Differentiation. 2022 Apr 14;125:35-44. doi: 10.1016/j.diff.2022.03.004. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease that is characterized by enhanced changes in stem cell differentiation and fibroblast proliferation. Lung resident mesenchymal stem cells (LR-MSCs) are important regulators of pathophysiological processes including tissue repair and inflammation, and evidence suggests that this cell population also plays an essential role in fibrosis. Our previous study demonstrated that Wnt/β-catenin signaling is aberrantly activated in the lungs of bleomycin-treated mice and induces myofibroblast differentiation of LR-MSCs. However, the underlying correlation between LR-MSCs and the Wnt/β-catenin signaling remains poorly understood. We found that Wnt8b was highly expressed by LR-MSCs undergoing myofibroblast differentiation. In vitro, Wnt8b promoted LR-MSCs differentiate into myofibroblasts via activating Wnt/β-catenin signaling. Moreover, siRNA-mediated inhibition of Wnt8b prevented Transforming growth factor (TGF)-β1-induced myofibroblast differentiation of LR-MSCs in vitro and ameliorated pulmonary fibrotic lesions. Our study identified Wnt proteins and Wnt/β-catenin signaling in pulmonary fibrosis in vitro and in vivo, and highlighted Wnt8b as a potential therapeutic target in pulmonary fibrosis. Moreover, these finding might provide a new perspective in the development of treatment strategies for IPF.

PMID:35487030 | DOI:10.1016/j.diff.2022.03.004

Ann Am Thorac Soc. 2022 May;19(5):833-844. doi: 10.1513/AnnalsATS.202102-172OC.

ABSTRACT

Rationale: Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia with impaired survival. Previous guidelines recommend antacid medication to improve respiratory outcomes in patients with IPF. Objectives: This systematic review was undertaken during the development of an American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax guideline. The clinical question was, "Should patients with IPF who have documented abnormal gastroesophageal reflux (GER) with or without symptoms of GER disease 1) be treated with antacid medication or 2) undergo antireflux surgery to improve respiratory outcomes?" Methods: Medline, Embase, the Cochrane Central Register of Controlled Trials, and the gray literature were searched through June 30, 2020. Studies that enrolled patients with IPF and 1) compared antacid medication to placebo or no medication or 2) compared antireflux surgery to no surgery were selected. Meta-analyses were performed when possible. Outcomes included disease progression, mortality, exacerbations, hospitalizations, lung function, respiratory symptoms, GER severity, and adverse effects/complications. Results: For antacid medication, when two studies were aggregated, there was no statistically significant effect on disease progression, defined as a 10% or more decline in FVC, more than 50-m decline in 6-minute walking distance, or death (risk ratio [RR], 0.88; 95% confidence interval [CI], 0.76-1.03). A separate study that could not be included in the meta-analysis found no statistically significant effect on disease progression when defined as a 5% or more decline in FVC or death (RR, 1.10; 95% CI, 1.00-1.21) and an increase in disease progression when defined as a 10% or more decline in FVC or death (RR, 1.28; 95% CI, 1.08-1.51). For antireflux surgery, there was also no statistically significant effect on disease progression (RR, 0.29; 95% CI, 0.06-1.26). Neither antacid medications nor antireflux surgery was associated with improvements in the other outcomes. Conclusions: There is insufficient evidence to conclude that antacid medication or antireflux surgery improves respiratory outcomes in patients with IPF, most of whom had not had abnormal GER confirmed. Well-designed and adequately powered prospective studies with objective evaluation for GER are critical to elucidate the role of antacid medication and antireflux surgery for respiratory outcomes in patients with IPF.

PMID:35486080 | DOI:10.1513/AnnalsATS.202102-172OC

Am J Respir Crit Care Med. 2022 May 1;205(9):e18-e47. doi: 10.1164/rccm.202202-0399ST.

ABSTRACT

Background: This American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax guideline updates prior idiopathic pulmonary fibrosis (IPF) guidelines and addresses the progression of pulmonary fibrosis in patients with interstitial lung diseases (ILDs) other than IPF. Methods: A committee was composed of multidisciplinary experts in ILD, methodologists, and patient representatives. 1) Update of IPF: Radiological and histopathological criteria for IPF were updated by consensus. Questions about transbronchial lung cryobiopsy, genomic classifier testing, antacid medication, and antireflux surgery were informed by systematic reviews and answered with evidence-based recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. 2) Progressive pulmonary fibrosis (PPF): PPF was defined, and then radiological and physiological criteria for PPF were determined by consensus. Questions about pirfenidone and nintedanib were informed by systematic reviews and answered with evidence-based recommendations using the GRADE approach. Results: 1) Update of IPF: A conditional recommendation was made to regard transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy in centers with appropriate expertise. No recommendation was made for or against genomic classifier testing. Conditional recommendations were made against antacid medication and antireflux surgery for the treatment of IPF. 2) PPF: PPF was defined as at least two of three criteria (worsening symptoms, radiological progression, and physiological progression) occurring within the past year with no alternative explanation in a patient with an ILD other than IPF. A conditional recommendation was made for nintedanib, and additional research into pirfenidone was recommended. Conclusions: The conditional recommendations in this guideline are intended to provide the basis for rational, informed decisions by clinicians.

PMID:35486072 | DOI:10.1164/rccm.202202-0399ST

PLoS Genet. 2022 Apr 28;18(4):e1010113. doi: 10.1371/journal.pgen.1010113. eCollection 2022 Apr.

ABSTRACT

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide association summary data from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828 = 53 and nrs505922 = 59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p = 1.32 x 10-199), and thrombosis ORrs505922 1.33, p = 2.2 x10-265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10-191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10-12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10-23, lupus OR 0.84, p = 3.97 x 10-06. PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10-13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.

PMID:35482673 | DOI:10.1371/journal.pgen.1010113

Clin Rehabil. 2022 Apr 28:2692155221095481. doi: 10.1177/02692155221095481. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the efficacy and safety of pulmonary rehabilitation for exercise tolerance and quality of life improvement in idiopathic pulmonary fibrosis.

METHODS: We searched PubMed, Cochrane Library, Embase, Web of Science, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Wanfang Database, and Chongqing VIP for randomized controlled trials that compared pulmonary rehabilitation with usual care for idiopathic pulmonary fibrosis. The risk of bias and certainty of evidence were assessed using Cochrane Collaboration's Risk of Bias tool and the Grading of Recommendations, Assessment, Development and Evaluation criteria.

RESULTS: Eleven trials in total with 549 participants. Compared with usual care, pulmonary rehabilitation significantly increased 6-minute walking distance (mean difference: 35.2m, 95% confidence intervals: 25.4m-44.9m; ten trials; 447 participants; moderate), decreased the St George's Respiratory Questionnaire total scores (mean difference: -9.11, 95% confidence intervals: -10.78 to -7.43; six trials; 303 participants; moderate), and reduced the modified Medical Research Council scores were lower (mean difference: -0.76, 95% confidence intervals: -1.25 to -0.27; three trials; 196 participants; low). Improvements were noted in forced vital capacity percent-predicted (mean difference: 4.88, 95% confidence intervals: 2.67 to 7.10; four trials; 214 participants; moderate) and diffusing capacity for carbon monoxide (mean difference: 4.71, 95% confidence intervals: 0.96 to 8.46; six trials; 358 participants; low).

CONCLUSIONS: Pulmonary rehabilitation may significantly improve exercise tolerance and quality of life in idiopathic pulmonary fibrosis patients, but the quality of evidence was low to moderate. Large sample, multicenter, randomized controlled trials are needed to verify the efficacy and safety of pulmonary rehabilitation.

PMID:35481421 | DOI:10.1177/02692155221095481

Open Med (Wars). 2022 Apr 7;17(1):689-693. doi: 10.1515/med-2022-0466. eCollection 2022.

ABSTRACT

The present report investigates the impact of a Telemedicine Service (TMS) on the management of Idiopathic Pulmonary Fibrosis (IPF) during coronavirus disease of 2019 (COVID-19) outbreak in Italy. The TMS comprised 3 phone numbers, active 12 h per day, and an email address, monitored every 4 h by trained physicians; chat- and videoconference-services were also offered. At the end of the study period, our staff contacted all patients, to get information about the final outcome (i.e. composite hospitalisations/all causes of death). Outcomes were compared with a cohort of patients who attended our unit in the same period of the previous year (when no TMS was available). 189 patients participated in the present study. From 11th March to 4th May 2020, 61% of patients made at least one TMS access, mostly by emails (53%), followed by phone calls (33%). With regard to the primary outcome, TMS patients experienced a significant lower rate of events of the 182 patients of the no-TMS cohort (p < 0.001). Specifically, a significant difference was observed for IPF hospitalisation (p < 0.001) whereas no differences were observed with regard to deaths (p = 0.64). TMS permits patients to be followed up even during COVID-19 lockdown, with an encouraging impact on outcomes.

PMID:35480400 | PMC:PMC8990874 | DOI:10.1515/med-2022-0466

Front Genet. 2022 Apr 11;13:855789. doi: 10.3389/fgene.2022.855789. eCollection 2022.

ABSTRACT

Background: Lung cancer is the most common comorbidity of idiopathic pulmonary fibrosis. Thus there is an urgent need for the research of IPF and carcinogenesis Objective: The objective of this study was to explore hub genes which are common in pulmonary fibrosis and lung cancer progression through bioinformatic analysis. Methods: All the analysis was performed in R software. Differentially expressed genes (DEGs) were explored by comparing gene expression profiles between IPF tissues and healthy lung tissues from GSE24206, GSE53845, GSE101286 and GSE110147 datasets. Venn Diagram analysis was used to identify the overlapping genes, while GO and KEGG pathway enrichment analysis were used to explore the biological functions of the DEGs using clusterprofiler package. Hub genes were identified by analyzing protein-protein interaction networks using Cytoscape software. Nomogram was constructed using the rms package. Tumor immune dysfunction and exclusion (TIDE) and Genomics of Drug Sensitivity in Cancer (GDSC) analysis was used to quantify the immunotherapy and chemotherapy sensitivity of non-small cell lung cancer (NSCLC) patients. Results: COL1A1, COL3A1, MMP1, POSTN1 and TIMP3 were identified as the top five hub genes. The five hub genes were used to construct a diagnostic nomogram that was validated in another IPF dataset. Since the hub genes were also associated with lung cancer progression, we found that the nomogram also had diagnostic value in NSCLC patients. These five genes achieved a statistically difference of overall survival in NSCLC patients (p < 0.05). The expression of the five hub genes was mostly enriched in fibroblasts. Fibroblasts and the hub genes also showed significant ability to predict the susceptibility of NSCLC patients to chemotherapy and immunotherapy. Conclusion: We identified five hub genes as potential biomarkers of IPF and NSCLC progression. This finding may give insight into the underlying molecular mechanisms of IPF and lung cancer progression and provides potential targets for developing new therapeutic agents for IPF patients.

PMID:35480306 | PMC:PMC9038140 | DOI:10.3389/fgene.2022.855789

J Bras Pneumol. 2022 Apr 20;48(2):e20210513. doi: 10.36416/1806-3756/e20210513.

NO ABSTRACT

PMID:35475868 | DOI:10.36416/1806-3756/e20210513

Toxicol Lett. 2022 Apr 23:S0378-4274(22)00086-8. doi: 10.1016/j.toxlet.2022.04.003. Online ahead of print.

ABSTRACT

Transforming growth factor (TGF)-β1-induced fibrotic changes in alveolar epithelium is a critical event in pulmonary fibrosis. Herein, we recognized that lncRNA mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG) was abnormally upregulated within human idiopathic pulmonary fibrosis (IPF) lung tissue, bleomycin (BLM)-caused pulmonary fibrotic model mice and TGF-β1-stimulated mice type II alveolar epithelial cells. In vivo, MIR100HG knockdown attenuated BLM-caused lung fibrogenesis in mice; in vitro, MIR100HG knockdown attenuated TGF-β1-induced fibrotic changes in mice type II alveolar epithelial cells. Through direct binding, MIR100HG knockdown upregulated microRNA-29a-3p (miR-29a-3p) expression; through serving as competing endogenous RNA for miR-29a-3p, MIR100HG knockdown downregulated TGF-beta activated kinase 1/MAP3K7 binding protein 1 (Tab1) expression. Finally, under TGF-β1 stimulation, Tab1 knockdown attenuated TGF-β1-induced fibrotic changes and partially attenuated the effects of miR-29a-3p inhibition. In conclusion, we demonstrated the aberrant upregulation of lncRNA MIR100HG in BLM-caused lung fibrogenesis and TGF-β1-stimulated MLE 12 cells. The MIR100HG/miR-29a-3p/Tab1 axis could modulate TGF-β1-induced fibrotic changes in type II alveolar epithelial cells and, thus, might be promising targets for pulmonary fibrosis therapy.

PMID:35472619 | DOI:10.1016/j.toxlet.2022.04.003

Ther Clin Risk Manag. 2022 Apr 19;18:429-437. doi: 10.2147/TCRM.S349185. eCollection 2022.

ABSTRACT

BACKGROUND: Correlations between idiopathic pulmonary fibrosis (IPF) and lung cancer have been discussed in many previous studies. In the present work, we evaluated the potential diagnostic value of serum levels of Th17 cell-related cytokines for the detection of lung cancer-associated IPF.

METHODS: Fifty-six patients who had been diagnosed with lung cancer-associated IPF were enrolled, and 59 patients with lung cancer but without IPF were also enrolled, and 60 healthy volunteers were served as the control group. The expression of IL-22, IL-23, and IL-17 was evaluated by enzyme-linked immunosorbent assay (ELISA) kits.

RESULTS: We observed that IL-22, IL-23 as well as IL-17 were significantly increased in the serum of lung cancer patients associated IPF; moreover, the results of ROC curve showed that the expression of IL-22, IL-23 and IL-17 can distinguish the lung cancer patients with lung cancer-associated IPF group; finally, the expression of IL-22, IL-23 and IL-17 was positively correlated with the degree of differentiation and metathesis of the tumor.

CONCLUSION: In conclusion, we first reported that IL-22, IL-23 and IL-17 were elevated in the serum of patients with lung cancer-associated IPF, and our data may provide novel evidence for the prevention and treatment of lung cancer-associated IPF.

PMID:35469293 | PMC:PMC9034872 | DOI:10.2147/TCRM.S349185

Am J Respir Cell Mol Biol. 2022 Apr 25. doi: 10.1165/rcmb.2021-0418OC. Online ahead of print.

ABSTRACT

Immune cells have been implicated in Idiopathic Pulmonary Fibrosis (IPF), but the phenotypes and effector mechanisms of these cells remain incompletely characterized. We performed mass cytometry to quantify immune/inflammatory cell subsets in lungs of 12 patients with IPF and 15 organ donors without chronic lung disease and utilized existing single-cell RNA-sequencing (scRNA-seq) data to investigate transcriptional profiles of immune cells over-represented in IPF. Among myeloid cells, we found increased numbers of alveolar macrophages (AMØs) and dendritic cells (DCs) in IPF, as well as a subset of monocyte-derived DC. In contrast, monocyte-like cells and interstitial macrophages were reduced in IPF. Transcriptomic profiling identified an enrichment for interferon-γ (IFN-γ) response pathways in AMØs and DCs from IPF, as well as antigen processing in DCs and phagocytosis in AMØs. Among T cells, we identified three subset of memory T cells that were increased in IPF, including CD4+ and CD8+ resident memory T cells (TRM), and CD8+ effector memory (TEMRA) cells. The response to IFN-γ pathway was enriched in CD4 TRM and CD8 TRM cells in IPF, along with T cell activation and immune response-regulating signaling pathways. Increased AMØs, DCs, and memory T cells were present in IPF lungs compared to control subjects. In IPF, these cells possess an activation profile indicating increased IFN-γ signaling and up-regulation of adaptive immunity in the lungs. Together, these studies highlight critical features of the immunopathogenesis of IPF.

PMID:35468042 | DOI:10.1165/rcmb.2021-0418OC

Comput Struct Biotechnol J. 2022 Mar 31;20:1642-1653. doi: 10.1016/j.csbj.2022.03.030. eCollection 2022.

ABSTRACT

Gefapixant/AF-219, a selective inhibitor of the P2X3 receptor, is the first new drug other than dextromethorphan to be approved for the treatment of refractory chronic cough (RCC) in nearly 60 years. To date, seven P2X subtypes (P2X1-7) activated by extracellular ATP have been cloned, and subtype selectivity of P2X inhibitors is a prerequisite for reducing side effects. We previously identified the site and mechanism of action of Gefapixant/AF-219 on the P2X3 receptor, which occupies a pocket consisting of the left flipper (LF) and lower body (LB) domains. However, the mechanism by which AF-219 selectively acts on the P2X3 receptor is unknown. Here, we combined mutagenesis, chimera construction, molecular simulations, covalent occupation and chemical synthesis, and find that the negative allosteric site of AF-219 at P2X3 is also present in other P2X subtypes, at least for P2X1, P2X2 and P2X4. By constructing each chimera of AF-219 sensitive P2X3 and insensitive P2X2 subtypes, the insensitive P2X2 subtype was made to acquire the inhibitory properties of AF-219 and AF-353, an analog of AF-219 with higher affinity. Our results suggest that the selectivity of AF-219/AF-353 for P2X3 over the other P2X subtypes is determined by a combination of the accessibility of P2X3 binding site and the internal shape of this pocket, a finding that could provide new perspectives for drug design against P2X3-mediated diseases such as RCC, idiopathic pulmonary fibrosis, hypertension and overactive bladder disorder.

PMID:35465163 | PMC:PMC9014320 | DOI:10.1016/j.csbj.2022.03.030

Front Med (Lausanne). 2022 Apr 7;9:889834. doi: 10.3389/fmed.2022.889834. eCollection 2022.

NO ABSTRACT

PMID:35462999 | PMC:PMC9021609 | DOI:10.3389/fmed.2022.889834

BMC Med Imaging. 2022 Apr 23;22(1):76. doi: 10.1186/s12880-022-00803-8.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a disease that primarily occurs in elderly individuals. However, it is difficult to diagnose and has a complex disease course. High-resolution computed tomography (HRCT) and lung function testing are crucial for its diagnosis and follow-up. However, the correlation of HRCT findings with lung function test results has not been extensively investigated.

METHODS: This study retrospectively analysed the medical records and images of patients with IPF. Patients with evident emphysema and lung cancer were excluded. The diagnosis of all the included cases was confirmed following a discussion among specialists from multiple disciplines. The correlation of HRCT findings, including fibrotic score, HRCT lung volume, pulmonary artery trunk (PA) diameter and pulmonary vascular volume (PVV), with lung function test parameters, such as forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), was analysed.

RESULTS: A total of 32 patients were included. Higher fibrotic and PVV scores were significantly correlated with lower DLCO (r = - 0.59, p = 0.01; r = - 0.43, p = 0.03, respectively) but not with FVC. Higher PVV score significantly correlated with higher fibrotic score (r = 0.59, p < 0.01) and PA diameter (r = 0.47, p = 0.006).

CONCLUSION: Our study demonstrated the structural and functional correlation of IPF. The extent of lung fibrosis (fibrotic score) and PVV score were associated with DLCO but not with FVC. The PA diameter, which reflects the pulmonary artery pressure, was found to be associated with the PVV score.

PMID:35461214 | DOI:10.1186/s12880-022-00803-8

Respir Res. 2022 Apr 22;23(1):100. doi: 10.1186/s12931-022-02027-4.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a highly heterogeneous and fatal lung disease. In addition to dense fibrous tissue, abnormal angiogenesis is also an important feature of IPF. Pigment epithelium-derived factor (PEDF) is an angiogenesis inhibitor and a potential anti-fibrous factor. The purpose of this experiment is to observe the effect of PEDF on bleomycin (BLM)-induced pulmonary fibrosis in rats.

METHODS: In vivo, pathological examination and detection of related factors were performed on pulmonary fibrosis induced by BLM in rats, and the temporal and spatial distribution of PEDF was investigated. Furthermore, lung gene delivery (PEDF-adeno-associated virus) was performed to investigate the effect of PEDF on pulmonary fibrosis. In vitro, lentiviral vectors were used to construct PEDF over-expression or knock out primary rat lung (PRL) fibroblasts. The effect of PEDF on fibroblast activation under TGF-β1 stimulation was evaluated, and the activation of TGF-β1/smad pathway and PPAR-γ expression (in the presence or absence of PPAR-γ inhibitors) were analyzed.

RESULTS: In vivo results showed that PEDF expression decreased during the inflammatory phase and increased during the fibrotic phase. PEDF could inhibit the progression of pulmonary fibrosis in rats. In vitro results showed that PEDF could effectively inhibit TGF-β1-stimulated fibroblast activation and reduce the production of α-SMA and collagen-I. PEDF could inhibit the TGF-β1/smad pathway by up-regulating the activity of PPAR-γ.

CONCLUSIONS: PEDF can act as an anti-fibrotic factor, inhibit fibroblast activation by upregulating PPAR-γ activity and reduce BLM-induced pulmonary fibrosis in rats.

PMID:35459189 | DOI:10.1186/s12931-022-02027-4

BMC Pulm Med. 2022 Apr 23;22(1):153. doi: 10.1186/s12890-022-01953-9.

ABSTRACT

BACKGROUND: Interstitial lung diseases (ILDs) include a variety of parenchymal lung diseases. The most common types of ILDs are idiopathic pulmonary fibrosis (IPF), autoimmune ILDs and hypersensitivity pneumonitis (HP). There is limited real world data on care patterns of patients with chronic fibrosing ILDs with a progressive phenotype other than IPF. Therefore, the aim of this study is to describe care patterns in these patients.

METHODS: This retrospective cohort study used claims data from 2015 to 2019 from the Optum Research Database. The study population included adults (≥ 18 years old) with at least two diagnosis codes for fibrosing ILD during the identification period (1OCT2016 to 31DEC2018). A claim-based algorithm for disease progression was used to identify patients likely to have a progressive fibrotic phenotype using progression proxies during the identification period. Index date was the first day of progression proxy identification after fibrosing ILD diagnosis. Patients were required to have continuous enrollment for 12 months before (baseline) and after (follow-up) index date. Patients with an IPF diagnosis were excluded. Descriptive statistics were used to describe the patient population and care patterns.

RESULTS: 11,204 patients were included in the study. Mean age of the patient population was 72.7 years, and 54.5% were female. Unclassified ILDs (48.0%), HP (25.2%) and autoimmune ILDs (16.0%) were the most common ILD types. Other respiratory conditions were prevalent among patients including chronic obstructive pulmonary disease (COPD) (58.9%), obstructive sleep apnea (OSA) (25.0%) and pulmonary hypertension (9.8%). During baseline, 65.3% of all patients had at least one pulmonology visit, this proportion was higher during follow-up, at 70.6%. Baseline and follow-up use for HRCT were 39.9% and 48.8%, and for pulmonary function tests were 43.7% and 48.5% respectively. Use of adrenal corticosteroids was higher during follow-up than during baseline (62.5% vs. 58.0%). Anti-inflammatory and immunosuppressive medication classes were filled by a higher percentage of patients during follow-up than during baseline.

CONCLUSIONS: Comprehensive testing is essential for diagnosis of a progressive phenotype condition, but diagnostic tests were underutilized. Patients with this condition frequently were prescribed anti-inflammatory and immunosuppressive medications.

PMID:35459138 | DOI:10.1186/s12890-022-01953-9

Pharmaceutics. 2022 Apr 7;14(4):813. doi: 10.3390/pharmaceutics14040813.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by irreversible lung scarring, which achieves almost 80% five-year mortality rate. Undeniably, commercially available pharmaceuticals, such as pirfenidone and nintedanib, exhibit certain effects on improving the well-being of IPF patients, but the stubbornly high mortality still indicates a great urgency of developing superior therapeutics against this devastating disease. As an emerging strategy, gene therapy brings hope for the treatment of IPF by precisely regulating the expression of specific genes. However, traditional administration approaches based on viruses severely restrict the clinical application of gene therapy. Nowadays, non-viral vectors are raised as potential strategies for in vivo gene delivery, attributed to their low immunogenicity and excellent biocompatibility. Herein, we highlight a variety of non-viral vectors, such as liposomes, polymers, and proteins/peptides, which are employed in the treatment of IPF. By respectively clarifying the strengths and weaknesses of the above candidates, we would like to summarize the requisite features of vectors for PF gene therapy and provide novel perspectives on design-decisions of the subsequent vectors, hoping to accelerate the bench-to-bedside pace of non-viral gene therapy for IPF in clinical setting.

PMID:35456646 | DOI:10.3390/pharmaceutics14040813

Cells. 2022 Apr 14;11(8):1341. doi: 10.3390/cells11081341.

ABSTRACT

Antibodies are central effectors of the adaptive immune response, widespread used therapeutics, but also potentially disease-causing biomolecules. Antibody folding catalysts in the plasma cell are incompletely defined. Idiopathic pulmonary fibrosis (IPF) is a fatal chronic lung disease with increasingly recognized autoimmune features. We found elevated expression of FK506-binding protein 11 (FKBP11) in IPF lungs where FKBP11 specifically localized to antibody-producing plasma cells. Suggesting a general role in plasma cells, plasma cell-specific FKBP11 expression was equally observed in lymphatic tissues, and in vitro B cell to plasma cell differentiation was accompanied by induction of FKBP11 expression. Recombinant human FKBP11 was able to refold IgG antibody in vitro and inhibited by FK506, strongly supporting a function as antibody peptidyl-prolyl cis-trans isomerase. Induction of ER stress in cell lines demonstrated induction of FKBP11 in the context of the unfolded protein response in an X-box-binding protein 1 (XBP1)-dependent manner. While deficiency of FKBP11 increased susceptibility to ER stress-mediated cell death in an alveolar epithelial cell line, FKBP11 knockdown in an antibody-producing hybridoma cell line neither induced cell death nor decreased expression or secretion of IgG antibody. Similarly, antibody secretion by the same hybridoma cell line was not affected by knockdown of the established antibody peptidyl-prolyl isomerase cyclophilin B. The results are consistent with FKBP11 as a novel XBP1-regulated antibody peptidyl-prolyl cis-trans isomerase and indicate significant redundancy in the ER-resident folding machinery of antibody-producing hybridoma cells.

PMID:35456020 | DOI:10.3390/cells11081341

Diagnostics (Basel). 2022 Apr 15;12(4):1002. doi: 10.3390/diagnostics12041002.

ABSTRACT

Antifibrotic therapy has changed the treatment paradigm for idiopathic pulmonary fibrosis (IPF); however, a subset of patients still experienced rapid disease progression despite treatment. This study aimed to determine whether CT-based radiomic features can predict therapeutic response to antifibrotic agents. In this retrospective study, 35 patients with IPF on antifibrotic treatment enrolled from two centers were divided into training (n = 26) and external validation (n = 9) sets. Clinical and pulmonary function data were collected. The patients were categorized into stable disease (SD) and progressive disease (PD) groups based on functional or radiologic criteria. From pretreatment non-enhanced high-resolution CT (HRCT) images, twenty-six radiomic features were extracted through whole-lung texture analysis, and six parenchymal patterns were quantified using dedicated imaging platforms. The predictive factors for PD were determined via univariate and multivariate logistic regression analyses. In the training set (SD/PD: 12/14), univariate analysis identified eight radiomic features and ground-glass opacity percentage (GGO%) as potential predicators of PD. However, multivariate analysis found that the single independent predictor was the sum entropy (accuracy, 80.77%; AUC, 0.75). The combined sum entropy-GGO% model improved the predictive performance in the training set (accuracy, 88.46%; AUC, 0.77). The overall accuracy of the combined model in the validation set (SD/PD: 7/2) was 66.67%. Our preliminary results demonstrated that radiomic features based on pretreatment HRCT could predict the response of patients with IPF to antifibrotic treatment.

PMID:35454050 | DOI:10.3390/diagnostics12041002

Biomedicines. 2022 Apr 5;10(4):851. doi: 10.3390/biomedicines10040851.

ABSTRACT

(1) Background: We explored, for the first time, the contribution of angiogenic T cells (TAng) in interstitial lung disease associated to autoimmune disease (AD-ILD+) as potential biomarkers of the disease, evaluating their role in the underlying vasculopathy and lung fibrosis. Additionally, the relationship of TAng with clinical manifestations and cellular and molecular endothelial dysfunction-related biomarkers was assessed. (2) Methods: We included 57 AD-ILD+ patients (21 with rheumatoid arthritis (RA)-ILD+, 21 with systemic sclerosis (SSc)-ILD+ and 15 with other AD-ILD+) and three comparative groups: 45 AD-ILD- patients (25 RA-ILD- and 20 SSc-ILD-); 21 idiopathic pulmonary fibrosis (IPF) patients; 21 healthy controls (HC). TAng were considered as CD3+CD184+CD31+ by flow cytometry. (3) Results: A similar TAng frequency was found between AD-ILD+ and IPF, being in both cases lower than that observed in AD-ILD- and HC. A lower TAng frequency was associated with negative Scl-70 status and lower FEV1/FVC ratio in SSc-ILD+, as well as with men in RA-ILD+ and non-specific interstitial pneumonia radiological pattern in other AD-ILD+. No relationship between TAng and endothelial progenitor cells, endothelial cells and vascular endothelial growth factor gene expression and protein levels was disclosed. (4) Conclusions: Our findings suggest TAng as potential biomarkers for the early diagnosis of ILD in AD.

PMID:35453601 | DOI:10.3390/biomedicines10040851