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

Antioxidants (Basel). 2022 Feb 3;11(2):307. doi: 10.3390/antiox11020307.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) can severely disrupt lung function, leading to fatal consequences, and there is currently a lack of specific therapeutic drugs. Bergenin is an isocoumarin compound with lots of biological functions including antioxidant activity. This study evaluated the potential beneficial effects of bergenin on pulmonary fibrosis and investigated the possible mechanisms. We found that bergenin alleviated bleomycin-induced pulmonary fibrosis by relieving oxidative stress, reducing the deposition of the extracellular matrix (ECM) and inhibiting the formation of myofibroblasts. Furthermore, we showed that bergenin could induce phosphorylation and expression of p62 and activation of Nrf2, Nrf2 was required for bergenin-induced p62 upregulation, and p62 knockdown reduced bergenin-induced Nrf2 activity. More importantly, knockdown of Nrf2 or p62 could abrogate the antioxidant activity of bergenin and the inhibition effect of bergenin on TGF-β-induced ECM deposition and myofibroblast differentiation. Thereby, a regulatory loop is formed between p62 and Nrf2, which is an important target for bergenin aimed at treating pulmonary fibrosis.

PMID:35204190 | DOI:10.3390/antiox11020307

Biomedicines. 2022 Jan 28;10(2):310. doi: 10.3390/biomedicines10020310.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is associated with several hallmarks of aging including telomere shortening, which can result from germline mutations in telomere related genes (TRGs). Here, we assessed the length and stability of telomeres as well as the integrity of chromosomes in primary lung fibroblasts from 13 IPF patients (including seven patients with pathogenic variants in TRGs) and seven controls. Automatized high-throughput detection of telomeric FISH signals highlighted lower signal intensity in lung fibroblasts from IPF patients, suggesting a telomere length defect in these cells. The increased detection of telomere loss and terminal deletion in IPF cells, particularly in TRG-mutated cells (IPF-TRG), supports the notion that these cells have unstable telomeres. Furthermore, fibroblasts from IPF patients with TRGs mutations exhibited dicentric chromosomes and anaphase bridges. Collectively, our study indicates that fibroblasts from IPF patients exhibit telomere and chromosome instability that likely contribute to the physiopathology.

PMID:35203522 | DOI:10.3390/biomedicines10020310

Cells. 2022 Feb 14;11(4):664. doi: 10.3390/cells11040664.

ABSTRACT

BACKGROUND: Fibroblastic foci (FF) are characteristic features of usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF) and one cardinal feature thought to represent a key mechanism of pathogenesis. Hence, FF have a high impact on UIP/IPF diagnosis in current guidelines. However, although less frequent, these histomorphological hallmarks also occur in other fibrotic pulmonary diseases. Currently, there is therefore a gap in knowledge regarding the underlying molecular similarities and differences of FF in different disease entities.

METHODS: In this work, we analyzed the compartment-specific gene expression profiles of FF in IPF and sarcoidosis in order to elucidate similarities and differences as well as shared pathomechanisms. For this purpose, we used laser capture microdissection, mRNA and protein expression analysis. Biological pathway analysis was performed using two different gene expression databases. As control samples, we used healthy lung tissue that was donated but not used for lung transplantation.

RESULTS: Based on Holm Bonferroni corrected expression data, mRNA expression analysis revealed a significantly altered expression signature for 136 out of 760 genes compared to healthy controls while half of these showed a similar regulation in both groups. Immunostaining of selected markers from each group corroborated these results. However, when comparing all differentially expressed genes with the fdr-based expression data, only 2 of these genes were differentially expressed between sarcoidosis and IPF compared to controls, i.e., calcium transport protein 1 (CAT1) and SMAD specific E3 ubiquitin protein ligase 1 (SMURF1), both in the sarcoidosis group. Direct comparison of sarcoidosis and IPF did not show any differentially regulated genes independent from the statistical methodology. Biological pathway analysis revealed a number of fibrosis-related pathways pronounced in IPF without differences in the regulatory direction.

CONCLUSIONS: These results demonstrate that FF of end-stage IPF and sarcoidosis lungs, although different in initiation, are similar in gene and protein expression, encouraging further studies on the use of antifibrotic agents in sarcoidosis.

PMID:35203313 | DOI:10.3390/cells11040664

Cells. 2022 Feb 11;11(4):630. doi: 10.3390/cells11040630.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease of unknown etiology. Different types of cells are involved in fibrogenesis, which is persistently physical and molecular stimulation, either directly or by interacting with bioactive molecules and extracellular vesicles (EVs). Current evidence suggests that EVs play an essential role in IPF development. EVs are released by a variety of cells, including fibroblasts, epithelial cells, and alveolar macrophages. In addition, EVs can transport bioactive molecules, such as lipids, proteins, and nucleic acids, which play a pivotal role in cellular communication. Several proposed mechanisms show that an acceptor cell can capture, absorb, or interact with EVs through direct fusion with the plasma membrane, ligand-receptor interaction, and endocytotic process, modifying the target cell. During fibrogenesis, the release of EVs is deregulated, increases the EVs amount, and the cargo content is modified. This alteration is closely associated with the maintenance of the fibrotic microenvironment. This review summarizes the current data on the participation of EVs secreted by the cells playing a critical role in IPF pathogenesis.

PMID:35203281 | DOI:10.3390/cells11040630

J Pediatr Hematol Oncol. 2022 Mar 1;44(2):e500-e502. doi: 10.1097/MPH.0000000000002266.

ABSTRACT

Pulmonary fibrosis caused by bleomycin-induced pneumonia (BIP) is the most important side effect limiting the use of bleomycin and is mainly treated with corticosteroids. However, 1% to 4% of patients do not respond to corticosteroid therapy. Idiopathic pulmonary fibrosis and BIP develop by similar pathophysiological mechanisms. Nintedanib is a tyrosine kinase inhibitor used successfully in the treatment of idiopathic pulmonary fibrosis and there is no information about its use in BIP treatment. Here, we would like to present a 13-year-old boy with Hodgkin lymphoma who developed BIP after 2 cycles of ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine) and 4 cycles of BAECOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), whose respiratory failure impaired despite corticosteroid therapy, but was successfully treated with nintedanib.

PMID:35200223 | DOI:10.1097/MPH.0000000000002266

Arthritis Rheumatol. 2022 Feb 23. doi: 10.1002/art.42075. Online ahead of print.

ABSTRACT

OBJECTIVE: To analyze the efficacy and safety of nintedanib in patients with fibrosing autoimmune disease-related interstitial lung diseases (ILDs) with a progressive phenotype.

METHODS: The INBUILD trial enrolled subjects with a fibrosing ILD other than idiopathic pulmonary fibrosis, with diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography, forced vital capacity (FVC) ≥45% predicted and diffusing capacity of the lungs for carbon monoxide ≥30%-<80% predicted. Subjects fulfilled protocol-defined criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Subjects were randomized to receive nintedanib or placebo. We assessed the rate of decline in FVC (mL/year) and adverse events over 52 weeks in the subgroup with autoimmune disease-related ILDs.

RESULTS: Among 170 subjects with autoimmune disease-related ILDs, the rate of decline in FVC over 52 weeks was -75.9 mL/year with nintedanib versus -178.6 mL/year with placebo (difference 102.7 mL/year [95% CI 23.2, 182.2]; nominal P=0.012). No heterogeneity was detected in the effect of nintedanib versus placebo across subgroups by ILD diagnosis (P=0.91). The most frequent adverse event was diarrhea, reported in 63.4% and 27.3% of subjects in the nintedanib and placebo groups, respectively. Adverse events led to permanent discontinuation of trial drug in 17.1% and 10.2% of subjects in the nintedanib and placebo groups, respectively.

CONCLUSION: In the INBUILD trial, nintedanib slowed the rate of decline in FVC in subjects with progressive fibrosing autoimmune disease-related ILDs, with adverse events that were manageable for most subjects.

PMID:35199968 | DOI:10.1002/art.42075