Ther Adv Respir Dis. 2022 Jan-Dec;16:17534666221135314. doi: 10.1177/17534666221135314.

ABSTRACT

BACKGROUND: Studies on the risk and protective factors for lung function decline and mortality in rheumatoid arthritis-related interstitial lung disease (RA-ILD) are limited.

OBJECTIVES: We aimed to investigate clinical factors and medication uses associated with lung function decline and mortality in RA-ILD.

METHODS: This retrospective cohort study examined the medical records of patients with RA-ILD who visited Severance Hospital between January 2006 and December 2019. We selected 170 patients with RA-ILD who had undergone at least one spirometry test and chest computed tomography scan. An absolute decline of ⩾10% in the functional vital capacity (FVC) was defined as significant decline in pulmonary function. Data for analysis were retrieved from electronic medical records.

RESULTS: Ninety patients (52.9%) were female; the mean age was 64.0 ± 10.2 years. Multivariate logistic regression showed that a high erythrocyte sediment rate level at baseline [odds ratio (OR) = 3.056; 95% confidence interval (CI) = 1.183-7.890] and methotrexate (MTX) use (OR = 0.269; 95% CI = 0.094-0.769) were risk and protective factors for lung function decline, respectively. Multivariate Cox regression analysis indicated that age ⩾65 years (OR = 2.723; 95% CI = 1.142-6.491), radiologic pattern of usual interstitial pneumonia (UIP) or probable UIP (OR = 3.948; 95% CI = 1.522-10.242), baseline functional vital capacity (FVC) % predicted (OR = 0.971; 95% CI = 0.948-0.994), and MTX use (OR = 0.284; 95% CI = 0.091-0.880) were predictive of mortality.

CONCLUSION: We identified risk and protective factors for lung function decline and mortality in patients with RA-ILD. MTX use was associated with favorable outcome in terms of both lung function and mortality in our cohort.

PMID:36346076 | DOI:10.1177/17534666221135314

Lung. 2022 Nov 8. doi: 10.1007/s00408-022-00589-0. Online ahead of print.

NO ABSTRACT

PMID:36348052 | DOI:10.1007/s00408-022-00589-0

J Adv Res. 2022 Nov 5:S2090-1232(22)00247-8. doi: 10.1016/j.jare.2022.10.018. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF), a life-threatening interstitial lung disease, is characterized by excessive activation and proliferation of fibroblasts and epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AEC) accompanied by a large amount of extracellular matrix aggregation. There are no therapies to reverse pulmonary fibrosis, and nintedanib and pirfenidone could only slow down the decline of lung function of IPF patients and delay their survival time. Niclosamide (Ncl) is an antihelminthic drug approved by FDA, which has been reported to have pleiotropic pharmacological activities in recent years, but it's almost complete insolubility in water limits its poor clinical application.

OBJECTIVES: To improve the water solubility of Ncl, explore its ability to reverse BLM-induced pulmonary fibrosis and its specific mechanism of action.

METHODS: The Niclosamide-loaded nanoparticles (Ncl-NPs) were formed by emulsification solvent evaporation method. A mouse model induced by bleomycin (BLM) was established to evaluate its effects and mechanisms of inhibiting and reversing fibrosis in vivo. The cell models treated by transforming growth factor-β1 (TGF-β1) were used to examine the mechanism of Ncl-NPs inhibiting fibrosis in vitro. Flow cytometry, IHC,IL-4-induced macrophage model and co-culture system were used to assess the effect of Ncl-NPs on M2 polarization of macrophages.

RESULTS: The Ncl-NPs improved the poor water solubility of Ncl. The lower dose of Ncl-NPs (2.5 mg/kg) showed the same effect of reversing established pulmonary fibrosis as free Ncl (5 mg/kg). Mechanistic studies revealed that Ncl-NPs blocked TGF-β/Smad and signaling transducer and activator of transcription 3 (Stat3) signaling pathways and inhibited the M2 polarization of macrophages. Additionally, H&E staining of the tissues initially showed the safety of Ncl-NPs.

CONCLUSION: These results indicate Ncl-NPs may serve as a new idea for the treatment of pulmonary fibrosis.

PMID:36347425 | DOI:10.1016/j.jare.2022.10.018

Respir Med. 2022 Oct 25;204:107015. doi: 10.1016/j.rmed.2022.107015. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease for which two effective antifibrotics, nintedanib and pirfenidone, are available. However, many patients receive a reduced dosage or pause treatment due to side effects although the impact of antifibrotic treatment reduction is uncertain.

METHODS: We retrospectively investigated the impact of antifibrotic treatment reduction on death in a large real-life IPF cohort. The primary endpoint of the analyses was time until death by any cause. Five patient groups were defined based on treatment intensity (full, reduced or no treatment) and the antifibrotic drug type (pirfenidone or nintedanib). Between group survival was compared using Cox proportional hazards analysis adjusted for age, sex, smoking status, and lung function at baseline.

RESULTS: 375 patients from the Danish PFBIO-cohort were followed from April 2016 until November 2021 with a median follow-up time of 1.84 years. Of patients receiving nintedanib and pirfenidone, 80.19% and 67.42% had reduced treatment, respectively, when considering the entire follow-up period. Treatment with nintedanib and pirfenidone was associated with improved survival compared to no antifibrotic treatment independent of treatment intensity (nintedanib: HR: 0.31, 95%-CI: 0.19-0.53, p < 0.001 & pirfenidone: HR: 0.26, 95%-CI: 0.16-0.42, p < 0.001). Nintedanib and pirfenidone in lower intensities were not associated with worse survival outcomes.

CONCLUSION: A substantial proportion of patients with IPF receive reduced antifibrotic treatment to ameliorate the side effects associated with a full dosage regime. Treatment with nintedanib and pirfenidone, independent of treatment intensity, was preferable over no antifibrotic treatment in improving survival and reduced dose appears to be a good alternative if full dose is not tolerated.

PMID:36347111 | DOI:10.1016/j.rmed.2022.107015

Respir Med. 2022 Nov 3;205:107037. doi: 10.1016/j.rmed.2022.107037. Online ahead of print.

ABSTRACT

INTRODUCTION: Pulmonary fibrosis is a risk factor for the development of lung cancer. However, the low incidence of the pathology means that it is not well represented in thoracic surgery risk scoring systems. We aimed to assess whether short and long-term outcomes after lung resection for primary lung cancer were worse in patients with pre-existing pulmonary fibrosis.

METHODS: A total of 5029 consecutive patients undergoing lung resection for primary lung cancer between 2012 and 2018 in two UK centres were included. Primary outcomes were 90-day & 1-year mortality, post-operative complications and overall survival. Univariable analyses were used to compare outcomes between patients with and without pre-existing pulmonary fibrosis.

RESULTS: In total, 0.7% (n = 33) of patients had a pre-existing diagnosis of pulmonary fibrosis (idiopathic pulmonary fibrosis 48.5%, non-specific interstitial pneumonia 6.1%, unknown 45.5%). Overall, 90-day and 1-year mortality were all significantly higher amongst patients with fibrosis (90-day: 18.2% vs 3.6%, p < 0.001; 1-year: 36.4% vs 10.7%, p < 0.001). The rate of reintubation was significantly higher for patients with fibrosis (9.1% vs 2.9%, p = 0.038) yet there was no difference in post-operative length of stay between groups (fibrosis: 6 days [IQR 4-9 days] vs non-fibrosis: 5 days [IQR 4-8 days], p = 0.675). Overall survival was also significantly reduced for patients with pulmonary fibrosis (log-rank analysis, p < 0.001).

CONCLUSIONS: Despite its small size, this study suggests that short and long-term outcomes after lung resection are worse for patients with pre-existing pulmonary fibrosis. Segmental resections could be considered in these patients where oncologically appropriate to minimise peri-operative risk.

PMID:36347082 | DOI:10.1016/j.rmed.2022.107037

J Control Release. 2022 Nov 3;352:570-585. doi: 10.1016/j.jconrel.2022.10.045. Online ahead of print.

ABSTRACT

Pirfenidone (PRF), the first FDA-approved drug to treat idiopathic pulmonary fibrosis (IPF) and formulated as an oral dosage form, has many side effects. To enhance the therapeutic effect, we discovered a high-load nanoemulsion using a novel deep eutectic solvent (DES) and developed an inhalation drug with improved bioavailability. The DES of PRF and N-acetylcysteine were discovered, and their physicochemical properties were evaluated in this study. The mechanism of DES formation was confirmed by FT-IR and 1H NMR and suggested to involve hydrogen bonding. The DES nanoemulsion in which the nano-sized droplets were dispersed is optimized by mixing the DES and distilled water in a ratio. The in vivo pharmacokinetic study showed that the pulmonary route of administration is superior to that of the oral route, and the DES nanoemulsion is superior to that of the PRF solution in achieving better bioavailability and lung distribution. The therapeutic effect of PRF for IPF could be confirmed through in vivo pharmacodynamics studies, including lung function assessment, enzyme-linked immunosorbent assay, histology, and micro-computed tomography using the bleomycin-induced IPF rat model. In addition, the pulmonary route administration of PRF is advantageous in reducing the toxicity risk.

PMID:36341935 | DOI:10.1016/j.jconrel.2022.10.045

Respir Med Case Rep. 2022 Oct 25;40:101756. doi: 10.1016/j.rmcr.2022.101756. eCollection 2022.

ABSTRACT

BACKGROUND: Bronchial Dieulafoy's disease (BDD) is a rare vascular anomaly that was first described in 1995. The main symptom is recurrent hemoptysis. It can be diagnosed through angiography, bronchoscopy, and sometimes histology and endobronchial ultrasound scan (EBUS). Treatment includes embolization and surgery.

CASE PRESENTATION: A 77-year-old male with dyspnea and CT scan revealing an interstitial pattern underwent bronchoscopy for bronchoalveolar lavage (BAL). During bronchoscopy, a protruding white non-pulsatile lesion was biopsied. The biopsy triggered a massive hemorrhage, which required an embolization procedure. Bronchial Dieulafoy's disease was diagnosed. There was no need for surgery in this case. The interstitial pattern was diagnosed as idiopathic pulmonary fibrosis.

CONCLUSIONS: This report describes a novel case of BDD leading to bronchial hemorrhage. Considering the endoscopic differential diagnosis, including rather frequent carcinoid tumor and broncholithiasis, we highlight the need for extreme caution when considering endoscopic biopsy of protruding white lesions. Indeed, biopsy - or even contact - with a BDD lesion is frequently associated with massive hemorrhage. According to our review, BDD is the most hemorrhage-prone lesion when biopsied, associated with significant bleeding in 90% of cases and 30% mortality, compared with significant bleeding in only 2.6% of carcinoid tumors and 3.1% of broncholithiasis cases.This case of BDD is also original since associated with idiopathic pulmonary fibrosis. It is to our knowledge the first time that such an association has been reported.

PMID:36340864 | PMC:PMC9630769 | DOI:10.1016/j.rmcr.2022.101756

Breathe (Sheff). 2022 Sep;18(3):220074. doi: 10.1183/20734735.0074-2022. Epub 2022 Sep 13.

ABSTRACT

The PANTHER-IPF trial was a turning point in treatment of idiopathic pulmonary fibrosis (#IPF) highlighting the importance of randomised controlled trials in determining treatment strategies, even for rare diseases and/or potentially fatal acute events https://bit.ly/3Oi0KwD.

PMID:36340823 | PMC:PMC9584592 | DOI:10.1183/20734735.0074-2022

PeerJ. 2022 Oct 31;10:e14045. doi: 10.7717/peerj.14045. eCollection 2022.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease without effective treatments. Mitochondrial dysfunction weakens the ability of mesenchymal stem cells (MSCs) to repair the distal lung epithelium, which is a probable pathogenesis of IPF. In previous research, we found that cinnamaldehyde (CA) can maintain the mitochondrial morphology of MSCs.

METHODS: This present study evaluated the effect and mechanism of CA on murine lung MSCs using the hydrogen peroxide model. Antioxidant effects and mitochondrial function were determined using flow cytometry. The mRNA levels of mitochondrial dynamics and the expressions of autophagy-related proteins were also detected.

RESULTS: CA can increase the levels of SOD, MMP and ATP, decrease the rate of ROS and apoptosis, and restore the mitochondrial structure. CA can also improve the mRNA expression of MFN1, MFN2, FIS1, DRP1, OPA1, and PGC-1α, increase the expression of LC3 II and p62 and promote the PINK1/Parkin signaling pathway. Our results demonstrated that CA can control mitochondrial quality and avoid apoptosis, which may be associated with the regulation of the PINK1/Parkin signaling pathway.

PMID:36340192 | PMC:PMC9632461 | DOI:10.7717/peerj.14045

Lancet Digit Health. 2022 Nov 1:S2589-7500(22)00173-X. doi: 10.1016/S2589-7500(22)00173-X. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease with a variable clinical trajectory. Decline in forced vital capacity (FVC) is the main indicator of progression; however, missingness prevents long-term analysis of patterns in lung function. We aimed to identify distinct clusters of lung function trajectory among patients with idiopathic pulmonary fibrosis using machine learning techniques.

METHODS: We did a secondary analysis of longitudinal data on FVC collected from a cohort of patients with idiopathic pulmonary fibrosis from the PROFILE study; a multicentre, prospective, observational cohort study. We evaluated the imputation performance of conventional and machine learning techniques to impute missing data and then analysed the fully imputed dataset by unsupervised clustering using self-organising maps. We compared anthropometric features, genomic associations, serum biomarkers, and clinical outcomes between clusters. We also performed a replication of the analysis on data from a cohort of patients with idiopathic pulmonary fibrosis from an independent dataset, obtained from the Chicago Consortium.

FINDINGS: 415 (71%) of 581 participants recruited into the PROFILE study were eligible for further analysis. An unsupervised machine learning algorithm had the lowest imputation error among tested methods, and self-organising maps identified four distinct clusters (1-4), which was confirmed by sensitivity analysis. Cluster 1 comprised 140 (34%) participants and was associated with a disease trajectory showing a linear decline in FVC over 3 years. Cluster 2 comprised 100 (24%) participants and was associated with a trajectory showing an initial improvement in FVC before subsequently decreasing. Cluster 3 comprised 113 (27%) participants and was associated with a trajectory showing an initial decline in FVC before subsequent stabilisation. Cluster 4 comprised 62 (15%) participants and was associated with a trajectory showing stable lung function. Median survival was shortest in cluster 1 (2·87 years [IQR 2·29-3·40]) and cluster 3 (2·23 years [1·75-3·84]), followed by cluster 2 (4·74 years [3·96-5·73]), and was longest in cluster 4 (5·56 years [5·18-6·62]). Baseline FEV1 to FVC ratio and concentrations of the biomarker SP-D were significantly higher in clusters 1 and 3. Similar lung function clusters with some shared anthropometric features were identified in the replication cohort.

INTERPRETATION: Using a data-driven unsupervised approach, we identified four clusters of lung function trajectory with distinct clinical and biochemical features. Enriching or stratifying longitudinal spirometric data into clusters might optimise evaluation of intervention efficacy during clinical trials and patient management.

FUNDING: National Institute for Health and Care Research, Medical Research Council, and GlaxoSmithKline.

PMID:36333179 | DOI:10.1016/S2589-7500(22)00173-X

Acute Crit Care. 2022 Oct 28. doi: 10.4266/acc.2022.00444. Online ahead of print.

ABSTRACT

BACKGROUND: Delayed intubation is associated with poor prognosis in patients with respiratory failure. However, the effect of delayed intubation in patients with idiopathic pulmonary fibrosis (IPF) remains unknown. This study aimed to analyze whether timing of intubation after high-concentration oxygen therapy was associated with worse clinical outcomes in IPF patients.

METHODS.: This retrospective propensity score-matched study enrolled adult patients with IPF who underwent mechanical ventilation between January 2011 and July 2021. Patients were divided into early and delayed intubation groups. Delayed intubation was defined as use of high-concentration oxygen therapy for at least 48 hours before tracheal intubation. The primary outcome was intensive care unit (ICU) mortality, and a conditional logistic regression model was used to evaluate the association between timing of intubation and clinical outcomes.

RESULTS.: The median duration of high-concentration oxygen therapy before intubation was 0.5 days in the early intubation group (n=60) and 5.1 days in the delayed intubation group (n=36). The ICU mortality rate was 56.7% and 75% in the early and delayed intubation groups, respectively, before propensity matching (P=0.075). After matching for demographic and clinical covariates, 33 matched pairs were selected. In the propensity-matched cohort, delayed intubation significantly increased the risk of ICU mortality (adjusted odds ratio, 3.99; 95% confidence interval, 1.0215.63; P=0.046). However, in-hospital mortality did not differ significantly between the groups.

CONCLUSION.: : In patients with IPF, delayed intubation after initiation of high-concentration oxygen therapy was significantly associated with increased risk of ICU mortality compared to early intubation.

PMID:36330732 | DOI:10.4266/acc.2022.00444

Front Genet. 2022 Oct 18;13:1056103. doi: 10.3389/fgene.2022.1056103. eCollection 2022.

ABSTRACT

[This corrects the article DOI: 10.3389/fgene.2022.939175.].

PMID:36330436 | PMC:PMC9623333 | DOI:10.3389/fgene.2022.1056103

Eur Respir J. 2022 Nov 3:2201794. doi: 10.1183/13993003.01794-2022. Online ahead of print.

ABSTRACT

BACKGROUND: GLPG1205 is a selective functional antagonist of G-protein-coupled receptor 84, which plays an important role in fibrotic processes. This study assessed efficacy, safety, and tolerability of GLPG1205 for treatment of idiopathic pulmonary fibrosis (IPF).

METHODS: PINTA (NCT03725852) was a Phase 2, randomised, double-blind, placebo-controlled, proof-of-concept trial. Patients with IPF were randomised 2:1 to once daily oral GLPG1205 100 mg or placebo for 26 weeks and stratified to receive GLPG1205 alone or with local standard of care (nintedanib or pirfenidone). The primary endpoint was change from baseline in forced vital capacity (FVC); other endpoints were safety and tolerability, and lung volumes measured by imaging (high-resolution computed tomography). The study was not powered for statistical significance.

RESULTS: In total, 68 patients received study medication. Least squares mean (95% confidence interval) change from baseline in FVC at Week 26 was -33.68 (-112.0, 44.68) mL with GLPG1205 and -76.00 (-170.7, 18.71) mL with placebo (least squares mean difference, 42.33 [-81.84, 166.5] mL; p=0.50). Lung volumes by imaging declined -58.30 versus -262.72 mL (whole lung) and -33.68 versus -135.48 mL (lower lobes) with GLPG1205 versus placebo, respectively. Treatment with GLPG1205 versus placebo resulted in higher proportions of serious and severe treatment-emergent adverse events and treatment-emergent discontinuations, most apparent with nintedanib.

CONCLUSION: Treatment with GLPG1205 did not result in a significant difference in FVC decline versus placebo. GLPG1205 demonstrated a poorer safety and tolerability profile than placebo.

PMID:36328358 | DOI:10.1183/13993003.01794-2022

PLoS One. 2022 Nov 3;17(11):e0277007. doi: 10.1371/journal.pone.0277007. eCollection 2022.

ABSTRACT

BACKGROUND: Serologic testing for autoantibodies is recommended in interstitial lung diseases (ILDs), as connective tissue diseases (CTDs) are an important secondary cause. Myositis antibodies are associated with CTD-ILD, but clinical associations with other ILDs are unclear. In this study, associations of myositis antibodies in various ILDs were evaluated.

METHODS: 1463 ILD patients and 116 healthy subjects were screened for myositis antibodies with a line-blot assay on serum available at time of diagnosis. Additionally, bronchoalveolar lavage fluid (BALf) was analysed.

RESULTS: A total of 394 patients demonstrated reactivity to at least one antibody, including anti-Ro52 (36.0%), anti-Mi-2β (17.3%) and anti-Jo-1 (10.9%). Anti-Jo-1 (OR 6.4; p<0.100) and anti-Ro52 (OR 6.0; p<0.001) were associated with CTD-ILD. Interestingly, anti-Mi-2β was associated with idiopathic pulmonary fibrosis (IPF; OR 5.3; p = 0.001) and hypersensitivity pneumonitis (HP; OR 5.9; p<0.001). Furthermore, anti-Mi-2β was strongly associated with a histological usual interstitial pneumonia (UIP) pattern (OR 6.5; p < 0.001). Moreover, anti-Mi-2β reactivity was identified in BALf and correlated with serum anti-Mi-2β (r = 0.64; p = 0.002). No differences were found in survival rates between ILD patients with and without serum Mi-2β reactivity (hazard ratio 0.835; 95% CI 0.442-1.575; p = 0.577).

CONCLUSION: In conclusion, novel associations of antibody Mi-2β with fibrotic ILD were found. Furthermore, serum anti-Mi-2β was associated with a histological UIP pattern and presence of anti-Mi-2β in BALf. Possibly, anti-Mi-2β could be implemented as a future diagnostic biomarker for fibrotic ILD.

PMID:36327336 | DOI:10.1371/journal.pone.0277007

Front Endocrinol (Lausanne). 2022 Oct 17;13:1040526. doi: 10.3389/fendo.2022.1040526. eCollection 2022.

ABSTRACT

CTGF is a multifunctional protein and plays different roles in different cells and under different conditions. Pamrevlumab, a monoclonal antibody against CTGF, is an FDA approved drug for idiopathic pulmonary fibrosis (IPF) and Duchenne muscular dystrophy (DMD). Recent studies have shown that CTGF antibodies may potentially serve as a new drug for osteoarthritis (OA). Expression of CTGF is significantly higher in OA joints than in healthy counterparts. Increasing attention has been attracted due to its interesting roles in joint homeostasis. Joint homeostasis relies on normal cellular functions and cell-cell interactions. CTGF is essential for physiological activities of chondrocytes. Abnormal CTGF expression may cause cartilage degeneration. In this review, the physiological functions of CTGF in chondrocytes and related mechanisms are summarized. Changes in the related signaling pathways due to abnormal CTGF are discussed, which are contributing factors to inflammation, cartilage degeneration and synovial fibrosis in OA. The possibility of CTGF as a potential therapeutic target for OA treatment are reviewed.

PMID:36325449 | PMC:PMC9618584 | DOI:10.3389/fendo.2022.1040526

Front Pharmacol. 2022 Oct 17;13:1027332. doi: 10.3389/fphar.2022.1027332. eCollection 2022.

NO ABSTRACT

PMID:36324683 | PMC:PMC9620474 | DOI:10.3389/fphar.2022.1027332

J Med Case Rep. 2022 Nov 2;16(1):404. doi: 10.1186/s13256-022-03619-w.

ABSTRACT

BACKGROUND: We report a case of acute respiratory distress associated with a histological pattern of acute fibrinous and organizing pneumonia, and discuss the possible responsibility of flecainide therapy.

CASE PRESENTATION: A 61-year-old African woman developed a rapidly progressive dyspnea and required admission in the intensive care unit for orotracheal intubation and mechanical ventilation. Chest X-ray examination revealed bilateral infiltrates predominating in the basal part of both lungs. Lung computed tomography disclosed bilateral ground-glass opacities and septal thickening. After exclusion of the most common causes of infectious or immune pneumonia, a toxic origin was investigated and flecainide toxicity was considered. Lung biopsy was consistent with the unusual pattern of acute fibrinous and organizing pneumonia. Clinical and radiological improvement was noted after corticosteroid therapy, but the patient died from septic complications.

CONCLUSION: Flecainide-induced lung injury has rarely been reported in the literature and remains a diagnosis of exclusion. The histological pattern of acute fibrinous and organizing pneumonia has been previously observed with amiodarone. There are no firm guidelines for the treatment of acute fibrinous and organizing pneumonia, but some patients may positively respond to corticosteroids.

PMID:36320087 | DOI:10.1186/s13256-022-03619-w

Mol Divers. 2022 Nov 2. doi: 10.1007/s11030-022-10557-8. Online ahead of print.

ABSTRACT

Discoidin domain receptor 1 (DDR1) (EC Number 2.7.10.1) has recently been considered as a promising therapeutic target for idiopathic pulmonary fibrosis (IPF). However, none of the currently discovered DDR1 inhibitors have been included in clinical studies due to low target specificity or druggability limitations, necessitating various approaches to develop novel DDR1 inhibitors. In this study, to assure target specificity, a docking assessment of the DDR1 crystal structures was undertaken to find the well-differentiated crystal structure, and 4CKR was identified among many crystal structures. Then, using the best pharmacophore model and molecular docking, virtual screening of the ChEMBL database was done, and five potential molecules were identified as promising inhibitors of DDR1. Subsequently, all hit compound complex systems were validated using molecular dynamics simulations and MM/PBSA methods to assess the stability of the system after ligand binding to DDR1. Based on molecular dynamics simulations and hydrogen-bonding occupancy analysis, the DDR1-Cpd2, DDR1-Cpd17, and DDR1-Cpd18 complex systems exhibited superior stability compared to the DDR1-Cpd1 and DDR-Cpd33 complex systems. Meanwhile, when targeting DDR1, the descending order of the five hit molecules' binding free energies was Cpd17 (- 145.820 kJ/mol) > Cpd2 (- 131.818 kJ/mol) > Cpd18 (- 130.692 kJ/mol) > Cpd33 (- 129.175 kJ/mol) > Cpd1 (- 126.103 kJ/mol). Among them, Cpd2, Cpd17, and Cpd18 showed improved binding characteristics, indicating that they may be potential DDR1 inhibitors. In this research, we developed a high-hit rate, effective screening method that serves as a theoretical guide for finding DDR1 inhibitors for the development of IPF therapeutics.

PMID:36322341 | DOI:10.1007/s11030-022-10557-8

BMJ Case Rep. 2022 Nov 1;15(11):e249912. doi: 10.1136/bcr-2022-249912.

ABSTRACT

Organising pneumonia (OP) is a form of interstitial pneumonia characterised by inflammation and scarring leading to obstruction within the small airways and alveoli. Practice guidelines recommend treatment of moderate to severe OP with glucocorticoids; however, there have been cases of steroid-resistant OP successfully treated with rituximab. We describe a case of a woman in her 20s with rheumatoid arthritis who presented with pleuritic chest pain, haemoptysis and dyspnoea on exertion and was diagnosed with OP after multiple radiographic images and biopsies. The patient failed numerous treatment regimens, including corticosteroids, antibiotics and mycophenolate, but was successfully treated with rituximab. This case highlights the importance of identifying new therapeutic agents that will minimise the use of glucocorticoids in the treatment of OP.

PMID:36319035 | PMC:PMC9628664 | DOI:10.1136/bcr-2022-249912

Arch Bronconeumol. 2022 Oct 13:S0300-2896(22)00584-1. doi: 10.1016/j.arbres.2022.09.020. Online ahead of print.

NO ABSTRACT

PMID:36319518 | DOI:10.1016/j.arbres.2022.09.020