Eur Respir J. 2021 Mar 18;57(3):2004562. doi: 10.1183/13993003.04562-2020. Print 2021 Mar.

NO ABSTRACT

PMID:33737380 | DOI:10.1183/13993003.04562-2020

BMC Pulm Med. 2021 Mar 18;21(1):93. doi: 10.1186/s12890-021-01431-8.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) highly impacts patients on several life dimensions and challenges healthcare practices in providing high-quality care. Consequently, it is crucial to establish integrated care processes, maximizing patient value and patients' individual needs. The aim of the study was to shed light on the care trajectory based on the perspectives of patients and healthcare professionals.

METHODS: The study was conducted at a tertiary Belgian IPF centre of excellence. We conducted individual interviews with patients and healthcare professionals, guided by the Chronic Care Model (CCM) as a framework for integrated care. Thematic analysis was used to underpin data analysis.

RESULTS: Experiences were gathered of nine patients with IPF (aged 57-83 years, of which the informal caregivers were present at five interviews) and nine professionals involved in the IPF care trajectory. Our findings identified pitfalls and suggestions for improvement covering all elements of the CCM, primarily at the level of the individual patient and the care team. We covered suggestions to improve the team-based care and pro-active follow-up of patients' needs. Self-management support was highlighted as an important area and we identified possibilities, but also challenges regarding the use of patient-reported outcomes and eHealth-tools. Furthermore, the importance of continuous training for professionals and the implementation of guidelines in routine care was pointed out. Also, participants mentioned an opportunity to collaborate with community-based organizations and raised challenges regarding the overall health system. Lastly, the pertaining lack of IPF awareness and the disease burden on patients and their caregivers were covered.

CONCLUSIONS: Our research team has initiated a project aiming to optimize the current care delivery practice for IPF patients at a Belgian centre of excellence. These results will inform the further optimisation of the care program and the development of feasible supportive interventions.

PMID:33736646 | DOI:10.1186/s12890-021-01431-8

Biochem Biophys Res Commun. 2021 Mar 15;551:133-139. doi: 10.1016/j.bbrc.2021.02.127. Online ahead of print.

ABSTRACT

With undetermined etiology and limited treatment option, idiopathic pulmonary fibrosis (IPF) an age related disease is extremely lethal. Persistent injury of epithelial cells, abnormal activation of fibroblasts/myofibroblasts, and superabundant deposition of extracellular matrix protein pathologically characterize IPF. Redox imbalance is reported to play a vital role in both IPF development and senescence. This study aim to investigate whether and how Liproxstatin-1 (Lip-1), a strong lipid autoxidation inhibitor, regulates bleomycin (BLM) induced pulmonary fibrosis both in vivo and in vitro. It's demonstrated that Lip-1 exerted a potent anti-fibrotic function in BLM-induced mice pulmonary fibrosis via alleviating inflammatory, reshaping redox equilibrium, and ameliorating collagen deposition. Lip-1 reduced the level of reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA), promoted the expression of glutathione (GSH), catalase (CAT), and total superoxide dismutase (T-SOD) after BLM treatment. Moreover, in vitro experiments verified that Lip-1 protected A549 cells from BLM-induced injury and fibrosis. Lip-1 seemed to attenuate BLM-induced fibrosis by targeting ROS/p53/α-SMA signaling both in vivo and in vitro. In summary, this study demonstrates that Lip-1 administration performs a protective role in against pulmonary fibrosis and lights up the potential of Lip-1 treatment for patient with IPF in future.

PMID:33735625 | DOI:10.1016/j.bbrc.2021.02.127

Sci Transl Med. 2021 Mar 17;13(585):eaba2927. doi: 10.1126/scitranslmed.aba2927.

ABSTRACT

The mechanisms by which environmental exposures contribute to the pathogenesis of lung fibrosis are unclear. Here, we demonstrate an increase in cadmium (Cd) and carbon black (CB), common components of cigarette smoke (CS) and environmental particulate matter (PM), in lung tissue from subjects with idiopathic pulmonary fibrosis (IPF). Cd concentrations were directly proportional to citrullinated vimentin (Cit-Vim) amounts in lung tissue of subjects with IPF. Cit-Vim amounts were higher in subjects with IPF, especially smokers, which correlated with lung function and were associated with disease manifestations. Cd/CB induced the secretion of Cit-Vim in an Akt1- and peptidylarginine deiminase 2 (PAD2)-dependent manner. Cit-Vim mediated fibroblast invasion in a 3D ex vivo model of human pulmospheres that resulted in higher expression of CD26, collagen, and α-SMA. Cit-Vim activated NF-κB in a TLR4-dependent fashion and induced the production of active TGF-β1, CTGF, and IL-8 along with higher surface expression of TLR4 in lung fibroblasts. To corroborate ex vivo findings, mice treated with Cit-Vim, but not Vim, independently developed a similar pattern of fibrotic tissue remodeling, which was TLR4 dependent. Moreover, wild-type mice, but not PAD2-/- and TLR4 mutant (MUT) mice, exposed to Cd/CB generated high amounts of Cit-Vim, in both plasma and bronchoalveolar lavage fluid, and developed lung fibrosis in a stereotypic manner. Together, these studies support a role for Cit-Vim as a damage-associated molecular pattern molecule (DAMP) that is generated by lung macrophages in response to environmental Cd/CB exposure. Furthermore, PAD2 might represent a promising target to attenuate Cd/CB-induced fibrosis.

PMID:33731433 | DOI:10.1126/scitranslmed.aba2927

Biomed Pharmacother. 2021 Mar 14;138:111471. doi: 10.1016/j.biopha.2021.111471. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown etiology and poor prognosis. In IPF, aberrant extracellular matrix production by activated, hyperproliferative fibroblasts drives disease progression but the exact mechanisms by which this occurs remains undefined. The transcription factor nuclear factor kappa-B (NF-ĸB) has been suggested as a potential therapeutic target in IPF and therefore the aim of this study was to investigate the efficacy of ACT001, an NF-ĸB inhibitor, on primary fibroblasts derived from patients with and without IPF. Primary lung fibroblasts derived from eight patients with IPF and eight age-matched non-diseased controls (NDC) were treated with 0-10 µM ACT001 and the effects on fibroblast activity (viability and proliferation, fibroblast-to-myofibroblast transition, fibronectin expression), interleukin (IL)-6 and IL-8 cytokine release were quantified. ACT001 inhibited fibroblast activity in a concentration-dependent manner in both groups of fibroblasts. ACT001 inhibited IL-6 but not IL-8 production in unstimulated fibroblasts. ACT001 is a water-soluble compound with a stable half-life in plasma, thus making it an attractive candidate for further investigation as a therapeutic in IPF. This study adds to the growing body of literature that demonstrates anti-fibrotic activity of NF-ĸB inhibition in the context of IPF.

PMID:33730605 | DOI:10.1016/j.biopha.2021.111471

PLoS One. 2021 Mar 17;16(3):e0248415. doi: 10.1371/journal.pone.0248415. eCollection 2021.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited treatment options in which the telomere shortening is a strong predictive factor of poor prognosis. Mesenchymal stromal cells (MSC) administration is probed in several experimental induced lung pathologies; however, MSC might stimulate fibrotic processes. A therapy that avoids MSC side effects of transformation would be an alternative to the use of living cells. Membranes particles (MP) are nanovesicles artificially generated from the membranes of MSC containing active enzymes involved in ECM regeneration. We aimed to investigate the anti-fibrotic role of MP derived from MSC in an in vitro model of pulmonary fibrosis.

METHODS: Epithelial cells (A549) and lung fibroblasts, from IPF patients with different telomere length, were co-cultured with MP and TGF-β for 48h and gene expression of major pro-fibrotic markers were analyzed.

RESULTS: About 90% of both types of cells effectively took up MP without cytotoxic effects. MP decreased the expression of profibrotic proteins such as Col1A1, Fibronectin and PAI-1, in A549 cells. In fibroblasts culture, there was a different response in the inhibitory effect of MP on some pro-fibrotic markers when comparing fibroblast from normal telomere length patients (FN) versus short telomere length (FS), but both types showed an inhibition of Col1A1, Tenascin-c, PAI-1 and MMP-1 gene expression after MP treatment.

CONCLUSIONS: MP conserve some of the properties attributed to the living MSC. This study shows that MP target lung cells, via which they may have a broad anti-fibrotic effect.

PMID:33730089 | DOI:10.1371/journal.pone.0248415

Drug Des Devel Ther. 2021 Mar 8;15:997-1011. doi: 10.2147/DDDT.S288369. eCollection 2021.

ABSTRACT

BACKGROUND: T cells are important regulators of inflammation and, via release of mediators, can contribute to pulmonary fibrosis. Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease (ILD) and chronic fibrosing ILDs with a progressive phenotype. However, how nintedanib targets T cells has not been elucidated.

MATERIALS AND METHODS: We investigated the immunomodulatory effects of nintedanib on T cells and peripheral blood mononuclear cells isolated from healthy donors. Cells were pre-incubated with different concentrations of nintedanib and then stimulated for 24 hours with anti-CD3 with or without anti-CD28 and with or without different cytokines. Levels of interferon gamma (IFN-γ), interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12p70 and IL-13 were quantitated. Western blotting with primary antibodies against phospho-Lck-Y394, phospho-Lck-Y505, Lck-total and Cofilin examined the phosphorylation level of the Lck protein. In vitro T-cell proliferation, T-cell clustering and different T-cell populations were also assessed.

RESULTS: Nintedanib blocked T-cell activation through inhibiting Lck-Y394 phosphorylation. Pretreatment of T cells with nintedanib reduced cluster formation as a marker of activation and inhibited the release of IFN-γ, IL-2, IL-4, IL-5, IL-10, IL-12p70 and IL-13 at clinically relevant concentrations ranging from 5-77 nmol/L. Nintedanib did not alter T-cell proliferation or numbers of CD4+ and CD8+ T cells, but did increase stimulated Th17-like cells without increasing IL-17A levels.

CONCLUSION: These immunomodulatory effects may further explain how nintedanib slows the progression of pulmonary fibrosis in various ILDs.

PMID:33727792 | PMC:PMC7954282 | DOI:10.2147/DDDT.S288369

Respir Res. 2021 Mar 16;22(1):84. doi: 10.1186/s12931-021-01668-1.

ABSTRACT

BACKGROUND: In the INBUILD trial in patients with chronic fibrosing interstitial lung diseases (ILDs) and a progressive phenotype, nintedanib reduced the rate of ILD progression with adverse events that were manageable for most patients. We investigated the potential impact of immunomodulatory therapies on the efficacy and safety of nintedanib.

METHODS: Subjects with fibrosing ILDs other than idiopathic pulmonary fibrosis, who had shown progression of ILD within the prior 24 months despite management in clinical practice, were randomized to receive nintedanib or placebo. Certain immunomodulatory therapies were restricted for the first 6 months. We analyzed post-hoc the rate of decline in forced vital capacity (FVC) over 52 weeks in subgroups by glucocorticoid use at baseline and in analyses excluding subjects or FVC measurements taken after initiation of restricted immunomodulatory or antifibrotic therapies.

RESULTS: Of 663 subjects, 361 (54.4%) were taking glucocorticoids at baseline (353 at a dose of ≤ 20 mg/day). In the placebo group, the adjusted rate of decline in FVC (mL/year) over 52 weeks was numerically greater in subjects taking than not taking glucocorticoids at baseline (- 206.4 [SE 20.2] vs - 165.8 [21.9]). The difference between the nintedanib and placebo groups was 133.3 (95% CI 76.6, 190.0) mL/year in subjects taking glucocorticoids at baseline and 76.1 (15.0, 137.2) mL/year in subjects who were not (interaction P = 0.18). The effect of nintedanib on reducing the rate of FVC decline in analyses excluding subjects or measurements taken after initiation of restricted immunomodulatory or antifibrotic therapies was similar to the primary analysis. The adverse event profile of nintedanib was similar between subjects who did and did not use prohibited or restricted therapies at baseline or during treatment with trial drug.

CONCLUSIONS: In patients with progressive fibrosing ILDs, the effect of nintedanib on reducing FVC decline was not influenced by the use of immunomodulatory therapies. Nintedanib can be used in combination with immunomodulatory therapies in patients with progressive fibrosing ILDs. Trial registration ClinicalTrials.gov, NCT02999178. Registered 21 December 2016, https://clinicaltrials.gov/ct2/show/NCT02999178.

PMID:33726766 | DOI:10.1186/s12931-021-01668-1

Am J Respir Cell Mol Biol. 2021 Mar 16. doi: 10.1165/rcmb.2021-0101ED. Online ahead of print.

NO ABSTRACT

PMID:33725473 | DOI:10.1165/rcmb.2021-0101ED

Eur Radiol. 2021 Mar 16. doi: 10.1007/s00330-021-07798-w. Online ahead of print.

ABSTRACT

OBJECTIVES: The individual course of disease in idiopathic pulmonary fibrosis (IPF) is highly variable. Assessment of disease activity and prospective estimation of disease progression might have the potential to improve therapy management and indicate the onset of treatment at an earlier stage. The aim of this study was to evaluate whether regional ventilation, lung perfusion, and late enhancement can serve as early imaging markers for disease progression in patients with IPF.

METHODS: In this retrospective study, contrast-enhanced dual-energy CT scans of 32 patients in inspiration and delayed expiration were performed at two time points with a mean interval of 15.4 months. The pulmonary blood volume (PBV) images obtained in the arterial and delayed perfusion phase served as a surrogate for arterial lung perfusion and parenchymal late enhancement. The virtual non-contrast (VNC) images in inspiration and expiration were non-linearly registered to provide regional ventilation images. Image-derived parameters were correlated with longitudinal changes of lung function (FVC%, DLCO%), mean lung density in CT, and CT-derived lung volume.

RESULTS: Regional ventilation and late enhancement at baseline preceded future change in lung volume (R - 0.474, p 0.006/R - 0.422, p 0.016, respectively) and mean lung density (R - 0.469, p 0.007/R - 0.402, p 0.022, respectively). Regional ventilation also correlated with a future change in FVC% (R - 0.398, p 0.024).

CONCLUSION: CT-derived functional parameters of regional ventilation and parenchymal late enhancement are potential early imaging markers for idiopathic pulmonary fibrosis progression.

KEY POINTS: • Functional CT parameters at baseline (regional ventilation and late enhancement) correlate with future structural changes of the lung as measured with loss of lung volume and increase in lung density in serial CT scans of patients with idiopathic pulmonary fibrosis. • Functional CT parameter measurements in high-attenuation areas (- 600 to - 250 HU) are significantly different from normal-attenuation areas (- 950 to - 600 HU) of the lung. • Mean regional ventilation in functional CT correlates with a future change in forced vital capacity (FVC) in pulmonary function tests.

PMID:33725189 | DOI:10.1007/s00330-021-07798-w

Clin Respir J. 2021 Mar 15. doi: 10.1111/crj.13358. Online ahead of print.

ABSTRACT

INTRODUCTION: The inflammation and fibrosis in diffuse parenchymal lung diseases (DPLDs) in varied proportions gives rise to different patterns on radiology and histopathology. The radiological pattern on CT of the thorax most often allows us to make a diagnosis with varying levels of confidence, to optimize management. With a multidisciplinary team bringing the strengths of their individual domains of knowledge, clinical, radiological, histopathological and in many cases rheumatological, the level of confidence in making this diagnosis increases, often to the stage where the diagnosis is most often right, is concordant with the diagnosis achieved at histopathology and therefore obviates the need for lung biopsy which carries its own costs and risks of complications. Our study emphasizes the role of the Multidisciplinary team (MDT) in the management of DPLDs at a tertiary care referral center.

MATERIALS AND METHODS: Every case of DPLD presenting to our pulmonology department was discussed in an MDT meeting before subjecting them to any diagnostic intervention or therapy. A clinico-radiological diagnosis was made according to the 2002 ATS/ERS guidelines initially. Later an official ATS/ERS/JRS/ALAT statement on idiopathic pulmonary fibrosis and 2013 ATS/ERS consensus for the classification and diagnosis of idiopathic interstitial pneumonia was used. The concordance in our study was defined as the percentage of histopathological diagnoses that were identical to the clinico-radiological MDT diagnosis prior to the biopsy.

RESULTS: A total of 434 patients with DPLDs were evaluated. The MDT suggested biopsy for only 38.7% (168 / 434) patients since the pattern was very clear in 266 (61.3%) cases. As not all patients cionsented to undergo the biopsy procedure when recommended, histopathology was obtained in 102 patients. The histological diagnosis was concordant with the initial MDT diagnosis in 80.3% (82 / 102) of samples. On an individual basis CTD-ILD and sarcoidosis showed the best concordance (87%). In idiopathic NSIP cases, the histopathological diagnosis concurred in only 53.3% (8 / 15), out of which 8 were NSIP, 4 were UIP and 3 were reported as inadequate sampling on histopathology.

CONCLUSION: The MDT plays a crucial role in the diagnosis of DPLDs. Not every pattern requires biopsy confirmation. However, an iNSIP diagnosis by the MDT should probably be better confirmed by biopsy.

PMID:33721404 | DOI:10.1111/crj.13358

Am J Physiol Lung Cell Mol Physiol. 2021 Mar 10. doi: 10.1152/ajplung.00456.2020. Online ahead of print.

ABSTRACT

Despite modest improvement in patient outcomes from recent advances in pharmacotherapy targeting fibrogenic signaling pathways, IPF remains a major unsolved clinical problem. One reason for this is that available anti-fibrotic agents slow but do not arrest fibrotic progression. To arrest fibrotic progression, its obligatory drivers need to be identified. We previously discovered that fibrogenic mesenchymal progenitor cells (MPCs) are key drivers of fibrotic progression in IPF, serving as cells-of-origin for disease-mediating myofibroblasts. IPF MPCs have high levels of nuclear S100A4, which interacts with the proteasome to promote p53 degradation and self-renewal. However, the mechanism underlying S100A4 accumulation in the nucleus of IPF MPCs remains unknown. Here we show that hyaluronan (HA) is present in the fibroblastic focus together with CD44 expressing MPCs and that ligation of CD44 by HA triggers S100A4 nuclear translocation to support IPF MPC self-renewal. The mechanism involves HA-mediated formation of a CD44/S100A4/transportin1 complex, which promotes S100A4 nuclear import. In a humanized mouse model of pulmonary fibrosis, IPF MPC fibrogenicity was significantly attenuated by: i) knockdown of CD44; or ii) introduction of a S100A4 mutant construct which prevents S100A4 nuclear import. These data indicate that signaling through the HA/CD44/S100A4 axis is an integral component of IPF MPC fibrogenicity.

PMID:33719561 | DOI:10.1152/ajplung.00456.2020

ERJ Open Res. 2021 Mar 8;7(1):00014-2021. doi: 10.1183/23120541.00014-2021. eCollection 2021 Jan.

ABSTRACT

Pneumomediastinum in severe #COVID19 presentations could be due to a lung parenchymal retractive process generated by intense inflammation as in acute exacerbation of idiopathic pulmonary fibrosis or MDA-5 acute interstitial lung disease https://bit.ly/3qzBYMW.

PMID:33718492 | PMC:PMC7938049 | DOI:10.1183/23120541.00014-2021

Front Immunol. 2021 Feb 26;12:630096. doi: 10.3389/fimmu.2021.630096. eCollection 2021.

ABSTRACT

Background: Distal airway metaplasia may precede honeycombing in progressive fibrosing interstitial lung disease (ILD). The SCGB1A1+ bronchiolar-specific club cell may play a role in this aberrant regenerative process. Objective: To assess the presence of club cells in the small airways of patients suffering from ILD. Methods: Small airways (internal diameter <2 mm) in lung samples [surgical lung biopsy (SLB) and/or transbronchial lung cryobiopsy (TBLC)] from 14 patients suffering from ILD and 10 controls were morphologically assessed and stained for SCGB1A1. SCGB1A1 was weighted by epithelial height as a marker of airway generation (SCGB1A1/EH). Correlations between clinical, functional, and high-resolution CT (HRCT) prognostic factors and histomorphometry were assessed. Results: Small airways from samples with ILD patterns were significantly less dense in terms of SCGB1A1+ cells [0.064 (0.020-0.172)] as compared to controls' sample's small airways [0.393 (0.082-0.698), p < 0.0001]. Usual interstitial pneumonia (UIP) patterns most frequently contained small airways with limited or absent SCGB1A1 expression (SCGB1A1/EH <0.025): UIP (18/33; 55%) as compared with non-UIP patterns (4/31; 13%) or controls (0/29; 0%): p < 0.0001. In addition, correlations with HRCT indicated a significant negative relationship between SCGB1A1 and bronchiectasis as a feature of bronchiolization (Rho -0.63, p < 0.001) and a positive relationship with both forced vital capacity (FVC) and Hounsfield unit (HU)-distribution pattern in kurtosis (Rho 0.38 and 0.50, respectively, both p < 0.001) as markers of fibrotic changes. Conclusion: Compared with controls, the small airways of patients with ILD more often lack SCGB1A1, especially so in UIP. Low densities of SCGB1A1-marked cells correlate with bronchiectasis and fibrotic changes. Further research investigating SCGB1A1 staining as a pathological feature of the bronchiolization process is merited.

PMID:33717159 | PMC:PMC7952638 | DOI:10.3389/fimmu.2021.630096

Front Pharmacol. 2021 Feb 25;12:596492. doi: 10.3389/fphar.2021.596492. eCollection 2021.

ABSTRACT

Pulmonary fibrosis (PF) could severely disrupt the normal lung architecture and function with fatal consequences. Currently, there is no effective treatment for PF or idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the effects of Sodium Houttuyfonate (SH) on bleomycin (BLM) induced PF mice model. Our results indicated that SH could attenuate BLM induced lung injury by reducing the inflammation, fibrogenesis and lung/body weight ratio. The proposed mechanisms for the protective effects of SH include: 1) improvement of pulmonary function in BLM mice, for instance, it can elevate the vital capacity (VC), increase the forced expiratory flow at 50% of forced vital capacity (FEF50) and improve other pulmonary function indices; 2) inhibition of collagen formation in BLM mice; 3) attenuation of the elevation of inflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), which are triggered by BLM administration; 4) reduction of the mRNA level and protein production of transforming growth factor-β1 (TGF-β1) in BLM mice. Furthermore, it was found that the protective effects of SH against BLM induced PF in mice was comparable to that of prednisone acetate (PA) tablets, a widely used drug for immunological diseases. Although Houttuynia Cordata Thunb has been widely used in China for lung infection and inflammation, the mechanism has not yet been fully elucidated. Our study provides the evidence that SH is an effective compound against pulmonary injury, irritation and fibrogenesis.

PMID:33716736 | PMC:PMC7947865 | DOI:10.3389/fphar.2021.596492

Int Immunopharmacol. 2021 Mar 11;95:107525. doi: 10.1016/j.intimp.2021.107525. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease limited to the lungs. Immunological dysregulation may significantly participate in the pathophysiology of IPF. The immunological responses to nintedanib therapy in IPF patients were investigated for the first time in this study.

MATERIALS AND METHODS: Fifty IPF patients (median age (IQR) 69 (65-75) years; 38 males), were selected retrospectively. Flowcytometry analysis were performed to phenotype immunological biomarkers in peripheral blood from IPF patients after 1 year of antifibrotic therapy and a group of healthy volunteers.

RESULTS: Before starting antifibrotic treatment, IPF patients showed increased CD1d+CD5+ (p = 0.0460), Treg (p = 0.0354), T effector (CD25highCD127high) (p = 0.0336), central cells (CD4+CD45RA-) (p = 0.0354), effector cells (CD4+CD45RA+) (p = 0.0249) and follicular cell percentages (p = 0.0006), notably Tfh1 (p = 0.0412) and Tfh17 (p = 0.0051) cell percentages, in respect with healthy controls (HC). After nintedanib therapy, Breg (p = 0.0302), T effector (p = 0.0468), Th17.1 (p = 0.0146) and follicular cells (p = 0.0006), notably Tfh1 (p = 0.0006) and Tfh17 (p = 0.0182) cell percentages, were significantly decreased. In the logistic regression, Tfh panel showed a significant area under the receiver operating characteristics curve (AUROC) to distinguish IPF than HC (90.5%), as well as t0 and t1 (99.3%).

CONCLUSION: In conclusion, the immunological results obtained in this study demonstrate that nintedanib significantly helps to restore immunological responses in IPF patients. These findings will be useful in the search for biomarkers predictive of response to antifibrotic treatment.

PMID:33714885 | DOI:10.1016/j.intimp.2021.107525

EBioMedicine. 2021 Mar 10;65:103277. doi: 10.1016/j.ebiom.2021.103277. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity.

METHODS: The genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. We performed a Mendelian randomization (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P<5 × 10-8) in previous genome-wide association studies (GWAS) were used as instrumental variables (IVs). Effect estimates of those IVs on COVID-19 severity were gathered from the GWAS meta-analysis by the COVID-19 Host Genetics Initiative (4,336 cases & 623,902 controls).

FINDINGS: We detected a positive genetic correlation of IPF with COVID-19 severity (rg=0·31 [95% CI 0·04-0·57], P = 0·023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1·05, [95% CI 0·92-1·20], P = 0·43). However, outlier analysis revealed that the IPF risk allele rs35705950 at MUC5B had a different effect compared with the other variants. When rs35705950 was excluded, MR results provided evidence that genetically increased risk of IPF has a causal effect on COVID-19 severity (OR 1·21, [95% CI 1·06-1·38], P = 4·24 × 10-3). Furthermore, the IPF risk-allele at MUC5B showed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0·86, [95% CI 0·73-1·00], P = 2·99 × 10-2) .

INTERPRETATION: The strongest genetic determinant of IPF, rs35705950 at MUC5B, seems to confer protection against COVID-19, whereas the combined effect of all other IPF risk loci seem to confer risk of COVID-19 severity. The observed effect of rs35705950 could either be due to protective effects of mucin over-production on the airways or a consequence of selection bias due to (1) a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation and/or (2) due to survival bias of the rs35705950 non-IPF risk allele carriers. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, with a possible selection bias as an explanation, further investigation is needed to address this apparent paradox between variance at MUC5B and other IPF genetic risk factors.

FUNDING: Novo Nordisk Foundation and Oak Foundation.

PMID:33714028 | DOI:10.1016/j.ebiom.2021.103277

Thorax. 2021 Mar 12:thoraxjnl-2020-216370. doi: 10.1136/thoraxjnl-2020-216370. Online ahead of print.

ABSTRACT

To explore the role of extracellular vesicles (EVs) in chronic lung diseases.EVs are emerging as mediators of intercellular communication and possible diagnostic markers of disease. EVs harbour cargo molecules including RNA, lipids and proteins that they transfer to recipient cells. EVs are intercellular communicators within the lung microenvironment. Due to their disease-specific cargoes, EVs have the promise to be all-in-one complex multimodal biomarkers. EVs also have potential as drug carriers in chronic lung disease.Descriptive discussion of key studies of EVs as contributors to disease pathology, as biomarkers and as potential therapies with a focus on chronic obstructive pulmonary disorder (COPD), cystic fibrosis (CF), asthma, idiopathic pulmonary fibrosis and lung cancer.We provide a broad overview of the roles of EV in chronic respiratory disease. Recent advances in profiling EVs have shown their potential as biomarker candidates. Further studies have provided insight into their disease pathology, particularly in inflammatory processes across a spectrum of lung diseases. EVs are on the horizon as new modes of drug delivery and as therapies themselves in cell-based therapeutics.EVs are relatively untapped sources of information in the clinic that can help further detail the full translational nature of chronic lung disorders.

PMID:33712504 | DOI:10.1136/thoraxjnl-2020-216370

Respir Res. 2021 Mar 12;22(1):80. doi: 10.1186/s12931-021-01671-6.

ABSTRACT

BACKGROUND: Short-term exposure to ozone and nitrogen dioxide is a risk factor for acute exacerbation (AE) of idiopathic pulmonary fibrosis (AE-IPF). The comprehensive roles of exposure to fine particulate matter in AE-IPF remain unclear. We aim to investigate the association of short-term exposure to fine particulate matter with the incidence of AE-IPF and to determine the exposure-risk time window during 3 months before the diagnosis of AE-IPF.

METHODS: IPF patients were retrospectively identified from the nationwide registry in Japan. We conducted a case-control study to assess the correlation between AE-IPF incidence and short-term exposure to eight air pollutants, including particulate matter < 2.5 µm (PM2.5). In the time-series data, we compared monthly mean exposure concentrations between months with AE (case months) and those without AE (control months). We used multilevel mixed-effects logistic regression models to consider individual and institutional-level variables, and also adjusted these models for several covariates, including temperature and humidity. An additional analysis with different monthly lag periods was conducted to determine the risk-exposure time window for 3 months before the diagnosis of AE-IPF.

RESULTS: Overall, 152 patients with surgically diagnosed IPF were analyzed. AE-IPF was significantly associated with an increased mean exposure level of nitric oxide (NO) and PM2.5 30 days prior to AE diagnosis. Adjusted odds ratio (OR) with a 10 unit increase in NO was 1.46 [95% confidence interval (CI) 1.11-1.93], and PM2.5 was 2.56 (95% CI 1.27-5.15). Additional analysis revealed that AE-IPF was associated with exposure to NO during the lag periods lag 1, lag 2, lag 1-2, and lag 1-3, and PM2.5 during the lag periods lag 1 and lag 1-2.

CONCLUSIONS: Our results show that PM2.5 is a risk factor for AE-IPF, and the risk-exposure time window related to AE-IPF may lie within 1-2 months before the AE diagnosis. Further investigation is needed on the novel findings regarding the exposure to NO and AE-IPF.

PMID:33711988 | DOI:10.1186/s12931-021-01671-6

J Mater Chem B. 2021 Mar 12. doi: 10.1039/d0tb02997a. Online ahead of print.

ABSTRACT

Gold nanoparticles (AuNPs) have been extensively employed for computed tomography (CT) imaging in cell labeling and tracking because of their strong X-ray attenuation coefficient and excellent biocompatibility. However, the design and synthesis of stimuli-responsive AuNPs to modulate their endocytosis and exocytosis for optimal cell labeling and tracking are promising but challenging. Herein, we report an innovative labeling strategy based on temperature-responsive AuNPs (TRAuNPs) with high cell labeling efficiency and extended intracellular retention duration. We have manifested that the TRAuNP labeling imposes a negligible adverse effect on the function of human mesenchymal stem cells (hMSCs). Further experiment with idiopathic pulmonary fibrosis (IPF) model mice has demonstrated the feasibility of TRAuNP labeling for long time CT imaging tracking of transplanted hMSCs. What's more, the survival of transplanted hMSCs could also be monitored simultaneously using bioluminescence imaging after the expression of luciferase reporter genes. Therefore, we believe that this dual-modal labeling and tracking strategy enables visualization of the transplanted hMSCs in vivo, which may provide an important insight into the role of stem cells in the IPF therapy.

PMID:33711088 | DOI:10.1039/d0tb02997a