Int J Med Sci. 2022 Aug 15;19(9):1417-1429. doi: 10.7150/ijms.73305. eCollection 2022.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease characterized by peripheral distribution of bilateral pulmonary fibrosis that is more pronounced at the base. IPF has a short median survival time and a poor prognosis. Therefore, it is necessary to identify effective prognostic indicators to guide the treatment of patients with IPF. Methods: We downloaded microarray data of bronchoalveolar lavage cells from the Gene Expression Omnibus (GEO), containing 176 IPF patients and 20 controls. The top 5,000 genes in the median absolute deviation were classified into different color modules using weighted gene co-expression network analysis (WGCNA), and the modules significantly associated with both survival time and survival status were identified as prognostic modules. We used Lasso Cox regression and multivariate Cox regression to search for hub genes related to prognosis from the differentially expressed genes (DEGs) in the prognostic modules and constructed a risk model and nomogram accordingly. Moreover, based on the risk model, we divided IPF patients into high-risk and low-risk groups to determine the biological functions and immune cell subtypes associated with the prognosis of IPF using gene set enrichment analysis and immune cell infiltration analysis. Results: A total of 153 DEGs located in the prognostic modules, three (TPST1, MRVI1, and TM4SF1) of which were eventually defined as prognostic hub genes. A risk model was constructed based on the expression levels of the three hub genes, and the accuracy of the model was evaluated using time-dependent receiver operating characteristic (ROC) curves. The areas under the curve for 1-, 2-, and 3-year survival rates were 0.862, 0.885, and 0.833, respectively. The results of enrichment analysis showed that inflammation and immune processes significantly affected the prognosis of patients with IPF. The degree of mast and natural killer (NK) cell infiltration also increases the prognostic risk of IPF. Conclusions: We identified three hub genes as independent molecular markers to predict the prognosis of patients with IPF and constructed a prognostic model that may be helpful in promoting therapeutic gains for IPF patients.

PMID:36035368 | PMC:PMC9413564 | DOI:10.7150/ijms.73305

Oxid Med Cell Longev. 2022 Aug 17;2022:5265616. doi: 10.1155/2022/5265616. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that leads rapidly to death. The present study is aimed at discovering the in-depth pathogenesis of IPF, exploring the role of adiponectin/carnitine palmityl transferase 1A- (APN/CPT1A-) mediated fatty acid metabolism during the development of IPF, and excavating its potential mechanism. Here, THP-1 cells were differentiated into M0 macrophages, followed by polarization to M1 macrophages upon hypoxia. Subsequently, lung fibroblast HFL-1 cells were stimulated by M1 macrophages to simulate hypoxia-related IPF condition in vitro. It was discovered that the stimulation of M1 macrophages promoted fibroblast proliferation and fibrosis formation in vitro, accompanied with a disorder of the APN/CPT1A pathway, an overproduction of lipid peroxides, and a low level of autophagy in HFL-1 cells. Thereafter, APN treatment or CPT1A overexpression greatly suppressed above lipid peroxide accumulation, fibroblast proliferation, and fibrosis but activated autophagy in vitro. Furthermore, an in vivo IPF rat model was established by injection of bleomycin (BLM). Consistently, CPT1A overexpression exerted a protective role against pulmonary fibrosis in vivo; however, the antifibrosis property of CPT1A was partly abolished by 3-methyladenine (an autophagy inhibitor). In summary, APN/CPT1A-mediated fatty acid metabolism exerted its protective role in IPF partly through activating autophagy, shedding a new prospective for the treatment of IPF.

PMID:36035217 | PMC:PMC9402305 | DOI:10.1155/2022/5265616

Respirology. 2022 Aug 28. doi: 10.1111/resp.14355. Online ahead of print.

NO ABSTRACT

PMID:36031719 | DOI:10.1111/resp.14355

Adv Mater. 2022 Aug 27:e2205083. doi: 10.1002/adma.202205083. Online ahead of print.

ABSTRACT

Lung fibrosis, as one of the major post-COVID complications, is a progressive and ultimately fatal disease without a cure. Here, we introduce an organ- and disease-specific in vitro mini-lung fibrosis model equipped with non-invasive real-time monitoring of cell mechanics as a functional readout. To establish an intricate multi-culture model under physiologic conditions, we developed a biomimetic ultrathin basement (BETA) membrane (<1 μm) with unique properties, including biocompatibility, permeability, and high elasticity (<10 kPa) for cell culturing under air-liquid interface (ALI) and cyclic mechanical stretch conditions. The human-based triple co-culture fibrosis model, which includes epithelial and endothelial cell lines combined with primary fibroblasts from idiopathic pulmonary fibrosis (IPF) patients established on the BETA membrane, is integrated into a millifluidic bioreactor system (CIVIC) with dose-controlled aerosolized drug delivery, mimicking inhalation therapy. We show the real-time measurement of cell/tissue stiffness (and compliance) as a clinical biomarker of the progression/attenuation of fibrosis upon drug treatment, which was confirmed for inhaled Nintedanib -an FDA-approved anti-fibrosis drug. The mini-lung fibrosis model allows the combined longitudinal testing of pharmacodynamics and pharmacokinetics of drugs, which is expected to enhance the predictive capacity of preclinical models and hence facilitate the development of approved therapies for lung fibrosis. This article is protected by copyright. All rights reserved.

PMID:36030365 | DOI:10.1002/adma.202205083

Chest. 2022 Aug 24:S0012-3692(22)03641-8. doi: 10.1016/j.chest.2022.07.027. Online ahead of print.

NO ABSTRACT

PMID:36029835 | DOI:10.1016/j.chest.2022.07.027

Tissue Eng Part A. 2022 Aug 27. doi: 10.1089/ten.TEA.2022.0054. Online ahead of print.

ABSTRACT

Human lung organoids (HLOs) are enabling the study of human lung development and disease by modelling native organ tissue structure, cellular composition, and cellular organization. In this report, we demonstrate that human lung organoids (HLOs) derived from human pluripotent stem cells (hPSCs) cultured in alginate, a fully defined non-animal product substrate, exhibit enhanced cellular differentiation compared to HLOs cultured in the commercially available Matrigel. More specifically, we observed an earlier onset and increase in the number of multi-ciliated cells, along with mucus producing MUC5AC+ goblet-like cells that were not observed in HLOs cultured in Matrigel. The epithelium in alginate-grown HLOs was organized in a pseudostratified epithelium with airway basal cells lining the basal lamina, but with the apical surface of cells on the exterior of the organoid. We further observed that HLOs cultured in Matrigel exhibited mesenchymal overgrowth that was not present in alginate cultures. The containment of the mesenchyme within HLOs in alginate enabled modeling of key features of Idiopathic Pulmonary Fibrosis (IPF) by treatment with TGFβ. TGFβ treatment resulted in morphological changes including an increase in mesenchymal growth, increased expression of IPF markers, and decreased numbers of alveolar-like cells. This culture system provides a model to study the interaction of the mesenchyme with the epithelium during lung development and diseased states such as IPF.

PMID:36029210 | DOI:10.1089/ten.TEA.2022.0054

Eur Respir J. 2022 Aug 25:2200577. doi: 10.1183/13993003.00577-2022. Online ahead of print.

ABSTRACT

Whole genome sequencing (WGS) can detect variants and estimate telomere length. The clinical utility of WGS in estimating risk, progression, and survival of pulmonary fibrosis patients is unknown. In this observational cohort study, we performed WGS on 949 idiopathic pulmonary fibrosis or familial pulmonary fibrosis patients to determine rare and common variant genotypes, estimate telomere length, and assess the association of genomic factors with clinical outcomes. WGS estimates of telomere length correlated with quantitative PCR (R=0.65) and Southern blot (R=0.71) measurements. Rare, deleterious, qualifying variants were found in 14% of the total cohort, with a five-fold increase in those with a family history of disease versus those without (25% versus 5%). Most rare qualifying variants (85%) were found in telomere-related genes and were associated with shorter telomere lengths. Rare qualifying variants have a greater effect on telomere length than a polygenic risk score (PRS) calculated using 20 common variants previously associated with telomere length. The common variant PRS predicted telomere length only in sporadic disease. Reduced transplant-free survival was associated with rare qualifying variants, shorter qPCR-measured telomere lengths, and the absence of MUC5B promoter (rs35705950) SNP, but not with WGS-estimated telomere length or the common variant PRS. Disease progression was associated with both measures of telomere length (qPCR-measured and WGS-estimated), rare qualifying variants, and the common variant PRS. As a single test, WGS can inform pulmonary fibrosis genetic-mediated risk, evaluate functional effect of telomere-related variants by estimating telomere length, and prognosticate clinically relevant disease outcomes.

PMID:36028256 | DOI:10.1183/13993003.00577-2022

Curr Probl Cardiol. 2022 Aug 23:101368. doi: 10.1016/j.cpcardiol.2022.101368. Online ahead of print.

ABSTRACT

Idiopathic pleuroparenchymal fibroelastosis (iPPFE) is a little-known entity with unique clinical, radiological, and pathological features. iPPFE is chronic interstitial pneumonia characterized by the thickening of elastic fibers in the pleura and subpleural parenchyma involving the upper lobes. Computed tomography pulmonary angiography (CTPA) usually depicts bilateral pleural thickening, with a left scalloped appearance that conditions retraction of the structures of the superior mediastinum and both pulmonary hila, associated with pulmonary consolidations with bronchogram air and thickening of the peribronchovascular interstitium, in addition to areas of left apical air trapping. When severe enough, the disease leads to progressive loss of volume of the upper lobes, decreased body mass, and platythorax. Some patients with iPPFE follow an inexorably progressive course culminating in irreversible respiratory failure and premature death. Up to 20% of patients might develop pulmonary hypertension (PH); transthoracic echocardiography is used as a screening test for PH; right heart catheterization performed in a tertiary-care hospital will confirm the diagnosis. Because iPPFE can be easily confused and misdiagnosed with infectious pathologies, such as pulmonary tuberculosis, and easily confuse physicians with little expertise in diffuse interstitial lung diseases, knowing the differential diagnoses, clinical presentation, imaging, and complications of the iPPFE allows for an early diagnosis and gives patients who suffer from it a better quality of life. This report presents a comprehensive review of PPFEi, discussing severe precapillary pulmonary hypertension and the associated findings demonstrated by right heart catheterization (RHC), which be of interest for cardiopulmonologists.

PMID:36028054 | DOI:10.1016/j.cpcardiol.2022.101368

Am J Respir Crit Care Med. 2022 Aug 26. doi: 10.1164/rccm.202208-1579ED. Online ahead of print.

NO ABSTRACT

PMID:36018580 | DOI:10.1164/rccm.202208-1579ED

Am J Respir Crit Care Med. 2022 Aug 26. doi: 10.1164/rccm.202207-1437ED. Online ahead of print.

NO ABSTRACT

PMID:36018567 | DOI:10.1164/rccm.202207-1437ED

Front Oncol. 2022 Aug 9;12:907321. doi: 10.3389/fonc.2022.907321. eCollection 2022.

ABSTRACT

Despite the rare incidence of idiopathic pulmonary fibrosis (IPF), coexisting IPF and lung cancer is common. Both diseases have unfavorable outcomes and are often associated with impaired quality of life. In this study, we present a clinical case of a patient with coexisting IPF and lung adenocarcinoma who was successfully treated with nintedanib plus docetaxel as a second-line treatment, and achieved a substantial improvement in the quality of life. To our knowledge, very few cases in the literature address the concurrent treatment of both diseases, which makes this case a valuable illustration of a successful treatment strategy and a basis for future investigations.

PMID:36016602 | PMC:PMC9396293 | DOI:10.3389/fonc.2022.907321

Pharmaceuticals (Basel). 2022 Aug 22;15(8):1033. doi: 10.3390/ph15081033.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a rare and severe disease with a median survival of ∼3 years. Several risk factors have been identified, such as age, genetic predisposition, tobacco exposure, and gastro-oesophageal reflux disease (GERD). Prevalence of GERD in IPF is high and may affect 87% of patients, of whom only half (47%) report symptoms. Objective: The aim of this study is to review current evidence regarding the correlation between GERD and IPF and to evaluate the current studies regarding treatments for GERD-IPF. Methods: A review to identify research papers documenting an association between GERD and IPF was performed. Results: We identified several studies that have confirmed the association between GERD and IPF, with an increased acid exposure, risk of gastric aspiration and bile acids levels in these patients. Few studies focused their attention on GERD treatment, showing how antiacid therapy was not able to change IPF evolution. Conclusions: This review investigating the correlation between GERD and IPF has confirmed the hypothesized association. However, further large prospective studies are needed to corroborate and elucidate these findings with a focus on preventative and treatment strategies.

PMID:36015181 | DOI:10.3390/ph15081033

Int J Mol Sci. 2022 Aug 12;23(16):9028. doi: 10.3390/ijms23169028.

ABSTRACT

Double-stranded RNA adenosine deaminase 1 (ADAR1) is significantly down-regulated in fibroblasts derived from Idiopathic Pulmonary Fibrosis (IPF) patients, and its overexpression restored levels of miRNA-21, PELI1, and SPRY2. There are two ADAR1 isoforms in humans, ADAR1-p110 and ADAR1-p150, generated by an alternative promoter. Let-7d is considered an essential microRNA in Pulmonary Fibrosis (PF). In silico analysis revealed COL3A1 and SMAD2, proteins involved in the development of IPF, as Let-7d targets. We analyzed the role of ADAR1-p110 and ADAR1-p150 isoforms in the regulation of Let-7d maturation and the effect of this regulation on the expression of COL3A1 and SMAD2 in IPF fibroblast. We demonstrated that differential expression and subcellular distribution of ADAR1 isoforms in fibroblasts contribute to the up-regulation of pri-miR-Let-7d and down-regulation of mature Let-7d. Induction of overexpression of ADAR1 reestablishes the expression of pri-miR-Let-7d and Let-7d in lung fibroblasts. The reduction of mature Let-7d upregulates the expression of COL3A1 and SMAD2. Thus, ADAR1 isoforms and Let-7d could have a synergistic role in IPF, which is a promising explanation in the mechanisms of fibrosis development, and the regulation of both molecules could be used as a therapeutic approach in IPF.

PMID:36012303 | DOI:10.3390/ijms23169028

Cells. 2022 Aug 20;11(16):2595. doi: 10.3390/cells11162595.

ABSTRACT

The lung epithelium is constantly exposed to harmful agents present in the air that we breathe making it highly susceptible to damage. However, in instances of injury to the lung, it exhibits a remarkable capacity to regenerate injured tissue thanks to the presence of distinct stem and progenitor cell populations along the airway and alveolar epithelium. Mechanisms of repair are affected in chronic lung diseases such as idiopathic pulmonary fibrosis (IPF), a progressive life-threatening disorder characterized by the loss of alveolar structures, wherein excessive deposition of extracellular matrix components cause the distortion of tissue architecture that limits lung function and impairs tissue repair. Here, we review the most recent findings of a study of epithelial cells with progenitor behavior that contribute to tissue repair as well as the mechanisms involved in mouse and human lung regeneration. In addition, we describe therapeutic strategies to promote or induce lung regeneration and the cell-based strategies tested in clinical trials for the treatment of IPF. Finally, we discuss the challenges, concerns and limitations of applying these therapies of cell transplantation in IPF patients. Further research is still required to develop successful strategies focused on cell-based therapies to promote lung regeneration to restore lung architecture and function.

PMID:36010671 | DOI:10.3390/cells11162595

Cells. 2022 Aug 16;11(16):2540. doi: 10.3390/cells11162540.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a disease characterized by irreversible lung scarring. The pathophysiology is not fully understood, but the working hypothesis postulates that a combination of epithelial injury and myofibroblast differentiation drives progressive pulmonary fibrosis. We previously demonstrated that a reduction in extracellular pH activates latent TGF-β1, and that TGF-β1 then drives its own activation, creating a feed-forward mechanism that propagates myofibroblast differentiation. Given the important roles of extracellular pH in the progression of pulmonary fibrosis, we sought to identify whether pH mediates other cellular phenotypes independent of TGF-β1. Proton-sensing G-protein coupled receptors are activated by acidic environments, but their role in fibrosis has not been studied. Here, we report that the Ovarian Cancer G-Protein Coupled Receptor1 (OGR1 or GPR68) has dual roles in both promoting and mitigating pulmonary fibrosis. We demonstrate that OGR1 protein expression is significantly reduced in lung tissue from patients with IPF and that TGF-β1 decreases OGR1 expression. In fibroblasts, OGR1 inhibits myofibroblast differentiation and does not contribute to inflammation. However, in epithelial cells, OGR1 promotes epithelial to mesenchymal transition (EMT) and inflammation. We then demonstrate that sub-cellular localization and alternative signaling pathways may be responsible for the differential effect of OGR1 in each cell type. Our results suggest that strategies to selectively target OGR1 expression may represent a novel therapeutic strategy for pulmonary fibrosis.

PMID:36010617 | DOI:10.3390/cells11162540

Cells. 2022 Aug 11;11(16):2487. doi: 10.3390/cells11162487.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a form of usual interstitial pneumonia (UIP), though its origin is unknown [...].

PMID:36010564 | DOI:10.3390/cells11162487

Biomedicines. 2022 Aug 15;10(8):1973. doi: 10.3390/biomedicines10081973.

ABSTRACT

BACKGROUND: Nintedanib is an oral multitarget tyrosine kinase inhibitor approved for the treatment of patients with idiopathic pulmonary fibrosis (IPF). Recent evidence demonstrated that nintedanib reduced functional disease progression also in subjects with non-IPF progressive fibrosing interstitial lung disease (PF-ILD). However, real-life data on the effectiveness of nintedanib in PF-ILD and familial pulmonary fibrosis (FPF) are lacking.

METHODS: this retrospective monocentric study enrolled 197 patients affected with IPF, PF-ILD and FPF treated with nintedanib at the Referral Centre of Siena from 2014 to 2021. Pulmonary functional tests and survival data were collected throughout the observation period for the evaluation of mortality and disease progression outcomes.

RESULTS: nintedanib treatment significantly reduced the FVC decline rate in IPF and PF-ILD subgroups, but not in FPF subjects. No significant differences were observed among the subgroups in terms of survival, which appeared to be influenced by gender and impaired lung function (FVC &lt; 70% of predicted value). Concerning disease progression rate, a diagnosis of FPF is associated with more pronounced FVC decline despite nintedanib treatment.

CONCLUSIONS: our research studies the effectiveness and safety of nintedanib in reducing functional disease progression of IPF and PF-ILD. FPF appeared to be less responsive to nintedanib, even though no differences were observed in terms of survival.

PMID:36009520 | DOI:10.3390/biomedicines10081973

Front Med (Lausanne). 2022 Aug 8;9:964722. doi: 10.3389/fmed.2022.964722. eCollection 2022.

ABSTRACT

Patients with idiopathic pulmonary fibrosis are screened for circulating autoantibodies as part of the initial interstitial lung disease workup. Management of seropositive idiopathic pulmonary fibrosis is currently considered no different than that of lone idiopathic pulmonary fibrosis. Emerging data however suggest that the former may possess distinct characteristics in terms of pathophysiology, histopathology, prognosis and amenability to immunomodulation. In that context, the aim of our study was to evaluate the influence of autoantibody status on: (i) the decline of forced vital capacity; (ii) the decline of diffusing capacity of lung for carbon monoxide; and (iii) 3-year survival; in a cohort of 102 idiopathic pulmonary fibrosis patients. In a pilot sub-study, we also sought to evaluate whether changes in antibody status during disease course affect the aforementioned parameters by potentially reflecting activity of the autoimmunity component of the pro-fibrotic mechanism.

PMID:36004373 | PMC:PMC9393367 | DOI:10.3389/fmed.2022.964722

Front Pharmacol. 2022 Aug 8;13:949264. doi: 10.3389/fphar.2022.949264. eCollection 2022.

ABSTRACT

Rationale: Galectin-3 (Gal-3) drives fibrosis during chronic lung injury, however, its role in acute lung injury (ALI) remains unknown. Effective pharmacological therapies available for ALI are limited; identifying novel concepts in treatment is essential. GB0139 is a Gal-3 inhibitor currently under clinical investigation for the treatment of idiopathic pulmonary fibrosis. We investigate the role of Gal-3 in ALI and evaluate whether its inhibition with GB0139 offers a protective role. The effect of GB0139 on ALI was explored in vivo and in vitro. Methods: The pharmacokinetic profile of intra-tracheal (i.t.) GB0139 was investigated in C57BL/6 mice to support the daily dosing regimen. GB0139 (1-30 µg) was then assessed following acute i.t. lipopolysaccharide (LPS) and bleomycin administration. Histology, broncho-alveolar lavage fluid (BALf) analysis, and flow cytometric analysis of lung digests and BALf were performed. The impact of GB0139 on cell activation and apoptosis was determined in vitro using neutrophils and THP-1, A549 and Jurkat E6 cell lines. Results: GB0139 decreased inflammation severity via a reduction in neutrophil and macrophage recruitment and neutrophil activation. GB0139 reduced LPS-mediated increases in interleukin (IL)-6, tumor necrosis factor alpha (TNFα) and macrophage inflammatory protein-1-alpha. In vitro, GB0139 inhibited Gal-3-induced neutrophil activation, monocyte IL-8 secretion, T cell apoptosis and the upregulation of pro-inflammatory genes encoding for IL-8, TNFα, IL-6 in alveolar epithelial cells in response to mechanical stretch. Conclusion: These data indicate that Gal-3 adopts a pro-inflammatory role following the early stages of lung injury and supports the development of GB0139, as a potential treatment approach in ALI.

PMID:36003515 | PMC:PMC9393216 | DOI:10.3389/fphar.2022.949264

N Engl J Med. 2022 Aug 25;387(8):762. doi: 10.1056/NEJMc2209529.

NO ABSTRACT

PMID:36001725 | DOI:10.1056/NEJMc2209529