Acta Pharmacol Sin. 2021 Nov 24. doi: 10.1038/s41401-021-00808-z. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease characterized by destruction of lung parenchyma and deposition of extracellular matrix in interstitial and alveolar spaces. But known drugs for IPF are far from meeting clinical demands, validation of drug targets against pulmonary fibrosis is in urgent demand. Tyrosine kinase receptor DDRs has been considered as a potential therapeutic target for pulmonary fibrosis due to its pathological collagen binding property and the roles in regulating extracellular matrix remodeling. In this study we designed and synthesized a new indazole derivative XBLJ-13, and identified XBLJ-13 as a highly specific and potent DDRs inhibitor with anti-inflammation and anti-fibrosis activities. We first demonstrated that DDR1/2 was highly expressed in the lung tissues of IPF patients. Then we showed that XBLJ-13 potently inhibited DDR1 and DDR2 kinases with IC50 values of 17.18 nM and 15.13 nM, respectively. Among a panel of 34 kinases tested, XBLJ-13 displayed relatively high selectivity for DDRs with minimal inhibitory effect on PDGFR family and FGFR1, as well as Abl kinase that had high homology with DDRs. Extensive profiling of XBLJ-13 revealed that the new inhibitor had much lower toxicity than nintedanib and better pharmacokinetic properties in mice. Furthermore, pharmacodynamic evaluation conducted in bleomycin-induced pulmonary fibrosis mice showed that administration of XBLJ-13 (30, 60, 90 mg·kg-1·d-1, i.g.) for 12 days significantly and dose-dependently ameliorated lung inflammation and fibrosis. Together, this study confirms that DDRs kinase is a potential target for PF, Particularly, compound XBLJ-13 is a highly potent and specific DDRs inhibitor, along with good pharmacokinetics profiles, and preferable in vivo efficacy, suggesting that it is a potential candidate for the treatment of PF.

PMID:34819618 | DOI:10.1038/s41401-021-00808-z

Am J Respir Crit Care Med. 2021 Nov 24. doi: 10.1164/rccm.202109-2065OC. Online ahead of print.

ABSTRACT

RATIONALE: Fibrotic interstitial lung diseases (fILDs) represent a group of pathologic entities characterized by scarring of the lungs and high morbidity and mortality. Research investigating how socioeconomic and residential factors impact outcomes in patients with fILDs is lacking.

OBJECTIVES: To determine the association between neighborhood-level disadvantage and presentation severity, disease progression, lung transplant, and mortality in patients with fILD from the United States (U.S.) and Canada.

METHODS: Multi-center, international, prospective cohort study of 4729 patients with fILD from one U.S. and eight Canadian ILD registry sites. Neighborhood-level disadvantage was measured by the area deprivation index (ADI) in the U.S. and the Canadian Index of Multiple Deprivation (CIMD) in Canada.

MEASUREMENTS AND MAIN RESULTS: In the U.S., but not Canadian cohort, patients with fILD living in neighborhoods with the greatest disadvantage (top quartile) experience the highest risk of mortality (hazard ratio=1.51, p=0.002) and in subgroups of patients with idiopathic pulmonary fibrosis (IPF), the top quartile of disadvantage experienced the lowest odds of lung transplant (odds ratio=0.46, p=0.04). Greater disadvantage was associated with reduced baseline diffusion capacity for carbon monoxide (DLCO) in both cohorts, but it was not associated with baseline forced vital capacity (FVC) or FVC or DLCO decline in either cohort.

CONCLUSIONS: Patients with fILD who live in areas with greater neighborhood-level disadvantage in the U.S. experience higher mortality, and patients with IPF experience lower odds of lung transplant. These disparities are not seen in Canadian patients, which may indicate differences in access to care between the U.S. and Canada.

PMID:34818133 | DOI:10.1164/rccm.202109-2065OC

J Manag Care Spec Pharm. 2021 Dec;27(12):1724-1733. doi: 10.18553/jmcp.2021.27.12.1724.

ABSTRACT

BACKGROUND: Additional real-world studies are needed to more fully elucidate the effectiveness of antifibrotic treatment in slowing the progression of idiopathic pulmonary fibrosis (IPF). OBJECTIVE: To compare mortality and hospitalization between Medicare beneficiaries with IPF who initiate antifibrotic therapy and those who did not receive treatment. METHODS: A retrospective observational study of Medicare beneficiaries using the 100% Medicare Research Identifiable File was conducted. We included patients aged 67 years and over diagnosed with IPF (≥ 1 inpatient or ≥ 2 outpatient claims with IPF diagnosis, J84.112]) during the study period (January 1, 2010-December 31, 2017). Patients who initiated antifibrotic treatment (pirfenidone or nintedanib) between October 15, 2014 (FDA approval date) and December 31, 2017 (ie, treated patients) were compared with those who did not receive treatment during a historical period (January 1, 2012-October 14, 2014) before the availability of antifibrotics (ie, untreated historical controls). Patients were matched by propensity score, and the outcomes, mortality, and hospitalization (all cause and respiratory related) were compared using a Cox proportional hazards model. RESULTS: We identified 4,641 treated patients and 4,641 propensity score-matched controls who met all study criteria; 352 treated patients who lacked matches were excluded from the study. Cox regression analysis of treated patients vs matched controls showed a significantly lower risk of mortality (HR = 0.62, 95% CI = 0.57-0.68); lower risk of hospitalization (HR = 0.71, 95% CI = 0.67-0.76; HR = 0.70, 95% CI = 0.64-0.76); and lower rate in number of hospitalizations per month (incident rate ratio [IRR] = 0.65, 95% CI = 0.60-0.71; IRR = 0.65, 95% CI = 0.58-0.73). CONCLUSIONS: This study suggests that treatment with antifibrotics may confer a survival benefit and protection against all-cause and respiratory-related hospitalization for IPF patients. DISCLOSURES: This work was sponsored by F. Hoffmann-La Roche/Genentech, Inc. Corral is employed by Genentech, Inc. Reddy, Chang, Broder, and Gokhale are employed by Partnership for Health Analytic Research LLC, a health services research company, which was hired by Genentech to conduct this research. Mooney has received advisory board/consulting fees and research support from Genentech, unrelated to this work. Mooney also reports advisory board/consulting fees and research support from Boehringer Ingelheim; personal fees from Imvaria; and grants from Celgene and Pliant, unrelated to this work. Through their employment with Partnership for Health Analytic Research, Reddy, Chang, Broder, and Gokhale have been compensated to conduct research for AbbVie, Akcea, ASPC, Amgen, AstraZeneca, BMS, Boston Scientific Corporation, Celgene, Eisai, Ethicon, GRAIL, Helsinn, Illumina, Innovation and Value Initiative, Ionis, Jazz, Kite, Novartis, Otsuka, Pathnostics, PhRMA, Prothena, Sage, Verde Technologies, Genentech, Inc., Greenwich Biosciences, Inc., Mirum Pharmaceuticals, Inc., Sanofi US Services, Inc., Sunovion Pharmaceuticals, Inc., and Dompe US, Inc., unrelated to this work. This research was presented as an abstract at CHEST 2020 Annual Meeting (virtual), October 18-21, 2020, and American Thoracic Society 2020 Virtual Meeting, June 2020.

PMID:34818092 | DOI:10.18553/jmcp.2021.27.12.1724

BMC Pulm Med. 2021 Nov 23;21(1):382. doi: 10.1186/s12890-021-01684-3.

ABSTRACT

BACKGROUND: Remodeling of the extracellular matrix (ECM) is a central mechanism in the progression of idiopathic pulmonary fibrosis (IPF), and remodeling of type VI collagen has been suggested to be associated with disease progression. Biomarkers that reflect and predict the progression of IPF would provide valuable information for clinicians when treating IPF patients.

METHODS: Two serological biomarkers reflecting formation (PRO-C6) and degradation (C6M) of type VI collagen were evaluated in a real-world cohort of 178 newly diagnoses IPF patients. All patients were treatment naïve at the baseline visit. Blood samples and clinical data were collected from baseline, six months, and 12 months visit. The biomarkers were measured by competitive ELISA using monoclonal antibodies.

RESULTS: Patients with progressive disease had higher (P = 0.0099) serum levels of PRO-C6 compared to those with stable disease over 12 months with an average difference across all timepoints of 12% (95% CI 3-22), whereas C6M levels tended (P = 0.061) to be higher in patients with progressive disease compared with stable patients over 12 months with an average difference across all timepoints of 12% (95% CI - 0.005-27). Patients who did not receive antifibrotic medicine had a greater increase of C6M (P = 0.043) compared to treated patients from baseline over 12 months with an average difference across all timepoints of 12% (95% CI - 0.07-47). There were no differences in biomarker levels between patients receiving pirfenidone or nintedanib.

CONCLUSIONS: Type VI collagen formation was related to progressive disease in patients with IPF in a real-world cohort and antifibrotic therapy seemed to affect the degradation of type VI collagen. Type VI collagen formation and degradation products might be potential biomarkers for disease progression in IPF.

PMID:34814865 | DOI:10.1186/s12890-021-01684-3

PLoS One. 2021 Nov 23;16(11):e0260345. doi: 10.1371/journal.pone.0260345. eCollection 2021.

ABSTRACT

BACKGROUND: No medical treatment has proven efficacy for acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF), and this syndrome has a very high mortality. Based on data indicating humoral autoimmune processes are involved in IPF pathogenesis, we treated AE-IPF patients with an autoantibody reduction regimen of therapeutic plasma exchange, rituximab, and intravenous immunoglobulin. This study aimed to identify clinical and autoantibody determinants associated with survival after autoantibody reduction in AE-IPF.

METHODS: Twenty-four(24) AE-IPF patients received the autoantibody reduction regimen. Plasma anti-epithelial autoantibody titers were determined by HEp-2 indirect immunofluorescence assays in 22 patients.

RESULTS: Mean age of the patients was 70 + 7 years old, and 70% were male. Beneficial clinical responses that occurred early during therapy were a favorable prognostic indicator: supplemental O2 flows needed to maintain resting SaO2>92% significantly decreased and/or walk distances increased among all 10 patients who survived for at least one year. Plasma anti-HEp-2 autoantibody titers were ~-three-fold greater in survivors compared to non-survivors (p<0.02). Anti-HEp-2 titers >1:160 were present in 75% of the evaluable one-year survivors, compared to 29% of non-survivors, and 10 of 12 patients (83%) with anti-HEP-2 titers <1:160 died during the observation period (Hazard Ratio = 3.3, 95% Confidence Interval = 1.02-10.6, p = 0.047).

CONCLUSIONS: Autoantibody reduction therapy is associated with rapid reduction of supplemental oxygen requirements and/or improved ability to ambulate in many AE-IPF patients. Facile anti-epithelial autoantibody assays may help identify those most likely to benefit from these treatments.

PMID:34813613 | DOI:10.1371/journal.pone.0260345

Annu Rev Pathol. 2021 Nov 23. doi: 10.1146/annurev-pathol-042320-030240. Online ahead of print.

ABSTRACT

The pathogenesis of idiopathic pulmonary fibrosis (IPF) involves a complex interplay of cell types and signaling pathways. Recurrent alveolar epithelial cell (AEC) injury may occur in the context of predisposing factors (e.g., genetic, environmental, epigenetic, immunologic, and gerontologic), leading to metabolic dysfunction, senescence, aberrant epithelial cell activation, and dysregulated epithelial repair. The dysregulated epithelial cell interacts with mesenchymal, immune, and endothelial cells via multiple signaling mechanisms to trigger fibroblast and myofibroblast activation. Recent single-cell RNA sequencing studies of IPF lungs support the epithelial injury model. These studies have uncovered a novel type of AEC with characteristics of an aberrant basal cell, which may disrupt normal epithelial repair and propagate a profibrotic phenotype. Here, we review the pathogenesis of IPF in the context of novel bioinformatics tools as strategies to discover pathways of disease, cell-specific mechanisms, and cell-cell interactions that propagate the profibrotic niche. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:34813355 | DOI:10.1146/annurev-pathol-042320-030240

Lung. 2021 Nov 23. doi: 10.1007/s00408-021-00494-y. Online ahead of print.

ABSTRACT

PURPOSE: Connective tissue growth factor (CTGF) is an important mediator in fibrotic disease. Single nucleotide polymorphisms (SNPs) in CTGF have been found to be associated with different fibrotic diseases and CTGF protein was found to be upregulated in lung tissue, bronchoalveolar lavage cells, and plasma of idiopathic pulmonary fibrosis (IPF) patients. We investigated whether genetic variants predispose to sporadic IPF (spIPF), familial pulmonary fibrosis (FPF), and connective tissue disease associated ILD (CTD-ILD).

METHODS: In total, 294 patients with spIPF and 294 healthy individuals were genotyped for CTGF rs12526196, rs9402373, rs6918698, and rs9399005. For replication of CTGF rs6918698 findings in pulmonary fibrosis, 128 patients with FPF, 125 with CTD-ILD, and an independent control cohort of 130 individuals were included. Lung tissue of 6 IPF patients was stained for CTGF to assess pulmonary localization.

RESULTS: Of the four SNPs, only the minor allele frequency (MAF) of CTGF rs6918698 deviated between spIPF (MAF 0.41) and controls (MAF 0.47; OR 0.774 (0.615-0.975); p = 0.030). Further comparison of CTGF rs6918698G showed a difference between FPF (MAF 0.33) and controls (MAF 0.48; OR 0.545 (0.382-0.778); p = 0.001), but not with CTD-ILD. CTGF was localized in alveolar and bronchiolar epithelium, alveolar macrophages, myofibroblasts and endothelium and highly expressed in the basal cell layer of sandwich foci.

CONCLUSION: CTGF rs6918698G associates with spIPF and with FPF, but not with CTD-ILD in a Dutch cohort. CTGF is localized in lung tissue involved in IPF pathogenesis. Further research into the role of this SNP on CTGF expression and fibrogenesis is warranted.

PMID:34812907 | DOI:10.1007/s00408-021-00494-y

JCI Insight. 2021 Nov 22;6(22):e125635. doi: 10.1172/jci.insight.125635.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with limited treatment options. Despite endothelial cells (ECs) comprising 30% of the lung cellular composition, the role of EC dysfunction in pulmonary fibrosis (PF) remains unclear. We hypothesize that sterol regulatory element-binding protein 2 (SREBP2) plays a critical role in the pathogenesis of PF via EC phenotypic modifications. Transcriptome data demonstrate that SREBP2 overexpression in ECs led to the induction of the TGF, Wnt, and cytoskeleton remodeling gene ontology pathways and the increased expression of mesenchymal genes, such as snail family transcriptional repressor 1 (snai1), α-smooth muscle actin, vimentin, and neural cadherin. Furthermore, SREBP2 directly bound to the promoter regions and transactivated these mesenchymal genes. This transcriptomic change was associated with an epigenetic and phenotypic switch in ECs, leading to increased proliferation, stress fiber formation, and ECM deposition. Mice with endothelial-specific transgenic overexpression of SREBP2 (EC-SREBP2[N]-Tg mice) that were administered bleomycin to induce PF demonstrated exacerbated vascular remodeling and increased mesenchymal transition in the lung. SREBP2 was also found to be markedly increased in lung specimens from patients with IPF. These results suggest that SREBP2, induced by lung injury, can exacerbate PF in rodent models and in human patients with IPF.

PMID:34806652 | DOI:10.1172/jci.insight.125635

APL Bioeng. 2021 Nov 16;5(4):046102. doi: 10.1063/5.0054967. eCollection 2021 Dec.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease targeting the alveolar gas exchange apparatus, leading to death by asphyxiation. IPF progresses on a tissue scale through aberrant matrix remodeling, enhanced cell contraction, and subsequent microenvironment densification. Although two pharmaceuticals modestly slow progression, IPF patient survival averages less than 5 years. A major impediment to therapeutic development is the lack of high-fidelity models that account for the fibrotic microenvironment. Our goal is to create a three-dimensional (3D) platform to enable lung fibrosis studies and recapitulate IPF tissue features. We demonstrate that normal lung fibroblasts encapsulated in collagen microspheres can be pushed toward an activated phenotype, treated with FDA-approved therapies, and their fibrotic function quantified using imaging assays (extracellular matrix deposition, contractile protein expression, and microenvironment compaction). Highlighting the system's utility, we further show that fibroblasts isolated from IPF patient lungs maintain fibrotic phenotypes and manifest reduced fibrotic function when treated with epigenetic modifiers. Our system enables enhanced screening due to improved predictability and fidelity compared to 2D systems combined with superior tractability and throughput compared to 3D systems.

PMID:34805716 | PMC:PMC8598262 | DOI:10.1063/5.0054967

Front Med (Lausanne). 2021 Nov 4;8:751181. doi: 10.3389/fmed.2021.751181. eCollection 2021.

ABSTRACT

There are limited epidemiologic studies describing the global burden and geographic heterogeneity of interstitial lung disease (ILD) subtypes. We found that among seventeen methodologically heterogenous studies that examined the incidence, prevalence and relative frequencies of ILDs, the incidence of ILD ranged from 1 to 31.5 per 100,000 person-years and prevalence ranged from 6.3 to 71 per 100,000 people. In North America and Europe, idiopathic pulmonary fibrosis and sarcoidosis were the most prevalent ILDs while the relative frequency of hypersensitivity pneumonitis was higher in Asia, particularly in India (10.7-47.3%) and Pakistan (12.6%). The relative frequency of connective tissue disease ILD demonstrated the greatest geographic variability, ranging from 7.5% of cases in Belgium to 33.3% of cases in Canada and 34.8% of cases in Saudi Arabia. These differences may represent true differences based on underlying characteristics of the source populations or methodological differences in disease classification and patient recruitment (registry vs. population-based cohorts). There are three areas where we feel addition work is needed to better understand the global burden of ILD. First, a standard ontology with diagnostic confidence thresholds for comparative epidemiology studies of ILD is needed. Second, more globally representative data should be published in English language journals as current literature has largely focused on Europe and North America with little data from South America, Africa and Asia. Third, the inclusion of community-based cohorts that leverage the strength of large databases can help better estimate population burden of disease. These large, community-based longitudinal cohorts would also allow for tracking of global trends and be a valuable resource for collective study. We believe the ILD research community should organize to define a shared ontology for disease classification and commit to conducting global claims and electronic health record based epidemiologic studies in a standardized fashion. Aggregating and sharing this type of data would provide a unique opportunity for international collaboration as our understanding of ILD continues to grow and evolve. Better understanding the geographic and temporal patterns of disease prevalence and identifying clusters of ILD subtypes will facilitate improved understanding of emerging risk factors and help identify targets for future intervention.

PMID:34805219 | PMC:PMC8599270 | DOI:10.3389/fmed.2021.751181

Respiration. 2021 Nov 19:1-7. doi: 10.1159/000520034. Online ahead of print.

ABSTRACT

BACKGROUND: Radial probe endobronchial ultrasound-guided transbronchial lung biopsy (RP-EBUS-TBLB) is widely used for diagnosis of peripheral lung lesions (PLLs). To date, there have been no reports regarding the clinical outcomes of RP-EBUS-TBLB for PLLs in patients with idiopathic pulmonary fibrosis (IPF).

OBJECTIVES: This study was performed between October 2017 and December 2019 to identify the safety and diagnostic performance of RP-EBUS-TBLB in IPF patients.

METHODS: Patients were divided into the usual interstitial pneumonia (UIP) group (n = 39, 4%), the probable UIP group (n = 12, 1%), and the noninterstitial lung disease (non-ILD) group (n = 903, 95%).

RESULTS: The diagnostic yield was significantly lower in the UIP group than in the non-ILD group (62% vs. 76%; p = 0.042), but there were no significant differences between the UIP and probable UIP groups (62% vs. 83%; p = 0.293) or the probable UIP and non-ILD groups (83% vs. 76%; p = 0.741). Multivariate logistic analysis showed that the mean diameter of PLLs, positive bronchus sign on CT, and "within the lesion" status on EBUS were independently associated with success of the procedure. Especially, the presence of the UIP pattern on CT (OR, 0.385; 95% CI: 0.172-0.863; p = 0.020) was independently associated with failed diagnosis. Among patients with UIP, "within the lesion" status on EBUS (OR, 25.432; 95% CI: 2.321-278.666; p = 0.008) was shown to be a factor contributing to a successful diagnosis. Overall, there were no significant differences in complication rates among the 3 study groups.

CONCLUSION: RP-EBUS-TBLB can be performed safely with an acceptable diagnostic yield, even in patients with IPF.

PMID:34802001 | DOI:10.1159/000520034

Thorac Surg Clin. 2022 Feb;32(1):43-49. doi: 10.1016/j.thorsurg.2021.09.006.

ABSTRACT

The many socioeconomic disparities in the myriad of diagnoses that make up benign lung diseases are unfortunately a global issue that was most recently highlighted by the COVID-19 pandemic of 2020. In this chapter, we will be reviewing the socioeconomic disparities in benign lung disease from both a United States perspective as well as a global perspective. We will cover the spectrum of infectious, obstructive, and restrictive lung disease and review the evidence on how social disparities affect these populations and their access to medical care.

PMID:34801194 | DOI:10.1016/j.thorsurg.2021.09.006

Sci Rep. 2021 Nov 19;11(1):22574. doi: 10.1038/s41598-021-01992-y.

ABSTRACT

Mucin 1/Krebs von den Lungen-6 (KL-6) is proposed as a serum biomarker of several interstitial lung diseases (ILDs), including connective tissue disorders associated with ILD. However, it has not been studied in a large cohort of Caucasian antisynthetase syndrome (ASSD) patients. Consequently, we assessed the role of MUC1 rs4072037 and serum KL-6 levels as a potential biomarker of ASSD susceptibility and for the differential diagnosis between patients with ILD associated with ASSD (ASSD-ILD +) and idiopathic pulmonary fibrosis (IPF). 168 ASSD patients (149 ASSD-ILD +), 174 IPF patients and 523 healthy controls were genotyped for MUC1 rs4072037 T > C. Serum KL-6 levels were determined in a subgroup of individuals. A significant increase of MUC1 rs4072037 CC genotype and C allele frequencies was observed in ASSD patients compared to healthy controls. Likewise, MUC1 rs4072037 TC and CC genotypes and C allele frequencies were significantly different between ASSD-ILD+ and IPF patients. Additionally, serum KL-6 levels were significantly higher in ASSD patients compared to healthy controls. Nevertheless, no differences in serum KL-6 levels were found between ASSD-ILD+ and IPF patients. Our results suggest that the presence of MUC1 rs4072037 C allele increases the risk of ASSD and it could be a useful genetic biomarker for the differential diagnosis between ASSD-ILD+ and IPF patients.

PMID:34799647 | DOI:10.1038/s41598-021-01992-y

BMJ Open Respir Res. 2021 Nov;8(1):e000899. doi: 10.1136/bmjresp-2021-000899.

ABSTRACT

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Identifying patients early may allow intervention which could limit progression. The 'indeterminate for usual interstitial pneumonia' (iUIP) CT pattern, defined in the 2018 IPF guidelines, could be a precursor to IPF but there is limited data on how patients with iUIP progress over time.

OBJECTIVE: To evaluate the radiological progression of iUIP and explore factors linked to progression to IPF.

METHODS: We performed a retrospective analysis of a lung fibrosis clinic cohort (n=230) seen between 2013 and 2017. Cases with iUIP were identified; first ever CTs for each patient found and categorised as 'non-progressor' or 'progressors' (the latter defined as increase in extent of disease or to 'definite' or 'probable' UIP CT pattern) during their follow-up. Lung function trends, haematological data and patient demographics were examined to explore disease evolution and potential contribution to progression.

RESULTS: 48 cases with iUIP CT pattern were identified. Of these, 32 had follow-up CT scans, of which 23 demonstrated progression. 17 patients in this cohort were diagnosed with IPF over a mean (SD) period of 3.9 (±1.9) years. Monocyte (HR: 23, 95% CI: 1.6 to 340, p=0.03) and neutrophil levels (HR: 1.8, 95% CI: 1.3 to 2.3, p<0.001), obtained around the time of initial CT, were associated with progression to IPF using Cox proportional hazard modelling.

CONCLUSION: 53% of our evaluable patients with iUIP progressed to IPF over a mean of 4 years. Monocyte and neutrophil levels at initial CT were significantly associated with progression in disease. These data provide a single-centre analysis of the evolution of patients with iUIP CT pattern, and first signal for potential factors associated with progression to IPF.

PMID:34799353 | DOI:10.1136/bmjresp-2021-000899

Am J Respir Cell Mol Biol. 2021 Nov 19. doi: 10.1165/rcmb.2020-0504OC. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive and excessive accumulation of myofibroblasts and extracellular matrix in the lung. Connective-tissue growth factor (CTGF) exacerbates pulmonary fibrosis in radiation-induced lung fibrosis, and in this study, we demonstrate upregulation of CTGF in a rat lung fibrosis model induced by an adenovirus vector encoding active TGF-β1 (AdTGF-β1). We show that CTGF is also upregulated in patients with IPF. Expression of CTGF was upregulated in vascular smooth muscle cells cultured from fibrotic lungs on days 7 and 14 as well as endothelial cells sorted from fibrotic lungs on days 14 and 28. These findings suggest contributions of different cells in maintaining the fibrotic phenotype during fibrogenesis. Treatment of fibroblasts with recombinant CTGF along with TGF-β increases pro-fibrotic markers in fibroblasts, confirming the synergistic effect of recombinant CTGF with TGF-β in inducing pulmonary fibrosis. Also, fibrotic extracellular matrix upregulated CTGF expression, compared with normal extracellular matrix, suggesting that not only profibrotic mediators, but also a profibrotic environment contributes to fibrogenesis. We also showed that pamrevlumab, a CTGF inhibitory antibody, partially attenuates fibrosis in the model. These results suggest that pamrevlumab could be an option for treatment of pulmonary fibrosis.

PMID:34797990 | DOI:10.1165/rcmb.2020-0504OC

Clin Exp Rheumatol. 2021 Nov 3. Online ahead of print.

ABSTRACT

OBJECTIVES: The present study aimed to compare the post-lung transplant survival and complications of connective tissue disease (CTD)-related interstitial lung disease (ILD) and/or pulmonary arterial hypertension with idiopathic pulmonary fibrosis (IPF).

METHODS: The clinical data of patients with CTD-ILD or IPF who received lung transplantation between 2015 and 2020 were retrospectively reviewed. Cumulative survival rates after transplantation were estimated using the Kaplan-Meier method.

RESULTS: The study included 31 patients with confirmed CTD-ILD and 98 with IPF. Patients with CTD-ILD were significantly younger (53.2 ± 13.7 vs. 62.3 ± 7.2 years, p=0.001) and more likely female (61.3% vs. 7.1%, p<0.001) than patients with IPF. No significant difference was noticed in the 1-year and 5-year survival rates between CTD-ILD and IPF patients (1-year, 73.2% vs 71.4%, p=0.76; 5-year, 69.1% vs. 39.5%, p=0.21). The incidence of primary graft dysfunction was significantly higher in CTD-ILD patients (90.3% vs. 70.4%, p=0.03), while there was no significant difference in primary graft dysfunction-related mortality (6.5% vs. 6.1%, p=0.95) between the two groups.

CONCLUSIONS: There was no significant difference in post-lung transplant survival and complications between CTD-ILD and IPF.

PMID:34796840

J Thorac Dis. 2021 Oct;13(10):5776-5787. doi: 10.21037/jtd-21-771.

ABSTRACT

BACKGROUND: Current guideline conditionally recommends regular use of anti-reflux medication in idiopathic pulmonary fibrosis (IPF). However, the effect of anti-reflux therapy in this group remains controversial. We systematically reviewed literatures to evaluate whether anti-reflux therapy could ameliorate pulmonary function in IPF.

METHODS: We performed electronic search in PubMed, Embase and CENTRAL (Cochrane Central Register of Controlled Trials) to identify original articles published in English language. We included randomized controlled trials (RCTs) and observational studies regarding anti-reflux therapy on pulmonary function in IPF. Qualitative and quantitative analyses were conducted. In quantitative analysis, the inverse-variance method with fixed-effect model was used to analyze pooled data.

RESULTS: Fifteen studies (2 RCTs and 13 observational studies) including 3,891 patients with IPF were included. Pooled analysis suggested that anti-reflux therapy did not improve forced vital capacity (FVC)% predicted [mean difference (MD) =0.88, 95% confidence interval (CI): -0.22 to 1.98, P=0.12, I2 =0%, 8 studies, n=3,076], diffusing capacity of the lung for carbon monoxide (DLCO) % predicted (MD =0.75, 95% CI: -0.13 to 1.62, P=0.10, I2 =0%, 8 studies, n=3,073), and FVC decline (MD =0.02, 95% CI: -0.01 to 0.04, P=0.29, I2 =17%, 5 studies, n=1,586) in IPF.

DISCUSSION: Anti-reflux therapy may not ameliorate pulmonary function in IPF. However, adequately powered studies are warranted to validate the present findings.

PMID:34795926 | PMC:PMC8575825 | DOI:10.21037/jtd-21-771

BMJ Open Respir Res. 2021 Nov;8(1):e001063. doi: 10.1136/bmjresp-2021-001063.

ABSTRACT

The factors determining disease course and survival in fibrotic hypersensitivity pneumonitis (fHP) have not been fully elucidated.The aim of this study was to describe the characteristics of patients with fHP in a real-world cohort and investigate factors associated with worse outcomes. We aimed to explore the use of neutrophil to lymphocyte ratio (NLR) and peripheral blood monocyte levels in predicting mortality.

METHODS: A retrospective, multicentre, observational UK cohort study.

RESULTS: Patients with fHP were significantly younger than those with idiopathic pulmonary fibrosis (IPF) (median age fHP 73 vs IPF 75 years) and were much more likely to be woman (fHP 61% vs IPF 26%). In almost half of all fHP cases (49%, n=104/211), no causative antigen was identified from either the history or specific antigen testing. Overall, fHP was associated with a better survival than IPF, although median survival of both groups was poor (fHP 62 months vs IPF 52 months).IPF survival in patients with a high NLR was significantly lower than those with a low NLR (44 vs 83 months). A monocyte count ≥0.95 K/uL also predicted significantly poorer outcomes for patients with IPF compared with <0.95 K/uL (33 vs 57 months). In contrast, NLR and monocyte count did not predict survival in the fHP cohort.

CONCLUSIONS: Although fHP has a statistically lower mortality than IPF, absolute survival time of both conditions is poor. High baseline NLR and absolute monocyte counts predict worse survival in IPF but not in fHP, highlighting the potential for divergence in their pathogenic mechanisms.

PMID:34794958 | DOI:10.1136/bmjresp-2021-001063

Pulm Pharmacol Ther. 2021 Nov 15:102099. doi: 10.1016/j.pupt.2021.102099. Online ahead of print.

ABSTRACT

BACKGROUND: The antifibrotic drugs nintedanib and pirfenidone reduce disease progression in idiopathic pulmonary fibrosis (IPF) and have also shown to improve survival. Switching first-line antifibrotic drug may required in IPF due to disease progression or intolerable adverse effects. The aim of this study was to assess the safety and efficacy of second-line antifibrotic treatment in patients with IPF.

MATERIAL AND METHODS: This retrospective, multicenter study was conducted at three referral interstitial lung disease centerswho received first-line antifibrotics more than one month and switched the treatment to a second-line antifibrotic agent during January 2016-June 2021. The drug's safety was evaluated based on the type of adverse effect. Disease progression was defined as an absolute decline in FVC of >10% within 12 months with or without radiological progression.

RESULTS: Among 629 consecutive patients with IPF, 66 patients switched antifibrotics. The median duration of antifibrotics was 13 (1-41) months prior to the switch, and 14 (2-42) months after the switch. The mean age was 70.6 ± 8.9 years and, median FVC (%) was 72.1 ± 18.7 at the initiation of first-line antifibrotics. The most common reason for the switch was disease progression (56%) followed by severe adverse effects (SAEs) (44%). SAEs were significantly less observed after the switch compared before the switch (43.9% vs12.1%, respectively, p < 0.001). Eighteen patients had adverse effects due to second-line antifibrotics. Among these patients, 10 had mild adverse effects and 8 had severe adverse effects. While there was no change in the FVC (%) values in 30.3% patients 12 months after the first-lineantifibrotic treatment (before the switch), there was no change in the FVC (%) values in 40% patients at the end of 12 months after the switch. Fourteen patients (42.4%) who received antifibrotic treatment before the switch had more than 10% decline in FVC (%) at the end of 12 months. Eight patients (32.0%) had 10% or more decline in FVC (%) 12 months after the switch.

CONCLUSION: Patients with IPF who do not tolerate first-lineantifibrotic treatment or those showing disease progression despite treatment, switching antifibrotics may be a feasible management strategy.

PMID:34793978 | DOI:10.1016/j.pupt.2021.102099

FASEB J. 2021 Dec;35(12):e22039. doi: 10.1096/fj.202100346R.

ABSTRACT

OTUB1 is one of the most highly expressed deubiquitinases, counter-regulating the two most abundant ubiquitin chain types. OTUB1 expression is linked to the development and progression of lung cancer and idiopathic pulmonary fibrosis in humans. However, the physiological function of OTUB1 is unknown. Here, we show that constitutive whole-body Otub1 deletion in mice leads to perinatal lethality by asphyxiation. Analysis of (single-cell) RNA sequencing and proteome data demonstrated that OTUB1 is expressed in all lung cell types with a particularly high expression during late-stage lung development (E16.5, E18.5). At E18.5, the lungs of animals with Otub1 deletion presented with increased cell proliferation that decreased saccular air space and prevented inhalation. Flow cytometry-based analysis of E18.5 lung tissue revealed that Otub1 deletion increased proliferation of major lung parenchymal and mesenchymal/other non-hematopoietic cell types. Adult mice with conditional whole-body Otub1 deletion (wbOtub1del/del ) also displayed increased lung cell proliferation in addition to hyperventilation and failure to adapt the respiratory pattern to hypoxia. On the molecular level, Otub1 deletion enhanced mTOR signaling in embryonic and adult lung tissues. Based on these results, we propose that OTUB1 is a negative regulator of mTOR signaling with essential functions for lung cell proliferation, lung development, adult lung tissue homeostasis, and respiratory regulation.

PMID:34793600 | DOI:10.1096/fj.202100346R