J Ethnopharmacol. 2022 Jul 19:115568. doi: 10.1016/j.jep.2022.115568. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Zukamu Granules (ZKMG) is one of the representative Uygur patent drugs widely used in China, which is included in the National Essential Drugs List (2018 edition). As the first choice for common cold treatment in Uygur medicine theory, it has unique anti-inflammatory and antitussive efficacy.

AIM OF THE STUDY: According to the recent inflammatory hypothesis, the abnormal proliferation, autophagy and apoptosis process of lung cells especially alveolar macrophages (AMs) may play an important role in the progress of idiopathic pulmonary fibrosis (IPF). Therefore, we came up with a novel treatment approach for IPF by regulating the balance of AMs "autophagy - apoptosis", and took ZKMG as the sample drug for our research.

MATERIALS AND METHODS: Network pharmacology approach was conducted to predict the active components and intersected targets between ZKMG and inflammation. PPI network, GO and KEGG enrichment analysis were screened and analyzed to predict the anti-inflammatory mechanism of ZKMG. Biological experiment adopted from 128 rats, and hematoxylin-eosin staining, flow cytometry and RT-PCR were performed to examine the pathological morphology, HYP contents in lung tissue, AMs counting, AMs apoptosis, AMs phagocytosis rate, mRNA relative quantity determination of 3 key factors associated with AMs "autophagy - apoptosis" and mRNA relative quantity determination of AMs surface receptor signaling pathway.

RESULTS: The predicted results showed that the mechanism of ZKMG in anti-inflammatory was related to the response and elimination of inflammatory stimuli, the intervention of apoptosis and surface receptor signaling pathways of cells. The verification experiments showed that excessive apoptosis and insufficient autophagy of AMs always existed in the progression of IPF. ZKMG could inhibit AMs proliferation, significantly reduce AMs apoptosis rate, intervene the binding of the Bcl-2 to Beclin 1, inhibit the Caspase 3 activation, stimulate the enhancement of AMs phagocytosis, and inhibit the high expression of TLR4/MyD88/NF-κB surface receptor signaling pathway, which may partly retard the fibrosis process.

CONCLUSION: By inhibiting proliferation, enhancing phagocytosis, inhibiting the formation of Bcl-2 complex, and inhibiting the high expression of MYD88-dependent TLR4 signaling pathway, ZKMG can regulate the balance of AMs "autophagy - apoptosis" in the alveolitis stage to retard the fibrosis process partly. With a comprehensive strategy of "target prediction - experimental verification", we have demonstrated that inhibiting the apoptosis and promoting autophagy activity of AMs may suggest a new perspective for IPF treatment, which would provide reference for the subsequent development.

PMID:35868548 | DOI:10.1016/j.jep.2022.115568

Am J Respir Crit Care Med. 2022 Jul 22. doi: 10.1164/rccm.202207-1260LE. Online ahead of print.

NO ABSTRACT

PMID:35868030 | DOI:10.1164/rccm.202207-1260LE

Chin Med J (Engl). 2022 Jul 25. doi: 10.1097/CM9.0000000000002118. Online ahead of print.

ABSTRACT

Extracellular vesicles (EVs) are anuclear particles composed of lipid bilayers that contain nucleic acids, proteins, lipids, and organelles. EVs act as an important mediator of cell-to-cell communication by transmitting biological signals or components, including lipids, proteins, messenger RNAs, DNA, microRNAs, organelles, etc, to nearby or distant target cells to activate and regulate the function and phenotype of target cells. Under physiological conditions, EVs play an essential role in maintaining the homeostasis of the pulmonary milieu but they can also be involved in promoting the pathogenesis and progression of various respiratory diseases including chronic obstructive pulmonary disease, asthma, acute lung injury/acute respiratory distress syndrome, idiopathic pulmonary fibrosis (IPF), and pulmonary artery hypertension. In addition, in multiple preclinical studies, EVs derived from mesenchymal stem cells (EVs) have shown promising therapeutic effects on reducing and repairing lung injuries. Furthermore, in recent years, researchers have explored different methods for modifying EVs or enhancing EVs-mediated drug delivery to produce more targeted and beneficial effects. This article will review the characteristics and biogenesis of EVs and their role in lung homeostasis and various acute and chronic lung diseases and the potential therapeutic application of EVs in the field of clinical medicine.

PMID:35866573 | DOI:10.1097/CM9.0000000000002118

Front Immunol. 2022 Jul 5;13:905727. doi: 10.3389/fimmu.2022.905727. eCollection 2022.

ABSTRACT

BACKGROUND: Treatment responsiveness to corticosteroids is excellent for cryptogenic organizing pneumonia (COP) and sarcoidosis, but suboptimal for idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). We hypothesise that the differential expression of IL-17 contributes to variable corticosteroid sensitivity in different interstitial lung diseases.

OBJECTIVE: To determine the associations among expression of IL-17, glucocorticoid receptor-β and responsiveness to corticosteroid treatment in interstitial lung diseases.

METHODS: Immunohistochemical (IHC) staining was performed on formalin-fixed paraffin-embedded (FFPE) lung tissues obtained by bronchoscopic, CT-guided or surgical biopsies, and quantified by both cell counting (% positive cells) by individuals and by software IHC Profiler plugin of ImageJ (opacity density score). We studied the effect of IL-17 on corticosteroid sensitivity in human fibroblast MRC5 cell line.

RESULTS: Compared with specimens from patients with COP (n =13) and sarcoidosis (n =13), those from IPF patients (n = 21) had greater GR-β and IL-17 expression and neutrophil infiltration. Radiographic progression after oral corticosteroid treatment was positively correlated with the expression in IL-17 and GR-β/GR-α ratio in all patients (COP, sarcoidosis and IPF) and also within the IPF subgroup only. IL-17 expression level was positively associated with GR-β and GR-β/GR-α ratio. In MRC5 cells, exogenous IL-17 increased the production of collagen I and up-regulated GR-β expression and dexamethasone's suppressive effect on collagen I production was impaired by IL-17, and silencing IL-17 receptor A gene attenuated the effect of IL-17.

CONCLUSION: Up-regulation of GR-β/GR-α ratio by IL-17 could be associated with the relative corticosteroid-insensitivity of IPF.

PMID:35865549 | PMC:PMC9294725 | DOI:10.3389/fimmu.2022.905727

Ann Thorac Surg. 2022 Jul 18:S0003-4975(22)00967-5. doi: 10.1016/j.athoracsur.2022.05.069. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis guidelines changed the high-resolution computed tomography (HRCT) pattern from three to four categories in 2018. We assessed the relationship between surgical outcomes and HRCT patterns according to the 2018 guideline.

METHODS: Among 1503 patients who underwent pulmonary resection for clinical stage Ⅰ-Ⅲ lung cancer at our institution between January 2007 and June 2019, 218 with interstitial lung abnormalities based on preoperative HRCT were retrospectively investigated. We reclassified all interstitial lung abnormalities cases with preoperative HRCT from 3 patterns of the previous (2011th): "usual interstitial pneumonia (UIP)," "Possible," and "Inconsistent with UIP" into 4 patterns: "UIP," "Probable UIP," "Indeterminate," and "Alternative Diagnosis" according to the new consensus guideline of idiopathic pulmonary fibrosis (2018th). The occurrence of acute exacerbations and survival were analyzed, and its association with HRCT pattern was investigated.

RESULTS: Interstitial lung abnormalities cases were reclassified as UIP (n=55[25.2%]), probable UIP (n=36[16.5%]), indeterminate UIP (n=56[25.7%]), and alternative diagnosis (n=71[32.6%]). Twenty-one patients developed acute exacerbations (UIP pattern n=9 [16.4%], probable UIP n=5 [13.9%], indeterminate n=3 [5.4%], and alternative diagnosis n=4 [5.6%]). Multivariable Cox regression revealed that UIP pattern or probable UIP pattern of the 2018th guideline was an independent risk factor for severe acute exacerbations (grade III-Ⅴ) [odds ratio 6.81; 95% confidence interval 1.42-32.60] and postoperative overall survival [hazard ratio 3.12; 95% confidence interval 1.70-5.73].

CONCLUSIONS: UIP and probable UIP patterns were risk factors for postoperative severe acute exacerbations and mortality. 2018th guidelines' HRCT patterns could stratify outcomes of lung resection.

PMID:35863399 | DOI:10.1016/j.athoracsur.2022.05.069

PLoS One. 2022 Jul 21;17(7):e0271665. doi: 10.1371/journal.pone.0271665. eCollection 2022.

ABSTRACT

BACKGROUND AND OBJECTIVE: The epidemiology of interstitial lung diseases (ILDs) in developing countries remains unknown. The objective of this study was to estimate the incidence, prevalence, and national burden of ILDs in India.

METHODS: Data of consecutive subjects (aged >12 years) with ILDs included in a registry between March 2015 and February 2020 were analyzed retrospectively. The proportion of each ILD subtype was determined. The crude annual incidence and prevalence of ILDs for our region were estimated. Subsequently, the primary estimates of the national annual incident and prevalent burden of ILD and its subtypes were calculated. Alternative estimates for each ILD subtype were calculated using the current and a large, previous Indian study (n = 1,084). Data were analyzed using SPSS version 22 and are presented descriptively.

RESULTS: A total of 2,005 subjects (mean age, 50.7 years; 47% men) were enrolled. Sarcoidosis (37.3%) was the most common ILD subtype followed by connective tissue disease (CTD)-related ILDs (19.3%), idiopathic pulmonary fibrosis (IPF, 17.0%), and hypersensitivity pneumonitis (HP, 14.4%). The crude annual incidence and prevalence of ILDs were 10.1-20.2 and 49.0-98.1, respectively per 100,000 population. The best primary estimates for the crude national burden of all ILDs, sarcoidosis, CTD-ILD, IPF, HP, and other ILDs (in thousands) were 433-867, 213-427, 75-150, 51-102, 54-109, and 39-78. The respective alternative estimates (in thousands) were sarcoidosis, 127-254; CTD-ILD, 81-162; IPF, 46-91; HP, 130-261; other ILDs, 49-98.

CONCLUSION: In contrast to developed countries, sarcoidosis and HP are the ILDs with the highest burden in India.

PMID:35862355 | DOI:10.1371/journal.pone.0271665

Curr Opin Pulm Med. 2022 Jul 22. doi: 10.1097/MCP.0000000000000902. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: The aim of this study was to summarize quantitative computed tomography (CT) and machine learning data in fibrotic lung disease and to explore the potential application of these technologies in pulmonary sarcoidosis.

RECENT FINDINGS: Recent data in the use of quantitative CT in fibrotic interstitial lung disease (ILD) are covered. Machine learning includes deep learning, a branch of machine learning particularly suited to medical imaging analysis. Deep learning imaging biomarker research in ILD is currently undergoing accelerated development, driven by technological advances in image processing and analysis. Fundamental concepts and goals related to deep learning imaging research in ILD are discussed. Recent work highlighted in this review has been performed in patients with idiopathic pulmonary fibrosis (IPF). Quantitative CT and deep learning have not been applied to pulmonary sarcoidosis, although there are recent deep learning data in cardiac sarcoidosis.

SUMMARY: Pulmonary sarcoidosis presents unsolved problems for which quantitative CT and deep learning may provide unique solutions: in particular, the exploration of the long-standing question of whether sarcoidosis should be viewed as a single disease or as an umbrella term for disorders that might usefully be considered as separate diseases.

PMID:35861463 | DOI:10.1097/MCP.0000000000000902

Curr Opin Pulm Med. 2022 Jul 19. doi: 10.1097/MCP.0000000000000907. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Pleuroparenchymal fibroelastosis (PPFE) is a clinico-radiologic-pathologic interstitial lung disease (ILD) characterized by fibrosis that has upper lobe and subpleural predominance, involving both the visceral pleura and the subjacent subpleural lung parenchyma, and comprises dense fibroelastic changes with prominent elastosis of the alveolar walls together with fibrous thickening of the visceral pleura. The goal of this review is to summarize the state-of-the-art understanding in PPFE.

RECENT FINDINGS: PPFE was described in an increasing number of conditions. The course of disease is heterogeneous. Idiopathic PPFE, cases associated with telomerase-related gene mutations, cases related to a history of chemotherapy, and cases combining PPFE with a pattern of usual interstitial pneumonia, may have a particularly poor prognosis. Well-conducted retrospective studies identified marked PPFE features in approximately 10% of patients with idiopathic pulmonary fibrosis, 11% of patients with systemic sclerosis-associated ILD, 6.5% of patients with rheumatoid arthritis-associated ILD, and 23% of patients with hypersensitivity pneumonitis. Drug therapy has not been evaluated prospectively. A small retrospective study suggests that nintedanib may slow disease progression. However, whether the efficacy of antifibrotics is comparable in PPFE and in other forms of progressive pulmonary fibrosis warrants further evaluation.

SUMMARY: Accumulating data indicate that PPFE features are associated with poor prognosis in fibrosing ILDs. Further research on the management of PPFE is warranted.

PMID:35855575 | DOI:10.1097/MCP.0000000000000907

AMIA Annu Symp Proc. 2022 May 23;2022:206-215. eCollection 2022.

ABSTRACT

Analyzing gene co-expression networks can help in the discovery of biological processes and regulatory mechanisms underlying normal or perturbed states. Unlike standard differential analysis, network-based approaches consider the interactions between the genes involved leading to biologically relevant results. Applying such network-based methods to jointly analyze multiple transcriptomic networks representing independent disease cohorts or studies could lead to the identification of more robust gene modules or gene regulatory networks. We present gene2gauss, a novel feature learning framework that is capable of embedding genes as multivariate gaussian distributions by taking into account their long-range interaction neighborhoods across multiple transcriptomic studies. Using multiple gene co-expression networks from idiopathic pulmonary fibrosis, we demonstrate that these multi-dimensional gaussian features are suitable for identifying regulons of known transcription factors (TF). Using standard TF-target libraries, we demonstrate that the features from our method are highly relevant in comparison with other feature learning approaches on transcriptomic data.

PMID:35854722 | PMC:PMC9285176

Am J Respir Crit Care Med. 2022 Jul 19. doi: 10.1164/rccm.202206-1195LE. Online ahead of print.

NO ABSTRACT

PMID:35853164 | DOI:10.1164/rccm.202206-1195LE

JCI Insight. 2022 Jul 19:e156115. doi: 10.1172/jci.insight.156115. Online ahead of print.

ABSTRACT

Usual Interstitial Pneumonia (UIP) is a histological pattern characteristic of Idiopathic Pulmonary Fibrosis (IPF). The UIP pattern is patchy with histologically normal lung adjacent to dense fibrotic tissue. At this interface, fibroblastic foci (FF) are present and are sites where myofibroblasts and extracellular matrix (ECM) accumulate. Utilizing laser capture microdissection coupled mass spectrometry (LCM-MS), we interrogated the FF, adjacent mature scar, and adjacent alveoli in 6 fibrotic (UIP/IPF) specimens plus 6 non-fibrotic alveolar specimens as controls. The data were subject to qualitative and quantitative analysis, and histologically validated. We found that the fibrotic alveoli protein signature is defined by immune deregulation as the strongest category. The fibrotic mature scar classified as end-stage fibrosis whereas the FF contained an overabundance of a distinctive ECM compared to non-fibrotic control. Furthermore, the FF is positive for both TGFB1 and TGFB3, whereas the aberrant basaloid cell lining of the FF is predominantly positive for TGFB2. In conclusion, spatial proteomics demonstrated distinct protein compositions in the histologically defined regions of UIP/IPF tissue. These data revealed that the FF is the main site of collagen biosynthesis and that the adjacent alveoli are abnormal. This new and essential information will inform future mechanistic studies on fibrosis progression.

PMID:35852874 | DOI:10.1172/jci.insight.156115

Folia Med (Plovdiv). 2021 Aug 31;63(4):582-585. doi: 10.3897/folmed.63.e56088.

ABSTRACT

The idiopathic pulmonary hemosiderosis is a rare, life-threatening condition observed mainly in children and characterized by recurrent episodes of diffuse alveolar hemorrhages. The disease is characterized by the triad of hemoptysis, alveolar infiltrates in chest radiography, and iron-deficiency anemia. The recurrent episodes of alveolar hemorrhage can lead to chronic iron-deficiency anemia and irreversible pulmonary fibrosis; therefore, early diagnosis and treatment are crucial to the outcome of the disease.The idiopathic pulmonary hemosiderosis is a rare, life-threatening condition observed mainly in children and characterized by recurrent episodes of diffuse alveolar hemorrhages. The disease is characterized by the triad of hemoptysis, alveolar infiltrates in chest radiography, and iron-deficiency anemia. The recurrent episodes of alveolar hemorrhage can lead to chronic iron-deficiency anemia and irreversible pulmonary fibrosis; therefore, early diagnosis and treatment are crucial to the outcome of the disease.

PMID:35851160 | DOI:10.3897/folmed.63.e56088

Intern Med J. 2022 Jul 18. doi: 10.1111/imj.15887. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary hypertension (PH) is an important complication of interstitial lung disease (ILD), as its development confers a poor prognosis. There are no specific recommendations for methods of assessment for PH in ILD populations. This study aimed to determine current assessment practices for PH in an Australian ILD centre.

METHODS: In the Austin Health ILD database, 162 consecutive patients with idiopathic pulmonary fibrosis or connective tissue disease-associated ILD were identified and retrospectively evaluated for methods of PH assessment with transthoracic echocardiography (TTE), serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and right heart catheterisation, in relation to patient demographic and physiological parameters.

RESULTS: The median follow up was 30 (14.4-56.4) months. At baseline, vital capacity was 80.0±18.4% predicted and diffusing capacity for carbon monoxide was 59.6±15.2% predicted. Evaluation for PH was performed in 147 (90.7%) patients, among whom 105 (64.8%) had TTE performed at least once. At the initial TTE, 33.7% patients had high probability of PH, defined as RVSP > 40 mmHg + RAp and/or right ventricular dysfunction. At the time of the most recent TTE, these criteria were met in 45 (52.3%) patients. Elevated serum NT-proBNP levels during the first year were observed in 47 (38.8%) patients. Only 14 (8.6%) patients had right heart catheterisation.

CONCLUSION: Our institutional PH assessment practice in ILD demonstrates a substantial prevalence of probable PH at baseline. As new therapies emerge for the treatment of PH in ILD, well-defined screening practices are important in this population for early identification and optimal management. This article is protected by copyright. All rights reserved.

PMID:35848362 | DOI:10.1111/imj.15887

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