Mod Pathol. 2022 Feb 28. doi: 10.1038/s41379-022-01053-3. Online ahead of print.

ABSTRACT

This editorial focuses on common issues that surround the diagnosis of usual interstitial pneumonia (UIP), a clinically significant pathologic diagnosis. Most of these issues stem from conflation of the pathologically defined entity UIP with the clinically defined entity IPF. A pathologic or radiologic diagnosis of UIP is required for the clinical/multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF) but it has also been described in several other clinical settings. I offer my viewpoint on 5 important questions. 1. Is UIP a diagnosis or a "pattern"?

ANSWER: UIP is a pathologic diagnosis and is better conceptualized as a "pattern" than as a specific clinical entity. Since all cases of UIP require pattern recognition, adding the word "pattern" to UIP is redundant. 2. Is pathology the gold standard for UIP?

ANSWER: Yes. 3. How do you "prove" etiology of a given case of UIP?

ANSWER: "Soft" histologic features can raise the possibility of certain etiologies but the final determination of etiology comes from the multidisciplinary team. With few exceptions, there are no findings pathognomonic for any etiology in UIP. 4. Does UIP imply IPF?

ANSWER: No. 5. What should we do when pathology and HRCT are discordant?

ANSWER: This depends on the specifics of the discrepancy. When HRCT suggests a non-UIP diagnosis such as NSIP and histology shows UIP, histology has been shown to predict prognosis in multiple studies. In other settings, the radiologic impression based on HRCT is often proven to be incorrect by the histologic findings.

PMID:35228663 | DOI:10.1038/s41379-022-01053-3

Respirology. 2022 Feb 27. doi: 10.1111/resp.14231. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Demographic and clinical variables, measured at baseline or over time, have been associated with mortality in subjects with progressive fibrosing interstitial lung diseases (ILDs). We used data from the INPULSIS trials in subjects with idiopathic pulmonary fibrosis (IPF) and the INBUILD trial in subjects with other progressive fibrosing ILDs to assess relationships between demographic/clinical variables and mortality.

METHODS: The relationships between baseline variables and time-varying covariates and time to death over 52 weeks were analysed using pooled data from the INPULSIS trials and, separately, the INBUILD trial using a Cox proportional hazards model.

RESULTS: Over 52 weeks, 68/1061 (6.4%) and 33/663 (5.0%) subjects died in the INPULSIS and INBUILD trials, respectively. In the INPULSIS trials, a relative decline in forced vital capacity (FVC) >10% predicted within 12 months (hazard ratio [HR] 3.77) and age (HR 1.03 per 1-year increase) were associated with increased risk of mortality, while baseline FVC % predicted (HR 0.97 per 1-unit increase) and diffusing capacity of the lungs for carbon monoxide (DLCO) % predicted (HR 0.77 per 1-unit increase) were associated with lower risk. In the INBUILD trial, a relative decline in FVC >10% predicted within 12 months (HR 2.60) and a usual interstitial pneumonia-like fibrotic pattern on HRCT (HR 2.98) were associated with increased risk of mortality, while baseline DLCO % predicted (HR 0.95 per 1-unit increase) was associated with lower risk.

CONCLUSION: These data support similarity in the course of lung injury between IPF and other progressive fibrosing ILDs and the value of FVC decline as a predictor of mortality.

PMID:35224814 | DOI:10.1111/resp.14231

Respir Med Case Rep. 2022;36:101615. doi: 10.1016/j.rmcr.2022.101615. Epub 2022 Feb 20.

ABSTRACT

A 70-year-old man diagnosed with idiopathic pulmonary fibrosis (IPF) one year earlier developed progressive exertional dyspnea 3 weeks after onset of coronavirus disease 2019 (COVID-19). High-resolution computed tomography showed new extensive ground-glass opacities with rapidly progressive honeycombing. Although he was diagnosed with acute exacerbation (AE) of IPF triggered by COVID-19 and received methylprednisolone pulse therapy twice within one month, there was no improvement of oxygenation and lung involvement. Three months after COVID-19 onset, it was decided to provide best supportive care. An AE of IPF as a sequela of COVID-19, which is recognized as macrophage activation syndrome, is fatal, and in this case, the measurement of serum heme oxygenase-1, which is a macrophage activation biomarker involved in pulmonary cellular protection against oxidative stress, was useful for tracking disease activity.

PMID:35223424 | PMC:PMC8858429 | DOI:10.1016/j.rmcr.2022.101615

J Oncol. 2022 Feb 16;2022:4402536. doi: 10.1155/2022/4402536. eCollection 2022.

ABSTRACT

Nonsmall cell lung cancer (NSCLC) accounts for the majority of lung cancers. Studies have revealed the regulatory role of lncRNAs in cancer pathogenesis and their potential use as diagnostic and prognostic biomarkers. The epidermal growth factor receptor antisense RNA 1 (EGFR-AS1) has been reported to be upregulated in NSCLC tissues, while its detailed mechanism in lung cancer needs to be explored. DNA damage-regulated autophagy modulator 1 (DRAM1) has been known to act as a tumor suppressor in NSCLC, and miR-524-5p has been reported to be a biomarker in idiopathic pulmonary fibrosis and different lung disorders. Our investigation revealed that EGFR-AS1 is highly expressed in lung cancer tissues, and its knockdown inhibited lung cancer cell invasion and viability and reduced tumor growth in vivo. We also found that EGFR-AS1 targets miR-524-5p, and there was a negative correlation between their expressions in lung cancer tissues. Simultaneously, miR-524-5p has been found to promote DRAM1 expression. In addition, the inhibition of miR-524-5p diminished DRAM1 protein expression and promoted lung cancer cell invasion. Our study has revealed that EGFR-AS1 contributes to the pathogenesis of NSCLC by inhibiting autophagic-lysosomal degradation via targeting the miR-524-5p/DRAM1 axis. This finding elucidated for the first time the role of EGFR-AS1 in lung cancer progression and the positive regulatory function of miR-524-5p in regulating DRAM1 protein and suppressing lung cancer progression. This novel mechanism provided a better insight into the pathogenesis of lung cancer and presented a better strategy for the treatment of lung cancer.

PMID:35222643 | PMC:PMC8866007 | DOI:10.1155/2022/4402536

Front Immunol. 2022 Feb 10;13:837188. doi: 10.3389/fimmu.2022.837188. eCollection 2022.

ABSTRACT

BACKGROUND: High expression of chemokine (C-X3-C motif) receptor 1 (CX3CR1) was shown to contribute to the progression of many fibrotic diseases. However, there is still no study for the role of CX3CR1 in idiopathic pulmonary fibrosis (IPF). Therefore, we aimed to identify CX3CR1-related immune infiltration genes (IIGs) in IPF and establish a combined risk model to evaluate the prognosis of IPF.

METHODS: A discovery cohort of IPF patients (GSE70867) was downloaded from the Gene Expression Omnibus dataset. We identified the composition of 22 kinds of immune cells infiltration by CIBERSORT. The Cox regression model with the LASSO method was used for identifying prognostic genes and developing CX3CR1-related IIGs. Kaplan-Meier was applied to plot the survival curve of prognosis model. Peripheral blood mononuclear cell (PBMC) and bronchoalveolar lavage fluid (BALF) were collected to be tested by quantitative reverse transcriptase-PCR (qRT-PCR) from 15 clinical samples, including 8 healthy controls (HC), 4 patients with usual interstitial pneumonia (UIP) and 3 patients with pulmonary fibrosis (FIB).

RESULTS: We found that high expression of CX3CR1 in BALF contributed to the poor prognosis in IPF patients. ALR4C, RAB37, GPR56, MARCKS, PXN and RASSF2 were identified as CX3CR1-related IIGs, which were highly expressed in PBMC of UIP/FIB patients than that of HC. Moreover, the expression of PXN was higher in FIB patients' PBMC than that of UIP ones. In the cohort of IPF patients, high infiltration of activated NK cells in BALF caused poor survival compared to low infiltration group. The infiltration of activated NK was regulated by CX3CR1-related IIGs. The combined risk model predicted that high expression of CX3CR1-related IIGs and high infiltrated activated NK cells caused poor prognosis in IPF patients.

CONCLUSION: We identified a group of CX3CR1-related IIGs in IPF patients. This combined risk model provided new insights in the prognosis and therapy of IPF.

PMID:35222428 | PMC:PMC8866189 | DOI:10.3389/fimmu.2022.837188

Front Immunol. 2022 Feb 10;13:820347. doi: 10.3389/fimmu.2022.820347. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease of unknown etiology. Myofibroblasts are organized in peculiar subepithelial fibroblasts foci (FF), where they abnormally persist and exclude lymphocytes by unclear mechanisms. FF are the source of an excessive extracellular matrix, which results in progressive stiffening and destruction of the lung architecture. We hypothesized that the absence of T cells inside the FF could be related, at least partially, to an inefficient function of lymphocytes induced by IPF fibroblasts. Here, we evaluated the effect of a supernatant from IPF fibroblasts on T-cell apoptosis and migration capacity. Data showed that IPF fibroblasts secrete pro-apoptotic molecules (both from extrinsic and intrinsic pathways), generating a microenvironment that induces apoptosis of T cells at 3 h of culture, despite a weak anti-apoptotic profile exhibited by these T cells. At 24 h of culture, the supernatants from both IPF and control fibroblasts provoked T-cell death. However, at this time of culture, IPF fibroblasts caused a marked decrease in T-cell migration; in contrast, control lung fibroblasts induced an increase of T-cell migration. The reduction of T-cell migratory capacity provoked by IPF fibroblasts was associated with a negative regulation of RHOA and ROCK, two essential GTPases for migration, and was independent of the expression of chemokine receptors. In conclusion, our findings demonstrate that IPF fibroblasts/myofibroblasts induce apoptosis and affect T-cell migration, revealing a mechanism involved in the virtual absence of T lymphocytes inside the FF.

PMID:35222396 | PMC:PMC8866565 | DOI:10.3389/fimmu.2022.820347

Front Immunol. 2022 Feb 10;13:760776. doi: 10.3389/fimmu.2022.760776. eCollection 2022.

ABSTRACT

BACKGROUND: Although chitin is absent in humans, chitinases are present in healthy subjects and show dysregulated expression in a variety of diseases resulting from abnormal tissue injury and repair responses. It was shown that chitotriosidase (chitinase 1/CHIT1) and structurally-related chitinase 3-like 1 protein (CHI3L1/YKL-40) play important roles in the pathobiology of idiopathic pulmonary fibrosis (IPF), however little is known about their longitudinal serum levels and relationship to clinical measures in IPF.

METHODS: The present study is the first to evaluate serial measurements of serum CHIT1 activity and YKL-40 concentrations in patients with IPF starting antifibrotic treatment and followed up for 24 months. In addition, baseline serum CHIT1 and YKL-40 were compared between patients with IPF and control subjects, and possible CHIT1 and YKL-40 relationships to longitudinal clinical assessments in IPF were explored.

RESULTS: Baseline serum CHIT1 activity and YKL-40 concentrations were significantly elevated in patients with IPF compared to control subjects and showed similar discriminatory ability in distinguishing IPF from controls. No significant differences between the median serum CHIT1 activity and YKL-40 concentration measured over a study follow-up were noted. We found significantly elevated baseline serum CHIT1 activity in the progressors compared with the stables in the first year, while significantly increased baseline serum CHIT1 activity was noted in the stables compared to the progressors in the second year. Additionally, we observed a significant negative correlation between a change in serum YKL-40 concentration and a change in forced vital capacity (FVC) % predicted (% pred.) in the stables subgroup, whereas, a change in serum CHIT1 activity correlated negatively with a change in FVC% pred. in the progressors subgroup.

CONCLUSIONS: This explorative study findings add further evidence that CHIT1 and YKL-40 are upregulated in patients with IPF, and suggest that longitudinally stable serum CHIT1 activity and YKL-40 concentration levels may potentially be associated with the antifibrotic treatment response. In addition, our findings are supporting the possible role of CHIT1 and YKL-40 as candidate diagnostic and prognostic biomarkers in IPF. Further research is needed to validate present study findings.

PMID:35222369 | PMC:PMC8866556 | DOI:10.3389/fimmu.2022.760776

Rev Mal Respir. 2022 Feb 24:S0761-8425(21)00414-9. doi: 10.1016/j.rmr.2021.11.003. Online ahead of print.

ABSTRACT

INTRODUCTION: The main objective of this work was to investigate a possible link between lung density, small pulmonary vessels, and pulmonary hypertension (PH) in patients with progressive fibrosing interstitial lung disease (PF-ILD).

METHODS: The study focused on patients with PF-ILD, all of whom underwent right cardiac catheterization and chest computed tomography prior to lung transplantation. Computed tomography scans were analyzed quantitatively for density and pulmonary vascularity. The relationship between computed tomography features and PH was investigated.

RESULTS: Fifty-one patients with usual interstitial pneumonia (UIP) damage on lung explant were included. mPAP was positively correlated with lung mass (r=0.36, P=0.03) and lung volume (r=0.43, P=0.007). Patients with severe PH had more voxels lower than -856 Hounsfield Units (HU) (+16%, P=0.02), fewer voxels greater than -700 HU (-20%, P=0.03), and a higher lung volume (+1.57L, P=0.007) compared to patients without PH. No correlation was found between vascularization and HTP.

CONCLUSIONS: Patients with PF-ILD and severe PH have lower lung density than patients with moderate or without PH.

PMID:35221162 | DOI:10.1016/j.rmr.2021.11.003

Clin Chim Acta. 2022 Feb 24:S0009-8981(22)00072-9. doi: 10.1016/j.cca.2022.02.015. Online ahead of print.

ABSTRACT

BACKGROUND: Interleukin-36 (IL-36) family is associated with several fibrosis-related disorders and connective tissue diseases. However, their expression in idiopathic pulmonary fibrosis (IPF) and connective tissue disease-interstitial lung disease (CTD-ILD) is unknown.

METHODS: We included 19 CTD-ILD patients, 16 IPF patients, and 27 healthy control subjects. Determination of serum concentrations of IL-36α, IL-36γ and IL-36 receptor antagonist (IL-36Ra) was performed by ELISA. The value of biomarkers for the diagnosis and assessment of ILD was assessed by lung function tests and high-resolution computed tomography.

RESULTS: Serum concentrations of IL-36α and IL-36γ in patients with CTD-ILD and IPF were significantly higher than that in healthy controls, whereas serum IL-36Ra concentrations were not significantly different between the 3 groups. Increased IL-36 levels correlated with disease severity in IPF patients. ROC curve analysis showed that the AUC was 0.9931 for IL-36α and 0.8194 for IL-36γ in IPF group. In CTD-ILD group, the AUC was 0.9825 for IL-36α and 0.7973 for IL-36γ.

CONCLUSIONS: We demonstrated an imbalance in the agonist and antagonist profiles of IL-36 cytokines in ILD. IL-36 cytokines may be a new diagnostic or therapeutic target in ILD, especially in IPF.

PMID:35219714 | DOI:10.1016/j.cca.2022.02.015

Respir Res. 2022 Feb 26;23(1):39. doi: 10.1186/s12931-022-01964-4.

ABSTRACT

BACKGROUND: Recent studies have demonstrated that airway basal stem cells (BCs) transplantation can ameliorate bleomycin-induced idiopathic pulmonary fibrosis (IPF) through lung regeneration promotion. However, BCs under oxidative stress in the alveolar microenvironment are poor in survival, causing unsatisfied efficacy of BCs transplantation. In this study, we investigated whether Coenzyme Q10(CoQ10) counteracts oxidative stress in the alveolar microenvironment, thus improved the efficacy of BCs transplantation for IPF treatment.

METHODS: The protective effects of CoQ10 on H2O2-induced BCs apoptosis and cytoplasmic reactive oxygen species (ROS) level were tested by flow cytometry in vitro. The therapeutic effects of BCs combined with CoQ10 were compared to a single BCs transplantation protocol in IPF treatment after 2 weeks and were evaluated by parameters including changes of body weight and survival rate, as well as various levels of pulmonary inflammation, α-SMA expression and hydroxyproline (HYP) in IPF mouse lung tissues.

RESULTS: CoQ10 preincubation with BCs (10 mM, 24 h) significantly reduced the late apoptosis of BCs and the number of oxidative stressful BCs as a result of H2O2 stimulation (1 mM, 6 h) in vitro. IPF mouse model was constructed through bleomycin (5 mg/kg) intratracheal instillation. Bleomycin-induced IPF mice showed weight loss continuously and mortality increased progressively during modeling. Serious pulmonary inflammatory cell infiltration, collagen fiber proliferation, and collagen protein deposition were observed in lung tissues of IPF mice. Though BCs transplantation alone improved indicators above in bleomycin-induced IPF mice to some extent, the combination with CoQ10 improved the transplantation efficacy and obtained better therapeutic effects.

CONCLUSION: CoQ10 blocked H2O2-induced apoptosis of BCs and ROS production in vitro, and enhanced the efficacy of BCs transplantation against bleomycin-induced IPF in mice.

PMID:35219329 | DOI:10.1186/s12931-022-01964-4

Ann Thorac Surg. 2022 Feb 23:S0003-4975(22)00232-6. doi: 10.1016/j.athoracsur.2022.01.062. Online ahead of print.

ABSTRACT

Dendriform pulmonary ossification (DPO) is a rare condition defined as disseminated, widespread heterotopic bone formation within the lungs. This condition is associated with restrictive pulmonary disease, such as interstitial pneumonia or fibrosis. The clinical features and pathophysiology of DPO, however, remain unclear. We report a case of a 66-year-old male with idiopathic pulmonary fibrosis accompanied by DPO who was treated with a double lung transplant. His postoperative course was uneventful without recurrence of DPO.

PMID:35218702 | DOI:10.1016/j.athoracsur.2022.01.062

Pharmacoepidemiol Drug Saf. 2022 Feb 26. doi: 10.1002/pds.5421. Online ahead of print.

ABSTRACT

OBJECTIVE: Large electronic medical record (EMR) databases can facilitate epidemiology research into uncommon diseases such as interstitial lung disease (ILD). Given the rarity and diagnostic difficulty of ILD, the validity of the coding in EMR requires clarification. We aimed to assess the validity of International Classification of Diseases, 9th Revision (ICD-9) code algorithms for identifying ILD in the territory-wide electronic medical health record system of Clinical Data Analysis and Reporting System (CDARS) in Hong Kong.

METHOD: Patients who visited the Queen Mary Hospital in 2005-18 with ILD were identified using the following ICD-9 codes: post-inflammatory pulmonary fibrosis (PPF; ICD-9: 515), idiopathic fibrosing alveolitis (IFA; ICD-9: 516.3), connective tissue disease-associated interstitial lung disease (CTD-ILD; ICD-9: 517.2, 517.8, 714.81), sarcoidosis (ICD-9: 135) and extrinsic allergic alveolitis (EAA; ICD-9: 495). A random selection was conducted in cases with diagnostic code of PPF and IFA, where a relative higher case number was identified. All the cases of CTD-ILD, sarcoidosis and EAA were included in validation for relatively small case number.

RESULTS: 269 cases were validated using medical record review by a respiratory specialist. The overall positive predictive value (PPV) was 79% (95% CI, 74 to 84%). In subgroup analysis, true positive case numbers of PPF, IFA, CTD-ILD, sarcoidosis and EAA were 74 / 100 (74%), 95 / 100 (95%), 11 / 15 (73%), 27 / 32 (84%) and 6 / 22 (27%), respectively.

CONCLUSIONS: This was the first ICD-9 coding validation for ILD in Hong Kong CDARS. Our study demonstrated that using ICD-9 algorithms 515, 516.3, 517.2, 517.8, 714.81 and 135 enhanced identifications of ILDs with PPV that was reliable to support utility of CDARS database for further clinical research on ILDs. The validity is particularly high with 516.3. This article is protected by copyright. All rights reserved.

PMID:35218107 | DOI:10.1002/pds.5421

Int J Mol Sci. 2022 Feb 15;23(4):2162. doi: 10.3390/ijms23042162.

ABSTRACT

BACKGROUND: The aim of the research presented here was to find a set of parameters enabling discrimination between three types of fibroblasts, i.e., healthy ones and those derived from two disorders mimicking each other: idiopathic pulmonary fibrosis (IPF), and nonspecific interstitial pneumonia (NSIP).

METHODS: The morphology and growth of cells were traced using fluorescence microscopy and analyzed quantitatively using cell proliferation and substrate cytotoxicity indices. The viability of cells was recorded using MTS assays, and their stiffness was examined using atomic force microscopy (AFM) working in force spectroscopy (FS) mode. To enhance any possible difference in the examined parameters, experiments were performed with cells cultured on substrates of different elasticities. Moreover, the chemical composition of cells was determined using time-of-flight secondary ion mass spectrometry (ToF-SIMS), combined with sophisticated analytical tools, i.e., Multivariate Curve Resolution (MCR) and Principal Component Analysis (PCA).

RESULTS: The obtained results demonstrate that discrimination between cell lines derived from healthy and diseased patients is possible based on the analysis of the growth of cells, as well as their physical and chemical properties. In turn, the comparative analysis of the cellular response to altered stiffness of the substrates enables the identification of each cell line, including distinguishing between IPF- and NSIP-derived fibroblasts.

PMID:35216278 | DOI:10.3390/ijms23042162

Int J Mol Sci. 2022 Feb 15;23(4):2159. doi: 10.3390/ijms23042159.

ABSTRACT

Inflammatory bowel diseases (IBD) are chronic and relapsing gastrointestinal disorders, where a significant proportion of patients are unresponsive or lose response to traditional and currently used therapies. In the current study, we propose a new concept for anti-inflammatory treatment based on a selective acidic mammalian chitinase (AMCase) inhibitor. The functions of chitinases remain unclear, but they have been shown to be implicated in the pathology of various inflammatory disorders regarding the lung (asthma, idiopathic pulmonary fibrosis) and gastrointestinal tract (IBD and colon cancer). The aim of the study is to investigate the impact of AMCase inhibitor (OAT-177) on the dextran sulfate sodium (DSS)-induced models of colitis. In the short-term therapeutic protocol, OAT-177 given intragastrically in a 30 mg/kg dose, twice daily, produced a significant (p < 0.001) anti-inflammatory effect, as shown by the macroscopic score. Additionally, OAT-177 significantly decreased TNF-α mRNA levels and MPO activity compared to DSS-only treated mice. Intraperitoneal administration of OAT-177 at a dose of 50 mg/kg caused statistically relevant reduction of the colon length. In the long-term therapeutic protocol, OAT-177 given intragastrically in a dose of 30 mg/kg, twice daily, significantly improved colon length and body weight compared to DSS-induced colitis. This is the first study proving that AMCase inhibitors may have therapeutic potential in the treatment of IBD.

PMID:35216274 | DOI:10.3390/ijms23042159

Int J Mol Sci. 2022 Feb 14;23(4):2119. doi: 10.3390/ijms23042119.

ABSTRACT

Fibroblasts play a central role in diseases associated with excessive deposition of extracellular matrix (ECM), including idiopathic pulmonary fibrosis. Investigation of different properties of fibroblasts, such as migration, proliferation, and collagen-rich ECM production is unavoidable both in basic research and in the development of antifibrotic drugs. In the present study we developed a cost-effective, 96-well plate-based method to examine the migration of fibroblasts, as an alternative approach to the gold standard scratch assay, which has numerous limitations. This article presents a detailed description of our transient agarose spot (TAS) assay, with instructions for its routine application. Advantages of combined use of different functional assays for fibroblast activation in drug development are also discussed by examining the effect of nintedanib-an FDA approved drug against IPF-on lung fibroblasts.

PMID:35216230 | DOI:10.3390/ijms23042119

Cell Mol Life Sci. 2022 Feb 25;79(3):151. doi: 10.1007/s00018-022-04189-2.

ABSTRACT

Endoplasmic reticulum (ER) and mitochondria (mito) play a vital role in alveolar type II cell (AEC2) homeostasis and are both stressed in patients with idiopathic pulmonary fibrosis (IPF). Up to now, no data are available with regard to ER-mito cross talk and tethering under conditions of IPF. We here demonstrate that ER-mitochondrial tethering is reduced upon experimental ER stress in vitro and in the IPF AECII ex vivo, and this is-at least in part-due to decreased phosphofurin acidic cluster sorting protein 2 (PACS-2, also called PACS2) protein levels. PACS2 levels are influenced by its interaction with the transient receptor potential cation channel subfamily V member 1 (TRPV1) and can be experimentally modified by the TRPV1-modulating drug capsaicin (CPS). Employing alveolar epithelial cells with overexpression of the terminal ER stress signaling factor Chop or the IPF-associated surfactant protein C mutation (SPCΔexon4) in vitro, we observed a restoration of PACS2 levels upon treatment with CPS. Similarly, treatment of precision cut lung slices from IPF patients with CPS ex vivo forwarded similar effects. Importantly, in all models such kind of intervention also greatly reduced the extent of alveolar epithelial apoptosis. We therefore conclude that therapeutic targeting of the PACS2-TRPV1 axis represents an interesting novel, epithelial-protective approach in IPF.

PMID:35212819 | DOI:10.1007/s00018-022-04189-2

Case Rep Pulmonol. 2022 Feb 15;2022:9942432. doi: 10.1155/2022/9942432. eCollection 2022.

ABSTRACT

Interstitial lung diseases (ILDs) are heterogeneous in their clinical presentation. Making a differential diagnosis of ILD requires a thorough medical history, clinical examination, serologies, high-resolution computed tomography (CT) scan, and, in some cases, bronchoalveolar lavage or surgical lung biopsy. Multidisciplinary discussion is recommended to improve diagnostic confidence. ILDs have a variable and unpredictable clinical course. Patients should be closely monitored to ensure that progression of ILD is detected promptly. This involves regular assessment of symptoms, lung function, and, where appropriate, high-resolution CT. Patients with some fibrosing ILDs may respond well to immunosuppressants, but even patients who respond well to immunosuppressants initially may later show deterioration despite appropriate management. The tyrosine kinase inhibitor nintedanib has been approved for the treatment of idiopathic pulmonary fibrosis, other chronic fibrosing ILDs with a progressive phenotype, and systemic sclerosis-associated ILD. The three case studies described in this article illustrate the challenges in the diagnosis and management of patients with fibrosing ILDs and the importance of taking a multidisciplinary and individualized approach to care, including regular monitoring and consideration of whether a patient's drug regimen needs to be changed when there is evidence of disease progression.

PMID:35211349 | PMC:PMC8863484 | DOI:10.1155/2022/9942432

Front Genet. 2022 Feb 8;13:780010. doi: 10.3389/fgene.2022.780010. eCollection 2022.

ABSTRACT

Aging plays a significant role in the occurrence and development of idiopathic pulmonary fibrosis (IPF). In this study, we aimed to identify and verify potential aging-associated genes involved in IPF using bioinformatic analysis. The mRNA expression profile dataset GSE150910 available in the Gene Expression Omnibus (GEO) database and R software were used to identify the differentially expressed aging-related genes involved in IPF. Hub gene expression was validated by other GEO datasets. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on differentially expressed aging-related genes. Subsequently, aging-related genes were further screened using three techniques (least absolute shrinkage and selection operator (LASSO) regression, support vector machine, and random forest), and the receiver operating characteristic curves were plotted based on screening results. Finally, real-time quantitative polymerase chain reaction (qRT-PCR) was performed to verify the RNA expression of the six differentially expressed aging-related genes using the blood samples of patients with IPF and healthy individuals. Sixteen differentially expressed aging-related genes were detected, of which the expression of 12 were upregulated and four were downregulated. GO and KEGG enrichment analyses indicated the presence of several enriched terms related to senescence and apoptotic mitochondrial changes. Further screening by LASSO regression, support vector machine, and random forest identified six genes (IGF1, RET, IGFBP2, CDKN2A, JUN, and TFAP2A) that could serve as potential diagnostic biomarkers for IPF. Furthermore, qRT-PCR analysis indicated that among the above-mentioned six aging-related genes, only the expression levels of IGF1, RET, and IGFBP2 in patients with IPF and healthy individuals were consistent with the results of bioinformatic analysis. In conclusion, bioinformatics analysis identified 16 potential aging-related genes associated with IPF, and clinical sample validation suggested that among these, IGF1, RET, and IGFBP2 might play a role in the incidence and prognosis of IPF. Our findings may help understand the pathogenesis of IPF.

PMID:35211155 | PMC:PMC8863089 | DOI:10.3389/fgene.2022.780010

Eur Respir J. 2022 Feb 24:2103175. doi: 10.1183/13993003.03175-2021. Online ahead of print.

NO ABSTRACT

PMID:35210317 | DOI:10.1183/13993003.03175-2021

Biomolecules. 2022 Feb 9;12(2):283. doi: 10.3390/biom12020283.

ABSTRACT

Abnormalities in airway epithelia and lung parenchyma are found in Atp8b1 mutant mice, which develop pulmonary fibrosis after hyperoxic insult. Microarray and ingenuity pathway analysis (IPA) show numerous transcripts involved in ciliogenesis are downregulated in 14-month (14 M) -old Atp8b1 mouse lung compared with wild-type C57BL/6. Lung epithelium of Atp8b1 mice demonstrate apical abnormalities of ciliated and club cells in the bronchial epithelium on transmission electron microscopy (TEM). Matrix metalloproteinase 7 (MMP7) regulates of ciliogenesis and is a biomarker for idiopathic pulmonary fibrosis (IPF) in humans. Mmp7 transcript and protein expression are significantly upregulated in 14 M Atp8b1 mutant mouse lung. MMP7 expression is also increased in bronchoalveolar lavage fluid (BAL). Immunohistochemistry is localized MMP7 to bronchial epithelial cells in the Atp8b1 mutant. In conclusion, MMP7 is upregulated in the aged Atp8b1 mouse model, which displays abnormal ciliated cell and club cell morphology. This mouse model can facilitate the exploration of the role of MMP7 in epithelial integrity and ciliogenesis in IPF. The Atp8b1 mutant mouse is proposed as a model for IPF.

PMID:35204783 | DOI:10.3390/biom12020283