Pulm Pharmacol Ther. 2021 Jun 21:102051. doi: 10.1016/j.pupt.2021.102051. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease. Although anti-fibrotic treatments, such as pirfenidone, are available that reduce the rate of disease progression, these medications have limitations in tolerability, and IPF patients still have poor prognoses. GDC-3280, an orally available small molecule that was designed to improve upon pirfenidone's activity, has anti-fibrotic activity in animal models. This first-in-human, phase 1 trial evaluated GDC-3280 to determine its safety, tolerability, and pharmacokinetics (PK).

METHODS: Single and multiple ascending-doses of GDC-3280 were administered to healthy volunteers in two parts. Part A consisted of 6 treatment groups, each receiving a single, oral dose of GDC-3280 (25-1600 mg) or placebo in the fasted state. Part A also assessed the effect of food and coadministration of a proton pump inhibitor (rabeprazole) on the tolerability and PK of single doses of 400- and 800-mg GDC-3280. Part B consisted of 3 treatment groups who received either 200- or 275-mg GDC-3280 twice daily or 525-mg once daily after a low-fat meal for 7 days. The trial monitored treatment-emergent adverse events (TEAEs) and assessed the pharmacokinetics of GDC-3280 in blood and urine samples.

RESULTS: Fifty-six subjects (42 GDC-3280, 14 placebo) in Part A and 24 subjects (18 GDC-3280, 6 placebo) in Part B received treatment. No deaths, serious adverse events, or dose-limiting adverse events occurred, and no subjects withdrew due to a TEAE. In both Parts A and B, most TEAEs were mild. The most frequent TEAEs in Part A were headache and nausea. TEAEs occurred more often when GDC-3280 was administered with food. Pretreatment and coadministration with rabeprazole had no effect on GDC-3280 tolerability. In Part B, the most frequent TEAEs were nausea, dizziness, nasal congestion, and cough. Transient, treatment-related increases in serum creatinine occurred at doses greater than 400 mg in Part A (12%-18% from baseline) and after multiple doses in each group in Part B (20%-34% from baseline). GDC-3280 was generally readily absorbed with a median tmax < 4.0 hours following single- or repeat-dose oral administration. In Part A, less-than-dose-proportional increases in systemic exposure occurred, and in Part B, dose-proportional increases occurred within the dose range tested. At doses of 200 mg or lower, more than 50%-70% of orally administered doses were recovered in urine as unchanged GDC-3280 when subjects received a single dose of GDC-3280, suggesting renal excretion is one of the major routes of elimination. Administration of single doses of 400- and 800-mg GDC-3280 after a meal caused statistically significant increases in exposure due to increased rates of absorption compared to the fasted state. Pretreatment and coadministration of rabeprazole dosing led to decreases in exposure compared to GDC-3280 alone, indicating a weak drug-drug interaction. Following repeat dose administration, steady-state plasma concentrations of GDC-3280 were achieved within 2 days with an apparent terminal half-life (t1/2) between 5 and 6 hours.

CONCLUSIONS: Single and multiple doses of GDC-3280 were generally well tolerated, with acceptable safety and pharmacokinetic profiles that support twice-daily, oral administration with food in future clinical trials.

PMID:34166834 | DOI:10.1016/j.pupt.2021.102051

Ann Transl Med. 2021 May;9(10):900. doi: 10.21037/atm-20-4934.

ABSTRACT

There is a very well-established and complex interplay between gastroesophageal reflux and lung disease. This is particularly true in end-stage lung disease and post-lung transplant patients. Numerous studies have shown that in patients who are undergoing pre-lung transplant evaluations for diseases such as idiopathic pulmonary fibrosis (IPF), emphysema, connective tissue disease, there is a high prevalence of gastroesophageal reflux and esophageal dysmotility. Post-lung transplant, many of the reflux issues persist or worsen, and there is some evidence to suggest that this leads to worsened long-term allograft function and bronchiolitis obliterans. Anti-reflux operations in patients with lung disease have been shown to be safe in both the pre and post-lung transplant setting and lead to improved reflux symptoms, as well as protecting against reflux induced allograft dysfunction in the post-lung transplant patients. Barrett's esophagus and esophageal malignancy are also not unheard of in these patients, and select patients may benefit from operative intervention. This review discusses the links between gastroesophageal reflux and lung transplant patients in both the pre and post-transplant setting. We also review the approach to the workup of esophageal disease in the pre-lung transplant setting as well as the surgical management of this unique group of patients.

PMID:34164534 | PMC:PMC8184450 | DOI:10.21037/atm-20-4934

SAGE Open Med. 2021 Jun 6;9:20503121211023357. doi: 10.1177/20503121211023357. eCollection 2021.

ABSTRACT

BACKGROUND: The INPULSIS trials revealed that nintedanib reduced the decline in lung function in patients with idiopathic pulmonary fibrosis. We aimed to evaluate the efficacy and safety of nintedanib in Japanese idiopathic pulmonary fibrosis patients in real-world settings.

METHOD: Medical records of idiopathic pulmonary fibrosis patients, who received treatment with nintedanib in five institutions between July 2015 and June 2017, were reviewed. Patients with % forced vital capacity ⩾50% and % predicted diffusing capacity of the lung carbon monoxide ⩾30% were classified as the moderate group and those with more impaired lung functions as the severe group.

RESULT: Among 158 patients analyzed, 132 (84.6%) were classified as the moderate group and 26 (15.4%) as the severe group. In the moderate group, changes in forced vital capacity in 12 months were significantly different between before and after nintedanib administration (-253 ± 163 vs -125 ± 235 mL; p = 0.0027). In contrast, changes in forced vital capacity in 12 months were not significantly changed by nintedanib treatment in the severe group (-353 ± 250 vs -112 ± 341 mL; p = 0.2374). Incidence of acute exacerbation was higher in the severe group than in the moderate group (30.8% vs 18.9%). The overall survival of the moderate and the severe groups was 17.2 and 10.1 months.

CONCLUSION: In real-world practice, nintedanib showed comparable efficacy to those observed in previous trials. In the severe group, the efficacy of nintedanib might be limited.

PMID:34164129 | PMC:PMC8188975 | DOI:10.1177/20503121211023357

Am J Physiol Lung Cell Mol Physiol. 2021 Jun 23. doi: 10.1152/ajplung.00615.2020. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an incurable genetic disease that affects 5 million people worldwide. The gain-of-function MUC5B promoter variant rs35705950 is the dominant genetic risk factor for IPF yet has a low penetrance. This raises the possibility that other genes and transcripts affect the penetrance of MUC5B. Previously, we have shown that the concentration of Muc5b in bronchoalveolar epithelia is directly associated with the extent and persistence of bleomycin-induced lung fibrosis in mice. In this study, we investigated whether bleomycin-induced lung injury is Muc5b dependent in genetically divergent strains of mice. Specifically, mice from the eight Diversity Outbred (DO) founders were phenotyped for Muc5b expression and lung fibrosis three weeks after intratracheal bleomycin administration. While we identified strains with low Muc5b expression and minimal lung fibrosis (CAST/EiJ and PWK/PhJ) and strains with high Muc5b expression and extensive lung fibrosis (NZO/H1LtJ and WSB/EiJ), there also were strains that did not demonstrate a clear relationship between Muc5b expression and lung fibrosis (129S1/SvlmJ, NOD/ShiLtJ, and C57BL/6J, A/J). Hierarchical clustering suggests that other factors may work in concert with or potentially independent of Muc5b to promote bleomycin-induced lung injury and fibrosis. This study suggests that these strains and their recombinant inbred crosses may prove helpful in identifying the genes and transcripts that interact with Muc5b and cause lung fibrosis.

PMID:34160296 | DOI:10.1152/ajplung.00615.2020

Respir Res. 2021 Jun 17;22(1):181. doi: 10.1186/s12931-021-01779-9.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease that leads to respiratory failure and death. Although there is a greater understanding of the etiology of this disease, accurately predicting the disease course in individual patients is still not possible. This study aimed to evaluate serum cytokines/chemokines as potential biomarkers that can predict outcomes in IPF patients.

METHODS: A multi-institutional prospective two-stage discovery and validation design using two independent cohorts was adopted. For the discovery analysis, serum samples from 100 IPF patients and 32 healthy controls were examined using an unbiased, multiplex immunoassay of 48 cytokines/chemokines. The serum cytokine/chemokine values were compared between IPF patients and controls; the association between multiplex measurements and survival time was evaluated in IPF patients. In the validation analysis, the cytokines/chemokines identified in the discovery analysis were examined in serum samples from another 81 IPF patients to verify the ability of these cytokines/chemokines to predict survival. Immunohistochemical assessment of IPF-derived lung samples was also performed to determine where this novel biomarker is expressed.

RESULTS: In the discovery cohort, 18 cytokines/chemokines were significantly elevated in sera from IPF patients compared with those from controls. Interleukin-1 receptor alpha (IL-1Rα), interleukin-8 (IL-8), macrophage inflammatory protein 1 alpha (MIP-1α), and cutaneous T-cell-attracting chemokine (CTACK) were associated with survival: IL-1Rα, hazard ratio (HR) = 1.04 per 10 units, 95% confidence interval (95% CI) 1.01-1.07; IL-8, HR = 1.04, 95% CI 1.01-1.08; MIP-1α, HR = 1.19, 95% CI 1.00-1.36; and CTACK, HR = 1.12 per 100 units, 95% CI 1.02-1.21. A replication analysis was performed only for CTACK because others were previously reported to be potential biomarkers of interstitial lung diseases. In the validation cohort, CTACK was associated with survival: HR = 1.14 per 100 units, 95% CI 1.01-1.28. Immunohistochemistry revealed the expression of CTACK and CC chemokine receptor 10 (a ligand of CTACK) in airway and type II alveolar epithelial cells of IPF patients but not in those of controls.

CONCLUSIONS: CTACK is a novel prognostic biomarker of IPF. Trial registration None (because of no healthcare intervention).

PMID:34158044 | DOI:10.1186/s12931-021-01779-9

EBioMedicine. 2021 Jun 19;69:103439. doi: 10.1016/j.ebiom.2021.103439. Online ahead of print.

ABSTRACT

BACKGROUND: COVID-19 has been associated with Interstitial Lung Disease features. The immune transcriptomic overlap between Idiopathic Pulmonary Fibrosis (IPF) and COVID-19 has not been investigated.

METHODS: we analyzed blood transcript levels of 50 genes known to predict IPF mortality in three COVID-19 and two IPF cohorts. The Scoring Algorithm of Molecular Subphenotypes (SAMS) was applied to distinguish high versus low-risk profiles in all cohorts. SAMS cutoffs derived from the COVID-19 Discovery cohort were used to predict intensive care unit (ICU) status, need for mechanical ventilation, and in-hospital mortality in the COVID-19 Validation cohort. A COVID-19 Single-cell RNA-sequencing cohort was used to identify the cellular sources of the 50-gene risk profiles. The same COVID-19 SAMS cutoffs were used to predict mortality in the IPF cohorts.

FINDINGS: 50-gene risk profiles discriminated severe from mild COVID-19 in the Discovery cohort (P = 0·015) and predicted ICU admission, need for mechanical ventilation, and in-hospital mortality (AUC: 0·77, 0·75, and 0·74, respectively, P < 0·001) in the COVID-19 Validation cohort. In COVID-19, 50-gene expressing cells with a high-risk profile included monocytes, dendritic cells, and neutrophils, while low-risk profile-expressing cells included CD4+, CD8+ T lymphocytes, IgG producing plasmablasts, B cells, NK, and gamma/delta T cells. Same COVID-19 SAMS cutoffs were also predictive of mortality in the University of Chicago (HR:5·26, 95%CI:1·81-15·27, P = 0·0013) and Imperial College of London (HR:4·31, 95%CI:1·81-10·23, P = 0·0016) IPF cohorts.

INTERPRETATION: 50-gene risk profiles in peripheral blood predict COVID-19 and IPF outcomes. The cellular sources of these gene expression changes suggest common innate and adaptive immune responses in both diseases.

PMID:34157486 | DOI:10.1016/j.ebiom.2021.103439

Adv Ther. 2021 Jun 17. doi: 10.1007/s12325-021-01786-8. Online ahead of print.

ABSTRACT

INTRODUCTION: Many fibrosing interstitial lung diseases (ILDs) develop a chronic progressive phenotype. While idiopathic pulmonary fibrosis, which is always progressive, is well characterized with established treatment options, the epidemiology of other chronic fibrosing ILDs with a progressive phenotype has not been widely investigated. Treatment options are limited, with a high unmet need. This claims database study estimates the incidence and prevalence of these diseases in the USA.

METHODS: Diagnosis, procedure and resource utilization codes from insurance claims were used to identify patients with fibrosing ILD and those with a chronic progressive phenotype among 37,565,644 adult patients in the IBM® MarketScan® Research Database 2012-2015. Two eligible ILD claims were required for a fibrosing ILD diagnosis. Progression was defined using a novel algorithm constituted by criteria considered proxies for progression. Patients were defined as having incident (new) or existing diagnoses based on claims during a 365-day period before study entry.

RESULTS: The estimated age- and sex-adjusted prevalence per 100,000 persons of fibrosing ILD (95% confidence interval) was 117.82 (116.56, 119.08) and of chronic fibrosing ILDs with a progressive phenotype was 70.30 (69.32, 71.27). The estimated adjusted incidence per 100,000 patient-years of fibrosing ILD was 51.56 (50.88, 52.24) and of chronic fibrosing ILDs with a progressive phenotype was 32.55 (32.01, 33.09). Among incident fibrosing ILD patients, 57.3% experienced progression over a median of 117 days (interquartile range 63-224), with largely comparable rates of progression among different diseases.

CONCLUSIONS: Chronic fibrosing ILDs with a progressive phenotype comprise a relatively new disease construct requiring varied approaches to obtain reliable estimates of prevalence and incidence. This is the first large claims database study using real-world data to provide estimates of the prevalence and incidence of these diseases among a very large segment of the US population and could form the groundwork for future studies.

PMID:34156606 | DOI:10.1007/s12325-021-01786-8

Respir Investig. 2021 Jun 18:S2212-5345(21)00089-7. doi: 10.1016/j.resinv.2021.05.008. Online ahead of print.

ABSTRACT

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a devastating and life-threatening condition during its clinical course. Biomarkers for precisely anticipating the prognosis of AE-IPF remain to be fully established. The objective of this study was to clarify whether S100A8 and S100A9, which are calcium-binding proteins mainly produced by activated neutrophils, are significant prognostic biomarkers in AE-IPF.

METHODS: Thirty-seven patients with AE-IPF who were diagnosed and treated at our hospital were retrospectively evaluated. The serum levels of S100A8 and S100A9 were measured using enzyme-linked immunosorbent assay, and the relationships between these levels and clinical parameters or prognosis were evaluated.

RESULTS: The serum levels of S100A8 (median 386.5 ng/mL) and S100A9 (median 60.2 ng/mL) in patients with AE-IPF were significantly higher than those in age-matched healthy controls and in patients at IPF diagnosis (p < 0.001 for all combinations). The serum levels of S100A8 negatively correlated with percent forced vital capacity (r = -0.356, p = 0.049) and positively correlated with peripheral white blood cell number (r = 0.509, p = 0.002). Immunohistochemical staining of autopsy lung specimens showed that neutrophils, present mainly in the alveolar septum, were positive for S100A8 and S100A9. Patients with AE-IPF with higher levels of S100A8 or S100A9 showed significantly worse 3-month survival than those with lower levels (log-rank test, both p = 0.028). Finally, in multivariate analysis, the serum levels of both S100A8 and S100A9 were significant prognostic factors (hazard ratio 4.032, p = 0.023 and hazard ratio 4.327, p = 0.012).

CONCLUSION: The serum levels of S100A8 and S100A9 at AE were significant prognostic biomarkers in patients with AE-IPF.

PMID:34154976 | DOI:10.1016/j.resinv.2021.05.008

Pulm Ther. 2021 Jun 21. doi: 10.1007/s41030-021-00162-9. Online ahead of print.

ABSTRACT

INTRODUCTION: Chronic cough is a highly problematic symptom for patients with idiopathic pulmonary fibrosis (IPF); limited therapeutic options are available. We evaluated gefapixant, a P2X3 receptor antagonist, for the treatment of chronic cough in IPF.

METHODS: This randomized, double-blind, placebo-controlled, crossover study included subjects with IPF. Sequence A included gefapixant 50 mg BID (period 1; 14 days) followed by placebo (period 2; 14 days); sequence B had the opposite sequence of treatments. This regimen was specified in a protocol amendment that modified the original active treatment regimen of gefapixant 50 mg BID for 10 days and 150 mg BID for 4 days. Patients randomized to the original treatment regimen were excluded from efficacy analyses but included in safety assessments. The primary efficacy endpoint was change from baseline in awake cough frequency (coughs/hour) from periods 1 and 2 combined. Adverse events (AEs) were monitored throughout the study.

RESULTS: A total of 51 subjects were randomized, 44 of whom were randomized to treatment sequences evaluated in the primary efficacy analysis (i.e., 22 subjects in sequence A and 22 subjects in sequence B); seven subjects received the treatment assigned before the protocol amendment and were excluded from efficacy analyses. The change from baseline in awake cough frequency from periods 1 and 2 combined (mixed model for repeated measures analysis) did not demonstrate a significant reduction versus placebo in cough at day 14 (p = 0.90); in a post hoc analysis of log-transformed data p value for reduction versus placebo at day 14 was 0.07. The most common AEs were related to taste (dysgeusia and ageusia).

CONCLUSIONS: Gefapixant was generally well tolerated but was not associated with a significant improvement in chronic cough in subjects with IPF as defined by the primary endpoint in this study.

TRIAL REGISTRATION: NCT02502097.

PMID:34152585 | DOI:10.1007/s41030-021-00162-9

Front Genet. 2021 Jun 3;12:652901. doi: 10.3389/fgene.2021.652901. eCollection 2021.

ABSTRACT

Silicosis is a fatal occupational lung disease which currently has no effective clinical cure. Recent studies examining the underlying mechanism of silicosis have primarily examined experimental models, which may not perfectly reflect the nature of human silicosis progression. A comprehensive profiling of the molecular changes in human silicosis lungs is urgently needed. Here, we conducted RNA sequencing (RNA-seq) on the lung tissues of 10 silicosis patients and 7 non-diseased donors. A total of 2,605 differentially expressed genes (DEGs) and critical pathway changes were identified in human silicosis lungs. Further, the DEGs in silicosis were compared with those in idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary diseases (COPD), to extend current knowledge about the disease mechanisms and develop potential drugs. This analysis revealed both common and specific regulations in silicosis, along with several critical genes (e.g., MUC5AC and FGF10), which are potential drug targets for silicosis treatment. Drugs including Plerixafor and Retinoic acid were predicted as potential candidates in treating silicosis. Overall, this study provides the first transcriptomic fingerprint of human silicosis lungs. The comparative transcriptome analyses comprehensively characterize pathological regulations resulting from silicosis, and provide valuable cues for silicosis treatment.

PMID:34149803 | PMC:PMC8210851 | DOI:10.3389/fgene.2021.652901

Hypertension. 2021 Jun 21:HYPERTENSIONAHA12117471. doi: 10.1161/HYPERTENSIONAHA.121.17471. Online ahead of print.

ABSTRACT

Pulmonary fibrosis is a common cause of pulmonary hypertension and its development is associated with aberrant HDAC (histone deacetylase) activities and altered fibrogenic gene expressions; however, whether the epigenetic alterations causally affect pulmonary fibrosis remains poorly understood. Here, we report that HDAC3 aberration and the resultant inhibition of Nrf2 (nuclear factor erythroid-derived 2-related factor-2), a master transcription factor of antioxidative stress, contribute significantly to pulmonary fibrogenesis. HDAC3 is preferentially upregulated with concomitant Nrf2 suppression in fibrotic lungs of both idiopathic pulmonary fibrosis patients and bleomycin-treated mice. Genetic knockout of HDAC3 or Nrf2 inversely resisted or exacerbated the fibrotic pathologies, respectively, suggesting that they are crucial regulators of pulmonary fibrosis with opposite functions. Intriguingly, a HDAC3-selective inhibitor RGFP966 effectively reduced the Nrf2 suppression and normalized the fibrosis and adverse expressions of major fibrogenic proteins, Nrf2 downstream antioxidant enzymes and inflammatory cytokines. Nrf2 promoter contains a putative binding motif for FOXM1 (Forkhead box M1), a profibrotic transcriptional factor. HDAC3 and FOXM1 inducibly bound to Nrf2 promoter locus containing the motif in lung tissues of bleomycin mice, accompanied by reduced local histone3 acetylation, which were relieved by RGFP966. In cultured lung cells, RGFP966 blockage of the Nrf2 suppression was partially attenuated by a FOXM1 inhibitor or when the FOXM1 motif was mutated; while in Nrf2 knockout mice, the antifibrotic effects of RGFP966 were largely reduced. Thus, HDAC3 aberration and its suppression of Nrf2 plays important roles in pulmonary fibrogenesis and strategies targeting HDAC3/Nrf2 axis by HDAC3 inhibition might potentially benefit patients with idiopathic pulmonary fibrosis and the related pulmonary fibrotic disorders.

PMID:34148362 | DOI:10.1161/HYPERTENSIONAHA.121.17471

Respiration. 2021 Jun 18:1-9. doi: 10.1159/000516508. Online ahead of print.

ABSTRACT

Interstitial lung diseases (ILDs) cover a wide heterogeneous group of disorders, both of unknown and known causes. Accurate diagnosis is essential but, at the same time, presents many challenges. Typically, the distinction between idiopathic pulmonary fibrosis and fibrotic hypersensitivity pneumonitis (HP) can prove extremely difficult. However, another major, but underestimated, challenge is the diagnosis of connective tissue disease-associated ILD (CTD-ILD), specifically when ILD is the initial manifestation or when extrapulmonary manifestations are subclinical. Antisynthetase syndrome (ASyS) is a characteristic example where lung involvement can be the predominant feature in the absence of other evidence suggestive of CTD. In ASyS, lung involvement can be the initial manifestation or muscle involvement can be subclinical with normal muscle enzymes. Furthermore, a negative antinuclear antibody test does not indicate autoantibody negativity in the context of ASyS. Imaging and pathology findings in ASyS are not specific and overlap with other ILDs. Finally, bronchoalveolar lavage can exhibit pronounced lymphocytosis (>30-40%). The latter, in combination with a history of exposure to an inciting antigen, can lead to an erroneous diagnosis of HP with obvious negative impact on patients' outcome. Herein, we report 3 female patients aged 61, 65, and 70 years and 1 male patient aged 43 years, with ASyS masquerading as HP and analyze the underlying reasons of misdiagnosis, aiming to raise awareness of the need for close collaboration between pulmonologists and rheumatologists.

PMID:34148050 | DOI:10.1159/000516508

J Biomed Opt. 2021 Jun;26(6). doi: 10.1117/1.JBO.26.6.066501.

ABSTRACT

SIGNIFICANCE: Idiopathic pulmonary fibrosis (IPF) patients have a poor prognosis with short lifespan following diagnosis as there are limited effective treatment options. Despite matrix stiffening being the hallmark of the disease there remains a lack of knowledge surrounding the underlying collagen alterations in the disease. Specifically, while increased collagen crosslinking has been implicated, the resulting effects on collagen macro/supramolecular changes have not been explored.

AIM: We sought to determine if second-harmonic generation (SHG) microscopy could characterize differences in the collagen architecture in 3D spheroid models of IPF grown under different crosslinking modulation conditions (promotion and inhibition).

APPROACH: We used SHG metrics based on the fiber morphology, relative SHG brightness, and macro/supramolecular structure by SHG polarization analyses to compare the structure of the IPF spheroids.

RESULTS: Comparison of the fiber morphology of the spheroids showed that the control group had the longest, straightest, and thickest fibers. The spheroids with crosslink enhancement and inhibition had the highest and lowest SHG conversion efficiencies, respectively, consistent with the resulting harmonophore density. SHG polarization analyses showed that the peptide pitch angle, alignment of collagen molecules, and overall chirality were altered upon crosslink modulation and were also consistent with reduced organization relative to the control group.

CONCLUSIONS: While no single SHG signature is associated with crosslinking, we show that the suite of metrics used here is effective in delineating alterations across the collagen architecture sizescales. The results largely mirror those of human tissues and demonstrate that the combination of 3D spheroid models and SHG analysis is a powerful approach for hypothesis testing the roles of operative cellular and molecular factors in IPF.

PMID:34145800 | DOI:10.1117/1.JBO.26.6.066501

Cell Mol Life Sci. 2021 Jun 18. doi: 10.1007/s00018-021-03874-y. Online ahead of print.

ABSTRACT

Fibrotic diseases take a very heavy toll in terms of morbidity and mortality equal to or even greater than that caused by metastatic cancer. In this review, we examine the pathogenesis of fibrotic diseases, mainly addressing triggers for induction, processes that lead to progression, therapies and therapeutic trials. For the most part, we have focused on two fibrotic diseases with lung involvement, idiopathic pulmonary fibrosis, in which the contribution of inflammatory mechanisms may be secondary to non-immune triggers, and systemic sclerosis in which the contribution of adaptive immunity may be predominant.

PMID:34145462 | DOI:10.1007/s00018-021-03874-y

Clin Respir J. 2021 Jun 18. doi: 10.1111/crj.13412. Online ahead of print.

ABSTRACT

INTRODUCTION: Patients with idiopathic pulmonary fibrosis (IPF) have reduced exercise capacity and often present exertional dyspnea and desaturation. The role of autonomic nervous system (ANS) as a pathogenetic contributor to this dysfunction has not been evaluated.

OBJECTIVE: To evaluate whether improvement of arterial oxygen saturation (SpO2) via oxygen supplementation results to ANS function improvement, during steady state submaximal exercise.

METHODS: This is a secondary analysis of a single-blind, randomized, placebo-controlled, cross-over trial including 12 IPF patients with isolated exertional desaturation. Following a maximal cardiopulmonary test (CPET), participants underwent two submaximal steady state tests during which they received either supplementary oxygen or medical air. Continuous beat-to-beat blood pressure measurements were recorded (Finapres Medical Systems, Amsterdam, The Netherlands). Autonomic function was assessed non-invasively by heart rate variability (HRV); root mean square of successive differences (RMSSD) and standard-deviation-Poincare-plot (SD1) were used as indices of parasympathetic output. Entropy and detrended fluctuation analysis (DFA) were also used.

RESULTS: During rest, oxygen supplementation did not significantly alter RMSSD and SD1. During exercise, subjects presented no significant alterations compared with baseline, in most HRV indices examined. There was no improvement of this behavior with O2 -supplementation. Approximate-entropy increased during exercise, with no differences between protocols.

CONCLUSIONS: IPF patients presented an inadequate adaptive response of their ANS to exercise and recovery. Although oxygen supplementation significantly prolonged exercise duration and prevented the substantial exertional desaturation, the blunted vagal response to steady-state exercise in these patients was not improved, suggesting that acute oxygen supplementation does not sufficiently improve ANS dysfunction in these patients.

PMID:34143559 | DOI:10.1111/crj.13412

Respirol Case Rep. 2021 Jun 6;9(7):e00800. doi: 10.1002/rcr2.800. eCollection 2021 Jul.

ABSTRACT

Telomeres are repetitive nucleotide sequences that prevent chromosomal shortening in cell replication. Short telomeres have been implicated in the pathogenesis of interstitial lung disease. Patients with short telomere related pulmonary fibrosis can have computed tomography (CT) findings inconsistent with pro-typical usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) pattern. They can have rapid progression and overall worse prognosis. Antifibrotic drugs, like pirfenidone, can be used to slow the progression of disease, but there is conflicting data in patients with Telomerase reverse transcriptase/Telomerase RNA component (TERT/TERC) mutations, hence genetic testing plays an important role in determining the therapeutic options. These patients should be referred for lung transplantation early. We present a case of rapidly progressive pulmonary fibrosis associated with short telomere.

PMID:34141436 | PMC:PMC8180387 | DOI:10.1002/rcr2.800

Sci Rep. 2021 Jun 17;11(1):12732. doi: 10.1038/s41598-021-92098-y.

ABSTRACT

Genetic alterations underlying the development of lung cancer in individuals with idiopathic pulmonary fibrosis (IPF) have remained unclear. To explore whether genetic alterations in IPF tissue contribute to the development of IPF-associated lung cancer, we here evaluated tumor mutation burden (TMB) and somatic variants in 14 paired IPF and tumor samples from patients with IPF-associated lung adenocarcinoma. We also determined TMB for 22 samples of lung adenocarcinoma from patients without IPF. TMB for IPF-associated lung adenocarcinoma was significantly higher than that for matched IPF tissue (median of 2.94 vs. 1.26 mutations/Mb, P = 0.002). Three and 102 somatic variants were detected in IPF and matched lung adenocarcinoma samples, respectively, with only one pair of specimens sharing one somatic variant. TMB for IPF-associated lung adenocarcinoma was similar to that for lung adenocarcinoma samples with driver mutations (median of 2.94 vs. 2.51 mutations/Mb) and lower than that for lung adenocarcinoma samples without known driver mutations (median of 2.94 vs. 5.03 mutations/Mb, P = 0.130) from patients without IPF. Our findings suggest that not only the accumulation of somatic mutations but other factors such as inflammation and oxidative stress might contribute to the development and progression of lung cancer in patients with IPF.

PMID:34140559 | DOI:10.1038/s41598-021-92098-y

J Appl Physiol (1985). 2021 Jun 17. doi: 10.1152/japplphysiol.00150.2021. Online ahead of print.

ABSTRACT

Three-dimensional imaging is essential to evaluate local abnormalities and understand structure-function relationships in an organ. However, quantifiable and interpretable methods to localize abnormalities remain unestablished. Visual assessments are prone to bias, machine learning methods depend on training images, and the underlying decision principle is usually difficult to interpret. Here, we developed a homological approach to mathematically define emphysema and fibrosis in the lungs on computed tomography (CT). Using persistent homology, the density of homological features, including connected components, tunnels, and voids, was extracted from the volumetric CT scans of lung diseases. A pair of CT values at which each homological feature appeared (birth) and disappeared (death) was computed by sweeping the threshold levels from higher to lower CT values. Consequently, fibrosis and emphysema were defined as voxels with dense voids having a longer lifetime (birth-death difference) and voxels with dense connected components having a lower birth, respectively. In an independent dataset including subjects with idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and combined pulmonary fibrosis and emphysema (CPFE), the proposed definition enabled accurate segmentation with comparable quality to deep learning in terms of Dice coefficients. Persistent homology-defined fibrosis was closely associated with physiological abnormalities such as impaired diffusion capacity and long-term mortality in subjects with IPF and CPFE, and persistent homology-defined emphysema was associated with impaired diffusion capacity in subjects with COPD. The present persistent homology-based evaluation of structural abnormalities could help explore the clinical and physiological impacts of structural changes and morphological mechanisms of disease progression.

PMID:34138650 | DOI:10.1152/japplphysiol.00150.2021

Evid Based Complement Alternat Med. 2021 May 28;2021:6615615. doi: 10.1155/2021/6615615. eCollection 2021.

ABSTRACT

BACKGROUND: Rho-related coiled helix forming protein kinase (Rho-ROCK) and another important fibrogenic factor-PDGF play a critical role in collagen deposition in rat lung tissue. Yifei decoction (YFT), a Chinese herbal decoction, has been used to treat idiopathic pulmonary fibrosis (IPF) in clinical practice and has produced positive outcomes; however, convincing evidence is currently lacking. The present study aimed to investigate the effects of YFT combined with MitoQ in rats with IPF and to explore the underlying mechanism.

METHODS: Rat IPF model was established by endotracheal injection of 5 mg/kg BleomycinA5 into the specific pathogen-free SD rats. MitoQ (6.5 μmol/kg once daily), YFT (10 ml/kg once daily), and MitoQ + YFT (6.5 μmol/kg + 10 ml/kg once daily) were used to treat the rat model for 4 weeks, respectively. The normal rats without IPF were used as the controls. After 4 weeks of drug treatment, lung histopathology was assessed. Immunohistochemistry was used to detect the expression of fibronectin and collagen IV in lung tissue. The expression of IL-6, IL-1β, TNF-α, GSH-Px, SOD, MDA, and hydroxyproline was determined by enzyme-linked immunosorbent assay. The expressions of TGFβ1, NOX4, PDGFR-β, and ROCK1 were determined using real-time quantitative PCR and Western blot.

RESULTS: After 4 weeks of drug treatment, comparison of the MitoQ + YFT group with the IPF group showed that lung injury scores, W/D, lung tissue hydroxyproline, fibronectin, collagen IV content, and IL-6, IL-1β, TNF-α, and MDA levels were significantly lower (P < 0.05), as well as the expression of TGFβ1, NOX4, PDGFR-β, and ROCK1, but the activity of GSH-Px and SOD was higher (P < 0.05).

CONCLUSION: MitoQ combined with YFT can improve lung injury in rats with pulmonary fibrosis by reducing the secretion of proinflammatory cytokines and inhibiting TGFβ1/NOX4 and PDGF/ROCK signaling pathways. It may provide a new method for the treatment of pulmonary fibrosis.

PMID:34135982 | PMC:PMC8177988 | DOI:10.1155/2021/6615615

Am J Physiol Lung Cell Mol Physiol. 2021 Jun 16. doi: 10.1152/ajplung.00594.2020. Online ahead of print.

ABSTRACT

Single-cell transcriptomics analyses of the fibrotic lung uncovered two cell states critical to lung injury recovery in the alveolar epithelium- a reparative transitional cell state in the mouse and a disease-specific cell state (KRT5-/KRT17+) in human idiopathic pulmonary fibrosis (IPF). The murine transitional cell state lies between the differentiation from type 2 (AT2) to type 1 pneumocyte (AT1), and the human KRT5-/KRT17+cell state may arise from the dysregulation of this differentiation process. We review major findings of single-cell transcriptomics analyses of the fibrotic lung and re-analyzed data from 7 single-cell RNA sequencing studies of human and murine models of IPF, focusing on the alveolar epithelium. Our comparative and cross-species single-cell transcriptomics analyses allowed us to further delineate the differentiation trajectories from AT2 to AT1 and AT2 to the KRT5-/KRT17+cell state. We observed AT1 cells in human IPF retain the transcriptional signature of the murine transitional cell state. Using pseudotime analysis, we recapitulated the differentiation trajectories from AT2 to AT1 and from AT2 to KRT5-/KRT17+ cell state in multiple human IPF studies. We further delineated transcriptional programs underlying cell state transitions and determined the molecular phenotypes at terminal differentiation. We hypothesize that in addition to the reactivation of developmental programs (SOX4, SOX9), senescence (TP63, SOX4) and the Notch pathway (HES1) are predicted to steer intermediate progenitors to the KRT5-/KRT17+cell state. Our analyses suggest that activation of SMAD3 later in the differentiation process may explain the fibrotic molecular phenotype typical of KRT5-/KRT17+cells.

PMID:34132117 | DOI:10.1152/ajplung.00594.2020