The microbiome in IPF: tissue is not the issue.

Thorax. 2021 Mar;76(3):218

Authors: Molyneaux PL

PMID: 33593961 [PubMed - in process]

Notch 3: A New Culprit in Fibrotic Lung Disease.

Am J Respir Cell Mol Biol. 2021 Feb 16;:

Authors: Gajjala P, Madala SK

PMID: 33591242 [PubMed - as supplied by publisher]

The natural history of idiopathic pulmonary fibrosis in a large European population: the role of age, sex and comorbidities.

Intern Emerg Med. 2021 Feb 14;:

Authors: Caminati A, Madotto F, Conti S, Cesana G, Mantovani L, Harari S

Abstract
Placebo arms of clinical trials provide an opportunity to investigate the natural history of idiopathic pulmonary fibrosis (IPF) but these patients are not representative of the real life IPF population. Objective of this article is to evaluate patients' characteristics of incident IPF cases and their impact on mortality and hospitalizations risk. We conducted a retrospective cohort study using data from administrative databases from 2000 to 2010. Based on different algorithms reported in literature, incident IPF cases were identified. We applied Cox proportional hazards models to assess relationship between patients' characteristics, mortality and hospitalization. According to three case definitions, we identified 2338, 460 and 1704 incident IPF cases. Mean age at diagnosis was about 72 years, the proportion of male varied between 59 and 62% and patients with at least one chronic disease were between 70 and 74%. Age, male sex and comorbidities were associated to worse outcomes. Congestive heart failure (CHF), diabetes and cancer were conditions associated to mortality, while those associated to hospitalization were CHF and chronic obstructive pulmonary disease. Our data source provided one of the largest samples of unselected patients with a long follow-up period. Using different algorithms proposed and validated in literature, we observed that mortality and hospitalization rate are high in patients with IPF and age, sex and comorbidities significantly affect clinical outcomes. Females show a significant survival advantage over males, even after adjusting for age and comorbidities. Patients with pre-existing diseases, especially those with pulmonary and cardiovascular diseases are at higher risk.

PMID: 33586036 [PubMed - as supplied by publisher]

Front Pharmacol. 2021 Jan 29;11:594139. doi: 10.3389/fphar.2020.594139. eCollection 2020.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling; however, the molecular mechanisms underlying its occurrence and development are not yet fully understood. Despite it having a variety of beneficial pharmacological activities, the effects of catalpol (CAT), which is extracted from Rehmannia glutinosa, in IPF are not known. In this study, the differentially expressed genes, proteins, and pathways of IPF in the Gene Expression Omnibus database were analyzed, and CAT was molecularly docked with the corresponding key proteins to screen its pharmacological targets, which were then verified using an animal model. The results show that collagen metabolism imbalance, inflammatory response, and epithelial-mesenchymal transition (EMT) are the core processes in IPF, and the TGF-β1/Smad3 and Wnt/β-catenin pathways are the key signaling pathways for the development of pulmonary fibrosis. Our results also suggest that CAT binds to TGF-βR1, Smad3, Wnt3a, and GSK-3β through hydrogen bonds, van der Waals bonds, and other interactions to downregulate the expression and phosphorylation of Smad3, Wnt3a, GSK-3β, and β-catenin, inhibit the expression of cytokines, and reduce the degree of oxidative stress in lung tissue. Furthermore, CAT can inhibit the EMT process and collagen remodeling by downregulating fibrotic biomarkers and promoting the expression of epithelial cadherin. This study elucidates several key processes and signaling pathways involved in the development of IPF, and suggests the potential value of CAT in the treatment of IPF.

PMID:33584272 | PMC:PMC7878558 | DOI:10.3389/fphar.2020.594139

Untargeted metabolomics of human plasma reveal lipid markers unique to chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.

Proteomics Clin Appl. 2021 Feb 13;:e2000039

Authors: Nambiar S, Tan DBA, Clynick B, Bong SH, Rawlinson C, Gummer J, Corte TJ, Glaspole I, Moodley YP, Trengove R

Abstract
Chronic obstructive pulmonary disease (COPD) is characterised by airway inflammation and progressive airflow limitation, whereas idiopathic pulmonary fibrosis (IPF) is characterised by a restrictive pattern due to fibrosis and impaired gas exchange. We undertook metabolomic analysis of blood samples in IPF, COPD and healthy controls (HC) to determine differences in circulating molecules and identify novel pathogenic pathways. An untargeted metabolomics using an ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometer (UHPLC-QTOF-MS) was performed to profile plasma of patients with COPD (n = 21), and IPF (n = 24) in comparison to plasma from healthy controls (HC; n = 20). The most significant features were identified using multiple database matching. One-way ANOVA and variable importance in projection (VIP) scores were also used to highlight metabolites that influence the specific disease groups. Non-polar metabolites such as fatty acids (FA) and membrane lipids were well resolved and a total of 4,805 features were identified. The most prominent metabolite composition differences in lipid mediators identified at ∼2-3 fold higher in both diseases compared to HC were palmitoleic acid, oleic acid and linoleic acid; and dihydrotestosterone was lower in both diseases. We demonstrated that COPD and IPF were characterised by systemic changes in lipid constituents such as essential FA sampled from circulating plasma. This article is protected by copyright. All rights reserved.

PMID: 33580915 [PubMed - as supplied by publisher]

[18F]FMISO PET/CT imaging of hypoxia as a non-invasive biomarker of disease progression and therapy efficacy in a preclinical model of pulmonary fibrosis: comparison with the [18F]FDG PET/CT approach.

Eur J Nucl Med Mol Imaging. 2021 Feb 13;:

Authors: Tanguy J, Goirand F, Bouchard A, Frenay J, Moreau M, Mothes C, Oudot A, Helbling A, Guillemin M, Bonniaud P, Cochet A, Collin B, Bellaye PS

Abstract
PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor outcome and limited therapeutic options. Imaging of IPF is limited to high-resolution computed tomography (HRCT) which is often not sufficient for a definite diagnosis and has a limited impact on therapeutic decision and patient management. Hypoxia of the lung is a significant feature of IPF but its role on disease progression remains elusive. Thus, the aim of our study was to evaluate hypoxia imaging with [18F]FMISO as a predictive biomarker of disease progression and therapy efficacy in preclinical models of lung fibrosis in comparison with [18F]FDG.
METHODS: Eight-week-old C57/BL6 mice received an intratracheal administration of bleomycin (BLM) at day (D) 0 to initiate lung fibrosis. Mice received pirfenidone (300 mg/kg) or nintedanib (60 mg/kg) by daily gavage from D9 to D23. Mice underwent successive PET/CT imaging at several stages of the disease (baseline, D8/D9, D15/D16, D22/D23) with [18F]FDG and [18F]FMISO. Histological determination of the lung expression of HIF-1α and GLUT-1 was performed at D23.
RESULTS: We demonstrate that mean lung density on CT as well as [18F]FDG and [18F]FMISO uptakes are upregulated in established lung fibrosis (1.4-, 2.6- and 3.2-fold increase respectively). At early stages, lung areas with [18F]FMISO uptake are still appearing normal on CT scans and correspond to areas which will deteriorate towards fibrotic lesions at later timepoints. Nintedanib and pirfenidone dramatically and rapidly decreased mean lung density on CT as well as [18F]FDG and [18F]FMISO lung uptakes (pirfenidone: 1.2-, 2.9- and 2.6-fold decrease; nintedanib: 1.2-, 2.3- and 2.5-fold decrease respectively). Early [18F]FMISO lung uptake was correlated with aggressive disease progression and better nintedanib efficacy.
CONCLUSION: [18F]FMISO PET imaging is a promising tool to early detect and monitor lung fibrosis progression and therapy efficacy.

PMID: 33580818 [PubMed - as supplied by publisher]

The role of viral and bacterial infections in the pathogenesis of IPF: a systematic review and meta-analysis.

Respir Res. 2021 Feb 12;22(1):53

Authors: Mostafaei S, Sayad B, Azar MEF, Doroudian M, Hadifar S, Behrouzi A, Riahi P, Hussen BM, Bayat B, Nahand JS, Moghoofei M

Abstract
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease. Several risk factors such as smoking, air pollution, inhaled toxins, high body mass index and infectious agents are involved in the pathogenesis of IPF. In the present study, this meta-analysis study investigates the prevalence of viral and bacterial infections in the IPF patients and any possible association between these infections with pathogenesis of IPF.
METHODS: The authors carried out this systematic literature review from different reliable databases such as PubMed, ISI Web of Science, Scopus and Google Scholar to December 2020.Keywords used were the following "Idiopathic pulmonary fibrosis", "Infection", "Bacterial Infection" and "Viral Infection", alone or combined together with the Boolean operators "OR", "AND" and "NOT" in the Title/Abstract/Keywords field. Pooled proportion and its 95% CI were used to assess the prevalence of viral and bacterial infections in the IPF patients.
RESULTS: In this systematic review and meta-analyses, 32 studies were selected based on the exclusion/inclusion criteria. Geographical distribution of included studies was: eight studies in American people, 8; in European people, 15 in Asians, and one in Africans. The pooled prevalence for viral and bacterial infections w ere 53.72% (95% CI 38.1-69.1%) and 31.21% (95% CI 19.9-43.7%), respectively. The highest and lowest prevalence of viral infections was HSV (77.7% 95% CI 38.48-99.32%), EBV (72.02%, 95% CI 44.65-90.79%) and Influenza A (7.3%, 95% CI 2.66-42.45%), respectively. Whereas the highest and lowest prevalence in bacterial infections were related to Streptococcus sp. (99.49%, 95% CI 96.44-99.9%) and Raoultella (1.2%, 95% CI 0.2-3.08%), respectively.
CONCLUSIONS: The results of this review were confirmed that the presence of viral and bacterial infections are the risk factors in the pathogenesis of IPF. In further analyses, which have never been shown in the previous studies, we revealed the geographic variations in the association strengths and emphasized other methodological parameters (e.g., detection method). Also, our study supports the hypothesis that respiratory infection could play a key role in the pathogenesis of IP.

PMID: 33579274 [PubMed - as supplied by publisher]

BMC Pulm Med. 2021 Feb 12;21(1):57. doi: 10.1186/s12890-021-01399-5.

ABSTRACT

BACKGROUND: Anti-synthetase syndrome (ASSD) is a chronic autoimmune condition characterized by antibodies directed against an aminoacycl transfer RNA synthetase (ARS) along with a group of clinical features including the classical clinical triad: inflammatory myopathy, arthritis, and interstitial lung disease (ILD). ASSD is highly heterogenous due to different organ involvement, and ILD is the main cause of mortality and function loss, which presents as different patterns when diagnosed. We designed this retrospective cohort to describe the clinical features and disease behaviour of ASSD associated ILD.

METHODS: Data of 108 cases of ASSD associated ILD were retrospectively collected in Beijing Chaoyang Hospital from December 2017 to March 2019. Data were obtained from the Electronic Medical Record system. Patients were divided into 5 groups according to distinct aminoacyl tRNA synthetase (ARS) antibodies.

RESULTS: Overall, 108 consecutive patients were recruited. 33 were JO-1 positive, 30 were PL-7 positive, 23 were EJ positive, 13 were PL-12 positive and 9 were OJ positive. The JO-1 (+) group had a significant higher rate of mechanic's hand (57.6%) than other 4 groups. Polymyositis/dermatomyositis (PM/DM) was diagnosed in 25 (23.1%) patients and no difference was observed among the 5 groups. The PL-7 (+) group had a higher frequency of UIP pattern (13.3%) than the other 4 groups but the difference was not significant, and the EJ (+) group had the most frequent OP pattern (78.2%), which was significantly higher than the PL-7 (+) (P < 0.001) and PL-12 (+) groups (P = 0.025). The median follow-up time was 10.7 months, during which no patients died. All received prednisone treatment, with or without immunosuppressants. At the 6-month follow-up, 96.3% of all patients (104/108) had a positive response to therapy, the JO-1 (+) and EJ (+) groups had a significantly higher improvement of forced vital capacity than the other 3 groups (P < 0.05), and the PL-7 group had the lowest FVC improvement (P < 0.05). The JO-1 (+) group and EJ (+) group had significantly higher anti-Ro-52 positive occurrence than the other 3 groups (P < 0.05).

CONCLUSION: Anti PL-7 antibody had the same frequency as anti-JO-1 in ASSD-ILD, in which the ILD pattern was different with distinct anti-ARS antibodies. Most ASSD-ILD had a positive response to steroid therapies, with or without immunosuppressants. The PL-7 (+) group had the highest occurrence of UIP pattern, and a significantly lower response to therapy.

PMID:33579248 | PMC:PMC7881640 | DOI:10.1186/s12890-021-01399-5

Surg Today. 2021 Feb 12. doi: 10.1007/s00595-021-02232-6. Online ahead of print.

ABSTRACT

PURPOSE: This study was performed to compare the outcome of lung transplantation (LT) for idiopathic pleuroparenchymal fibroelastosis (IPPFE) with that of LT for idiopathic pulmonary fibrosis (IPF).

METHODS: We reviewed, retrospectively, all adult patients who underwent LT for IPPFE or IPF in Japan between 1998 and 2018.

RESULTS: There were 100 patients eligible for this study (31 with IPPFE and 69 with IPF). Patients with IPPFE tended to have a significantly lower body mass index (BMI) than those with IPF (median, 16.7 vs. 22.6 kg/m2, respectively; P < 0.01). However, Kaplan-Meier survival curves showed no significant difference in overall survival between the groups. The BMI did not increase in patients with IPPFE, even 1 year after LT (pretransplant, 16.5 ± 3.2 kg/m2 vs. 1 year post-transplant, 15.6 ± 2.5 kg/m2; P = 0.08). The percent predicted forced vital capacity (%FVC) 1 year after LT was significantly lower in the IPPFE group than in the IPF group (48.4% ± 19.5% vs. 68.6% ± 15.5%, respectively; P < 0.01).

CONCLUSIONS: Despite extrapulmonary problems such as a flat chest, low BMI, and associated restrictive impairment persisting in patients with IPPFE, patient survival after LT for IPPFE or IPF was equivalent.

PMID:33576927 | DOI:10.1007/s00595-021-02232-6

Am J Respir Crit Care Med. 2021 Feb 15;203(4):P10-P11. doi: 10.1164/rccm.2034P10.

NO ABSTRACT

PMID:33576729 | DOI:10.1164/rccm.2034P10

Cancers (Basel). 2021 Jan 31;13(3):539. doi: 10.3390/cancers13030539.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a severe progressive interstitial lung disease. At 5-year follow-up, 15% of IPF patients develop lung cancer, which significantly reduces the survival rate. Here we review the literature on the clinical role of oncomarkers in IPF progression, and describe the trend of routine oncomarkers in IPF patients over the longest follow-up yet reported.

MATERIALS AND METHODS: A systematic search of the literature in PubMed was performed to find relevant studies published up to 24 September 2020. The most common oncomarkers were chosen to select papers related to pulmonary fibrosis. Then, 24 IPF patients and 25 non-IPF patients, followed at Careggi ILD Referral Centre and Siena Regional Referral Centre for ILD, were enrolled consecutively.

RESULTS: A few studies reported an association between serum oncomarkers and severity of IPF. NSE, CEA, Ca19.9, and Ca125 were higher in the IPF, than in the non-IPF, group at every follow-up (p < 0.05). Ca15.3 concentrations were higher in the IPF, than the non-IPF, group at t3 (p = 0.0080) and t4 (p = 0.0168). To improve the specificity and sensitivity of Ca15.3, a panel of biomarkers was analyzed, with the IPF group as dependent variable, and chitotriosidase, Cyfra 21.1, Ca15.3, Ca125, and Ca19.9 as independent variables.

CONCLUSIONS: This study focused on the discovery of multiple biomarker signatures, such as combinations of oncomarkers, that are widely and routinely available in biochemistry laboratories. The combination of clinical parameters and biological markers could help achieve more accurate results regarding prognosis and response to treatment in IPF. Our results could pave the way for a more "personalized" medical approach to patients affected by IPF.

PMID:33572642 | PMC:PMC7867006 | DOI:10.3390/cancers13030539

Cancers (Basel). 2021 Feb 9;13(4):689. doi: 10.3390/cancers13040689.

ABSTRACT

BACKGROUND: Krebs von den Lungen-6 (KL-6) was suggested as ILD biomarker including idiopathic pulmonary fibrosis (IPF). Lung cancer is one of the most severe comorbidity of IPF patients. This study aims to serially analyze KL-6 in IPF patients after 24 months of Nintedanib and to first investigate the biomarker behavior in IPF associated with adenocarcinoma.

MATERIALS AND METHODS: One hundred and forty-two ILD patients (median (IQR), 69 (63-75) years; 86 males) were retrospectively enrolled. Serial serum samples were collected from IPF patients before starting antifibrotic therapy and after 12 months. Serum KL-6 levels were measured by KL-6 reagent assay (Fujirebio Europe, UK).

RESULTS: Increased KL-6 concentrations were identified in IPF-LC patients than IPF, fibrotic hypersensitivity pneumonitis, and pulmonary fibrosis associated with autoimmune disease groups. A cut-off value was calculated to distinguish IPF and IPF-LC patients. IPF patients monitored for 24 months with Nintedanib showed persisted increased levels of KL-6 with a progressive decline of FVC percentages.

CONCLUSION: This preliminary study offers a first demonstration that very high serum concentrations of KL-6 in IPF-LC patients are associated with poor prognosis. Moreover, serial evaluation of serum KL-6 in IPF patients over 24 months of Nintedanib treatment revealed that most patients experienced a stabilization of lung function parameters and of serum concentrations of KL-6.

PMID:33572070 | DOI:10.3390/cancers13040689

PLoS One. 2021 Feb 11;16(2):e0246878. doi: 10.1371/journal.pone.0246878. eCollection 2021.

ABSTRACT

OBJECTIVE: Obstructive sleep apnea (OSA) are increasingly recognized as important features in diffuse parenchymal lung diseases (DPLDs) with differed prevalence and impact reported. The aim of this study is to systematically review the prevalence of comorbid OSA and characterize its impact on clinical and outcome measurements in adults with DPLDs.

METHODS: Publications addressing the prevalence of OSA in DPLDs and its impacts on DPLDs were selected from electronic databases. A random-effect model was used to estimate the pooled prevalence of OSA. Odds ratios (ORs) or mean differences (MDs) were used to assess the associations of OSA with clinical and outcome measurements. Heterogeneity was quantified by I2 with 95% confidence interval (95% CI).

RESULTS: 4 studies comprising 643 participants were included. Overall, the pooled prevalence of OSA among DPLDs was 72% (95% CI: 65-79%; I2 = 75.4%). Moderate-severe OSA was observed in 40% patients (95% CI: 28-52%; I2 = 90.8%). The prevalence was higher as 76% in idiopathic pulmonary fibrosis (IPF) patients than in connective tissue associated-ILD or sarcoidosis (60%). Although oxygen desaturation during sleep was greater in OSA group compared with non-OSA patients, there was no difference in lung function or systematic comorbidities between the two groups. The associations between OSA and the mortality or disease progression of DPLDs were also systematically reviewed.

CONCLUSION: In conclusion, OSA is a common comorbidity in DPLD patients, affecting approximately three in four patients, which may exacerbate the nocturnal desaturation and have negative influence on the outcomes. Larger studies with more homogeneous samples are warranted.

PMID:33571266 | PMC:PMC7877600 | DOI:10.1371/journal.pone.0246878

Hum Hered. 2021 Feb 10:1-13. doi: 10.1159/000513290. Online ahead of print.

ABSTRACT

INTRODUCTION: Studies that examine the role of rare variants in both simple and complex disease are increasingly common. Though the usual approach of testing rare variants in aggregate sets is more powerful than testing individual variants, it is of interest to identify the variants that are plausible drivers of the association. We present a novel method for prioritization of rare variants after a significant aggregate test by quantifying the influence of the variant on the aggregate test of association.

METHODS: In addition to providing a measure used to rank variants, we use outlier detection methods to present the computationally efficient Rare Variant Influential Filtering Tool (RIFT) to identify a subset of variants that influence the disease association. We evaluated several outlier detection methods that vary based on the underlying variance measure: interquartile range (Tukey fences), median absolute deviation, and SD. We performed 1,000 simulations for 50 regions of size 3 kb and compared the true and false positive rates. We compared RIFT using the Inner Tukey to 2 existing methods: adaptive combination of p values (ADA) and a Bayesian hierarchical model (BeviMed). Finally, we applied this method to data from our targeted resequencing study in idiopathic pulmonary fibrosis (IPF).

RESULTS: All outlier detection methods observed higher sensitivity to detect uncommon variants (0.001 < minor allele frequency, MAF > 0.03) compared to very rare variants (MAF <0.001). For uncommon variants, RIFT had a lower median false positive rate compared to the ADA. ADA and RIFT had significantly higher true positive rates than that observed for BeviMed. When applied to 2 regions found previously associated with IPF including 100 rare variants, we identified 6 polymorphisms with the greatest evidence for influencing the association with IPF.

DISCUSSION: In summary, RIFT has a high true positive rate while maintaining a low false positive rate for identifying polymorphisms influencing rare variant association tests. This work provides an approach to obtain greater resolution of the rare variant signals within significant aggregate sets; this information can provide an objective measure to prioritize variants for follow-up experimental studies and insight into the biological pathways involved.

PMID:33567433 | DOI:10.1159/000513290

Ann Am Thorac Soc. 2021 Feb 10. doi: 10.1513/AnnalsATS.202012-1479RL. Online ahead of print.

NO ABSTRACT

PMID:33567231 | DOI:10.1513/AnnalsATS.202012-1479RL

Cureus. 2021 Jan 4;13(1):e12482. doi: 10.7759/cureus.12482.

ABSTRACT

Fibrosis is the result of chronic inflammation and is known to pathologically occur in many organs and systems. Pirfenidone (PFD) is an anti-fibrotic known for its use in idiopathic pulmonary fibrosis (IPF). In addition to being an anti-fibrotic, it acts as an anti-inflammatory and antioxidant as well. There have been studies on PFD in other diseases, some clinical and others preclinical. We have compiled and reviewed them to highlight just how widespread PFD use could be. Among many benefits of PFD in IPF, PFD has effectively improved patients' survival in those who had an acute exacerbation of IPF and has reduced respiratory-related hospitalization, among few others. PFD also has shown an improvement in vital capacity in patients with chronic hypersensitive pneumonitis. Also, it has demonstrated anti-fibrotic effects in systemic sclerosis-associated interstitial lung disease. In other diseases outside the lungs, PFD has reversed insulin resistance and proven to be effective in non-alcoholic steatohepatitis (NASH). It has prevented blindness post-alkali injury to the eye and has proven to decrease the proliferation of mesothelioma cells, just to name a few. This review encourages further research in connection with PFD and its use in other diseases and PFD pros in IPF.

PMID:33564498 | PMC:PMC7861090 | DOI:10.7759/cureus.12482

Cell Death Discov. 2020 Jun 30;6(1):54. doi: 10.1038/s41420-020-0289-9.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic scarring disease in which aging, environmental exposure(s) and genetic susceptibility have been implicated in disease pathogenesis, however, the causes and mechanisms of the progressive fibrotic cascade are still poorly understood. As epithelial-mesenchymal interactions are essential for normal wound healing, through human 2D and 3D in vitro studies, we tested the hypothesis that IPF fibroblasts (IPFFs) dysregulate alveolar epithelial homeostasis. Conditioned media from IPFFs exaggerated the wound-healing response of primary human Type II alveolar epithelial cells (AECs). Furthermore, AECs co-cultured with IPFFs exhibited irregular epithelialization compared with those co-cultured with control fibroblasts (NHLFs) or AECs alone, suggesting that epithelial homeostasis is dysregulated in IPF as a consequence of the abnormal secretory phenotype of IPFFs. Secretome analysis of IPFF conditioned media and functional studies identified the matricellular protein, SPARC, as a key mediator in the epithelial-mesenchymal paracrine signaling, with increased secretion of SPARC by IPFFs promoting persistent activation of alveolar epithelium via an integrin/focal adhesion/cellular-junction axis resulting in disruption of epithelial barrier integrity and increased macromolecular permeability. These findings suggest that in IPF fibroblast paracrine signaling promotes persistent alveolar epithelial activation, so preventing normal epithelial repair responses and restoration of tissue homeostasis. Furthermore, they identify SPARC-mediated paracrine signaling as a potential therapeutic target to promote the restoration of lung epithelial homoestasis in IPF patients.

PMID:33563935 | DOI:10.1038/s41420-020-0289-9

Chest. 2021 Feb;159(2):475-476. doi: 10.1016/j.chest.2020.09.239.

NO ABSTRACT

PMID:33563432 | DOI:10.1016/j.chest.2020.09.239

Curr Mol Pharmacol. 2021 Feb 4. doi: 10.2174/1874467214666210204212533. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a serious disease with high mortality rate. Activation of transforming growth factor (TGF)-β1 production and signalling is considered the corner stone in the epithelial-mesenchymal transition (EMT) process. EMT plays a central role in development of fibrosis in many organs including the lungs. Activated platelets are an important source of TGF-β1 and play a pivotal role in EMT and fibrosis process. The antiplatelet, ticagrelor was previously found to inhibit the EMT in different types of cancer cells, but its ability to serve as an anti-pulmonary fibrosis (PF) agent was not previously investigated.

OBJECTIVE: In this study, we aim to investigate the potential ability of ticagrelor to ameliorate bleomycin-induced fibrosis in rats.

METHODS: PF was induced in rats by intratracheal BLM at a dose of 3 mg/kg. The effect of daily daily 20 mg/kg oral ticagrelor on different histological and biochemical parameters of fibrosis was investigated.

RESULTS: Our results revealed that ticagrelor can alleviate lung fibrosis. We found that ticagrelor inhibited TGF-β1 production and suppressed Smad3 activation and signaling pathway with subsequent inhibition of Slug and Snail. In addition, ticagrelor antagonized PI3K/AKT/mTOR pathway signaling. Moreover, ticagrelor inhibited the EMT that revealed by its ability to up-regulate the epithelial markers as E-cadherin (E-cad) and to decrease the expression of the mesenchymal markers as vimentin (VIM) and alpha-smooth muscle actin (α-SMA).

CONCLUSION: Our results suggest that the P2Y12 inhibitor, ticagrelor may have a therapeutic potential in reducing the progression of PF.

PMID:33563204 | DOI:10.2174/1874467214666210204212533

Aging Cell. 2021 Feb 8:e13314. doi: 10.1111/acel.13314. Online ahead of print.

ABSTRACT

Age-related diseases such as cancer, cardiovascular disease, kidney failure, and osteoarthritis have universal features: Their incidence rises exponentially with age with a slope of 6-8% per year and decreases at very old ages. There is no conceptual model which explains these features in so many diverse diseases in terms of a single shared biological factor. Here, we develop such a model, and test it using a nationwide medical record dataset on the incidence of nearly 1000 diseases over 50 million life-years, which we provide as a resource. The model explains incidence using the accumulation of senescent cells, damaged cells that cause inflammation and reduce regeneration, whose level rise stochastically with age. The exponential rise and late drop in incidence are captured by two parameters for each disease: the susceptible fraction of the population and the threshold concentration of senescent cells that causes disease onset. We propose a physiological mechanism for the threshold concentration for several disease classes, including an etiology for diseases of unknown origin such as idiopathic pulmonary fibrosis and osteoarthritis. The model can be used to design optimal treatments that remove senescent cells, suggeting that treatment starting at old age can sharply reduce the incidence of all age-related diseases, and thus increase the healthspan.

PMID:33559235 | DOI:10.1111/acel.13314