Tuberc Respir Dis (Seoul). 2022 Apr;85(2):122-136. doi: 10.4046/trd.2021.0141. Epub 2022 Jan 27.

ABSTRACT

Although chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) have distinct clinical features, both diseases may coexist in a patient because they share similar risk factors such as smoking, male sex, and old age. Patients with both emphysema in upper lung fields and diffuse ILD are diagnosed with combined pulmonary fibrosis and emphysema (CPFE), which causes substantial clinical deterioration. Patients with CPFE have higher mortality compared with patients who have COPD alone, but results have been inconclusive compared with patients who have idiopathic pulmonary fibrosis (IPF). Poor prognostic factors for CPFE include exacerbation, lung cancer, and pulmonary hypertension. The presence of interstitial lung abnormalities, which may be an early or mild form of ILD, is notable among patients with COPD, and is associated with poor prognosis. Various theories have been proposed regarding the pathophysiology of CPFE. Biomarker analyses have implied that this pathophysiology may be more closely associated with IPF development, rather than COPD or emphysema. Patients with CPFE should be advised to quit smoking and undergo routine lung function tests, and pulmonary rehabilitation may be helpful. Various pharmacologic agents and surgical approaches may be beneficial in patients with CPFE, but further studies are needed.

PMID:35385639 | DOI:10.4046/trd.2021.0141

Respir Res. 2022 Apr 5;23(1):81. doi: 10.1186/s12931-022-01998-8.

ABSTRACT

BACKGROUND: A small number of studies suggested that air pollution was associated with idiopathic pulmonary fibrosis (IPF) exacerbation, incidence and mortality. However, no studies to date were conducted in regions where air pollution is substantial. We aimed to investigate whether there are associations between acute increases in air pollution and hospitalization of patients with a confirmed primary diagnosis of IPF in Beijing.

METHODS: Daily count of IPF hospitalizations (International Classification of Disease-10th Revision, J84.1) was obtained from an administrative database for 2013-2017 while daily city-wide average concentrations of PM10, PM2.5, NO2, Ozone, SO2 were obtained from 35 municipal monitoring stations for the same period. The association between daily IPF hospitalization and average concentration of each pollutant was analyzed with a generalized additive model estimating Poisson distribution.

RESULTS: Daily 24-h mean PM2.5 concentration during 2013-2017 was 76.7 μg/m3. The relative risk (RR) of IPF hospitalization per interquartile range (IQR) higher (72 μg/m3) in PM2.5 was 1.049 (95% CI 1.024-1.074) and 1.031 (95% CI 1.007-1.056) for lag0 and moving averages 0-1 days respectively. No significant associations were observed for other lags. Statistically significant positive associations were also observed at lag0 with SO2, Ozone and NO2 (in men only). Positive associations were seen at moving averages 0-30 days for PM10 (RR per 86 μg/m3: 1.021, 95% CI 0.994-1.049), NO2 (RR per 30 μg/m3: 1.029, 95% CI 0.999-1.060), and SO2 (RR per 15 μg/m3: 1.060 (95% CI 1.025-1.097), but not with PM2.5 or Ozone.

CONCLUSIONS: Despite improvement in air quality since the implementation of clean air policy in 2013, acute exposure to higher levels of air pollution is significantly associated with IPF hospitalization in Beijing. Air quality policy should be continuously enforced to protect vulnerable IPF populations as well as the general public.

PMID:35382829 | DOI:10.1186/s12931-022-01998-8

J Pharm Pharm Sci. 2022;25:137-148. doi: 10.18433/jpps32306.

ABSTRACT

Periostin is a matricellular, nonstructural protein belonging to the fasciclin family and is encoded by the POSTN gene in humans. Periostin plays an important role in maintaining a normal tissue matrix in the lungs. Despite the vital role as a structural mediator in tissue growth and repair, periostin is involved in the pathogenic mechanism during tissue remodeling and fibrosis. Periostin is a chemoattractant mediator, promotes eosinophil recruitment and adhesion on the airways sub-epithelial membrane of asthmatic patients. POSTN gene was identified as one of the highly expressed genes induced by interleukins IL-13, IL-5 and IL-4 - the key cytokines of Th2 immune responses in the bronchial tissues of asthmatic patients. This review highlights the potential role of periostin as a validated biomarker in respiratory disease progression and its candidacy to predict the response to treatments targeting Th-2 cytokines in bronchial asthma. In addition, its potential role in COPD, IPF, lung cancer and lung infection, is also speculated. Keywords Periostin, Asthma, Pneumonia, COPD, Idiopathic pulmonary fibrosis, Biomarker.

PMID:35379385 | DOI:10.18433/jpps32306

Ecotoxicol Environ Saf. 2022 Apr 1;236:113451. doi: 10.1016/j.ecoenv.2022.113451. Online ahead of print.

ABSTRACT

Existing studies reported that some circular RNAs (circRNAs) play vital roles in the development of pulmonary fibrosis. However, few studies explored the biomarker potential of circRNAs for pulmonary fibrosis based on population data. Therefore, we aimed to identify peripheral blood circRNAs as potential biomarkers for diagnosing silicosis and idiopathic pulmonary fibrosis (IPF). In brief, an RNA-seq screening based on 4 silicosis cases and 4 controls was initially performed. Differentially expressed circRNAs were combined with the human serum circRNA dataset to identify overlapping serum-detectable circRNAs, followed by validation using the GEO dataset (3 IPF cases and 3 controls) and subsequent qRT-PCR, including 84 additional individuals. Following the above steps, 243 differentially expressed circRNAs were identified during the screening stage, with fold changes ≥ 1.5 and P < 0.05. Of note, the human serum circRNA dataset encompassed 28 of 243 circRNAs. GEO (GSE102660) validation revealed two highly expressed circRNAs (P < 0.05) in the IPF case group. Furthermore, at the enlarged sample validation stage, hsa_circ_0058493 was highly expressed in both silicosis and IPF cases (silicosis: P = 1.16 × 10-6; IPF: P = 7.46 × 10-5). Additionally, hsa_circ_0058493 expression was significantly increased in MRC-5 cells upon TGF-β1 treatment, while hsa_circ_0058493 knockdown inhibited the expression of fibrotic molecules by affecting the epithelial-mesenchymal transition process. These shreds of evidence indicated that hsa_circ_0058493 might serve as a novel biomarker for diagnosing silicosis and IPF.

PMID:35378401 | DOI:10.1016/j.ecoenv.2022.113451

Am J Respir Cell Mol Biol. 2022 Apr 4. doi: 10.1165/rcmb.2021-0428OC. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis is a progressive lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. Yes-associated protein (YAP) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. We previously identified HMG-CoA reductase inhibitors (statins) as YAP inhibitors based on a high-throughput small-molecule screen in primary human lung fibroblasts. Here we report that several Aurora kinase inhibitors were also identified from the top hits of this screen. MK-5108, a highly selective inhibitor for Aurora kinase A (AURKA), induced YAP phosphorylation and cytoplasmic retention, and significantly reduced profibrotic gene expression in human lung fibroblasts. The inhibitory effect on YAP nuclear translocation and profibrotic gene expression is specific to inhibition of AURKA, but not Aurora kinase B or C, and is independent of the Hippo pathway kinases LATS1 and LATS2. Further characterization of the effects of MK-5108 demonstrate that it inhibits YAP nuclear localization indirectly via effects on actin polymerization and TGFβ signaling. In addition, MK-5108 treatment reduced lung collagen deposition in the bleomycin mouse model of pulmonary fibrosis. Our results reveal a novel role for AURKA in YAP-mediated profibrotic activity in fibroblasts and highlight the potential of small-molecule screens for YAP inhibitors for identification of novel agents with anti-fibrotic activity.

PMID:35377835 | DOI:10.1165/rcmb.2021-0428OC

Exp Lung Res. 2022 Apr 4:1-14. doi: 10.1080/01902148.2022.2055227. Online ahead of print.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) is an interstitial disease of unknown origin, characterized by tissue fibrosis, for which currently there is no effective treatment. Macrophages, the main immune cells in lung tissue, are involved in the whole process of pulmonary fibrosis. In recent years, intercellular transformation has led to wide spread concern among pulmonary fibrosis researchers. Macrophages with flexible heterogeneity and plasticity participate in different physiological processes in the body. Cell chemokine receptor 8 (CCR8) is expressed in a variety of cells and plays a significant chemotactic role in the induction of cell activation and migration. It can also promote the differentiation of macrophages under certain environmental conditions. The current study is intended to explore the role of CCR8 in macrophage to myofibroblast transdifferentiation (MMT) in IPF. Methods: We conducted experiments using CCR8-specific small interfering RNA (siRNA), an autophagy inhibitor (3-methyladenine, 3-MA), and an agonist (rapamycin) to explore the underlying mechanisms of macrophage transdifferentiation into myofibroblast cells in transforming growth factor-beta (TGF-β)-induced pulmonary fibrosis. Results: TGF-β treatment increased the CCR8 protein level in a time- and dose-dependent manner in mouse alveolar macrophages, as well as macrophage transdifferentiation-related markers, including vimentin, collagen 1, and a-SMA, and cell migration. In addition, the levels of autophagy were enhanced in macrophages treated with TGF-β. We found that 3-MA, an autophagy inhibitor, decreased the expression levels of macrophage transdifferentiation-related markers and attenuated cell migration. Furthermore, the inhibition of CCR8 via CCR8-specific siRNA reduced the levels of autophagy and macrophage transdifferentiation-related markers, and inhibited the cell migration. Enhancing autophagy with rapamycin attenuated the inhibition effect of CCR8-specific siRNA on macrophage migration and the increase in myofibroblast marker proteins. Conclusions: Our findings showed that the macrophages exposed to TGF-β had the potential to transdifferentiate into myofibroblasts and CCR8 was involved in the process. The effect of CCR8 on TGF-β-induced macrophage transdifferentiation occurs mainly through autophagy. Targeting CCR8 may be a novel therapeutic strategy for the treatment of IPF.

PMID:35377281 | DOI:10.1080/01902148.2022.2055227

Br J Hosp Med (Lond). 2022 Mar 2;83(3):1-3. doi: 10.12968/hmed.2021.0201. Epub 2022 Mar 31.

NO ABSTRACT

PMID:35377209 | DOI:10.12968/hmed.2021.0201

Front Med (Lausanne). 2022 Mar 18;9:865334. doi: 10.3389/fmed.2022.865334. eCollection 2022.

NO ABSTRACT

PMID:35372425 | PMC:PMC8971624 | DOI:10.3389/fmed.2022.865334

Front Med (Lausanne). 2022 Mar 15;9:858339. doi: 10.3389/fmed.2022.858339. eCollection 2022.

ABSTRACT

Interstitial lung diseases (ILD) on the whole have variable prognoses, but there are those which manifest with fibrosis and are characterized by disease progression. Chief among these is idiopathic pulmonary fibrosis, but other ILDs, including autoimmune ILD and chronic hypersensitivity pneumonitis, may have a progressive fibrotic phenotype also. A usual interstitial pneumonia pattern of lung involvement is a prominent risk factor for such a course, suggesting shared fibrotic pathways that may be targeted by antifibrotic therapies. This brief review describes ILDs that are most commonly fibrotic, shared risk factors for development of PF-ILD, and evidence for antifibrotic use in their management.

PMID:35372405 | PMC:PMC8965041 | DOI:10.3389/fmed.2022.858339

Cureus. 2022 Feb 25;14(2):e22606. doi: 10.7759/cureus.22606. eCollection 2022 Feb.

ABSTRACT

Acute exacerbation (AE) in idiopathic pulmonary fibrosis (IPF) is unfortunate a deadly event with a very high mortality rate. Its occurrence is highly unpredictable, though few baseline risk factors have been identified. The revised definition of AE is more precise with clarity on defined parameters. However, no clear guidelines exist on treatment, with most therapies showing inconsistent benefits. Both the approved anti-fibrotic (pirfenidone and nintedanib) have shown equal efficacy in reducing the decline in lung functions, with few studies suggesting a drop in AE. We report a case of a patient with IPF with mildly impaired lung functions who was initiated on pirfenidone with dose titrated on a weekly basis but developed AE-IPF on day 10 of starting pirfenidone and after four days of doubling the dose from 600 mg/day to 1,200 mg/day. This raised the suspicion of whether pirfenidone played any role in this unfortunate event. With no response to conventional therapy of steroids and non-invasive ventilation for AE-IPF, initialization of nintedanib led to recovery with discharge of the patient in two weeks of hospitalization. This case highlights inadequacy in knowledge about the effects of these anti-fibrotics in IPF and recommends close monitoring in the future.

PMID:35371648 | PMC:PMC8957895 | DOI:10.7759/cureus.22606

Front Pharmacol. 2022 Mar 17;13:830554. doi: 10.3389/fphar.2022.830554. eCollection 2022.

ABSTRACT

Reactive oxygen species (ROS)-mediated alveolar epithelial cell (AEC) injury and apoptosis are considered to be the initiating link of idiopathic pulmonary fibrosis (IPF), and protecting AECs can alleviate IPF. This study aimed to explore the protective effect of number 2 Feibi recipe (FBR-2) medicated serum on H2O2-mediated oxidative stress injury in AECs and further explore its mechanism. We found that FBR-2 can regulate downstream antioxidant enzymes expression by activating nuclear factor erythroid 2-related factor 2 (Nrf2), reducing the level of intracellular ROS, protecting mitochondrial function and improving cell survival. FBR-2 can also activate mitophagy through the PINK1/Parkin pathway. Moreover, FBR-2 can inhibit apoptosis by blocking the mitochondrial apoptosis mechanism. In summary, these data indicate that FBR-2 medicated serum can inhibit H2O2-mediated oxidative stress damage in AECs by regulating the balance of mitophagy/apoptosis. This study provides new evidence for the antifibrotic effect of FBR-2 and provides new drug candidates for the clinical treatment of IPF.

PMID:35370684 | PMC:PMC8968876 | DOI:10.3389/fphar.2022.830554

Chron Respir Dis. 2022 Jan-Dec;19:14799731221089319. doi: 10.1177/14799731221089319.

ABSTRACT

IMPORTANCE: Cough is a common symptom in idiopathic interstitial lung diseases (ILDs), there is little information of its management in primary care. The objective of this study was to explore the frequency of cough-related consultations and the medications prescribed to patients with ILDs in primary care.

METHODS: This retrospective cohort study used electronic medical records (EMR) from Manitoba primary care providers participating in the Manitoba Primary Care Research Network repository (2014-2019). Cough-related consults and the subsequent medications prescribed to patients with ILDs were identified in the EMR.

RESULTS: 295 patients with ILDs were identified, 73 (25%) of them had 141 cough-related consultations (mean 1.9, SD 1.3) during the period studied. In 50 (35%) of the consultations, patients were prescribed one or more of the following: inhaled bronchodilators (34%), nasal corticoids (18%), codeine/opiates (18%), antibiotics (14%), inhaled corticoids (14%), proton pump inhibitors (8%), cough preparations (6%), antihistamines (4%), and oral corticoids (2%). 13 (26%) subsequent cough-related consultations were identified within 6 months, mainly among patients who were prescribed cough preparations, nasal corticoids, antihistamines, and antibiotics.

CONCLUSION: One-quarter of patients with ILDs consulted primary care due to cough, and about a third of them received a prescription to address potentially underlying causes of cough. Although further studies are required to explore the effect of the medications prescribed, recurrent cough consultations suggested that cough preparations, nasal corticoids, and antihistamines are among the least effective treatments. More research is needed to understand the causes and optimal treatment of cough in patients with ILDs.

PMID:35369764 | DOI:10.1177/14799731221089319

Kobe J Med Sci. 2021 Nov 2;67(3):E84-E91.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by progressive lung fibrosis and obliteration of normal alveolar structures. Myofibroblasts play a central role in the progression of IPF by producing excess amount of extracellular matrix, and these myofibroblasts show heterogenous origins including resident fibroblasts, epithelial cells via epithelial to mesenchymal transition (EMT) and endothelial cell (EC) via endothelial to mesenchymal transition (EndMT). Although lung aging has been considered as essential mechanisms through abnormal activation of epithelial cells and fibroblasts, little is known about a role of EC senescence in the pathogenesis of IPF. Here, we reveal a detrimental role of EC senescence in IPF by utilizing unique EC-specific progeroid mice. EC-specific progeroid mice showed deteriorated pulmonary fibrosis in association with an accelerated EndMT in the lungs after intratracheal bleomycin instillation. We further confirmed that premature senescent ECs were susceptible to EndMT in vitro. Because senescent cells affect nearby cells through senescence-associated secretory phenotype (SASP), we assessed a potential role of the EC-SASP in EMT and myofibroblastic transition of resident fibroblasts. EC-SASP enhanced the myofibroblastic transition in resident fibroblasts, while no effect was detected on EMT. Our data revealed a previously unknown role of EC senescence in the progression of IPF, and thus rejuvenating ECs and/or inhibiting EC-SASP is an attracting therapeutic strategy for the treatment of IPF.

PMID:35367994

PLoS Comput Biol. 2022 Apr 1;18(4):e1010025. doi: 10.1371/journal.pcbi.1010025. Online ahead of print.

ABSTRACT

Advances in single-cell RNA sequencing (scRNA-seq) have led to successes in discovering novel cell types and understanding cellular heterogeneity among complex cell populations through cluster analysis. However, cluster analysis is not able to reveal continuous spectrum of states and underlying gene expression programs (GEPs) shared across cell types. We introduce scAAnet, an autoencoder for single-cell non-linear archetypal analysis, to identify GEPs and infer the relative activity of each GEP across cells. We use a count distribution-based loss term to account for the sparsity and overdispersion of the raw count data and add an archetypal constraint to the loss function of scAAnet. We first show that scAAnet outperforms existing methods for archetypal analysis across different metrics through simulations. We then demonstrate the ability of scAAnet to extract biologically meaningful GEPs using publicly available scRNA-seq datasets including a pancreatic islet dataset, a lung idiopathic pulmonary fibrosis dataset and a prefrontal cortex dataset.

PMID:35363784 | DOI:10.1371/journal.pcbi.1010025

Am J Respir Crit Care Med. 2022 Apr 1. doi: 10.1164/rccm.202107-1769OC. Online ahead of print.

ABSTRACT

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a progressive and inevitably fatal condition for which there are a lack of effective biomarkers to guide therapeutic decision making.

RATIONALE: To determine the relationship between serum levels of the cytokeratin fragment CYFRA 21-1 and disease progression and mortality in individuals with IPF enrolled in the PROFILE study.

METHODS: CYFRA 21-1 was identified by immunohistochemistry in samples of human lung. Concentrations of CYFRA 21-1 were measured using an Elisa-based assay in serum, collected at baseline, 1- and 3-months, from 491 individuals with an incident diagnosis of IPF enrolled in the PROFILE study and from 100 control subjects. Study subjects were followed for a minimum of 3 years.

MEASUREMENTS AND MAIN RESULTS: CYFRA 21-1 localises to hyperplastic epithelium in IPF lung. CYFRA 21-1 levels were significantly higher in IPF subjects compared to healthy controls in both discovery (n=132) (control 0.96±0.81 ng/mL versus IPF; 2.34±2.15 ng/mL, p < 0.0001) and validation (n=359) (control; 2.21±1.54 ng/mL and IPF; 4.13±2.77 ng/mL, p<0.0001) cohorts. Baseline levels of CYFRA 21-1 distinguished individuals at risk of 12-month disease progression (C-statistic 0.70 (95% CI 0.61-0.79), p < 0.0001) and were predictive of overall-mortality (HR 1.12 (1.06-1.19) per 1 ng/mL increase in CYFRA 21-1, p=0.0001). Furthermore, 3-month change in levels of CYFRA 21-1 separately predicted 12-month and overall survival in both the discovery and validation cohorts.

CONCLUSIONS: CYFRA 21-1, a marker of epithelial damage and turnover, has the potential to be an important prognostic and therapeutic biomarker in individuals with IPF.

PMID:35363592 | DOI:10.1164/rccm.202107-1769OC

Sci Rep. 2022 Mar 31;12(1):5466. doi: 10.1038/s41598-022-09557-3.

ABSTRACT

Bone morphogenetic protein 1 (BMP1) belongs to the astacin/BMP1/tolloid-like family of zinc metalloproteinases, which play a fundamental role in the development and formation of extracellular matrix (ECM). BMP1 mediates the cleavage of carboxyl terminal (C-term) propeptides from procollagens, a crucial step in fibrillar collagen fiber formation. Blocking BMP1 by small molecule or antibody inhibitors has been linked to anti-fibrotic activity in the preclinical models of skin, kidney and liver fibrosis. Therefore, we reason that BMP1 may be important for the pathogenesis of lung fibrosis and BMP1 could be a potential therapeutic target for progressive fibrotic disease such as idiopathic pulmonary fibrosis (IPF). Here, we observed the increased expression of BMP1 in both human IPF lungs and mouse fibrotic lungs induced by bleomycin. Furthermore, we developed an inducible Bmp1 conditional knockout (cKO) mouse strain. We found that Bmp1 deletion does not protect mice from lung fibrosis triggered by bleomycin. Moreover, we found no significant impact of BMP1 deficiency upon C-term propeptide of type I procollagen (CICP) production in the fibrotic mouse lungs. Based on these results, we propose that BMP1 is not required for lung fibrosis in mice and BMP1 may not be considered a candidate therapeutic target for IPF.

PMID:35361882 | DOI:10.1038/s41598-022-09557-3

BMJ Open. 2022 Mar 31;12(3):e053625. doi: 10.1136/bmjopen-2021-053625.

ABSTRACT

INTRODUCTION: Non-cystic fibrosis (non-CF) bronchiectasis is a chronic pulmonary disorder that causes destruction and permanent dilatation of the airways, resulting in excessive sputum production, repeated infection and inflammation. A need for high-quality and specialised care has been highlighted in recent years. N-acetylcysteine (NAC) is a widely used mucolytic agent in respiratory diseases that not only possesses a property to enhance secretion clearance, but also exhibits antioxidant and anti-inflammatory effects. However, the efficacy and safety of NAC are not well described in idiopathic or postinfective non-CF bronchiectasis.

OBJECTIVE: This study aims to evaluate the efficacy and safety of NAC in patients with idiopathic or postinfective non-CF bronchiectasis.

METHODS AND ANALYSIS: PubMed/Medline, Embase, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials will be searched from inception to 1 March 2022 for eligible randomised controlled trials that investigating the effects of NAC on exacerbations, health-related quality of life, lung functions, sputum volume and colour, inflammation markers, exercise capacity and adverse events in patients with idiopathic or postinfective non-CF bronchiectasis, with ongoing trials being identified by searches on the websites of Chinese Clinical Trial Registry and ClinicalTrials.gov. Two independent reviewers will identify eligible studies, two will fulfil the data extraction and three will perform the quality appraisal. To generate more accurate analyses, the Grading of Recommendations Assessment, Development and Evaluation will be used to grade the evidence. χ2 test and I2 statistic will be used to assess heterogeneity. Subgroup analyses and meta-regression will be used to explore potential sources of heterogeneity. The potential publication bias will be examined using funnel plots.

ETHICS AND DISSEMINATION: No research ethics approval is required in this study because it is a systematic review. The results of this study are expected to be disseminated through peer-reviewed journals and conferences.

TRIAL REGISTRATION NUMBER: CRD42021239438.

PMID:35361640 | DOI:10.1136/bmjopen-2021-053625

Eur Respir J. 2022 Mar 31:2200380. doi: 10.1183/13993003.00380-2022. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease implicated as an independent risk factor for lung cancer. However, optimal treatment for advanced lung cancer with IPF remains to be established. We performed a randomised phase 3 trial to assess the efficacy and safety of nintedanib plus chemotherapy (experimental arm) compared with chemotherapy alone (standard-of-care arm) for advanced non-small cell lung cancer (NSCLC) with IPF.

METHODS: Chemotherapy-naïve advanced NSCLC patients with IPF were allocated to receive carboplatin (area under the curve of 6 on day 1) plus nab-paclitaxel (100 mg m-2 on days 1, 8, and 15) every 3 weeks with or without nintedanib (150 mg b.i.d., daily). The primary end point was exacerbation-free survival (EFS).

RESULTS: Between May 2017 and February 2020, 243 patients were enrolled. Median EFS was 14.6 months in the nintedanib plus chemotherapy group and 11.8 months in the chemotherapy group (HR, 0.89; 90% CI, 0.67-1.17; p=0.24), whereas median progression-free survival was 6.2 and 5.5 months, respectively (HR, 0.68; 95% CI, 0.50-0.92). Overall survival was improved by nintedanib in patients with nonsquamous histology (HR, 0.61; 95% CI, 0.40-0.93) and in those at GAP stage I (HR, 0.61; 95% CI, 0.38-0.98). Seven (2.9%) of 240 patients experienced acute exacerbation during study treatment.

CONCLUSIONS: The primary end point of the study was not met. However, carboplatin plus nab-paclitaxel was found to be effective and tolerable in advanced NSCLC patients with IPF. Moreover, nintedanib in combination with such chemotherapy improved overall survival in patients with nonsquamous histology.

PMID:35361630 | DOI:10.1183/13993003.00380-2022

Front Genet. 2022 Mar 11;13:821029. doi: 10.3389/fgene.2022.821029. eCollection 2022.

ABSTRACT

Aims: Current idiopathic pulmonary fibrosis (IPF) therapies usually show a poor outcome or treatment efficacy. The search for new risk factors has significant implications in preventing, delaying, and treating IPF. The association between obesity and the risk of IPF is not clear. This study aimed to investigate the role of different obesity types in IPF risk, which provides the possibility of weight loss as a new approach for IPF prevention. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effect of obesity on IPF risk. We collected summary data of genetically determined obesity-related traits, including body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) from large-scale consortia (the sample size ranging from 232,101 to 681,275), and genetic association with IPF from one of the largest meta-analyses including 2,668 cases. A total of 35-469 single nucleotide polymorphisms were selected as instrumental variables for obesity-related traits. We further performed multivariable MR to estimate the independent effect of BMI and WC on the risk of IPF. Results: Increased BMI and WC were associated with higher risk of IPF [odds ratio (OR) = 1.51, 95% confidence interval (CI) (1.22-1.87), p = 1.27 × 10-4, and OR = 1.71, 95% CI (1.08-2.72), p = 2.33 × 10-2, respectively]. Similar results for the BMI and WC were obtained in the replicated analysis. Subsequently, only the result for BMI survived following the multiple testing correction and showed good consistency with the weighted median estimator. Sensitivity analyses indicated that there was no heterogeneity or horizontal pleiotropy for MR estimations. Further multivariable MR suggested that the BMI showed the same direction and similar magnitude with that in the univariable MR analysis. There was little evidence to support the causal role of WHR on the risk of IPF in this study. Conclusion: Genetically determined BMI demonstrates a causal risk for IPF, which offers a novel insight into probing potential mechanisms. Meanwhile, these results also suggest that weight loss may be beneficial to IPF prevention.

PMID:35360873 | PMC:PMC8961741 | DOI:10.3389/fgene.2022.821029

Front Pharmacol. 2022 Mar 14;13:834604. doi: 10.3389/fphar.2022.834604. eCollection 2022.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disorder with a poor prognosis. Although dihydromyricetin (DHM), extracted from vine tea and other Ampelopsis species, has been proven to have anti-inflammatory and antioxidant functions, the effects of DHM on IPF remain unclear. Methods: The effects of DHM on the differentiation, migration, proliferation, and respiratory functions of primary mouse lung fibroblasts (PMLFs) and primary human lung fibroblasts (PHLFs) were detected by western blotting, the Transwell assay, EdU staining, and the Mito Stress test. Then, the impacts of DHM on bleomycin (BLM)-induced pulmonary fibrosis were evaluated by pathological staining, western blotting, and coimmunofluorescence staining. The signaling pathway influenced by DHM was also investigated. Results: DHM could regulate the differentiation of fibroblasts to myofibroblasts and suppress the abnormal migration, proliferation, and respiratory functions of myofibroblasts induced by TGF-β1 or myofibroblasts from IPF patients. DHM could also alleviate pulmonary fibrosis induced by BLM. All these effects were achieved by regulating the STAT3/p-STAT3/GLUT1 signaling pathway. Conclusion: DHM could regulate the abnormal functions of myofibroblasts induced by TGF-β1 and myofibroblasts from IPF patients and alleviate pulmonary fibrosis induced by BLM; thus, DHM might be a candidate medicinal treatment for IPF.

PMID:35359847 | PMC:PMC8964100 | DOI:10.3389/fphar.2022.834604