BMJ Case Rep. 2022 Dec 1;15(12):e253113. doi: 10.1136/bcr-2022-253113.

NO ABSTRACT

PMID:36455984 | PMC:PMC9716928 | DOI:10.1136/bcr-2022-253113

Respir Med. 2022 Nov 23;205:107060. doi: 10.1016/j.rmed.2022.107060. Online ahead of print.

NO ABSTRACT

PMID:36455497 | DOI:10.1016/j.rmed.2022.107060

Ir J Med Sci. 2022 Dec 1. doi: 10.1007/s11845-022-03241-1. Online ahead of print.

ABSTRACT

BACKGROUND: The SARS-CoV-2 pandemic has prompted clinicians to develop an early and effective treatment of viral infections. To date, vaccines, monoclonal antibodies, and antivirals are the cornerstone of therapy for SARS-CoV-2. AIFA approved the prescription of molnupiravir on 30/12/2021. Molnupiravir is a prodrug that causes the accumulation of errors in the viral genome.

METHODS: We prescribed molnupiravir to a total of 74 patients in a range between 26 and 96 years old and followed-up them for 30 days. 10 patients affected by idiopathic pulmonary fibrosis (IPF) were treated.

RESULTS: The follow-up showed that all of the treated patients presented a regression of symptoms. No patients were hospitalized and/or showed sequelae after the infection by SARS-CoV-2, even though the examined population was older and with more co-morbidities than other patients treated with different antivirals.

CONCLUSION: Molnupiravir is safe and well-tolerated by patients with high-risk of progression to severe COVID. No patients were hospitalized or showed sequelae, including all patients affected by IPF.

PMID:36454535 | DOI:10.1007/s11845-022-03241-1

Elife. 2022 Dec 1;11:e79543. doi: 10.7554/eLife.79543.

ABSTRACT

BACKGROUND: MicroRNAs (miRNA) and other components contained in extracellular vesicles may reflect the presence of a disease. Lung tissue, sputum, and sera of individuals with idiopathic pulmonary fibrosis (IPF) show alterations in miRNA expression. We designed this study to test whether urine and/or tissue derived exosomal miRNAs from individuals with IPF carry cargo that can promote fibrosis.

METHODS: Exosomes were isolated from urine (U-IPFexo), lung tissue myofibroblasts (MF-IPFexo), serum from individuals with IPF (n=16) and age/sex-matched controls without lung disease (n=10). We analyzed microRNA expression of isolated exosomes and their in vivo bio-distribution. We investigated the effect on ex vivo skin wound healing and in in vivo mouse lung models.

RESULTS: U-IPFexo or MF-IPFexo expressed miR-let-7d, miR-29a-5p, miR-181b-3p and miR-199a-3p consistent with previous reports of miRNA expression obtained from lung tissue/sera from patients with IPF. In vivo bio-distribution experiments detected bioluminescent exosomes in the lung of normal C57Bl6 mice within 5 min after intravenous infusion, followed by distribution to other organs irrespective of exosome source. Exosomes labeled with gold nanoparticles and imaged by transmission electron microscopy were visualized in alveolar epithelial type I and type II cells. Treatment of human and mouse lung punches obtained from control, non-fibrotic lungs with either U-IPFexo or MF-IPFexo produced a fibrotic phenotype. A fibrotic phenotype was also induced in a human ex vivo skin model and in in vivo lung models.

CONCLUSIONS: Our results provide evidence of a systemic feature of IPF whereby exosomes contain pro-fibrotic miRNAs when obtained from a fibrotic source and interfere with response to tissue injury as measured in skin and lung models.

FUNDING: This work was supported in part by Lester and Sue Smith Foundation and The Samrick Family Foundation and NIH grants R21 AG060338 (SE and MKG), U01 DK119085 (IP, RS, MTC).

PMID:36454035 | DOI:10.7554/eLife.79543

Medicine (Baltimore). 2022 Nov 25;101(47):e31877. doi: 10.1097/MD.0000000000031877.

ABSTRACT

BACKGROUND: At present, apart from lung transplantation, no drugs can effectively treat idiopathic pulmonary fibrosis (IPF). Therefore, it is imperative to explore new drugs to control or treat it. Traditional Chinese medicine (TCM) injections have been widely used in the field of IPF, but there is no comparison of their efficacy in the assisted improvement of IPF. Therefore, the purpose of this study is to network meta-analyze the efficacy and safety of 4 kinds of commonly used TCM injections assisted by conventional treatment to improve the disease.

METHODS: Used a computer to find the Randomized Controlled Trials (RCTs) from the 8 major databases (PubMed, EMbase, CENTRAL, MEDLINE, CBM, China National Knowledge Infrastructure, WanFang Database and VIP Chinese Science). Cochrane's risk assessment tool was used to evaluate the quality of the literature. The Grading of Recommendations Assessment, Development and Evaluation approach served to assess the certainty in the evidence of direct and indirect estimates. Revman5.3 (Review Manager (RevMan) Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.) and stata14.0 (Stata/SE 14.0 for Windows (64-bit). Revision Apr 22, 2015.Copyright 1985-2015 StataCorp LP). were used for Statistical analysis. Registration number: CRD42020220570.

RESULTS: After layer-by-layer screening, 20 RCTs were finally included, which include a total of 1363 patients and 4 kinds of RCT of TCM injection (12 studies on Danhong injection, 5 studies on Ligustrazine injection, 2 studies on Huangqi injection and 1 study on Dazhu hongjingtian injection). The results showed: Clinical effective rate: Danhong Injection (Odds ratio [OR] = 3.94, 95% CI [2.34, 6.64], moderate certainty of evidence), Huangqi injection (OR = 3.40, 95% CI [1.38, 8.41], moderate certainty of evidence) and Ligustrazine injection (OR = 2.74, 95% CI [1.62, 4.64], moderate certainty of evidence) combined with conventional treatment had better curative efficacy than that of the conventional treatment group. SUCRA Ranking: Danhong (80.5) > Huangqi (68.5) > Ligustrazine (52.9) > Dazhu hongjingtian (44.3) > Conventional treatment (3.8); Forced Expiratory Volume In 1s/Forced vital capacity%: SUCRA Ranking: Danhong (80.0) > Ligustrazine (62.9) > Conventional treatment (2.1); Carbon monoxide diffusing capacity%: SUCRA Ranking: Ligustrazine (89.9) > Dazhu hongjingtian (63.4) > Danhong (44.9) > Conventional treatment (1.8); Partial pressure of Oxygen: SUCRA Ranking: Dazhu Hongjingtian (87.1) > Danhong (78.8) > Ligustrazine (34.0) > Conventional treatment (0.0); Partial pressure of carbon dioxide: SUCRA Ranking: Danhong (99.3) > Ligustrazine (50.3) > Conventional treatment (0.4). No obvious adverse reactions were found in all studies.

CONCLUSION: The four TCM injections combined with conventional treatment can effectively improve the clinical indicators of patients with IPF, and the improvement effect of Danhong injection was more obvious.

PMID:36451506 | DOI:10.1097/MD.0000000000031877

Sci Rep. 2022 Nov 30;12(1):20668. doi: 10.1038/s41598-022-24985-x.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Currently, pirfenidone and nintedanib are the only FDA-approved drugs for the treatment of IPF and are now the standard of care. This is a significant step in slowing down the progression of the disease. However, the drugs are unable to stop or reverse established fibrosis. Several retrospective clinical studies indicate that proton pump inhibitors (PPIs; FDA-approved to treat gastroesophageal reflux) are associated with favorable outcomes in patients with IPF, and emerging preclinical studies report that PPIs possess antifibrotic activity. In this study, we evaluated the antifibrotic efficacy of the PPI esomeprazole when combined with pirfenidone in vitro and in vivo. In cell culture studies of IPF lung fibroblasts, we assessed the effect of the combination on several fibrosis-related biological processes including TGFβ-induced cell proliferation, cell migration, cell contraction, and collagen production. In an in vivo study, we used mouse model of TGFβ-induced lung fibrosis to evaluate the antifibrotic efficacy of esomeprazole/pirfenidone combination. We also performed computational studies to understand the molecular mechanisms by which esomeprazole and/or pirfenidone regulate lung fibrosis. We found that esomeprazole significantly enhanced the anti-proliferative effect of pirfenidone and favorably modulated TGFβ-induced cell migration and contraction of collagen gels. We also found that the combination significantly suppressed collagen production in response to TGFβ in comparison to pirfenidone monotherapy. In addition, our animal study demonstrated that the combination therapy effectively inhibited the differentiation of lung fibroblasts into alpha smooth muscle actin (αSMA)-expressing myofibroblasts to attenuate the progression of lung fibrosis. Finally, our bioinformatics study of cells treated with esomeprazole or pirfenidone revealed that the drugs target several extracellular matrix (ECM) related pathways with esomeprazole preferentially targeting collagen family members while pirfenidone targets the keratins. In conclusion, our cell biological, computational, and in vivo studies show that the PPI esomeprazole enhances the antifibrotic efficacy of pirfenidone through complementary molecular mechanisms. This data supports the initiation of prospective clinical studies aimed at repurposing PPIs for the treatment of IPF and other fibrotic lung diseases where pirfenidone is prescribed.

PMID:36450789 | DOI:10.1038/s41598-022-24985-x

Am J Respir Cell Mol Biol. 2022 Nov 30. doi: 10.1165/rcmb.2022-0219OC. Online ahead of print.

ABSTRACT

VISTA (also called PD-1H), a novel immune regulator expressed on myeloid and T lymphocyte lineages, is up-regulated in mouse and human idiopathic pulmonary fibrosis (IPF). However, the significance of VISTA and its therapeutic potential in regulating IPF has yet to be defined. To determine the role of VISTA and its therapeutic potential in IPF, the expression profile of VISTA was evaluated from human single-cell RNA sequencing data (IPF Cell Atlas). Inflammatory response and lung fibrosis were assessed in bleomycin-induced experimental pulmonary fibrosis models in VISTA-deficient mice compared with wild-type littermates. In addition, these outcomes were evaluated following VISTA agonistic antibody treatment in the wild-type pulmonary fibrosis mice. VISTA expression was increased in lung tissue-infiltrating monocytes of IPF patients. VISTA was induced in the myeloid population, mainly circulating monocyte-derived macrophages, during bleomycin-induced pulmonary fibrosis. Genetic ablation of VISTA drastically promoted pulmonary fibrosis, and bleomycin-induced fibroblast activation was dependent on the interaction between VISTA-expressing myeloid cells and fibroblasts. Treatment with VISTA agonistic antibody reduced fibrotic phenotypes accompanied by the suppression of lung innate immune and fibrotic mediators. In conclusion, these results suggest that VISTA up-regulation in pulmonary fibrosis may be a compensatory mechanism to limit inflammation and fibrosis, and stimulation of VISTA signaling using VISTA agonists effectively limit the fibrotic innate immune landscape and the consequent tissue fibrosis. Further studies are warranted to test VISTA as a novel therapeutic target for the IPF treatment.

PMID:36450109 | DOI:10.1165/rcmb.2022-0219OC

Transl Med UniSa. 2021 Dec 23;24(1):30-34. doi: 10.37825/2239-9754.1032. eCollection 2021.

ABSTRACT

Diffuse pulmonary ossification (DPO) is a rare condition of DLD (diffuse lung disease) characterized by the presence of metaplastic ectopic bone in the lungs and is less frequent in patients without a clear background of lung diseases. DPO is characterized by very small calcific nodules, often with bone mature located in both lungs and often in peripheral areas of the lungs. Two patterns of DPO have been recognized dendriform and nodular. The dendriform type is less common and is characterized by a coral-like network of bone spiculae along the alveolar septa and is often related to interstitial fibrosis or chronic obstructive lung disease [1]. Recent literature papers indicate that DPO may be a predictor of pulmonary fibrosis, is related to Usual Interstitial Pneumonia (UIP) pattern, and has a higher correlation with Idiopathic Pulmonary Fibrosis (IPF). We present a case of a 41-years-old male with persistent bronchitis who underwent a chest X-ray (CXR) that showed multiple pulmonary small calcified nodules in both lungs. These findings were then defined with a high-resolution computed tomography of the chest (HRCT) that showed multiple small nodules spread in both lungs with a "tree-like pattern". A lung biopsy was performed to confirm the radiological diagnostic hypothesis of DPO, and further pathological examination showed multifocal areas of mature bone tissue within the lung parenchyma.

PMID:36447744 | PMC:PMC9673915 | DOI:10.37825/2239-9754.1032

Cell Mol Bioeng. 2022 Jun 24;15(5):505-519. doi: 10.1007/s12195-022-00726-y. eCollection 2022 Oct.

ABSTRACT

Idiopathic pulmonary fibrosis is a chronic disease characterized by progressive lung scarring that inhibits gas exchange. Evidence suggests fibroblast-matrix interactions are a prominent driver of disease. However, available preclinical models limit our ability to study these interactions. We present a technique for synthesizing phototunable poly(ethylene glycol) (PEG)-based hybrid-hydrogels comprising healthy or fibrotic decellularized extracellular matrix (dECM) to decouple mechanical properties from composition and elucidate their roles in fibroblast activation. Here, we engineered and characterized phototunable hybrid-hydrogels using molecular techniques such as ninhydrin and Ellman's assays to assess dECM functionalization, and parallel-plate rheology to measure hydrogel mechanical properties. These biomaterials were employed to investigate the activation of fibroblasts from dual-transgenic Col1a1-GFP and αSMA-RFP reporter mice in response to changes in composition and mechanical properties. We show that reacting functionalized dECM from healthy or bleomycin-injured mouse lungs with PEG alpha-methacrylate (αMA) in an off-stoichiometry Michael-addition reaction created soft hydrogels mimicking a healthy lung elastic modulus (4.99 ± 0.98 kPa). Photoinitiated stiffening increased the material modulus to fibrotic values (11.48 ± 1.80 kPa). Percent activation of primary murine fibroblasts expressing Col1a1 and αSMA increased by approximately 40% following dynamic stiffening of both healthy and bleomycin hybrid-hydrogels. There were no significant differences between fibroblast activation on stiffened healthy versus stiffened bleomycin-injured hybrid-hydrogels. Phototunable hybrid-hydrogels provide an important platform for probing cell-matrix interactions and developing a deeper understanding of fibrotic activation in pulmonary fibrosis. Our results suggest that mechanical properties are a more significant contributor to fibroblast activation than biochemical composition within the scope of the hybrid-hydrogel platform evaluated in this study.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12195-022-00726-y.

PMID:36444345 | PMC:PMC9700547 | DOI:10.1007/s12195-022-00726-y

BMC Pulm Med. 2022 Nov 28;22(1):448. doi: 10.1186/s12890-022-02221-6.

ABSTRACT

BACKGROUND: Pulmonary rehabilitation (PR) is recommended in the treatment of people with idiopathic pulmonary fibrosis (IPF). Little is known about the experiences of people with IPF of PR. Due to Covid-19 there has been a rapid shift of PR services to remote/virtual delivery.

OBJECTIVE: To explore people living with IPFs experience of a virtual PR (VPR) programme.

METHODS: All patients with a diagnosis of IPF in a stable phase of the disease were invited to participate in virtual PR: a 10 week exercise programme delivered twice-weekly for one hour. One-to-one semi- structured interviews were conducted within one week following the programme. All interviews were recorded, transcribed and analysed using Braun and Clarke thematic analysis by two independent assessors.

RESULTS: N=13 participants took part in the semi-structured interviews, mean (standard deviation (SD)) age 69.5(10.4) years; 7M:6F. Mean (SD) FEV1 2.6(0.3)L, FVC 2.9(0.4)L. Four key themes were identified: 1) The impact of VPR on health and outlook, (2) The reality of VPR, (3) Being active after VPR and (4) Living with IPF during the COVID-19 Pandemic. Participants reported high levels of enjoyment and engagement with the programme regardless of the health benefits experienced. Most participants expressed a desire for a longer programme. Participants expressed different levels of maintenance with exercise since finishing the programme, specific motivators and strategies for maintenance included lung transplant, the maintenance of benefits from the programme and social support. COVID-19 and the restrictions imposed had some negative impacts on some participants lives, engaging with PR helped overcome some of these.

CONCLUSION: Despite the progressive nature of IPF, all participants expressed high levels of enjoyment with the programme. Future research should explore strategies for maintenance post PR and the optimum duration of PR for people with IPF.

PMID:36443780 | DOI:10.1186/s12890-022-02221-6

Clin Respir J. 2022 Nov 27. doi: 10.1111/crj.13564. Online ahead of print.

ABSTRACT

INTRODUCTION: The GAP model was widely used as a simple risk "screening" method for patients with idiopathic pulmonary fibrosis (IPF).

OBJECTIVES: We sought to validate the GAP model in Chinese patients with IPF to evaluate whether it can accurately predict the risk for mortality.

METHODS: A total of 212 patients with IPF diagnosed at China-Japan Friendship Hospital from 2015 to 2019 were enrolled. The latest follow-up ended in September 2022. Cumulative mortality of each GAP stage was calculated and compared based on Fine-Gray models for survival, and lung transplantation was treated as a competing risk. The performance of the model was evaluated in terms of both discrimination and calibration.

RESULTS: The cumulative mortality in patients with GAP stage III was significantly higher than that in those with GAP stage I or II (Gray's test p < 0.0001). The Harrell c-index for the GAP calculator was 0.736 (95% CI: 0.667-0.864). The discrimination for the GAP staging system were similar with that for the GAP calculator. The GAP model overestimated the mortality rate at 1- and 2-year in patients classified as GAP stage I (6.90% vs. 1.77% for 1-year, 14.20% vs. 6.78% for 2-year).

CONCLUSIONS: Our findings indicated that the GAP model overestimated the mortality rate in mild group.

PMID:36437511 | DOI:10.1111/crj.13564

J Am Coll Radiol. 2022 Nov;19(11S):S502-S512. doi: 10.1016/j.jacr.2022.09.018.

ABSTRACT

Pulmonary hypertension may be idiopathic or related to a large variety of diseases. Various imaging examinations may be helpful in diagnosing and determining the etiology of pulmonary hypertension. Imaging examinations discussed in this document include chest radiography, ultrasound echocardiography, ventilation/perfusion scintigraphy, CT, MRI, right heart catheterization, and pulmonary angiography. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer-reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer-reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

PMID:36436973 | DOI:10.1016/j.jacr.2022.09.018

J Transl Med. 2022 Nov 26;20(1):544. doi: 10.1186/s12967-022-03759-z.

ABSTRACT

Liver fibrosis is a liver disease in which there is an excessive buildup of extracellular matrix proteins, including collagen. By regulating cytokine production and the inflammatory response, heat shock proteins (HSPs) contribute significantly to a wider spectrum of fibrotic illnesses, such as lung, liver, and idiopathic pulmonary fibrosis by aiding in the folding and assembly of freshly synthesized proteins, HSPs serve as chaperones. HSP70 is one of the key HSPs in avoiding protein aggregation which induces its action by sending unfolded and/or misfolded proteins to the ubiquitin-proteasome degradation pathway and antagonizing influence on epithelial-mesenchymal transition. HSP47, on the other hand, is crucial for boosting collagen synthesis, and deposition, and fostering the emergence of fibrotic disorders. The current review aims to provide light on how HSP70 and HSP47 affect hepatic fibrogenesis. Additionally, our review looks into new therapeutic approaches that target HSP70 and HSP47 and could potentially be used as drug candidates to treat liver fibrosis, especially in cases of comorbidities.

PMID:36435779 | DOI:10.1186/s12967-022-03759-z

Pharmacol Res. 2022 Nov 23:106577. doi: 10.1016/j.phrs.2022.106577. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with high mortality and limited effective therapy. Herein, we reported that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), used in depression and anxiety treatment, also exhibited therapeutic activities in IPF. Fluvoxamine inhibited cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), restrained the activation of their downstream targets, including PERK/ eIF2α/ c-Myc/ miR-9-5p/ TBPL1 and TBK1/ YAP/ JNK1/2/ Bnip3/ CaMKII/ cofilin signaling, thus attenuated the activation and migration of fibroblasts upon TGF-β1 challenge. Fluvoxamine dose-dependently improved pulmonary function, decreased the expression of inflammatory factors, reduced excessive production of extracellular matrix, and thus alleviated bleomycin (BLM)-induced lung fibrosis in mice. Moreover, fluvoxamine at a dose of 10mg/ kg showed similar efficacy as pirfenidone (PFD) at a dose of 30mg/kg in a mice model of lung fibrosis. In summary, our results suggest that fluvoxamine is an effective anti-fibrotic agent for IPF.

PMID:36435270 | DOI:10.1016/j.phrs.2022.106577

Respir Med Res. 2022 Nov 23;83:100951. doi: 10.1016/j.resmer.2022.100951. Online ahead of print.

ABSTRACT

BACKGROUND: Real-world data regarding health-care resource use (HCRU) and costs of idiopathic pulmonary fibrosis (IPF) are scarce. In France, at the time of the study, pirfenidone and nintedanib were reimbursed for documented IPF only, with similar reimbursement criteria with regard to disease characteristics, prescription through a dedicated form, and IPF diagnosis established in a multidisciplinary setting. The objective of this study was to evaluate costs related to HCRU in patients newly treated with pirfenidone or nintedanib in 2015-2016, in France, using the exhaustive claims data of the French National Health System.

METHODS: Patients aged <50 years or who had pulmonary fibrosis secondary to an identified cause were excluded. HCRU-related costs up to 31 December 2017 were compared using generalized linear models adjusted for age, sex, year of treatment initiation, time to treatment initiation and proxies of disease severity identified during a pre-treatment period.

RESULTS: During the study period, a treatment with pirfenidone or nintedanib was newly initiated in 804 and 509 patients, respectively. No difference was found between groups for age, sex, time to treatment initiation, Charlson comorbidity score, and number of hospitalisations or medical visits prior to treatment initiation. As compared to pirfenidone, nintedanib was associated with higher costs for medications (1.2; 95% CI, 1.1-1.3) and medical visits (1.3; 95% CI, 1.2-1.4), as well as a higher global cost (1.1; 95% CI, 1.0-1.2). The costs of medical procedures, hospitalizations and indirect HCRU did not statistically differ between the two cohorts.

CONCLUSIONS: This observational study identified potential differences in HCRU-related costs under newly prescribed antifibrotic drugs, deserving further explorations.

PMID:36434913 | DOI:10.1016/j.resmer.2022.100951

Life (Basel). 2022 Nov 18;12(11):1918. doi: 10.3390/life12111918.

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an infectious viral disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). It is known that infection with SARS-CoV-2 can lead to various autoimmune and autoinflammatory diseases. There are few reports in the literature on the association between SARS-CoV-2 and autoimmune diseases, and the number of reports has been increasing since 2020. Autoimmune diseases and SARS-CoV-2 infections are intertwined in several ways. Both conditions lead to immune-mediated tissue damage, the immune response is accompanied by the increased secretion of inflammatory cytokines and both conditions can be treated using immunomodulatory drugs. Patients with certain autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, cardiac sarcoidosis, idiopathic pulmonary fibrosis, autoimmune hepatitis, multiple sclerosis and others, are more susceptible to SARS-CoV-2 infection, either because of the active autoimmune disease or because of the medications used to treat it. Conversely, SARS-CoV-2 infection can also cause certain autoimmune diseases. In this paper, we describe the development of autoimmune diseases after COVID-19 and the recovery from COVID-19 in people with autoimmune diseases.

PMID:36431053 | DOI:10.3390/life12111918

Int J Mol Sci. 2022 Nov 15;23(22):14088. doi: 10.3390/ijms232214088.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal interstitial lung disease with unknown etiology. Despite substantial progress in understanding the pathogenesis of pulmonary fibrosis and drug development, there is still no cure for this devastating disease. Fenbendazole (FBZ) is a benzimidazole compound that is widely used as an anthelmintic agent and recent studies have expanded the scope of its pharmacological effects and application prospect. This study demonstrated that FBZ treatment blunted bleomycin-induced lung fibrosis in mice. In vitro studies showed that FBZ inhibited the proliferation and migration of human embryo lung fibroblasts. Further studies showed that FBZ significantly inhibited glucose consumption, moderated glycolytic metabolism in fibroblasts, thus activated adenosine monophosphate-activated protein kinase (AMPK), and reduced the activation of the mammalian target of rapamycin (mTOR) pathway, thereby inhibiting transforming growth factor-β (TGF-β1)-induced fibroblast-to-myofibroblast differentiation and collagen synthesis. In summary, our data suggested that FBZ has potential as a novel treatment for pulmonary fibrosis.

PMID:36430565 | DOI:10.3390/ijms232214088

Int J Mol Sci. 2022 Nov 11;23(22):13920. doi: 10.3390/ijms232213920.

ABSTRACT

Early- and late-phase radiation-induced lung injuries, namely pneumonitis and lung fibrosis (RILF), severely constrain the maximum dose and irradiated volume in thoracic radiotherapy. As the most radiosensitive targets, epithelial cells respond to radiation either by undergoing apoptosis or switching to a senescent phenotype that triggers the immune system and damages surrounding healthy cells. Unresolved inflammation stimulates mesenchymal cells' proliferation and extracellular matrix (ECM) secretion, which irreversibly stiffens the alveolar walls and leads to respiratory failure. Although a thorough understanding is lacking, RILF and idiopathic pulmonary fibrosis share multiple pathways and would mutually benefit from further insights into disease progression. Furthermore, current normal tissue complication probability (NTCP) models rely on clinical experience to set tolerance doses for organs at risk and leave aside mechanistic interpretations of the undergoing processes. To these aims, we implemented a 3D agent-based model (ABM) of an alveolar duct that simulates cell dynamics and substance diffusion following radiation injury. Emphasis was placed on cell repopulation, senescent clearance, and intra/inter-alveolar bystander senescence while tracking ECM deposition. Our ABM successfully replicates early and late fibrotic response patterns reported in the literature along with the ECM sigmoidal dose-response curve. Moreover, surrogate measures of RILF severity via a custom indicator show qualitative agreement with published fibrosis indices. Finally, our ABM provides a fully mechanistic alveolar survival curve highlighting the need to include bystander damage in lung NTCP models.

PMID:36430398 | DOI:10.3390/ijms232213920

Am J Med Sci. 2022 Nov 22:S0002-9629(22)00463-3. doi: 10.1016/j.amjms.2022.11.002. Online ahead of print.

ABSTRACT

The term "subpleural sparing" refers to computed tomography (CT) images that indicate that there is limited disease/infiltrate in the immediate subpleural location. This observation is often associated with nonspecific interstitial pneumonitis and is a characteristic that distinguishes this pathology from usual interstitial pneumonitis (idiopathic pulmonary fibrosis). Subpleural sparing can also occur in acute respiratory disorders, including pulmonary contusion in children, acute lung disease associated with electronic cigarettes (vaping), and aspiration of exogenous lipids. Potential explanations for this observation include nonuniform distribution of lung injury/inflammation, nonuniform clearing/resolution of injury, and variations in CT image acquisition and presentation. The subpleural region contains lymphatic structures on the interior surface of the visceral pleura and in interlobular septa. The density of subpleural lymphatics decreases in more interior zones of the lung that largely contain alveolar-capillary units. These lymphatics transfer fluid and other inflammatory mediators from the peripheral lung into central lymphatics and veins. Consequently, the density and distribution of lymphatics could explain preferential clearing of the subpleural regions during acute injury. The acquisition of CT images also depends on the configuration of detectors, slice thickness, and the energy of the electron beam. Clinicians should carefully consider the disease process, lymphatic function and other clearance mechanisms, and the vagaries in CT image acquisition when they evaluate patients with subpleural sparing.

PMID:36427562 | DOI:10.1016/j.amjms.2022.11.002

Front Med (Lausanne). 2022 Nov 8;9:955125. doi: 10.3389/fmed.2022.955125. eCollection 2022.

ABSTRACT

OBJECTIVES: We sought to evaluate the prognostic value of blood routine parameters and biochemical parameters, especially inflammation-related biomarkers, and establish an inflammation-related prognostic model in Chinese patients with idiopathic pulmonary fibrosis (IPF).

MATERIAL/METHODS: Patients diagnosed as IPF at Beijing Chaoyang Hospital and aged 40 years and older were consecutively enrolled from June 2000 to March 2015, and finally, a total of 377 patients were enrolled in the derivation cohort. The follow-up ended in December 2016. We used Cox proportional hazard model to calculate the hazard ratio (HR) and establish the prognostic model. The discrimination and calibration of the prognostic model were evaluated in an independent validation cohort enrolled from China-Japan Friendship Hospital between January 2015 and December 2019.

RESULTS: Multivariate analysis revealed that patients with elevated monocyte-to-red blood cell count ratio (MRR) and monocyte counts showed increased risk of mortality. The clinical-physiological-biomarker (CPB) index and CPB stage we established in this study were a significant predictor, and the C-index for CPB index and CPB stage in the validation cohort was 0.635 (95% CI: 0.558-0.712) and 0.619 (95% CI: 0.544-0.694), respectively. Patients in CPB stage III had the poorest survival.

CONCLUSION: We developed and validated a new inflammation-related prognostic model (CPB index and CPB stage) which was integration of age, gender, FVC (%, predicted), DLCO (%, predicted), Charlson Comorbidity Index, and blood monocyte counts. This prediction model exhibited strong ability in predicting mortality in Chinese patients with IPF.

PMID:36425108 | PMC:PMC9679289 | DOI:10.3389/fmed.2022.955125