RA-ILD or IPF. %DLCO and hypoalbuminemia were predictive factors of AE in RA-ILD. The prognosis after AE of RA-ILD was significantly better than that of IPF. The most frequent cause of death in RA-ILD and IPF was AE.

PMID:35696743 | DOI:10.1016/j.rmed.2022.106898

Am J Respir Cell Mol Biol. 2022 Jun 13. doi: 10.1165/rcmb.2021-0445OC. Online ahead of print.

ABSTRACT

As shown in our previous studies, the intratracheal-administration of stanniocalcin-1 (STC1) ameliorates pulmonary fibrosis by reducing oxidative and endoplasmic reticulum stress through the uncoupling of respiration in a bleomycin (BLM)-treated mouse model. However, the overall effect of STC1 on metabolism was not examined. Therefore, we first conducted a comprehensive metabolomics analysis to screen the overall metabolic changes induced by STC1 in an alveolar epithelial cell line using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). The results were subsequently validated in multiple alveolar epithelial and fibroblast cell lines by performing precise analyses of each substance. STC1 stimulated glycolysis, acetyl-CoA synthesis, and the methionine and cysteine-glutathione pathways, which are closely related to the uncoupling of respiration, modulation of epigenetics and reduction in oxidative stress. These results are consistent with our previous study. Subsequently, we focused on the inhibitory factor SMAD7, which exerts an antifibrotic effect and is susceptible to epigenetic regulation. STC1 upregulates SMAD7 in an uncoupling protein 2-dependent manner, induces demethylation of the SMAD7 promoter region and acetylation of the SMAD7 protein in human alveolar epithelial and fibroblast cell lines and a BLM-treated mouse model, and subsequently attenuates fibrosis. The antifibrotic effects of STC1 may partially depend on the regulation of SMAD7. In the evaluation using lung tissue from idiopathic pulmonary fibrosis patients, SMAD7 expression and acetylation were high in the alveolar structure-preserving region and low in the fibrotic region. The intratracheal-administration of STC1 may prevent the development of pulmonary fibrosis by regulating the metabolism-mediated epigenetic modification of SMAD7 in patients.

PMID:35696344 | DOI:10.1165/rcmb.2021-0445OC

Am J Respir Crit Care Med. 2022 Jun 13. doi: 10.1164/rccm.202112-2684OC. Online ahead of print.

ABSTRACT

RATIONALE Reliable outcome prediction in patients with fibrotic lung disease using baseline high-resolution computed tomography (HRCT) data remains challenging. OBJECTIVES To evaluate the prognostic accuracy of a deep learning algorithm (SOFIA), trained and validated in the identification of UIP-like features on HRCT (UIP probability), in a large cohort of well characterised patients with progressive fibrotic lung disease, drawn from a national registry. METHODS SOFIA and radiologist-UIP probabilities were converted to PIOPED-based UIP probability categories (UIP not included in the differential: 0-4%, low probability of UIP: 5-29%, intermediate probability of UIP: 30-69%, high probability of UIP: 70-94%, and pathognomonic for UIP:95-100%) and their prognostic utility assessed using Cox proportional hazards modelling. MEASUREMENTS AND MAIN RESULTS On multivariable analysis adjusting for age, gender, guideline based radiologic diagnosis and disease severity (using total ILD extent on HRCT, %predicted FVC, DLco or the CPI), only SOFIA-UIP probability PIOPED categories predicted survival. SOFIA-PIOPED UIP probability categories remained prognostically significant in patients considered indeterminate (n=83) by expert radiologist consensus (HR1.73, p<0.0001, 95%CI 1.40-2.14). In patients undergoing surgical lung biopsy (SLB) (n=86), after adjusting for guideline-based histologic pattern and total ILD extent on HRCT, only SOFIA-PIOPED probabilities were predictive of mortality (HR1.75, p<0.0001, 95%CI 1.37-2.25). CONCLUSIONS Deep learning-based UIP probability on HRCT provides enhanced outcome prediction in patients with progressive fibrotic lung disease when compared to expert radiologist evaluation or guideline-based histologic pattern. In principle this tool may be useful in multidisciplinary characterisation of fibrotic lung disease. The utility of this technology as a decision support system when ILD expertise is unavailable requires further investigation.

PMID:35696341 | DOI:10.1164/rccm.202112-2684OC

Expert Rev Respir Med. 2022 Jun 13. doi: 10.1080/17476348.2022.2089116. Online ahead of print.

ABSTRACT

INTRODUCTION: Rheumatoid arthritis (RA) is the most common inflammatory autoimmune disease, characterised by symmetric destructive arthritis and synovitis. Lung involvement is frequent, including in the form of interstitial lung disease (ILD). RA-ILD often presents with a radiologic and pathologic pattern of usual interstitial pneumonia, similar to idiopathic pulmonary fibrosis, highlighting the similarities between the two diseases, but other patterns and pathological associations are described.

AREAS COVERED: This article reviews the pathogenesis of pulmonary fibrosis in the setting of rheumatoid arthritis as well as the current and future therapeutic options.

EXPERT OPINION: Pulmonary fibrosis in the setting of RA-ILD is an example of genotype-environment interaction and involves multiple mechanisms including autoimmunity, inflammation and fibrogenesis. Despite that ILD conveys most of the exceeding mortality in RA patients, there are no official guidelines for the management of RA-ILD. Attention should be paid to potential lung toxicity of RA treatment even though some of them might help stabilise the ILD. Current standard of care is often composed of glucocorticoids that may be associated with immunosuppressive therapy. Following the approval of antifibrotic therapy for ILDs with a progressive fibrosing phenotype, current works are evaluating the benefit of such treatment in RA-ILD.

PMID:35695895 | DOI:10.1080/17476348.2022.2089116

RSC Med Chem. 2022 Apr 1;13(5):610-621. doi: 10.1039/d1md00403d. eCollection 2022 May 25.

ABSTRACT

Pirfenidone (PFD) was the first approved drug by FDA for the treatment of idiopathic pulmonary fibrosis (IPF). However, the rapid metabolism of 5-methyl of PFD increases the risk of side effects in clinics. Thus, in this paper, a common practice that a stable amide bond linking various groups used to replace 5-methyl of PFD in medicinal chemistry was applied, and total 18 PFD derivatives were synthesized. All compounds were investigated for their antiproliferation activities against NIH3T3 cells and the structure-activity relationships of the target compounds were also discussed. Among them, YZQ17 possessed potent antiproliferation activity compared to PFD and better potency in inhibiting TGF-β-induced migration of NIH3T3 cells at a much lower concentration than that of PFD. In addition, YZQ17 dramatically inhibited the expression levels of fibrotic markers α-SMA, collagen I, and fibronectin. Moreover, further mechanistic studies confirmed that YZQ17 exhibited this considerable anti-fibrosis activity via the TGF-β/Smad2/3 dependent pathway. Finally, the results of human and rat liver microsomes assay in vitro and pharmacokinetic assay in rats confirmed that YZQ17 showed better pharmacokinetics than that of PFD. Collectively, the preliminary study of PFD derivatives modified by the amide group indicated that YZQ17 could be regarded as a lead compound for further investigation and optimization.

PMID:35694690 | PMC:PMC9132227 | DOI:10.1039/d1md00403d

J Thorac Dis. 2022 May;14(5):1450-1465. doi: 10.21037/jtd-21-1830.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal heterogeneous disease with a varied clinical course that is difficult to predict. Accurate predictive models are urgently needed to identify individuals with poor survival for the optimal timing of referral for transplantation and provide some clues for mechanistic research on disease progression.

METHODS: We obtained the gene expression profiles of bronchoalveolar lavage fluid (BALF) from the Gene Expression Omnibus. Individuals from the GPL14550 platform were assigned to the derivation cohort (n=112) and individuals from the GPL17077 platform to the validation cohort (n=64). Univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were applied to select candidate genes for overall survival. A nomogram model was constructed based on Cox hazard regression analysis. The model was assessed by C-statistic, calibration curve, and decision curve analysis (DCA) and was externally validated.

RESULTS: A nomogram model comprising seven genes was constructed. Excellent discrimination and calibration were observed in the derivation (C-index 0.815) and validation (C-index 0.812) cohorts. The AUCs for predicting 1-, 2- and 3-year survival were 0.857, 0.918, 0.930 in the derivation cohort and 0.850, 0.880, 0.925 in the validation cohort, respectively. DCA confirmed the clinical applicability of the model. A risk score based on the model was an independent prognostic predictor and could divide patients into high- and low-risk groups. The Kaplan-Meier analysis displayed that high-risk patients exhibited significantly poorer survival compared with low-risk patients. Gene Set Enrichment Analysis (GSEA) showed that high-risk patients were primarily enriched in inflammatory hallmarks, and single sample GSEA (ssGSEA) indicated that the high-risk group is closely correlated with the immune process. These lead to increased insight into mechanisms associated with IPF progression that inflammation mediated by immune response might be involved in the disease progression.

CONCLUSIONS: The novel BALF seven-gene model performed well in risk stratification and individualized survival prediction for patients with IPF, facilitating personalized management of IPF patients. It deepened the understanding of the role of inflammation in IPF progression, which needs to be further studied.

PMID:35693599 | PMC:PMC9186233 | DOI:10.21037/jtd-21-1830