Sci Rep. 2022 Nov 17;12(1):19819. doi: 10.1038/s41598-022-24406-z.

ABSTRACT

Drug-induced interstitial lung disease (DILD) occurs when drug exposure causes inflammation of the lung interstitium. DILD can be caused by different types of drugs, and some DILD patterns results in a high mortality rate; hence, DILD poses a serious problem in clinical practice as well as drug development, and strategies to diagnose and distinguish DILD from other lung diseases are necessary. We aimed to identify novel biomarkers for DILD by performing lipidomics analysis on plasma samples from patients with acute and recovery phase DILD. Having identified lysophosphatidylcholines (LPCs) as candidate biomarkers for DILD, we determined their concentrations using validated liquid chromatography/mass spectrometry biomarker assays. In addition, we evaluated the ability of LPCs to discriminate patients with acute phase DILD from those with recovery phase DILD, DILD-tolerant, or other lung diseases, and characterized their association with clinical characteristics. Lipidomics analysis revealed a clear decrease in LPC concentrations in the plasma of patients with acute phase DILD. In particular, LPC(14:0) had the highest discriminative index against recovery phase and DILD-tolerant patients. LPC(14:0) displayed no clear association with causal drugs, or subjects' backgrounds, but was associated with disease severity. Furthermore, LPC(14:0) was able to discriminate between patients with DILD and other lung diseases, including idiopathic interstitial pneumonia and lung disease associated with connective tissue disease. LPC(14:0) is a promising biomarker for DILD that could improve the diagnosis of DILD and help to differentiate DILD from other lung diseases, such as idiopathic interstitial pneumonia and connective tissue disease.

PMID:36396675 | PMC:PMC9671920 | DOI:10.1038/s41598-022-24406-z

Med Clin (Barc). 2022 Nov 14:S0025-7753(22)00542-5. doi: 10.1016/j.medcli.2022.09.018. Online ahead of print.

NO ABSTRACT

PMID:36396475 | DOI:10.1016/j.medcli.2022.09.018

Biomed Pharmacother. 2022 Nov 14;157:114015. doi: 10.1016/j.biopha.2022.114015. Online ahead of print.

ABSTRACT

The effectiveness of cancer nanotherapeutics is greatly restricted by the dense collagen network in solid tumors. Pirfenidone (PFD) is a clinically approved oral antifibrotic agent widely used to treat idiopathic pulmonary fibrosis. To investigate whether PFD can enhance the penetration and tumor delivery efficiency of Pegylated liposomal doxorubicin (PLD), colorectal cancer xenograft mice were administered PFD, PLD, or combined regimens. As expected, high-dose PFD (H-PFD, 270 mg/kg/day) combined with PLD (H-PFD + PLD) exhibited a significantly higher tumor inhibition rate than PLD monotherapy (75.09% vs. 60.87%). Similarly, the intra-tumoral doxorubicin level was markedly elevated using H-PFD pretreatment, which induced over 34% elevation compared to PLD treatment alone (3.37 ± 0.41 vs. 2.51 ± 0.19 µg/mL). Additionally, Masson's trichrome staining and immunohistochemistry results of the H-PFD + PLD group revealed an attenuation of collagen deposition in vivo, and the in vitro TGF-β1, α-SMA, and collagen protein expression were inhibited using PFD treatment. In contrast, although low-dose PFD (60 mg/kg/day) did not present superior benefits in promoting PLD penetration into tumors, it did downregulate collagen expression in vivo. This study provides a new strategy for PFD combined with chemotherapeutic drugs to improve the antitumor efficacy of nanomedicines.

PMID:36395611 | DOI:10.1016/j.biopha.2022.114015

Int J Gen Med. 2022 Nov 8;15:8081-8092. doi: 10.2147/IJGM.S386984. eCollection 2022.

ABSTRACT

OBJECTIVE: Biomarkers for the acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) are urgently needed to provide better patient management. We aimed to investigate whether serum 1,25(OH)2D3 (1,25-dihydroxy vitamin D3) levels predict AE-IPF and whether they could be a potential prognostic biomarker for IPF.

PARTICIPANTS AND METHODS: This prospective study included 72 patients with IPF (31 with stable IPF and 41 with AE-IPF). All participants were recruited during hospitalisation at Tianjin Chest Hospital and were followed up for at least 12 months. Demographics, comorbidities, arterial blood gas, and serum biochemical profile, radiological features, and anti-fibrotic therapy were evaluated. Serum concentrations of 1,25(OH)2D3 and transforming growth factor beta1 (TGFβ1) were detected using enzyme-linked immunosorbent assay (ELISA). Risk factors for AE-IPF were identified using multivariate analysis. Prognostic factors were assessed using Kaplan-Meier and Cox regression analyses.

RESULTS: Baseline values of alveolar-arterial oxygen difference (A-aDO2) (40.85 mmHg vs 29.2 mmHg, p =0.035), white blood cell counts (10.09 ± 4.2×109/L vs 7.46 ± 7.84×109/L, p <0.001), percentage of monocytes (7.36 ± 1.36% vs 6.6 ± 1.2%, p =0.017), C-reactive protein (CRP) (2.1 mg/dL vs 1.12 mg/dL, p =0.015) and procalcitonin (PCT) (36.59% vs 3.23%, p <0.001) were significantly higher in AE-IPF patients than in stable IPF patients. Instead, the mean concentration of serum calcium and 1,25(OH)2D3 at baseline were higher in IPF patients with stable disease than in those with acute exacerbation (2.17 ± 0.13 nmol/L vs 2.09 ± 0.13 nmol/L, p =0.023 and 16.62 pg/mL vs 11.58 pg/mL, p <0.001, respectively). In multivariate analysis, a higher proportion of patients with lower serum 1,25(OH)2D3 levels experienced AE-IPF (OR 0.884, 95% CI 0.791-0.987, p =0.029), and rising serum PCT level (PCT > 0.05 ng/mL) was associated with an increased risk of mortality (HR 3.664, 95% CI 1.010-12.900, p =0.043).

CONCLUSION: Decreased serum 1,25(OH)2D3 is associated with an increased risk of acute exacerbation for patients with IPF. A high serum PCT level is predictive of worse prognosis in IPF patients. 1,25(OH)2D3 may be a potential biomarker for AE-IPF, while PCT could be a prognostic biomarker for IPF.

PMID:36389018 | PMC:PMC9653052 | DOI:10.2147/IJGM.S386984

Front Pharmacol. 2022 Oct 28;13:1053356. doi: 10.3389/fphar.2022.1053356. eCollection 2022.

ABSTRACT

Background and objective: Idiopathic pulmonary fibrosis (IPF) is a critical disease, with limited treatments available. Clinical practices show that traditional Chinese medicine (TCM) has certain efficacy. This study was preliminarily to evaluate the efficacy and safety of TCM treatment based on syndrome differentiation in IPF. Methods: A study design of exploratory, multi-centers, randomized, double-blinded, placebo controlled trial has been adopted. A total of 80 IPF patients from four sub-centers were enrolled. All the patients were randomly assigned into TCM group (TCMG) or control group (CG) in 1:1. Patients in TCMG were given CM granules, as patients in CG given with the placebo of CM granule. All the patients received a 26-week treatment. The efficacy was assessed by acute exacerbations (AEs) of IPF, pulmonary function, clinical symptoms, dyspnea scores (mMRC), health-related quality of life (HRQoL), 6-min walk test (6MWT) and all-cause mortality. Safety has also been assessed. Results: A total of 67 patients completed the trial with 35 in TCM group and 32 in control group. Meaningful differences have been observed in mean changes in AEs (-1.56 times; 95% CI, -2.69 to -0.43, p = 0.01), DLco% (5.29; 95% CI, 0.76 to 9.81, p = 0.02), cough scores (-0.38 points; 95% CI, -0.73 to -0.04, p = 0.03), and 6MWT (30.43 m; 95% CI, 2.85 to 58.00, p = 0.03), with no statistical differences in FEV1, FVC, expectoration, chest tightness, Shortness of breath, Fatigue, Cyanosis, mMRC, CAT, SF-36, and SGRQ total scores in 26 weeks after treatment than before treatment. At of the end of follow-up, a total of 10 patients died, including three and seven in the TCM and control group respectively. And the HR (Hazard ratio) for CM granules in all-cause mortality was 0.39 (95% CI, 0.10-1.52). The drug-related adverse events were not observed. Conclusion: CM granules, as compared with placebo, could reduce frequencies of AEs, improve pulmonary function, HRQoL, exercise capacity and symptoms and signs for IPF to some extent with acceptable side-effect.

PMID:36386223 | PMC:PMC9649819 | DOI:10.3389/fphar.2022.1053356

BMC Pulm Med. 2022 Nov 17;22(1):422. doi: 10.1186/s12890-022-02232-3.

ABSTRACT

INTRODUCTION: Dysphagia occurs in multiple respiratory pathophysiologies, increasing the risk of pulmonary complications secondary to aspiration. Reflux associated aspiration and a dysregulated lung microbiome is implicated in Idiopathic Pulmonary Fibrosis (IPF), but swallowing dysfunction has not been described. We aimed to explore oropharyngeal swallowing in IPF patients, without known swallowing dysfunction.

METHODS: Fourteen consecutive outpatients with a secure diagnosis of IPF were recruited and the 10-item Eating Assessment Tool (Eat 10) used to assess patient perception of swallowing difficulty. Oropharyngeal swallowing was assessed in ten patients using Videofluoroscopy Swallow Studies (VFSS). The studies were rated using validated scales: Penetration-Aspiration Scale (PAS); standardised Modified Barium Swallow Impairment Profile (MBSImP).

RESULTS: EAT-10 scores indicated frank swallowing difficulty in 4/14 patients. Videofluoroscopy Studies showed that 3/10 patients had airway penetration, and one aspirated liquid without a cough response. Median MBSImp for oral impairment was 5, range [3-7] and pharyngeal impairment 4, range [1-14] indicating, overall mild alteration to swallowing physiology.

CONCLUSION: We conclude that people with IPF can show a range of swallowing dysfunction, including aspiration into an unprotected airway. To our knowledge, this is the first report on swallowing physiology and safety in IPF. We believe a proportion of this group may be at risk of aspiration. Further work is indicated to fully explore swallowing in this vulnerable group.

PMID:36384569 | DOI:10.1186/s12890-022-02232-3

Rev Med Suisse. 2022 Nov 16;18(804):2162-2168. doi: 10.53738/REVMED.2022.18.804.2162.

ABSTRACT

Lung cancer is the leading cause of cancer mortality in the developed world. Diffuse fibrosing interstitial lung disease (ILD) consist of a heterogeneous group that includes idiopathic pulmonary fibrosis (IPF). Diffuse ILD is a risk factor for the development of lung cancer which on its own is associated with an increased risk of morbidity and mortality. Despite common mechanisms between fibrogenesis and carcinogenesis, the underlying pathogenesis of lung cancer and fibrosis overlap is poorly understood. The clinical management of these patients remains a medical challenge requiring a multidisciplinary approach, particularly in view of the risk of acute exacerbation of fibrosing ILD following most lung cancer treatments, leading to a considerable negative outcome on overall prognosis.

PMID:36382977 | DOI:10.53738/REVMED.2022.18.804.2162

Sci Rep. 2022 Nov 15;12(1):19577. doi: 10.1038/s41598-022-24011-0.

ABSTRACT

Progressive fibrosing interstitial lung diseases (PF-ILDs) have a poor prognosis and may be resistant to corticosteroids and/or immunosuppressants, but antifibrotic therapies such as nintedanib and pirfenidone have been shown to slow the deterioration of lung function. The aim of this study was to identify the characteristic cellular profile of bronchoalveolar lavage fluid at diagnostic bronchoscopy for predicting PF-ILDs, defined as fibrotic diseases on chest high-resolution computed tomography with more than a 5% relative decline in the percent predicted value of forced vital capacity (FVC) over 6 months. The proportions of inflammatory cells, CCR6-CXCR3- T helper type 2 (Th2) cells among conventional CD4+ T cells in bronchoalveolar lavage fluid (BALF) and peripheral blood, were measured by flowcytometry. The proportion of lymphocytes in BALF was significantly higher in non-PF-ILD patients than in PF-ILD patients. The proportion of Th2 cells in BALF, but not in peripheral blood, was significantly higher in PF-ILD patients than in non-PF-ILD patients. Multivariate analysis showed that a greater population of Th2 cells in BALF was the only indicator for PF-ILDs. An increased proportion of Th2 cells in BALF is associated with greater deterioration of lung function in fibrotic interstitial lung diseases.

PMID:36380088 | DOI:10.1038/s41598-022-24011-0

Biomarkers. 2022 Nov 15:1-15. doi: 10.1080/1354750X.2022.2148744. Online ahead of print.

ABSTRACT

BACKGROUND: There is an increasing number of studies on the diagnostic and prognostic biomarkers associated with IPF. The purpose of this study was to explore the diagnostic and prognostic value of secreted phosphoprotein 1 (SPP1) in IPF.

METHODS: Using five database, appropriate studies were included. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and 95% confidence intervals (CIs) were calculated. Pooled hazard ratios (HRs) and 95% CIs related to prognosis were calculated.

RESULTS: Thirteen studies were included in the meta-analyses. The pooled sensitivity, specificity, PLR, NLR and DOR were 0.84 (95% CI 0.72-0.91), 0.89 (95% CI 0.83-0.94), 7.94 (95% CI 4.63-13.62), 0.18 (95% CI 0.10-0.33), 43.08 (95% CI 15.88-116.84) for SPP1 in the differential diagnosis of IPF and healthy people. The pooled sensitivity, specificity, PLR, NLR and DOR were 0.97 (95% CI 0.57-1.00), 0.93 (95% CI 0.73-0.98), 13.87 (95% CI 3.26-58.99), 0.03 (95% CI 0-0.68), 446.91 (95% CI 21.02-9504.41) for SPP1 to differentiate IPF and lung cancer patients. High SPP1 expression predicts poor prognosis for IPF patients (HR= 1.42, 95% CI = 1.27 and 1.58, P < 0.001).

CONCLUSIONS: SPP1 is a potential diagnostic and prognostic biomarker for IPF patients.

PMID:36377416 | DOI:10.1080/1354750X.2022.2148744

Respir Res. 2022 Nov 15;23(1):313. doi: 10.1186/s12931-022-02241-0.

ABSTRACT

BACKGROUND: Pulmonary hypertension (PH) associated to idiopathic pulmonary fibrosis (IPF) portends a poor prognosis. IL-11 has been implicated in fibrotic diseases, but their role on pulmonary vessels is unknown. Here we analyzed the contribution of IL-11 to PH in patients with IPF and the potential mechanism implicated.

METHODS: Pulmonary arteries, lung tissue and serum of control subjects (n = 20), IPF (n = 20) and PH associated to IPF (n = 20) were used to study the expression and localization of IL-11 and IL-11Rα. Two models of IL-11 and bleomycin-induced lung fibrosis associated to PH were used in Tie2-GFP transgenic mice to evaluate the contribution of IL-11 and endothelial cells to pulmonary artery remodeling. The effect of IL-11 and soluble IL-11Rα on human pulmonary artery endothelial cells and smooth muscle cell transformations and proliferation were analyzed.

RESULTS: IL-11 and IL-11Rα were over-expressed in pulmonary arteries and serum of patients with PH associated to IPF vs IPF patients without PH. Recombinant mice (rm)IL-11 induced lung fibrosis and PH in Tie2-GFP mice, activating in vivo EnMT as a contributor of pulmonary artery remodeling and lung fibrosis. Transient transfection of siRNA-IL-11 reduced lung fibrosis and PH in Tie2-GFP bleomycin model. Human (h)rIL-11 and soluble hrIL-11Rα induced endothelial to mesenchymal transition (EnMT) and pulmonary artery smooth muscle cell to myofibroblast-like transformation, cell proliferation and senescence in vitro.

CONCLUSIONS: IL-11 and IL-11Rα are overexpressed in pulmonary arteries of PH associated to IPF patients, and contributes to pulmonary artery remodeling and PH.

PMID:36376885 | DOI:10.1186/s12931-022-02241-0

Clin Lung Cancer. 2022 Oct 13:S1525-7304(22)00210-8. doi: 10.1016/j.cllc.2022.10.003. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with interstitial lung disease (ILD) may have a poor prognosis after lung cancer surgery because of respiratory complications and increased recurrence rates due to limited resection. Few studies have investigated prognosis after surgery by matching clinical variables between patients with and without ILD.

PATIENTS AND METHODS: Medical records of patients who underwent lung cancer surgery between January 2010 and August 2020 at a referral hospital in South Korea were reviewed. Patients with ILD were identified based on preoperative computed tomography findings. Through propensity score matching, the clinical outcomes and prognoses of patients with (ILD group) and without ILD (control group) were compared.

RESULTS: Of 1629 patients, 113 (6.9%) patients with ILD were identified, of whom 104 patients were matched. Before matching, patients with ILD had higher mean age, proportion of men, and rates of sublobar resection and squamous cell carcinoma than those without ILD. After matching, there was no significant difference in postoperative mortality rates between the control and ILD groups. The 5-year survival rate was significantly lower in the ILD group (66%) than in the control group (78.8%; P= .007). The 5-year survival rate of the ILD-GAP (Gender, Age, Physiology) stage III group (12.6%) was significantly lower than that of the ILD-GAP stage I (73.5%) and II groups (72.6%; P< .0001). Multivariable Cox analysis demonstrated that idiopathic pulmonary fibrosis, higher clinical stage, and recurrence were independent prognostic factors for mortality.

CONCLUSION: Concomitant ILD negatively affects long-term prognosis after lung cancer surgery, and ILD subtype and physiological severity assessment help predict prognosis after surgery.

PMID:36376171 | DOI:10.1016/j.cllc.2022.10.003

Lancet Respir Med. 2022 Nov 11:S2213-2600(22)00359-9. doi: 10.1016/S2213-2600(22)00359-9. Online ahead of print.

ABSTRACT

BACKGROUND: Rituximab is often used as rescue therapy in interstitial lung disease (ILD) associated with connective tissue disease (CTD), but has not been studied in clinical trials. This study aimed to assess whether rituximab is superior to cyclophosphamide as a treatment for severe or progressive CTD associated ILD.

METHODS: We conducted a randomised, double-blind, double-dummy, phase 2b trial to assess the superiority of rituximab compared with cyclophosphamide. Patients aged 18-80 years with severe or progressive ILD related to scleroderma, idiopathic inflammatory myositis, or mixed CTD, recruited across 11 specialist ILD or rheumatology centres in the UK, were randomly assigned (1:1) to receive rituximab (1000 mg at weeks 0 and 2 intravenously) or cyclophosphamide (600 mg/m2 body surface area every 4 weeks intravenously for six doses). The primary endpoint was rate of change in forced vital capacity (FVC) at 24 weeks compared with baseline, analysed using a mixed-effects model with random intercepts, adjusted for baseline FVC and CTD type. Prespecified secondary endpoints reported in this Article were change in FVC at 48 weeks versus baseline; changes from baseline in 6 min walk distance, diffusing capacity of the lung for carbon monoxide (DLCO), physician-assessed global disease activity (GDA) score, and quality-of-life scores on the St George's Respiratory Questionnaire (SGRQ), King's Brief Interstitial Lung Disease (KBILD) questionnaire, and European Quality of Life Five-Dimension (EQ-5D) questionnaire at 24 and 48 weeks; overall survival, progression-free survival, and time to treatment failure; and corticosteroid use. All endpoints were analysed in the modified intention-to-treat population, which comprised all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT01862926).

FINDINGS: Between Dec 1, 2014, and March 31, 2020, we screened 145 participants, of whom 101 participants were randomly allocated: 50 (50%) to receive cyclophosphamide and 51 (50%) to receive rituximab. 48 (96%) participants in the cyclophosphamide group and 49 (96%) in the rituximab group received at least one dose of treatment and were included in analyses; 43 (86%) participants in the cyclophosphamide group and 42 (82%) participants in the rituximab group completed 24 weeks of treatment and follow-up. At 24 weeks, FVC was improved from baseline in both the cyclophosphamide group (unadjusted mean increase 99 mL [SD 329]) and the rituximab group (97 mL [234]); in the adjusted mixed-effects model, the difference in the primary endpoint at 24 weeks was -40 mL (95% CI -153 to 74; p=0·49) between the rituximab group and the cyclophosphamide group. KBILD quality-of-life scores were improved at 24 weeks by a mean 9·4 points (SD 20·8) in the cyclophosphamide group and 8·8 points (17·0) in the rituximab group. No significant differences in secondary endpoints were identified between the treatment groups, with the exception of change in GDA score at week 48, which favoured cyclophosphamide (difference 0·90 [95% CI 0·11 to 1·68]). Improvements in lung function and respiratory-related quality-of-life measures were observed in both treatment groups. Lower corticosteroid exposure over 48 weeks of follow-up was recorded in the rituximab group. Two (4%) of 48 participants who received cyclophosphamide and three (6%) of 49 who received rituximab died during the study, all due to complications of CTD or ILD. Overall survival, progression-free survival, and time to treatment failure did not significantly differ between the two groups. All participants reported at least one adverse event during the study. Numerically fewer adverse events were reported by participants receiving rituximab (445 events) than those receiving cyclophosphamide (646 events). Gastrointestinal and respiratory disorders were the most commonly reported adverse events in both groups. There were 62 serious adverse events of which 33 occurred in the cyclophosphamide group and 29 in the rituximab group.

INTERPRETATION: Rituximab was not superior to cyclophosphamide to treat patients with CTD-ILD, although participants in both treatment groups had increased FVC at 24 weeks, in addition to clinically important improvements in patient-reported quality of life. Rituximab was associated with fewer adverse events. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with CTD-ILD requiring intravenous therapy.

FUNDING: Efficacy and Mechanism Evaluation Programme (Medical Research Council and National Institute for Health Research, UK).

PMID:36375479 | DOI:10.1016/S2213-2600(22)00359-9

Int Immunopharmacol. 2022 Nov 11;113(Pt B):109427. doi: 10.1016/j.intimp.2022.109427. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fibrotic interstitial lung disease with lesions confined to the lungs and is prevalent in the middle-aged and elderly population. The average survival time after diagnosis of IPF is only 3-5 years, and the mortality rate is higher than that of most tumours. IPF is called a "tumour-like disease". Entrectinib is a new oral formulation developed by Roche and was approved by the FDA to treat a wide variety of tumours. In this study, we explored the potential effects and mechanisms of entrectinib on pulmonary fibrosis in vitro and in vivo. In vivo studies showed that entrectinib is effective in alleviating bleomycin-induced pulmonary fibrosis. In vitro studies demonstrated that entrectinib dose-dependently inhibits TGF-β1/non-Smad signaling and attenuates TGF-β1-induced fibroblast activation and epithelial-mesenchymal transition (EMT). In conclusion, entrectinib blocks TGF-β1-induced lung fibroblast activation and EMT and then attenuates bleomycin-induced pulmonary fibrosis in mice.

PMID:36375321 | DOI:10.1016/j.intimp.2022.109427

EBioMedicine. 2022 Nov 11;86:104351. doi: 10.1016/j.ebiom.2022.104351. Online ahead of print.

ABSTRACT

BACKGROUND: Coronavirus Disease 2019 (COVID-19) can lead to the development of acute respiratory distress syndrome (ARDS). In some patients with non-resolvable (NR) COVID-19, lung injury can progress rapidly to the point that lung transplantation is the only viable option for survival. This fatal progression of lung injury involves a rapid fibroproliferative response and takes on average 15 weeks from initial symptom presentation. Little is known about the mechanisms that lead to this fulminant lung fibrosis (FLF) in NR-COVID-19.

METHODS: Using a pre-designed unbiased PCR array for fibrotic markers, we analyzed the fibrotic signature in a subset of NR-COVID-19 lungs. We compared the expression profile against control lungs (donor lungs discarded for transplantation), and explanted tissue from patients with idiopathic pulmonary fibrosis (IPF). Subsequently, RT-qPCR, Western blots and immunohistochemistry were conducted to validate and localize selected pro-fibrotic targets. A total of 23 NR-COVID-19 lungs were used for RT-qPCR validation.

FINDINGS: We revealed a unique fibrotic gene signature in NR-COVID-19 that is dominated by a hyper-expression of pro-fibrotic genes, including collagens and periostin. Our results also show a significantly increased expression of Collagen Triple Helix Repeat Containing 1(CTHRC1) which co-localized in areas rich in alpha smooth muscle expression, denoting myofibroblasts. We also show a significant increase in cytokeratin (KRT) 5 and 8 expressing cells adjacent to fibroblastic areas and in areas of apparent epithelial bronchiolization.

INTERPRETATION: Our studies may provide insights into potential cellular mechanisms that lead to a fulminant presentation of lung fibrosis in NR-COVID-19.

FUNDING: National Institute of Health (NIH) Grants R01HL154720, R01DK122796, R01DK109574, R01HL133900, and Department of Defense (DoD) Grant W81XWH2110032 to H.K.E. NIH Grants: R01HL138510 and R01HL157100, DoD Grant W81XWH-19-1-0007, and American Heart Association Grant: 18IPA34170220 to H.K.-Q. American Heart Association: 19CDA34660279, American Lung Association: CA-622265, Parker B. Francis Fellowship, 1UL1TR003167-01 and The Center for Clinical and Translational Sciences, McGovern Medical School to X.Y.

PMID:36375315 | DOI:10.1016/j.ebiom.2022.104351

Sci Rep. 2022 Nov 12;12(1):19408. doi: 10.1038/s41598-022-24157-x.

ABSTRACT

No clinical study has compared lung or lobe volumes on computed tomography (CT) between the supine and standing positions in patients with idiopathic lung fibrosis (IPF). This study aimed to compare lung and lobe volumes between the supine and standing positions and evaluate the correlations between the supine/standing lung volumes on CT and pulmonary function in patients with IPF. Twenty-three patients with IPF underwent a pulmonary function test and both low-dose conventional (supine position) and upright CT (standing position) during inspiration breath-holds. The volumes of the total lungs and lobes were larger in the standing than in the supine position in patients with IPF (all p < 0.05). Spearman's correlation coefficients between total lung volumes on chest CT in supine/standing positions and vital capacity (VC) or forced VC (FVC) were 0.61/0.79 or 0.64/0.80, respectively. CT-based volumes on upright CT were better correlated with VC and FVC than those on supine CT. Lung and lobe volumes in the standing position may be useful biomarkers to assess disease severity or therapeutic effect in patients with IPF.

PMID:36371537 | DOI:10.1038/s41598-022-24157-x

Chest. 2022 Nov 9:S0012-3692(22)04056-9. doi: 10.1016/j.chest.2022.11.002. Online ahead of print.

ABSTRACT

BACKGROUND: In some patients with progressive fibrosing interstitial lung disease (ILD), disease is caused by carriage of a mutation in a surfactant related gene (SRG) such as, SFTPC, SFTPA2 (SFTP) or ABCA3. However, no aggregated data on disease evolution and treatment outcome has ever been presented for these patients.

RESEARCH QUESTION: In adult ILD patients with an SRG mutation, what is the course of lung function after diagnosis and under treatment and the survival in comparison with sporadic idiopathic pulmonary fibrosis (sIPF) and familial pulmonary fibrosis (FPF)?

STUDY DESIGN AND METHODS: We retrospectively examined the clinical course of a cohort of adults SRG patients by screening 48 subjects from 20 families with an SRG mutation for availability of clinical follow-up data. For comparison, 248 FPF and 575 sIPF patients were included.

RESULTS: Twenty-three ILD patients (median age: 45, 11 male) with an SRG mutation fulfilled criteria. At diagnosis, SRG patients were younger and less often male, but had lower FVC (72 %predicted) and DLCO (46 %predicted) compared to FPF and sIPF. In SRG, median FVC decline 6 months after diagnosis was -40ml and median transplant-free survival in SRG was 44 months and not different from FPF and sIPF. FVC course was not different between the three cohorts, however, significant larger decrease in FVC was found while patients received immunomodulatory (IMD) or antifibrotic (AF) treatment compared to no treatment. Subsequent analysis in SRG showed that SFTP patients (n=7) treated 6 months with AF drugs had stable lung function with a median change in FVC of +40ml (IQR 130), while SRG patients treated with IMD drugs showed a variable response dependent on the gene involved.

INTERPRETATION: This study shows that ILD patients with an SRG mutation have progressive loss of lung function with severely reduced survival despite possible beneficial effects of treatment.

PMID:36370864 | DOI:10.1016/j.chest.2022.11.002

Expert Rev Respir Med. 2022 Nov 12. doi: 10.1080/17476348.2022.2145948. Online ahead of print.

ABSTRACT

INTRODUCTION: Many data already suggested that cancer and IPF are underlined by a number of common pathogenic biologic pathways. However fewer data regards the interconnections, in terms of synergy or increased toxicities, of drugs used in cancer and IPF. Particularly, how the specific therapy influences the concurrent condition and prognostic factors of response in patients with both lung cancer and IPF are far to be clarified. Similarly, identification of features of IPF patients with higher risk of developing pulmonary adverse events when treated with chemotherapy, immune checkpoint inhibitors, TKIs, or radio-therapy is of primary importance in clinical practice.

AREAS COVERED: We will discuss the scientific rationale, based on the extensive analysis of literature data, by consulting several databases for combining anticancer and antifibrotic treatments and for the design of novel therapeutic strategies. The role of immunotherapy in cancer aroused in IPF context will be discussed with specific interested, based on the continuously increasing role of immune checkpoint inhibition against lung tumors.

EXPERT OPINION: This work will help to improve knowledge according to a multidisciplinary perspective on a rare and orphan subset of patients, as those affected by cancer and IPF which identify an unmet clinical need. A better management during each phase of disease progression will require the design innovative trials and the development of new drugs and molecules both in the oncologic and respiratory medicine pipelines.

PMID:36369920 | DOI:10.1080/17476348.2022.2145948

Respir Res. 2022 Nov 11;23(1):308. doi: 10.1186/s12931-022-02236-x.

ABSTRACT

Idiopathic pulmonary fibrosis, the archetype of pulmonary fibrosis (PF), is a chronic lung disease of a poor prognosis, characterized by progressively worsening of lung function. Although histology is still the gold standard for PF assessment in preclinical practice, histological data typically involve less than 1% of total lung volume and are not amenable to longitudinal studies. A miniaturized version of computed tomography (µCT) has been introduced to radiologically examine lung in preclinical murine models of PF. The linear relationship between X-ray attenuation and tissue density allows lung densitometry on total lung volume. However, the huge density changes caused by PF usually require manual segmentation by trained operators, limiting µCT deployment in preclinical routine. Deep learning approaches have achieved state-of-the-art performance in medical image segmentation. In this work, we propose a fully automated deep learning approach to segment right and left lung on µCT imaging and subsequently derive lung densitometry. Our pipeline first employs a convolutional network (CNN) for pre-processing at low-resolution and then a 2.5D CNN for higher-resolution segmentation, combining computational advantage of 2D and ability to address 3D spatial coherence without compromising accuracy. Finally, lungs are divided into compartments based on air content assessed by density. We validated this pipeline on 72 mice with different grades of PF, achieving a Dice score of 0.967 on test set. Our tests demonstrate that this automated tool allows for rapid and comprehensive analysis of µCT scans of PF murine models, thus laying the ground for its wider exploitation in preclinical settings.

PMID:36369209 | DOI:10.1186/s12931-022-02236-x

Respir Res. 2022 Nov 11;23(1):307. doi: 10.1186/s12931-022-02221-4.

ABSTRACT

BACKGROUND: Patients with interstitial lung disease (ILD) require regular physician visits and referral to specialist ILD clinics. Difficulties or delays in accessing care can limit opportunities to monitor disease trajectory and response to treatment, and the COVID-19 pandemic has added to these challenges. Therefore, home monitoring technologies, such as home handheld spirometry, have gained increased attention as they may help to improve access to care for patients with ILD. However, while several studies have shown that home handheld spirometry in ILD is acceptable for most patients, data from clinical trials are not sufficiently robust to support its use as a primary endpoint. This review discusses the challenges that were encountered with handheld spirometry across three recent ILD studies, which included home spirometry as a primary endpoint, and highlights where further optimisation and research into home handheld spirometry in ILD is required. Rate of decline in forced vital capacity (FVC) as measured by daily home handheld spirometry versus site spirometry was of primary interest in three recently completed studies: STARLINER (NCT03261037), STARMAP and a Phase II study of pirfenidone in progressive fibrosing unclassifiable ILD (NCT03099187). Unanticipated practical and technical issues led to problems with estimating FVC decline. In all three studies, cross-sectional correlations for home handheld versus site spirometry were strong/moderate at baseline and later timepoints, but longitudinal correlations were weak. Other issues observed with the home handheld spirometry data included: high within-patient variability in home handheld FVC measurements; implausible longitudinal patterns in the home handheld spirometry data that were not reflected in site spirometry; and extreme estimated rates of FVC change.

CONCLUSIONS: Home handheld spirometry in ILD requires further optimisation and research to ensure accurate and reliable FVC measurements before it can be used as an endpoint in clinical trials. Refresher training, automated alerts of problems and FVC changes, and patient support could help to overcome some practical issues. Despite the challenges, there is value in incorporating home handheld spirometry into clinical practice, and the COVID-19 pandemic has highlighted the potential for home monitoring technologies to help improve access to care for patients with ILD.

PMID:36369156 | DOI:10.1186/s12931-022-02221-4

Biomater Sci. 2022 Nov 11. doi: 10.1039/d2bm00827k. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease that progressively and irreversibly alters the lung parenchyma, eventually leading to respiratory failure. The study of this disease has been historically challenging due to the myriad of complex processes that contribute to fibrogenesis and the inherent difficulty in accurately recreating the human pulmonary environment in vitro. Here, we describe a poly(ethylene glycol) PEG hydrogel-based three-dimensional model for the co-culture of primary murine pulmonary fibroblasts and alveolar epithelial cells that reproduces the micro-architecture, cell placement, and mechanical properties of healthy and fibrotic lung tissue. Co-cultured cells retained normal levels of viability up to at least three weeks and displayed differentiation patterns observed in vivo during IPF progression. Interrogation of protein and gene expression within this model showed that myofibroblast activation required both extracellular mechanical cues and the presence of alveolar epithelial cells. Differences in gene expression indicated that cellular co-culture induced TGF-β signaling and proliferative gene expression, while microenvironmental stiffness upregulated the expression of genes related to cell-ECM interactions. This biomaterial-based cell culture system serves as a significant step forward in the accurate recapitulation of human lung tissue in vitro and highlights the need to incorporate multiple factors that work together synergistically in vivo into models of lung biology of health and disease.

PMID:36366982 | DOI:10.1039/d2bm00827k