Cell Biol Toxicol. 2022 Jul 25. doi: 10.1007/s10565-022-09743-z. Online ahead of print.

ABSTRACT

N-acetyltransferase 10 (NAT10), a nuclear acetyltransferase and a member of the GNAT family, plays critical roles in RNA stability and translation processes as well as cell proliferation. Little is known about regulatory effects of NAT10 in lung epithelial cell proliferation. We firstly investigated NTA10 mRNA expression in alveolar epithelial types I and II, basal, ciliated, club, and goblet/mucous epithelia from heathy and patients with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, lung adenocarcinoma, para-tumor tissue, and systemic sclerosis, respectively. We selected A549 cells for representative of alveolar epithelia or H1299 and H460 cells as airway epithelia with different genetic backgrounds and studied dynamic responses of NAT10-down-regulated epithelia to high temperature, lipopolysaccharide, cigarette smoking extract (CSE), drugs, radiation, and phosphoinositide 3-kinase (PI3K) inhibitors at various doses. We also compared transcriptomic profiles between alveolar and airway epithelia, between cells with or without NAT10 down-regulation, between early and late stages, and between challenges. The present study demonstrated that NAT10 expression increased in human lung epithelia and varied among epithelial types, challenges, and diseases. Knockdown of NAT10 altered epithelial mitochondrial functions, dynamic responses to LPS, CSE, or PI3K inhibitors, and transcriptomic phenomes. NAT10 regulates biological phenomes, and behaviors are more complex and are dependent upon multiple signal pathways. Thus, NAT10-associated signal pathways can be a new alternative for understanding the disease and developing new biomarkers and targets.

PMID:35877022 | DOI:10.1007/s10565-022-09743-z

Eur J Nucl Med Mol Imaging. 2022 Jul 25. doi: 10.1007/s00259-022-05908-4. Online ahead of print.

ABSTRACT

PURPOSE: Integrins αv are key molecules in the pathogenesis of fibrosis in multiple organs. To assess the potential utility of integrin αvβ3 imaging for idiopathic pulmonary fibrosis (IPF), we evaluated an 18F-FPP-RGD2 PET probe in a rat model of bleomycin-induced lung fibrosis.

METHODS: Pulmonary fibrosis was induced by single intratracheal instillation of bleomycin (3 mg/rat). Positron emission tomography (PET)/computerized tomography scans were performed 4 weeks after bleomycin administration using 18F-FPP-RGD2. Total distribution volume (VT) was estimated using one-tissue/two-compartment, two-tissue/three-compartment models, and Logan graphical analysis (Logan plot; t* = 30 min). Plasma-free fractions were estimated from images of the left ventricle. Correlation between Logan VT and lung pathology was assessed by Spearman's rank correlation.

RESULTS: Histopathological evaluation demonstrated the development of fibrosis in IPF-model group. Integrin αv protein expression and lung radioactivity were higher in IPF-model group compared with control group. The lung radioactivity of 18F-FPP-RGD2 rapidly reached the peak after administration and then gradually decreased, whereas left ventricular radioactivity rapidly disappeared. Logan graphical analysis was found to be suitable for 18F-FPP-RGD2 kinetic analysis in the IPF-model lung. Logan VT values for 18F-FPP-RGD2 were significantly higher in IPF rats compared with control rats and strongly correlated with lung fibrosis, pathology, integrin αv protein expression, and oxygen partial pressure.

CONCLUSION: Our findings demonstrate that the integrin αvβ3 PET probe 18F-FPP-RGD2 can detect pathophysiological changes in lungs, including fibrosis accompanying upregulated integrin αv of IPF-model rats. These findings support the utility of 18F-FPP-RGD2 PET imaging for the pathophysiological evaluation of pulmonary fibrosis.

PMID:35876866 | DOI:10.1007/s00259-022-05908-4

J Manag Care Spec Pharm. 2022 Aug;28(8):871-880. doi: 10.18553/jmcp.2022.28.8.871.

ABSTRACT

BACKGROUND: Progressive fibrosing interstitial lung disease (ILD) is a relatively new clinical concept describing a variety of ILDs characterized by progressive pulmonary fibrosis with associated lung function decline and worsening chest imaging. Little is known about health care resource utilization (HCRU) and costs associated with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF). This study analyzed the adjusted HCRU and cost burden among patients with incident non-IPF progressive fibrosing ILD vs matched patients with incident fibrosing ILD that had not yet progressed. METHODS: This was a retrospective study of insured US adults newly diagnosed with non-IPF fibrosing ILD from October 2016 to June 2019, conducted using administrative claims data from the Optum Research Database. Progressive disease was identified using claims-based proxies comprising health care utilization associated with management of progressive fibrosing ILD. Patients in the progressive population were 1:1 propensity score matched to not-yet-progressed patients on the basis of baseline demographic and clinical characteristics. All-cause HCRU and health care costs were presented as weighted per-patient-per-month (PPPM) measures to account for variable follow-up. Differences in study outcomes between matched cohorts were evaluated using Z-tests for continuous measures and Rao-Scott tests for binary measures. RESULTS: The postmatch cohorts comprised 11,025 patients with evidence of progression matched to 11,025 patients with not-yet-progressed fibrosing ILD. Mean (SD) weighted PPPM counts of follow-up health care encounters were significantly higher for the progressive vs not-yet-progressed cohort: ambulatory visits, 4.2 (3.6) vs 3.1 (3.3); emergency department visits, 0.3 (0.5) vs 0.1 (0.3); and inpatient (IP) stays, 0.1 (0.2) vs 0.0 (0.1) (P < 0.001 for all). Among patients with an IP stay, those with progressive disease had more inpatient days than those with not-yet-progressed disease (mean [SD] 1.6 [2.4] days vs 1.0 [1.3] days, P < 0.001). Mean weighted PPPM (SD) all-cause health care costs were also significantly higher for progressive vs not-yet-progressed patients, including total costs ($4,382 [$9,597] vs $2,243 [$4,162], P < 0.001), medical costs ($3,662 [$9,150] vs $1,627 [$3,524], P < 0.001), and pharmacy costs ($720 [$2,097] vs $616 [$2,070], P = 0.002). The difference in medical costs between cohorts was driven primarily by higher inpatient costs for progressive vs not-yet-progressed patients ($1,729 [$7,557] vs $523 [$2,118], P < 0.001). CONCLUSIONS: Progressive fibrosing ILD carries a substantial economic and health care burden. Among patients with incident non-IPF fibrosing ILD, all-cause HCRU and costs were significantly higher for those with a progressive phenotype than for matched patients whose disease had not yet progressed. The cost differential was driven primarily by hospitalizations, which were longer and more frequent for the progressive cohort. Disclosures: This work was funded by Boehringer Ingelheim Pharmaceuticals, Inc. Drs Conoscenti and Shetty are employees of Boehringer Ingelheim (BI). Dr Singer was an employee of BI at the time the study was conducted. Dr Brown was a paid consultant for BI for this study. Dr Bengtson, Ms Anderson, and Dr Brekke are employees of Optum, which was contracted by BI to conduct the study. Medical writing assistance was provided by Yvette Edmonds, PhD (Optum), and was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc.

PMID:35876293 | DOI:10.18553/jmcp.2022.28.8.871

Respirology. 2022 Jul 25. doi: 10.1111/resp.14333. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Prediction of disease course in patients with progressive pulmonary fibrosis remains challenging. The purpose of this study was to assess the prognostic value of lung fibrosis extent quantified at computed tomography (CT) using data-driven texture analysis (DTA) in a large cohort of well-characterized patients with idiopathic pulmonary fibrosis (IPF) enrolled in a national registry.

METHODS: This retrospective analysis included participants in the Australian IPF Registry with available CT between 2007 and 2016. CT scans were analysed using the DTA method to quantify the extent of lung fibrosis. Demographics, longitudinal pulmonary function and quantitative CT metrics were compared using descriptive statistics. Linear mixed models, and Cox analyses adjusted for age, gender, BMI, smoking history and treatment with anti-fibrotics were performed to assess the relationships between baseline DTA, pulmonary function metrics and outcomes.

RESULTS: CT scans of 393 participants were analysed, 221 of which had available pulmonary function testing obtained within 90 days of CT. Linear mixed-effect modelling showed that baseline DTA score was significantly associated with annual rate of decline in forced vital capacity and diffusing capacity of carbon monoxide. In multivariable Cox proportional hazard models, greater extent of lung fibrosis was associated with poorer transplant-free survival (hazard ratio [HR] 1.20, p < 0.0001) and progression-free survival (HR 1.14, p < 0.0001).

CONCLUSION: In a multi-centre observational registry of patients with IPF, the extent of fibrotic abnormality on baseline CT quantified using DTA is associated with outcomes independent of pulmonary function.

PMID:35875881 | DOI:10.1111/resp.14333

Intern Med. 2022 Jul 22. doi: 10.2169/internalmedicine.9736-22. Online ahead of print.

ABSTRACT

A 79-year-old man was admitted with worsening cough, dyspnea, and increased ground-glass opacity on chest computed tomography (CT). He had been diagnosed with idiopathic pulmonary fibrosis given the absence of an identifiable cause of interstitial pneumonia, chest CT findings, and absence of lymphocytosis in bronchoalveolar lavage (BAL) fluid. Meticulous history taking revealed extensive exposure to inciting antigens contained in chicken fertilizer before symptom worsening. A re-evaluation with BAL showed lymphocytosis, and clinical improvement with antigen avoidance confirmed the diagnosis of fibrotic hypersensitivity pneumonitis (fHP). A re-evaluation with BAL at disease deterioration after possible exposure to inciting antigen can facilitate a correct fHP diagnosis.

PMID:35871594 | DOI:10.2169/internalmedicine.9736-22

Stem Cell Rev Rep. 2022 Jul 23. doi: 10.1007/s12015-022-10422-z. Online ahead of print.

ABSTRACT

Several attempts have been made to reconstruct the whole lung using pluripotent stem cells (PSCs) to treat terminal stage diseases, such as chronic obstructive pulmonary disease [COPD] and idiopathic pulmonary fibrosis [IPF], for which whole-organ transplantation is currently the only treatment option. The development of induced differentiation technologies has made it possible to regenerate lungs from the 'bottom-up' via stepwise protocols. Nonetheless, the earliest lung multipotent progenitors, namely lung primordial stem cells, have not been identified to date. Considering the intricate crosstalk network that regulates lung development, stepwise protocols to differentiate PSCs into lung progenitors have raised some key questions: (1) the heterogeneity of these induced progenitors, and (2) obtaining a high-purity population. One important strategy to overcome these hurdles is to identify relevant markers or factors that regulate the complex network in lung morphogenesis according to those erected in vivo and ex vivo experiments. For screening lung primordial stem cells, several markers are 'on the shelf', and this review explores the most common or substantiated candidates. We artificially divided these markers into positive selecting and negative limiting proximal or distal markers as well as early progenitor markers that can be used to identify lung primordial stem cell, which represents the earliest progenitor during lung morphogenesis.

PMID:35871209 | DOI:10.1007/s12015-022-10422-z

EBioMedicine. 2022 Jul 20;82:104185. doi: 10.1016/j.ebiom.2022.104185. Online ahead of print.

ABSTRACT

BACKGROUND: In the aftermath of Covid-19, some patients develop a fibrotic lung disease, i.e., post-COVID-19 lung disease (PCLD), for which we currently lack insights into pathogenesis, disease models, or treatment options.

METHODS: Using an AI-guided approach, we analyzed > 1000 human lung transcriptomic datasets associated with various lung conditions using two viral pandemic signatures (ViP and sViP) and one covid lung-derived signature. Upon identifying similarities between COVID-19 and idiopathic pulmonary fibrosis (IPF), we subsequently dissected the basis for such similarity from molecular, cytopathic, and immunologic perspectives using a panel of IPF-specific gene signatures, alongside signatures of alveolar type II (AT2) cytopathies and of prognostic monocyte-driven processes that are known drivers of IPF. Transcriptome-derived findings were used to construct protein-protein interaction (PPI) network to identify the major triggers of AT2 dysfunction. Key findings were validated in hamster and human adult lung organoid (ALO) pre-clinical models of COVID-19 using immunohistochemistry and qPCR.

FINDINGS: COVID-19 resembles IPF at a fundamental level; it recapitulates the gene expression patterns (ViP and IPF signatures), cytokine storm (IL15-centric), and the AT2 cytopathic changes, e.g., injury, DNA damage, arrest in a transient, damage-induced progenitor state, and senescence-associated secretory phenotype (SASP). These immunocytopathic features were induced in pre-clinical COVID models (ALO and hamster) and reversed with effective anti-CoV-2 therapeutics in hamsters. PPI-network analyses pinpointed ER stress as one of the shared early triggers of both diseases, and IHC studies validated the same in the lungs of deceased subjects with COVID-19 and SARS-CoV-2-challenged hamster lungs. Lungs from tg-mice, in which ER stress is induced specifically in the AT2 cells, faithfully recapitulate the host immune response and alveolar cytopathic changes that are induced by SARS-CoV-2.

INTERPRETATION: Like IPF, COVID-19 may be driven by injury-induced ER stress that culminates into progenitor state arrest and SASP in AT2 cells. The ViP signatures in monocytes may be key determinants of prognosis. The insights, signatures, disease models identified here are likely to spur the development of therapies for patients with IPF and other fibrotic interstitial lung diseases.

FUNDING: This work was supported by the National Institutes for Health grants R01- GM138385 and AI155696 and funding from the Tobacco-Related disease Research Program (R01RG3780).

PMID:35870428 | DOI:10.1016/j.ebiom.2022.104185

J Ethnopharmacol. 2022 Jul 19:115568. doi: 10.1016/j.jep.2022.115568. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Zukamu Granules (ZKMG) is one of the representative Uygur patent drugs widely used in China, which is included in the National Essential Drugs List (2018 edition). As the first choice for common cold treatment in Uygur medicine theory, it has unique anti-inflammatory and antitussive efficacy.

AIM OF THE STUDY: According to the recent inflammatory hypothesis, the abnormal proliferation, autophagy and apoptosis process of lung cells especially alveolar macrophages (AMs) may play an important role in the progress of idiopathic pulmonary fibrosis (IPF). Therefore, we came up with a novel treatment approach for IPF by regulating the balance of AMs "autophagy - apoptosis", and took ZKMG as the sample drug for our research.

MATERIALS AND METHODS: Network pharmacology approach was conducted to predict the active components and intersected targets between ZKMG and inflammation. PPI network, GO and KEGG enrichment analysis were screened and analyzed to predict the anti-inflammatory mechanism of ZKMG. Biological experiment adopted from 128 rats, and hematoxylin-eosin staining, flow cytometry and RT-PCR were performed to examine the pathological morphology, HYP contents in lung tissue, AMs counting, AMs apoptosis, AMs phagocytosis rate, mRNA relative quantity determination of 3 key factors associated with AMs "autophagy - apoptosis" and mRNA relative quantity determination of AMs surface receptor signaling pathway.

RESULTS: The predicted results showed that the mechanism of ZKMG in anti-inflammatory was related to the response and elimination of inflammatory stimuli, the intervention of apoptosis and surface receptor signaling pathways of cells. The verification experiments showed that excessive apoptosis and insufficient autophagy of AMs always existed in the progression of IPF. ZKMG could inhibit AMs proliferation, significantly reduce AMs apoptosis rate, intervene the binding of the Bcl-2 to Beclin 1, inhibit the Caspase 3 activation, stimulate the enhancement of AMs phagocytosis, and inhibit the high expression of TLR4/MyD88/NF-κB surface receptor signaling pathway, which may partly retard the fibrosis process.

CONCLUSION: By inhibiting proliferation, enhancing phagocytosis, inhibiting the formation of Bcl-2 complex, and inhibiting the high expression of MYD88-dependent TLR4 signaling pathway, ZKMG can regulate the balance of AMs "autophagy - apoptosis" in the alveolitis stage to retard the fibrosis process partly. With a comprehensive strategy of "target prediction - experimental verification", we have demonstrated that inhibiting the apoptosis and promoting autophagy activity of AMs may suggest a new perspective for IPF treatment, which would provide reference for the subsequent development.

PMID:35868548 | DOI:10.1016/j.jep.2022.115568

Am J Respir Crit Care Med. 2022 Jul 22. doi: 10.1164/rccm.202207-1260LE. Online ahead of print.

NO ABSTRACT

PMID:35868030 | DOI:10.1164/rccm.202207-1260LE

Chin Med J (Engl). 2022 Jul 25. doi: 10.1097/CM9.0000000000002118. Online ahead of print.

ABSTRACT

Extracellular vesicles (EVs) are anuclear particles composed of lipid bilayers that contain nucleic acids, proteins, lipids, and organelles. EVs act as an important mediator of cell-to-cell communication by transmitting biological signals or components, including lipids, proteins, messenger RNAs, DNA, microRNAs, organelles, etc, to nearby or distant target cells to activate and regulate the function and phenotype of target cells. Under physiological conditions, EVs play an essential role in maintaining the homeostasis of the pulmonary milieu but they can also be involved in promoting the pathogenesis and progression of various respiratory diseases including chronic obstructive pulmonary disease, asthma, acute lung injury/acute respiratory distress syndrome, idiopathic pulmonary fibrosis (IPF), and pulmonary artery hypertension. In addition, in multiple preclinical studies, EVs derived from mesenchymal stem cells (EVs) have shown promising therapeutic effects on reducing and repairing lung injuries. Furthermore, in recent years, researchers have explored different methods for modifying EVs or enhancing EVs-mediated drug delivery to produce more targeted and beneficial effects. This article will review the characteristics and biogenesis of EVs and their role in lung homeostasis and various acute and chronic lung diseases and the potential therapeutic application of EVs in the field of clinical medicine.

PMID:35866573 | DOI:10.1097/CM9.0000000000002118

Front Immunol. 2022 Jul 5;13:905727. doi: 10.3389/fimmu.2022.905727. eCollection 2022.

ABSTRACT

BACKGROUND: Treatment responsiveness to corticosteroids is excellent for cryptogenic organizing pneumonia (COP) and sarcoidosis, but suboptimal for idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). We hypothesise that the differential expression of IL-17 contributes to variable corticosteroid sensitivity in different interstitial lung diseases.

OBJECTIVE: To determine the associations among expression of IL-17, glucocorticoid receptor-β and responsiveness to corticosteroid treatment in interstitial lung diseases.

METHODS: Immunohistochemical (IHC) staining was performed on formalin-fixed paraffin-embedded (FFPE) lung tissues obtained by bronchoscopic, CT-guided or surgical biopsies, and quantified by both cell counting (% positive cells) by individuals and by software IHC Profiler plugin of ImageJ (opacity density score). We studied the effect of IL-17 on corticosteroid sensitivity in human fibroblast MRC5 cell line.

RESULTS: Compared with specimens from patients with COP (n =13) and sarcoidosis (n =13), those from IPF patients (n = 21) had greater GR-β and IL-17 expression and neutrophil infiltration. Radiographic progression after oral corticosteroid treatment was positively correlated with the expression in IL-17 and GR-β/GR-α ratio in all patients (COP, sarcoidosis and IPF) and also within the IPF subgroup only. IL-17 expression level was positively associated with GR-β and GR-β/GR-α ratio. In MRC5 cells, exogenous IL-17 increased the production of collagen I and up-regulated GR-β expression and dexamethasone's suppressive effect on collagen I production was impaired by IL-17, and silencing IL-17 receptor A gene attenuated the effect of IL-17.

CONCLUSION: Up-regulation of GR-β/GR-α ratio by IL-17 could be associated with the relative corticosteroid-insensitivity of IPF.

PMID:35865549 | PMC:PMC9294725 | DOI:10.3389/fimmu.2022.905727

Ann Thorac Surg. 2022 Jul 18:S0003-4975(22)00967-5. doi: 10.1016/j.athoracsur.2022.05.069. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis guidelines changed the high-resolution computed tomography (HRCT) pattern from three to four categories in 2018. We assessed the relationship between surgical outcomes and HRCT patterns according to the 2018 guideline.

METHODS: Among 1503 patients who underwent pulmonary resection for clinical stage Ⅰ-Ⅲ lung cancer at our institution between January 2007 and June 2019, 218 with interstitial lung abnormalities based on preoperative HRCT were retrospectively investigated. We reclassified all interstitial lung abnormalities cases with preoperative HRCT from 3 patterns of the previous (2011th): "usual interstitial pneumonia (UIP)," "Possible," and "Inconsistent with UIP" into 4 patterns: "UIP," "Probable UIP," "Indeterminate," and "Alternative Diagnosis" according to the new consensus guideline of idiopathic pulmonary fibrosis (2018th). The occurrence of acute exacerbations and survival were analyzed, and its association with HRCT pattern was investigated.

RESULTS: Interstitial lung abnormalities cases were reclassified as UIP (n=55[25.2%]), probable UIP (n=36[16.5%]), indeterminate UIP (n=56[25.7%]), and alternative diagnosis (n=71[32.6%]). Twenty-one patients developed acute exacerbations (UIP pattern n=9 [16.4%], probable UIP n=5 [13.9%], indeterminate n=3 [5.4%], and alternative diagnosis n=4 [5.6%]). Multivariable Cox regression revealed that UIP pattern or probable UIP pattern of the 2018th guideline was an independent risk factor for severe acute exacerbations (grade III-Ⅴ) [odds ratio 6.81; 95% confidence interval 1.42-32.60] and postoperative overall survival [hazard ratio 3.12; 95% confidence interval 1.70-5.73].

CONCLUSIONS: UIP and probable UIP patterns were risk factors for postoperative severe acute exacerbations and mortality. 2018th guidelines' HRCT patterns could stratify outcomes of lung resection.

PMID:35863399 | DOI:10.1016/j.athoracsur.2022.05.069

PLoS One. 2022 Jul 21;17(7):e0271665. doi: 10.1371/journal.pone.0271665. eCollection 2022.

ABSTRACT

BACKGROUND AND OBJECTIVE: The epidemiology of interstitial lung diseases (ILDs) in developing countries remains unknown. The objective of this study was to estimate the incidence, prevalence, and national burden of ILDs in India.

METHODS: Data of consecutive subjects (aged >12 years) with ILDs included in a registry between March 2015 and February 2020 were analyzed retrospectively. The proportion of each ILD subtype was determined. The crude annual incidence and prevalence of ILDs for our region were estimated. Subsequently, the primary estimates of the national annual incident and prevalent burden of ILD and its subtypes were calculated. Alternative estimates for each ILD subtype were calculated using the current and a large, previous Indian study (n = 1,084). Data were analyzed using SPSS version 22 and are presented descriptively.

RESULTS: A total of 2,005 subjects (mean age, 50.7 years; 47% men) were enrolled. Sarcoidosis (37.3%) was the most common ILD subtype followed by connective tissue disease (CTD)-related ILDs (19.3%), idiopathic pulmonary fibrosis (IPF, 17.0%), and hypersensitivity pneumonitis (HP, 14.4%). The crude annual incidence and prevalence of ILDs were 10.1-20.2 and 49.0-98.1, respectively per 100,000 population. The best primary estimates for the crude national burden of all ILDs, sarcoidosis, CTD-ILD, IPF, HP, and other ILDs (in thousands) were 433-867, 213-427, 75-150, 51-102, 54-109, and 39-78. The respective alternative estimates (in thousands) were sarcoidosis, 127-254; CTD-ILD, 81-162; IPF, 46-91; HP, 130-261; other ILDs, 49-98.

CONCLUSION: In contrast to developed countries, sarcoidosis and HP are the ILDs with the highest burden in India.

PMID:35862355 | DOI:10.1371/journal.pone.0271665

Curr Opin Pulm Med. 2022 Jul 22. doi: 10.1097/MCP.0000000000000902. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: The aim of this study was to summarize quantitative computed tomography (CT) and machine learning data in fibrotic lung disease and to explore the potential application of these technologies in pulmonary sarcoidosis.

RECENT FINDINGS: Recent data in the use of quantitative CT in fibrotic interstitial lung disease (ILD) are covered. Machine learning includes deep learning, a branch of machine learning particularly suited to medical imaging analysis. Deep learning imaging biomarker research in ILD is currently undergoing accelerated development, driven by technological advances in image processing and analysis. Fundamental concepts and goals related to deep learning imaging research in ILD are discussed. Recent work highlighted in this review has been performed in patients with idiopathic pulmonary fibrosis (IPF). Quantitative CT and deep learning have not been applied to pulmonary sarcoidosis, although there are recent deep learning data in cardiac sarcoidosis.

SUMMARY: Pulmonary sarcoidosis presents unsolved problems for which quantitative CT and deep learning may provide unique solutions: in particular, the exploration of the long-standing question of whether sarcoidosis should be viewed as a single disease or as an umbrella term for disorders that might usefully be considered as separate diseases.

PMID:35861463 | DOI:10.1097/MCP.0000000000000902

Curr Opin Pulm Med. 2022 Jul 19. doi: 10.1097/MCP.0000000000000907. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Pleuroparenchymal fibroelastosis (PPFE) is a clinico-radiologic-pathologic interstitial lung disease (ILD) characterized by fibrosis that has upper lobe and subpleural predominance, involving both the visceral pleura and the subjacent subpleural lung parenchyma, and comprises dense fibroelastic changes with prominent elastosis of the alveolar walls together with fibrous thickening of the visceral pleura. The goal of this review is to summarize the state-of-the-art understanding in PPFE.

RECENT FINDINGS: PPFE was described in an increasing number of conditions. The course of disease is heterogeneous. Idiopathic PPFE, cases associated with telomerase-related gene mutations, cases related to a history of chemotherapy, and cases combining PPFE with a pattern of usual interstitial pneumonia, may have a particularly poor prognosis. Well-conducted retrospective studies identified marked PPFE features in approximately 10% of patients with idiopathic pulmonary fibrosis, 11% of patients with systemic sclerosis-associated ILD, 6.5% of patients with rheumatoid arthritis-associated ILD, and 23% of patients with hypersensitivity pneumonitis. Drug therapy has not been evaluated prospectively. A small retrospective study suggests that nintedanib may slow disease progression. However, whether the efficacy of antifibrotics is comparable in PPFE and in other forms of progressive pulmonary fibrosis warrants further evaluation.

SUMMARY: Accumulating data indicate that PPFE features are associated with poor prognosis in fibrosing ILDs. Further research on the management of PPFE is warranted.

PMID:35855575 | DOI:10.1097/MCP.0000000000000907

AMIA Annu Symp Proc. 2022 May 23;2022:206-215. eCollection 2022.

ABSTRACT

Analyzing gene co-expression networks can help in the discovery of biological processes and regulatory mechanisms underlying normal or perturbed states. Unlike standard differential analysis, network-based approaches consider the interactions between the genes involved leading to biologically relevant results. Applying such network-based methods to jointly analyze multiple transcriptomic networks representing independent disease cohorts or studies could lead to the identification of more robust gene modules or gene regulatory networks. We present gene2gauss, a novel feature learning framework that is capable of embedding genes as multivariate gaussian distributions by taking into account their long-range interaction neighborhoods across multiple transcriptomic studies. Using multiple gene co-expression networks from idiopathic pulmonary fibrosis, we demonstrate that these multi-dimensional gaussian features are suitable for identifying regulons of known transcription factors (TF). Using standard TF-target libraries, we demonstrate that the features from our method are highly relevant in comparison with other feature learning approaches on transcriptomic data.

PMID:35854722 | PMC:PMC9285176

Am J Respir Crit Care Med. 2022 Jul 19. doi: 10.1164/rccm.202206-1195LE. Online ahead of print.

NO ABSTRACT

PMID:35853164 | DOI:10.1164/rccm.202206-1195LE

JCI Insight. 2022 Jul 19:e156115. doi: 10.1172/jci.insight.156115. Online ahead of print.

ABSTRACT

Usual Interstitial Pneumonia (UIP) is a histological pattern characteristic of Idiopathic Pulmonary Fibrosis (IPF). The UIP pattern is patchy with histologically normal lung adjacent to dense fibrotic tissue. At this interface, fibroblastic foci (FF) are present and are sites where myofibroblasts and extracellular matrix (ECM) accumulate. Utilizing laser capture microdissection coupled mass spectrometry (LCM-MS), we interrogated the FF, adjacent mature scar, and adjacent alveoli in 6 fibrotic (UIP/IPF) specimens plus 6 non-fibrotic alveolar specimens as controls. The data were subject to qualitative and quantitative analysis, and histologically validated. We found that the fibrotic alveoli protein signature is defined by immune deregulation as the strongest category. The fibrotic mature scar classified as end-stage fibrosis whereas the FF contained an overabundance of a distinctive ECM compared to non-fibrotic control. Furthermore, the FF is positive for both TGFB1 and TGFB3, whereas the aberrant basaloid cell lining of the FF is predominantly positive for TGFB2. In conclusion, spatial proteomics demonstrated distinct protein compositions in the histologically defined regions of UIP/IPF tissue. These data revealed that the FF is the main site of collagen biosynthesis and that the adjacent alveoli are abnormal. This new and essential information will inform future mechanistic studies on fibrosis progression.

PMID:35852874 | DOI:10.1172/jci.insight.156115

Folia Med (Plovdiv). 2021 Aug 31;63(4):582-585. doi: 10.3897/folmed.63.e56088.

ABSTRACT

The idiopathic pulmonary hemosiderosis is a rare, life-threatening condition observed mainly in children and characterized by recurrent episodes of diffuse alveolar hemorrhages. The disease is characterized by the triad of hemoptysis, alveolar infiltrates in chest radiography, and iron-deficiency anemia. The recurrent episodes of alveolar hemorrhage can lead to chronic iron-deficiency anemia and irreversible pulmonary fibrosis; therefore, early diagnosis and treatment are crucial to the outcome of the disease.The idiopathic pulmonary hemosiderosis is a rare, life-threatening condition observed mainly in children and characterized by recurrent episodes of diffuse alveolar hemorrhages. The disease is characterized by the triad of hemoptysis, alveolar infiltrates in chest radiography, and iron-deficiency anemia. The recurrent episodes of alveolar hemorrhage can lead to chronic iron-deficiency anemia and irreversible pulmonary fibrosis; therefore, early diagnosis and treatment are crucial to the outcome of the disease.

PMID:35851160 | DOI:10.3897/folmed.63.e56088

Intern Med J. 2022 Jul 18. doi: 10.1111/imj.15887. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary hypertension (PH) is an important complication of interstitial lung disease (ILD), as its development confers a poor prognosis. There are no specific recommendations for methods of assessment for PH in ILD populations. This study aimed to determine current assessment practices for PH in an Australian ILD centre.

METHODS: In the Austin Health ILD database, 162 consecutive patients with idiopathic pulmonary fibrosis or connective tissue disease-associated ILD were identified and retrospectively evaluated for methods of PH assessment with transthoracic echocardiography (TTE), serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and right heart catheterisation, in relation to patient demographic and physiological parameters.

RESULTS: The median follow up was 30 (14.4-56.4) months. At baseline, vital capacity was 80.0±18.4% predicted and diffusing capacity for carbon monoxide was 59.6±15.2% predicted. Evaluation for PH was performed in 147 (90.7%) patients, among whom 105 (64.8%) had TTE performed at least once. At the initial TTE, 33.7% patients had high probability of PH, defined as RVSP > 40 mmHg + RAp and/or right ventricular dysfunction. At the time of the most recent TTE, these criteria were met in 45 (52.3%) patients. Elevated serum NT-proBNP levels during the first year were observed in 47 (38.8%) patients. Only 14 (8.6%) patients had right heart catheterisation.

CONCLUSION: Our institutional PH assessment practice in ILD demonstrates a substantial prevalence of probable PH at baseline. As new therapies emerge for the treatment of PH in ILD, well-defined screening practices are important in this population for early identification and optimal management. This article is protected by copyright. All rights reserved.

PMID:35848362 | DOI:10.1111/imj.15887