Front Oncol. 2022 Jun 30;12:946039. doi: 10.3389/fonc.2022.946039. eCollection 2022.

ABSTRACT

BACKGROUND: Genetic studies previously reported that variants in TERT-CLPTM1L genes were related to susceptibility of cancer and non-cancer diseases. However, conclusions were not always concordant.

METHODS: We performed meta-analyses to assess correlations between 23 variants within TERT-CLPTM1L region and susceptibility to 12 cancers and 1 non-cancer disease based on data in 109 papers (involving 139,510 cases and 208,530 controls). Two approaches (false-positive report probability test and Venice criteria) were adopted for assessing the cumulative evidence of significant associations. Current study evaluated the potential role of these variants based on data in Encyclopedia of DNA Elements (ENCODE) Project.

RESULTS: Thirteen variants were statistically associated with susceptibility to 11 cancers and 1 non-cancer disease (p < 0.05). Besides, 12 variants with eight cancers and one non-cancer disease were rated as strong evidence (rs2736098, rs401681, and rs402710 in bladder cancer; rs2736100, rs2853691, and rs401681 in esophageal cancer; rs10069690 in gastric cancer; rs2736100 and rs2853676 in glioma; rs2242652, rs2736098, rs2736100, rs2853677, rs31489, rs401681, rs402710, rs465498, and rs4975616 in lung cancer; rs2736100 in idiopathic pulmonary fibrosis and myeloproliferative neoplasms; and rs401681 in pancreatic and skin cancer). According to data from ENCODE and other public databases, 12 variants with strong evidence might fall within putative functional regions.

CONCLUSIONS: This paper demonstrated that common variants of TERT-CLPTM1L genes were related to susceptibility to bladder, esophageal, gastric, lung, pancreatic, and skin cancer, as well as to glioma, myeloproliferative neoplasms, and idiopathic pulmonary fibrosis, and, besides, the crucial function of the TERT-CLPTM1L region in the genetic predisposition to human diseases is elucidated.

PMID:35847915 | PMC:PMC9279858 | DOI:10.3389/fonc.2022.946039

Acta Pharm Sin B. 2022 Apr;12(4):1943-1962. doi: 10.1016/j.apsb.2021.11.012. Epub 2021 Nov 17.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with a median survival time of 3-5 years. Inaccurate diagnosis, limited clinical therapy and high mortality together indicate that the development of effective therapeutics for IPF is an urgent need. In recent years, it was reported that DDRs are potential targets in anti-fibrosis treatment. Based on previous work we carried out further structure modifications and led to a more selective inhibitor 47 by averting some fibrosis-unrelated kinases, such as RET, AXL and ALK. Extensive profiling of compound 47 has demonstrated that it has potent DDR1/2 inhibitory activities, low toxicity, good pharmacokinetic properties and reliable in vivo anti-fibrosis efficacy. Therefore, we confirmed that discoidin domain receptors are promising drug targets for IPF, and compound 47 would be a promising candidate for further drug development.

PMID:35847490 | PMC:PMC9279635 | DOI:10.1016/j.apsb.2021.11.012

Evid Based Complement Alternat Med. 2022 Jul 6;2022:5943322. doi: 10.1155/2022/5943322. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal and incurable chronic interstitial lung disease with an unknown etiology. Recent evidence suggests that epithelial-mesenchymal transition (EMT) is one of the possible factors in the pathogenesis of pulmonary fibrosis. Glycyrrhizic acid (GA) is a natural active ingredient extracted from the root of the traditional Chinese herb licorice, which has been shown in previous studies to have the effect of alleviating lung injury. In this study, our objective was to investigate whether GA could ameliorate pulmonary fibrosis by altering EMT, as well as the therapeutic potential of changing core fucosylation (CF) to target EMT-related pathways. First, we verified that GA partially reverses EMT in a rat model of bleomycin-induced lung interstitial fibrosis, alleviating pulmonary fibrosis, and implying that GA has antifibrotic potential. Next, we discovered that GA attenuated lung interstitial fibrosis by reducing CF modifications to some extent. Interestingly, we found that GA therapy reduced the expression of phosphorylated Smad2/3 (p-Smad2/3) and β-catenin in the EMT pathway and that GA inhibited the modification of TGF-βR and WNT receptor proteins by CF, suggesting that GA may interfere with the EMT process by modulating TGF-βR, WNT core fucosylation modifications to attenuate pulmonary fibrosis. In conclusion, these findings indicate that GA could be a potential therapeutic agent for IPF, and further support the idea that targeting CF alterations could be a novel technique for the treatment of diseases involving EMT.

PMID:35845568 | PMC:PMC9279030 | DOI:10.1155/2022/5943322

Clin Gastroenterol Hepatol. 2022 Jul 13:S1542-3565(22)00650-4. doi: 10.1016/j.cgh.2022.05.056. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Hepatitis B virus (HBV) infection frequently leads to liver fibrosis and is the leading cause of hepatocellular carcinoma (HCC) and cirrhosis in Asia Pacific. Pirfenidone is approved by FDA for treatment of idiopathic pulmonary fibrosis and hydronidone is a novel structural modification of pirfenidone with the aim of reducing hepatoxicity. We aimed to investigate the safety and efficacy of hydronidone in patients with chronic hepatitis B (CHB) associated liver fibrosis.

METHODS: This was a 52-week multicenter, randomized, double-blind, placebo-controlled, phase 2 study at 8 centers in China. CHB patients with biopsied documented liver fibrosis were eligible and were randomly assigned into receiving daily placebo or hydronidone orally (180 mg/day ,270 mg/day or 360 mg/day). All enrolled subjects also received entecavir 0.5 mg/day. A second liver biopsy was performed at week 52. The primary endpoint was defined as fibrosis improvement (reduction of at least one Ishak score at week 52 of treatment).

RESULTS: From June 25, 2015, to September 5, 2019, 168 CHB patients with liver fibrosis met the inclusion/exclusion criteria and were subsequently randomized, 43 in the placebo group and 125 in the hydronidone groups (42 in the 180mg group, 42 in the 270mg group, and 41 in the 360mg group). The fibrosis improvement endpoint was achieved by 11 (25.6%) patients in placebo group and 17 (40.5%) patients in the 180 mg group (p=0.12), 23 (54.8%)patients in the 270 mg group (p=0.006) and 18 (43.90%) patients in the 360 mg group (p=0.08). The improvement rate was 58/125 (46.4%) in the combined hydronidone group (p=0.014). The overall safety profile and incidence of serious adverse events were similar among the groups.

CONCLUSIONS: Hydronidone plus entecavir showed clinically significant histological improvement of liver fibrosis in CHB patients and the dose of 270 mg showed best efficacy of fibrosis regression. Further studies are required to assess the long-term effectiveness of hydronidone in regression of hepatic fibrosis.

CLINICALTRIALS: gov number, NCT02499562.

PMID:35842120 | DOI:10.1016/j.cgh.2022.05.056

Respir Res. 2022 Jul 15;23(1):189. doi: 10.1186/s12931-022-02101-x.

ABSTRACT

BACKGROUND: PDGFR-inhibition by the tyrosine kinase inhibitor (TKI) nintedanib attenuates the progress of idiopathic pulmonary fibrosis (IPF). However, the effects of PDGF-BB on the airway tone are almost unknown. We studied this issue and the mechanisms beyond, using isolated perfused lungs (IPL) of guinea pigs (GPs) and precision-cut lung slices (PCLS) of GPs and humans.

METHODS: IPL: PDGF-BB was perfused after or without pre-treatment with the TKI imatinib (perfused/nebulised) and its effects on the tidal volume (TV), the dynamic compliance (Cdyn) and the resistance were studied.

PCLS (GP): The bronchoconstrictive effects of PDGF-BB and the mechanisms beyond were evaluated. PCLS (human): The bronchoconstrictive effects of PDGF-BB and the bronchorelaxant effects of imatinib were studied. All changes of the airway tone were measured by videomicroscopy and indicated as changes of the initial airway area.

RESULTS: PCLS (GP/human): PDGF-BB lead to a contraction of airways. IPL: PDGF-BB decreased TV and Cdyn, whereas the resistance did not increase significantly. In both models, inhibition of PDGFR-(β) (imatinib/SU6668) prevented the bronchoconstrictive effect of PDGF-BB. The mechanisms beyond PDGF-BB-induced bronchoconstriction include activation of MAP2K and TP-receptors, actin polymerisation and Ca2+-sensitisation, whereas the increase of Ca2+ itself and the activation of EP1-4-receptors were not of relevance. In addition, imatinib relaxed pre-constricted human airways.

CONCLUSIONS: PDGFR regulates the airway tone. In PCLS from GPs, this regulatory mechanism depends on the β-subunit. Hence, PDGFR-inhibition may not only represent a target to improve chronic airway disease such as IPF, but may also provide acute bronchodilation in asthma. Since asthma therapy uses topical application. This is even more relevant, as nebulisation of imatinib also appears to be effective.

PMID:35841089 | DOI:10.1186/s12931-022-02101-x

J Cell Commun Signal. 2022 Jul 15. doi: 10.1007/s12079-022-00686-y. Online ahead of print.

ABSTRACT

Interleukin-17A (IL-17A) is one of the member of IL-17 family consisting of other five members (IL-17B to IL-17F). The Gamma delta (γδ) T cells and T helper 17 (Th17) cells are the major producers of IL-17A. Aberrant signaling by IL-17A has been implicated in the pathogenesis of several autoimmune diseases including idiopathic pulmonary fibrosis, acute lung injury, chronic airway diseases, and cancer. Activation of the IL-17A/IL-17 receptor A (IL-17RA) system regulates phosphoinositide 3-kinase/AKT serine/threonine kinase/mammalian target of rapamycin (PI3K/AKT/mTOR), mitogen-activated protein kinases (MAPKs) and activation of nuclear factor-κB (NF-κB) mediated signaling pathways. The IL-17RA activation orchestrates multiple downstream signaling cascades resulting in the release of pro-inflammatory cytokines such as interleukins (IL)-1β, IL-6, and IL-8, chemokines (C-X-C motif) and promotes neutrophil-mediated immune response. Considering the biomedical importance of IL-17A, we developed a pathway resource of signaling events mediated by IL-17A/IL-17RA in this study. The curation of literature data pertaining to the IL-17A system was performed manually by the NetPath criteria. Using data mined from the published literature, we describe an integrated pathway reaction map of IL-17A/IL-17RA consisting of 114 proteins and 68 reactions. That includes detailed information on IL-17A/IL-17RA mediated signaling events of 9 activation/inhibition events, 17 catalysis events, 3 molecular association events, 68 gene regulation events, 109 protein expression events, and 6 protein translocation events. The IL-17A signaling pathway map data is made freely accessible through the WikiPathways Database ( https://www.wikipathways.org/index.php/Pathway : WP5242).

PMID:35838944 | DOI:10.1007/s12079-022-00686-y

Curr Opin Pulm Med. 2022 Jul 16. doi: 10.1097/MCP.0000000000000894. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: We highlight recent advances in the understanding of how environmental and occupational exposures increase the risk of developing interstitial lung disease (ILD), and how to evaluate a patient for potential exposures.

RECENT FINDINGS: A review of emerging literature suggests that environmental and occupational exposures can be directly causal, as in the case of the pneumoconioses and smoking-related ILDs, or one of many contributors to disease, as in the case of idiopathic pulmonary fibrosis (IPF). Regardless of the level of association, exposures are clearly prevalent across all ILD subtypes studied.

SUMMARY: Inhalational exposures are increasingly recognized as an important component in the development of ILDs, and novel exposure-disease associations continue to be discovered. These exposures represent potential opportunities for further understanding the pathobiology of disease and for the prevention of these often progressive and debilitating disorders. Prospective, comprehensive data collection regarding occupational and environmental exposures are needed in ILD patients to fully elucidate specific antigens and their relationships to disease incidence and outcomes. Systematically collected exposure information will also inform potential interventions to remediate exposures and thus mitigate the course of frequently progressive and fatal diseases.

PMID:35838370 | DOI:10.1097/MCP.0000000000000894

Curr Opin Pulm Med. 2022 Jul 16. doi: 10.1097/MCP.0000000000000893. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: In chronic pulmonary sarcoidosis, the transition from the inflammatory to the fibrotic stage of the lungs occurs in about 10-20% of cases, eventually causing end-stage fibrotic disease. To date, pathogenetic mechanisms and clinical management remain challenging; thus, we highlight the recent evidence in pulmonary fibrotic processes, clinical signs for an early detection and the potential role of the current investigated antifibrotic agents and promising targeted therapies.

RECENT FINDINGS: Recent findings of relevant key cellular pathways can be considered as a glimmer of light in the complexity of sarcoidosis. In some patients, granulomas persist and serve as a nidus for fibrosis growth, sustained by several fibrosis-stimulating cytokines. Preclinical studies have detected profibrotic, antifibrotic and pleiotropic T cells as promoters of fibrosis. Epigenetics, genetics and transcriptomics research can lead to new target therapies. Antifibrotic drug nintedanib has shown a positive effect on non-idiopathic pulmonary fibrosis fibrotic lung diseases including fibrotic sarcoidosis; other antifibrotic drugs are under investigation.

SUMMARY: Pulmonary fibrosis strongly impacts the outcome of sarcoidosis, and a better understanding of the underlying pathogenic mechanisms can facilitate the development of novel treatments, improving clinical care and life expectancy of these patients. The greatest challenge is to investigate effective antifibrotic therapies once fibrosis develops. The role of these findings in fibrotic sarcoidosis can be translated into other interstitial lung diseases characterized by the coexistence of inflammatory and fibrotic processes.

PMID:35838359 | DOI:10.1097/MCP.0000000000000893

Allergy Asthma Immunol Res. 2022 Jul;14(4):361-378. doi: 10.4168/aair.2022.14.4.361.

ABSTRACT

Asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis are representative chronic respiratory diseases (CRDs). Although they differ in terms of disease presentation, they are all thought to arise from unresolved inflammation. Neutrophils are not only the first responders to acute inflammation, but they also help resolve the inflammation. Notably, emerging clinical studies show that CRDs are associated with systemic and local elevation of neutrophils. Moreover, murine studies suggest that airway-infiltrating neutrophils not only help initiate airway inflammation but also prolong the inflammation. Given this background, this review describes neutrophil-mediated immune responses in CRDs and summarizes the completed, ongoing, and potential clinical trials that test the therapeutic value of targeting neutrophils in CRDs. The review also clarifies the importance of understanding how neutrophils interact with other immune cells and how these interactions contribute to chronic inflammation in specific CRDs. This information may help identify future therapeutic strategies for CRDs.

PMID:35837821 | DOI:10.4168/aair.2022.14.4.361

Front Artif Intell. 2022 Jun 28;5:918888. doi: 10.3389/frai.2022.918888. eCollection 2022.

ABSTRACT

Research on rare diseases has received increasing attention, in part due to the realized profitability of orphan drugs. Biomedical informatics holds promise in accelerating translational research on rare disease, yet challenges remain, including the lack of diagnostic codes for rare diseases and privacy concerns that prevent research access to electronic health records when few patients exist. The Integrated Clinical and Environmental Exposures Service (ICEES) provides regulatory-compliant open access to electronic health record data that have been integrated with environmental exposures data, as well as analytic tools to explore the integrated data. We describe a proof-of-concept application of ICEES to examine demographics, clinical characteristics, environmental exposures, and health outcomes among a cohort of patients enriched for phenotypes associated with cystic fibrosis (CF), idiopathic bronchiectasis (IB), and primary ciliary dyskinesia (PCD). We then focus on a subset of patients with CF, leveraging the availability of a diagnostic code for CF and serving as a benchmark for our development work. We use ICEES to examine select demographics, co-diagnoses, and environmental exposures that may contribute to poor health outcomes among patients with CF, defined as emergency department or inpatient visits for respiratory issues. We replicate current understanding of the pathogenesis and clinical manifestations of CF by identifying co-diagnoses of asthma, chronic nasal congestion, cough, middle ear disease, and pneumonia as factors that differentiate patients with poor health outcomes from those with better health outcomes. We conclude by discussing our preliminary findings in relation to other published work, the strengths and limitations of our approach, and our future directions.

PMID:35837616 | PMC:PMC9274244 | DOI:10.3389/frai.2022.918888

Exp Ther Med. 2022 Jun 15;24(2):518. doi: 10.3892/etm.2022.11445. eCollection 2022 Aug.

ABSTRACT

Interstitial pneumonia is a pulmonary interstitial inflammatory and fibrosis disease with a variety of causes that causes respiratory disorders and threatens the lives of patients. The present study aimed to investigate the expression of interleukin (IL)-10 in peripheral blood of patients with interstitial pneumonia and its biological functions in pulmonary fibroblasts. A total of 42 patients with idiopathic pulmonary fibrosis (IPF) and 20 healthy subjects were included. ELISA was used to determine IL-10 concentration in serum from the patients and healthy subjects. Primary fibroblasts were isolated from lung tissue successfully and determined by morphology. The CCK-8 assay was performed to determine the effect of IL-10 expression on cell viability. Western blotting was used to determine COL1a1, COL1a2 and IL-10R1 protein expression. Flow cytometry was used for cell cycle analysis and to determine the number of IL-10+ cells. Expression of IL-10 in serum from IPF patients was higher compared to that from healthy subjects. IL-10 promoted the viability and collagen synthesis and secretion of MRC-5 cells and primary pulmonary fibroblasts. IL-10 and IL-10 receptor (R) 1 served regulatory roles in the viability and collagen synthesis of MRC-5 cells. The ratio of peripheral mononuclear lymphocytes with positive expression of IL-10 was elevated in peripheral blood from patients with IPF. The present study demonstrated that IL-10 expression in peripheral blood of patients with IPF is increased significantly compared with healthy subjects. Activation of the IL-10/IL-10R1 signaling pathway promoted the viability and collagen synthesis and secretion of pulmonary fibroblasts, leading to pulmonary fibrosis. The present study provided experimental basis for further understanding the development mechanism of pulmonary fibrosis.

PMID:35837039 | PMC:PMC9257754 | DOI:10.3892/etm.2022.11445

Theranostics. 2022 Jul 4;12(11):5125-5137. doi: 10.7150/thno.74809. eCollection 2022.

ABSTRACT

Background: Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) has a poor prognosis and lacks effective therapy. Animal models that mimic AE-IPF can greatly accelerate investigation of its pathogenesis and development of effective therapy. However, there are few reports of animal models of AE-IPF caused by bacteria. Thus, our study aimed to establish a mouse model of bacterium-induced AE-IPF and explore the potential pathogenic mechanism of AE-IPF. Methods: Mice were instilled intranasally with bleomycin (BLM) followed by non-typeable Haemophilus influenzae (NTHi) strain NT127. Murine survival, bacterial load, body weight and pulmonary histopathological changes were evaluated. We analyzed the T cell and inflammatory cell responses in the lungs. Results: Infection with 107 CFU NT127 triggered AE in mice with PF induced by 30 μg BLM. Compared with BLM-instilled mice, the BLM/NT127-treated mice showed more obvious airway inflammation, lower survival rate, higher inflammatory cell response, and increased proportions and numbers of IL-17+CD4+, IL-17+ γδ T, IL-22+CD4+ and regulatory T (Treg) cells in lungs. γδ T cells were the predominant source of IL-17. IL-17 gene knockout mice with AE-IPF had quicker body weight recovery, milder pulmonary inflammation and fibrosis, stronger IL-22+CD4+T, TGF-β+ γδ T and Treg cell responses, and weaker neutrophil and eosinophil responses than wild-type mice with AE-IPF. Conclusions: NTHi infection after BLM-induced IPF can cause AE-IPF in a murine model. This novel model can be used to investigate the pathogenesis of AE-IPF and develop new therapies for AE-IPF caused by bacteria. IL-17 is essential for the development of AE-IPF, and it may be a new therapeutic target for bacteria-induced AE-IPF.

PMID:35836804 | PMC:PMC9274745 | DOI:10.7150/thno.74809

Anim Health Res Rev. 2022 Jun;23(1):72-81. doi: 10.1017/S1466252322000020.

ABSTRACT

Acute interstitial pneumonia (AIP) of cattle has been recognized for many decades. While the pathogenesis and risk factors for this condition in pastured cattle are relatively well characterized, there remains a poor understanding of the disease as it occurs in intensively fed cattle such as in beef feedlots. Specifically, in pastured cattle, AIP results from excessive ruminal production of the pneumotoxicant 3-methylindole (3-MI). In feedlot cattle, the evidence to substantiate the role of 3-MI is comparatively deficient and further investigations into the cause, pathogenesis, and control are sorely needed. This review highlights our current understanding of AIP with a focus on the disease as it occurs in feedlot cattle. Additionally, it illustrates the need for further work in understanding the specific animal factors (e.g. the ruminal microbiome, and the role of concurrent diseases), management factors (e.g. animal stocking and vaccination protocols), and dietary factors (e.g. dietary supplements) that may impact the development of AIP and which are relatively unique to the feedlot setting. All stakeholders in the beef industry stand to benefit from a greater understanding of what remains a pressing yet poorly understood issue in beef production.

PMID:35833480 | DOI:10.1017/S1466252322000020

Cell Commun Signal. 2022 Jul 14;20(1):104. doi: 10.1186/s12964-022-00921-4.

ABSTRACT

BACKGROUND: Lung resident mesenchymal stem cells (LR-MSCs) play an important role in idiopathic pulmonary fibrosis (IPF) by transforming into myofibroblasts, thereby losing their repair ability. Evidence suggests that key proteins of multiple signaling pathways are involved in myofibroblast differentiation of LR-MSCs, such as β-Catenin and GLI family zinc finger 1 (GLI1). These proteins are regulated by SUMO (small ubiquitin-like modifier) modification, which is a post-translational modification that promotes protein degradation, while Sumo specific protein 1 (SENP1)-mediated deSUMOylation produces the opposite biological effects. Therefore, we speculated that SENP1 might be a potential target for treating pulmonary fibrosis by preventing the myofibroblast differentiation of LR-MSCs.

METHODS: LR-MSCs were isolated from mice by using immunomagnetic beads. The extracted LR-MSCs were identified by flow cytometric analysis and multilineage differentiation assays. Lentivirus packaged shRNA silenced the expression of SENP1 in vitro and vivo. The silencing efficacy of SENP1 was verified by real-time quantitative PCR. The effect of down-regulated SENP1 on the myofibroblast differentiation of LR-MSCs was assessed by Immunofluorescence and Western blot. Immunoprecipitation was used to clarify that SENP1 was a key target for regulating the activity of multiple signaling pathways in the direction of LR-MSCs differentiation. LR-MSCs resident in the lung was analyzed with in vivo imaging system. HE and Masson staining was used to evaluate the therapeutic effect of LR-MSCs with SENP1 down-regulation on the lung of BLM mice.

RESULTS: In this study, we found that the myofibroblast differentiation of LR-MSCs in IPF lung tissue was accompanied by enhanced SENP1-mediated deSUMOylation. The expression of SENP1 increased in LR-MSCs transition of bleomycin (BLM)-induced lung fibrosis. Interfering with expression of SENP1 inhibited the transformation of LR-MSCs into myofibroblasts in vitro and in vivo and restored their therapeutic effect in BLM lung fibrosis. In addition, activation of the WNT/β-Catenin and Hedgehog/GLI signaling pathways depends on SENP1-mediated deSUMOylation.

CONCLUSIONS: SENP1 might be a potential target to restore the repair function of LR-MSCs and treat pulmonary fibrosis. Video Abstract.

PMID:35836260 | DOI:10.1186/s12964-022-00921-4

J Heart Lung Transplant. 2022 Jun 19:S1053-2498(22)01991-X. doi: 10.1016/j.healun.2022.06.012. Online ahead of print.

ABSTRACT

Almost 25% of patients with pulmonary fibrosis referred for lung transplantation have a germline rare variant of a telomere-related gene. Acquired TERT promoter mutations may counterbalanced the germline defect and reduce the risk of hematological complications in this population. In a series of 34 patients with a germline telomere-related gene mutation who underwent lung transplantation, 12 (35%) patients had at least 1 acquired TERT promoter mutation. Six patients presented myelodysplasia before lung transplantation, with no difference between patients with and without an acquired TERT promoter mutation. After lung transplantation, myelodysplasia developed in only 1 of 8 patients with an acquired TERT promoter mutation versus 7 of 18 patients without a mutation. Survival did not differ between patients with and without an acquired mutation. The presence of an acquired TERT promoter mutation could be associated with reduced hematological complications after transplantation and with better outcome in telomere-related gene mutation carriers but requires further study.

PMID:35835678 | DOI:10.1016/j.healun.2022.06.012

Pharmacol Res. 2022 Jul 11:106349. doi: 10.1016/j.phrs.2022.106349. Online ahead of print.

ABSTRACT

Rare diseases refer to diseases with very low prevalence. Along with the support of national policies and improvement of research capability, a new landscape for orphan drug is emerging in China. To identity unmet clinical needs and provide insight on the development of orphan drugs, we reviewed the changes over time of orphan drug clinical trials in China from 2012 to 2022. A total of 261 trials of 40 drugs were initiated, of which 66.3% trials were sponsored by Chinese local pharmaceutical enterprises. Among the 261 trials, chemical drugs (about 63.6%) and biological products (35.6%) account for the high proportions, and traditional Chinese medicine (0.8%) was the least; the indications mainly focused on homozygous hypercholesterolemia, hemophilia, multiple sclerosis and idiopathic pulmonary fibrosis; single-arm study design was applied to 50% of the clinical trials, with an average sample size of 52 participants. Additionally, totally 122 trials were completed by January 2022, of which the average duration time was 15.7 months for new drug and 3.5 months for generic drug, respectively. The trends over time illustrated that remarkable progress has been achieved in development of orphan drugs in China since 2012.Given the large patient pool and the rising capability of innovation, it is believed that China will contribute more to the global drug pipelines for rare diseases.

PMID:35835367 | DOI:10.1016/j.phrs.2022.106349

Clin Transl Med. 2022 Jul;12(7):e935. doi: 10.1002/ctm2.935.

ABSTRACT

BACKGROUND: Exaggerated fibroblast proliferation is a well-known feature in idiopathic pulmonary fibrosis (IPF) which may be - in part - due to insufficient autophagy, a lysosome dependent cellular surveillance pathway. Bcl2-associated athanogene 3 (BAG3) is a pivotal co-chaperone of the autophagy pathway. Here, we studied whether therapeutic modulation of BAG3-mediated autophagy can rescue insufficient autophagy and impact IPF fibroblast proliferation.

METHODS: Primary interstitial fibroblasts or precision cut lung slices (PCLS) of IPF lungs were treated with (1) the antifibrotic drug pirfenidone (Pirf), (2) the demethylating agent 5-azacytidine (Aza), (3) the BAG3 modulator cantharidin (Ctd). Autophagy flux was measured following pretreatment with the autophagy inhibitors or by GFP-RFP-LC3B transfection followed by drug treatments. Proliferation was measured by 5-bromo-2'-deoxyuridine assay. BAG3, filamin C (FLNC), proliferating-cell-nuclear-antigen (PCNA), collagen1A1 (COL1A1) and autophagy proteins were assessed by immunoblotting or immunofluorescence. Loss of function experiments were performed by siRNA mediated knockdown of BAG3.

RESULTS: In comparison with healthy donors, increased BAG3 protein was observed in IPF lung homogenates and IPF fibroblasts. In addition, the substrate of BAG3-mediated autophagy, FLNC, was increased in IPF fibroblasts, implying insufficient activation of BAG3-dependent autophagy. Therapeutic modulation of this pathway using Aza and Ctd alone or in combination with the IPF therapy drug Pirf rescued the insufficient BAG3-mediated autophagy and decreased fibroblast proliferation. Such effects were observed upon therapeutic modulation of BAG3 but not upon knock down of BAG3 per se in IPF fibroblasts. Similarly, PCLS of IPF patients showed a significant decrease in collagen deposition in response to these drugs, either alone or in a more potent form in combination with Pirf.

CONCLUSIONS: Our study reveals that repurposing drugs that modulate autophagy regulating proteins render therapeutic benefits in IPF. Fine tuning of this pathway may hence signify a promising therapeutic strategy to ameliorate antifibrotic properties and augment the efficacy of current IPF therapy.

PMID:35834635 | DOI:10.1002/ctm2.935

Theranostics. 2022 May 26;12(10):4513-4535. doi: 10.7150/thno.72269. eCollection 2022.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrotic disease with high mortality. Currently, pirfenidone and nintedanib are the only approved drugs for IPF by the U.S. Food and Drug Administration (FDA), but their efficacy is limited. The activation of multiple phosphotyrosine (pY) mediated signaling pathways underlying the pathological mechanism of IPF has been explored. A Src homology-2 (SH2) superbinder, which contains mutations of three amino acids (AAs) of natural SH2 domain has been shown to be able to block phosphotyrosine (pY) pathway. Therefore, we aimed to introduce SH2 superbinder into the treatment of IPF. Methods: We analyzed the database of IPF patients and examined pY levels in lung tissues from IPF patients. In primary lung fibroblasts obtained from IPF patient as well as bleomycin (BLM) treated mice, the cell proliferation, migration and differentiation associated with pY were investigated and the anti-fibrotic effect of SH2 superbinder was also tested. In vivo, we further verified the safety and effectiveness of SH2 superbinder in multiple BLM mice models. We also compared the anti-fibrotic effect and side-effect of SH2 superbinder and nintedanib in vivo. Results: The data showed that the cytokines and growth factors pathways which directly correlated to pY levels were significantly enriched in IPF. High pY levels were found to induce abnormal proliferation, migration and differentiation of lung fibroblasts. SH2 superbinder blocked pY-mediated signaling pathways and suppress pulmonary fibrosis by targeting high pY levels in fibroblasts. SH2 superbinder had better therapeutic effect and less side-effect compare to nintedanib in vivo. Conclusions: SH2 superbinder had significant anti-fibrotic effects both in vitro and in vivo, which could be used as a promising therapy for IPF.

PMID:35832075 | PMC:PMC9254236 | DOI:10.7150/thno.72269

Eur Respir Rev. 2022 Jul 12;31(165):210220. doi: 10.1183/16000617.0220-2021. Print 2022 Sep 30.

ABSTRACT

Pulmonary hypertension (PH) is known to complicate various forms of interstitial lung disease (ILD), including idiopathic pulmonary fibrosis, the interstitial pneumonias and chronic hypersensitivity pneumonitis. Pathogenesis of PH-ILD remains incompletely understood, and probably has overlap with other forms of pre-capillary pulmonary hypertension. PH-ILD carries a poor prognosis, and is associated with increased oxygen requirements, and a decline in functional capacity and exercise tolerance. Despite most patients having mild-moderate pulmonary hypertension, more severe pulmonary hypertension and signs of right heart failure are observed in a subset of cases. Clinical suspicion and findings on pulmonary function, computed tomography and echocardiography are often the initial steps towards diagnosis. Definitive diagnosis is obtained by right heart catheterisation demonstrating pre-capillary pulmonary hypertension. Drugs approved for pulmonary arterial hypertension have been investigated in several randomised controlled trials in PH-ILD patients, leading to discouraging results until the recent INCREASE study. This review provides an overview of the current understanding, approach to diagnosis and recent advances in treatment.

PMID:35831007 | DOI:10.1183/16000617.0220-2021

Am J Respir Crit Care Med. 2022 Jul 13. doi: 10.1164/rccm.202205-0868LE. Online ahead of print.

NO ABSTRACT

PMID:35830489 | DOI:10.1164/rccm.202205-0868LE