Massive Fibrosis Research Articles

Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas.

A hallmark feature of pancreatic ductal adenocarcinoma (PDAC) is massive intratumoral fibrosis, designated as desmoplasia. Desmoplasia is characterized by the expansion of cancer-associated fibroblasts (CAFs) and a massive increase in extracellular matrix (ECM). During fibrogenesis, distinct genes become reactivated specifically in fibroblasts, e.g., the disintegrin metalloprotease, ADAM12. Previous studies have shown that immunotherapeutic ablation of ADAM12+ cells reduces fibrosis in various organs. In preclinical mouse models of PDAC, we observe ADAM12 expression in CAFs as well as in tumor cells but not in healthy mouse pancreas. Therefore, we tested prophylactic and therapeutic vaccination against ADAM12 in murine PDAC and observed delayed tumor growth along with a reduction in CAFs and tumor desmoplasia. This is furthermore associated with vascular normalization and alleviated tumor hypoxia. The ADAM12 vaccine induces a redistribution of CD8+ T cells within the tumor and cytotoxic responses against ADAM12+ cells. In summary, vaccination against the endogenous fibroblast target ADAM12 effectively depletes CAFs, reduces desmoplasia and delays the growth of murine PDACs. These results provide proof-of-principle for the development of vaccination-based immunotherapies to treat tumor desmoplasia.

Women in Coal Mining-Radiographic Findings of Women Participants in the Coal Workers' Health Surveillance Program 1970-2022.

Objective: To describe the work experience and respiratory health of women coal miners in the United States using Coal Workers' Health Surveillance Program (CWHSP) data. Methods: Analysis included CWHSP participants with self-reported sex of female between January 1, 1970, and December 31, 2022, and examined radiographic surveillance, demographics, and job history. National Institute for Occupational Safety and Health-certified physicians classified chest radiographs. Results: Among 8,182 women participants, most worked <10 years and a majority reported working in non-dusty jobs. Among 3,392 with ≥1 year of coal mining tenure, 18 (0.5%) had evidence of pneumoconiosis, with no cases of progressive massive fibrosis. Conclusion: Women coal miners participating in the CWSHP had short mining careers and low pneumoconiosis prevalence. Few worked in the most dusty jobs, indicating limited exposure to coal mine dust. This underscores the need to explore women's roles in mining, and for improved gender-specific employment reporting. Such changes can enhance health and work conditions for women in male-dominated industries.

Integrating routine blood biomarkers and artificial intelligence for supporting diagnosis of silicosis in engineered stone workers.

Engineered stone silicosis (ESS), primarily caused by inhaling respirable crystalline silica, poses a significant occupational health risk globally. ESS has no effective treatment and presents a rapid progression from simple silicosis (SS) to progressive massive fibrosis (PMF), with respiratory failure and death. Despite the use of diagnostic methods like chest x-rays and high-resolution computed tomography, early detection of silicosis remains challenging. Since routine blood tests have shown promise in detecting inflammatory markers associated with the disease, this study aims to assess whether routine blood biomarkers, coupled with machine learning techniques, can effectively differentiate between healthy individuals, subjects with SS, and PMF. To this end, 107 men diagnosed with silicosis, ex-workers in the engineered stone (ES) sector, and 22 healthy male volunteers as controls not exposed to ES dust were recruited. Twenty-one primary biochemical markers derived from peripheral blood extraction were obtained retrospectively from clinical hospital records. Relief-F features selection technique was applied, and the resulting subset of 11 biomarkers was used to build five machine learning models, demonstrating high performance with sensitivities and specificities in the best case greater than 82% and 89%, respectively. The percentage of lymphocytes, the angiotensin-converting enzyme, and lactate dehydrogenase indexes were revealed, among others, as blood biomarkers with significant cumulative importance for the machine learning models. Our study reveals that these biomarkers could detect a chronic inflammatory status and potentially serve as a supportive tool for the diagnosis, monitoring, and early detection of the progression of silicosis.

In Situ Lung Dust Analysis by Automated Field Emission Scanning Electron Microscopy With Energy Dispersive X-ray Spectroscopy: A Method for Assessing Inorganic Particles in Lung Tissue From Coal Miners.

Overexposure to respirable coal mine dust can cause severe lung disease including progressive massive fibrosis (PMF). Field emission scanning electron microscopy with energy dispersive x-ray spectroscopy (FESEM-EDS) has been used for in situ lung dust particle analysis for evaluation of disease etiology. Automating such work can reduce time, costs, and user bias. To develop and test an automated FESEM-EDS method for in situ analysis of inorganic particles in coal miner lung tissue. We programmed an automated FESEM-EDS procedure to collect particle size and elemental data, using lung tissue from 10 underground coal miners with PMF and 4 control cases. A statistical clustering approach was used to establish classification criteria based on particle chemistry. Data were correlated to PMF/non-PMF areas of the tissue, using corresponding brightfield microscopy images. Results for each miner case were compared with a separate corresponding analysis of particles recovered following tissue digestion. In situ analysis of miner tissues showed higher particle number densities than controls and densities were generally higher in PMF than non-PMF areas. Particle counts were typically dominated by aluminum silicates with varying percentages of silica. Compared to digestion results for the miner tissues, in situ results indicated lower density of particles (number per tissue volume), larger size, and a lower ratio of silica to total silicates-probably due to frequent particle clustering in situ. Automated FESEM-EDS analysis of lung dust is feasible in situ and could be applied to a larger set of mineral dust-exposed lung tissues to investigate specific histologic features of PMF and other dust-related occupational diseases.

Measuring lung diffusing capacity: an opportunity for improved medical surveillance and disability evaluation of coal miners

ObjectivesSpirometry is the primary lung function test utilised for medical surveillance and disability examination for coal mine dust lung disease. However, spirometry likely underestimates physiologic impairment. We sought to characterise...

Analysis of Immune Cell Subsets in Peripheral Blood from Patients with Engineered Stone Silica-Induced Lung Inflammation.

Silicosis caused by engineered stone (ES-silicosis) is an emerging worldwide issue characterized by inflammation and fibrosis in the lungs. To our knowledge, only a few reports have investigated leukocyte/lymphocyte subsets in ES-silicosis patients. The present study was designed to explore the proportions of the main lymphocyte subsets in ES-silicosis patients stratified into two groups, one with simple silicosis (SS) and the other with a more advanced state of the disease, defined as progressive massive fibrosis (PMF). The proportions of B (memory and plasmablasts) cells, T (helper, cytotoxic, regulatory) cells, and natural killer (NK) (regulatory and cytotoxic) cells were investigated by multiparameter flow cytometry in 91 ES-silicosis patients (53 SS patients and 38 PMF patients) and 22 healthy controls (HC). Although the total number of leukocytes did not differ between the groups studied, lymphopenia was observed in patients compared to healthy controls. Compared with those in healthy controls, the proportions of memory B cells, naïve helper T cells, and the CD4+/CD8+ T cells' ratio in the peripheral blood of patients with silicosis were significantly decreased, while the percentages of plasma cells, memory helper T cells, and regulatory T cells were significantly increased. For the NK cell subsets, no significant differences were found between the groups studied. These results revealed altered cellular immune processes in the peripheral blood of patients with ES-silicosis and provided further insight into silicosis pathogenesis.

Influence of Mesh Design and Surface Treatments on Particle Transport and Fate in a Vibration-Enhanced Flooded Bed Dust Scrubber

Respirable coal mine dust (RCMD) is one of the biggest occupational health hazards for underground coal miners. Dusty mining environments can cause long-term health problems, including pneumoconiosis and progressive massive fibrosis. The Mine Safety and Health Administration (MSHA) has recently revised regulations promoting enhanced dust mitigation technologies, which have sparked renewed interest in the development of dust mitigation technologies. The flooded bed dust scrubber (FBS) is one of the most widely used technologies; however, it is limited by technical challenges, the most notable being the potential to clog. Recent studies have shown that applying vibration to filter mesh can improve the overall efficiency of the scrubber and that the system can be readily integrated to existing continuous mining equipment using an energy harvesting approach. In this follow-up study, the impact of mesh design and surface modification on system efficiency was examined using different vibrating liquid-coated stainless-steel mesh panels in a laboratory-scale FBS. Based on the two-way interaction data from a multi-factor experimental design, the results show that the performance of the system can be optimized by using hydrophilic 20- or 30-layer filters and by excitation frequencies between 67 and 134 Hz. This laboratory study suggests that a 20-layer mesh screen with hydrophilic surface applications and optimized vibration parameters can perform similar to that of a 30-layer static mesh, which is typically used in industrial units.

Antifibrotic effect of the P2X7 receptor antagonist A740003 against acute myocardial infarction-induced fibrotic remodelling

Post-acute myocardial infarction (AMI) fibrosis is a pathophysiologic process characterised by activation of the profibrotic mediator, transforming growth factor-β (TGF-β). AMI is associated with a substantial increase in the levels of extracellular adenosine triphosphate (eATP), which acts on the purinergic P2X7-receptor (P2X7-R) and triggers an inflammatory response that contributes to myocardial fibrotic remodelling. P2X7-R has been implicated in several cardiovascular diseases; however, its role in the regulation of cardiac fibrosis remains unclear. Therefore, the current study aimed to determine the effect of the P2X7-R antagonist, A740003, on post-AMI fibrosis, via the profibrotic TGF-β1/Smad signalling pathway, and elucidate whether its effect is mediated via the modulation of GSK-3β. AMI was induced by surgical ligation of the left anterior descending coronary artery, Thereafter, animals were divided into groups: sham control, MI-untreated, MI-vehicle, and MI-A740003 (50 mg/kg/day) and treated for seven days accordingly. The heart weight/body weight ratio of untreated-ligated rats significantly increased by 15.1 %, creatine kinase‐MB (CK‐MB) significantly increased by 40 %, troponin‐I levels significantly increased by 25.4 %, and lactate dehydrogenase significantly increased by 47.2 %, indicating myocardial damage confirmed by morphological changes and massive cardiac fibrosis. The protein expression of cardiac fibronectin, TGF-β1, and p-Smad2 were also upregulated by 143 %, 40 %, and 8 %, respectively, indicating cardiac fibrosis. The treatment of ligated rats with A740003 led to improvement in all the above-mentioned parameters. Overall, A740003 exhibits potential cardio-protective effects on post-AMI fibrotic remodelling in the animal model of AMI through P2X7-R blockade, possibly by downregulating the profibrotic TGF-β1/Smad signalling pathway and restoring GSK-3β phosphorylation. Altogether, treatment with A740003 could serve as a new cardioprotective strategy to attenuate post-AMI fibrotic remodelling.

Immunogenetics of Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disorder characterized by massive fibrosis, vascular damage, and immune imbalance. Advances in rheumatology and immunology over the past two decades have led to a redefinition of systemic sclerosis, shifting from its initial perception as primarily a "hyperfibrotic" state towards a recognition of systemic sclerosis as an immune-mediated disease. Consequently, the search for genetic markers has transitioned from focusing on fibrotic mechanisms to exploring immune regulatory pathways. Immunogenetics, an emerging field at the intersection of immunology, molecular biology, and genetics has provided valuable insights into inherited factors that influence immunity. Data from genetic studies conducted thus far indicate that alterations in genetic messages can significantly impact disease risk and progression. While certain genetic variations may confer protective effects, others may exacerbate disease susceptibility. This paper presents a comprehensive review of the most relevant genetic changes that influence both the risk and course of systemic sclerosis. Special emphasis is placed on factors regulating the immune response, recognizing their pivotal role in the pathogenesis of the disease.

Erasmus syndrome: A rare case report

Erasmus syndrome is a rare clinical entity in which systemic sclerosis develops following exposure to silica with or without development of silicosis. There are very few cases reported in literature from India. Here we report a case of Erasmus syndrome in a 52 years male who is a stone crusher by occupation for last 22 years presented with dry cough, low grade irregular fever, progressive shortness of breath, slowly progressive sclerodactyly and features suggestive of Raynaud’s phenomenon. Radiological evaluations revealed multiple subpleural and centrilobular nodules in bilateral upper, lower lobes and right middle lobe, conglomerated nodular opacities (progressive massive fibrosis- PMF). There was pleural thickening and calcification, bronchial dilatation and fibrosis, calcified right hilar and mediastinal lymphadenopathy. Serological markers like Anti Scl-70 antibody came out to be positive (3+) Based on clinical features diagnosis of systemic sclerosis was made. Based on exposure history and radiology silicosis was diagnosed. Association of silicosis and systemic sclerosis establishes the diagnosis of Erasmus syndrome. Treatment was started with Prednisone, cyclophosphamide and Nifedipine. Strict avoidance to cold and regular follow-up was advised.

Progressive Massive Fibrosis Identified at Federally Funded Black Lung Clinics in the US

This study of US Black Lung Clinics (established to treat coal miners) reports the prevalence of progressive massive fibrosis identified through June 2023.

Silicosis Among Immigrant Engineered Stone (Quartz) Countertop Fabrication Workers in California

Key Points Question What are the characteristics of patients in California with silicosis from occupational exposure to dust from engineered stone (quartz), a popular material that is high in silica content and that is used to fabricate countertops? Findings In this case series of 52 patients, the median age was 45 years at diagnosis, and nearly all were Latino immigrant men. Diagnosis was delayed in 58%, with 38% presenting with advanced disease (progressive massive fibrosis), and 19% died. Meaning In California, silicosis associated with occupational exposure to dust from engineered stone primarily occurred among young Latino immigrant men; many patients presented with severe disease, and some cases were fatal.

Should we rely on frozen section during the reimplantation stage of revision knee arthroplasty?

To compare Frozen Section (FS) results during the reimplantation stage of revision knee arthroplasty, in patients without clinical signs of infection but with preoperative inconclusive serum inflammatory markers. Sections were revisited the day after surgery. Intraoperative FS (iFS) was accepted as positive when the presence of >5 polymorphonuclear neutrophils (PMNLs) in 5 separate high-power fields was determined according to the consensus criteria of the International Consensus on Musculoskeletal Infection. The clinical outcomes, cultures and diagnostic values of iFS and review FS (rFS) were analyzed. No complications developed after reimplantation in 66 (84.6%) of the 78 evaluated patients. Complications developed in 12 patients, six of whom were treated with re-explantation, four with arthrodesis and two with above-the-knee amputation. Both iFS and rFS yielded insignificant sensitivity and specificity (25% and 45.5%, 25% and 45%, respectively). There was no statistically significant difference between definitive culture and iFS and rFS. iFS evaluation is insufficient to exclude recovery from periprosthetic joint infection (PJI). Diagnosis of recurrence of infection in patients with indefinite serum inflammatory markers between the explantation and reimplantation interval remains challenging due to massive fibrosis that makes proper tissue sampling difficult. The attending physician should closely monitor clinical findings.

Silicosis Complicated by Progressive Massive Fibrosis

Silicosis Complicated by Progressive Massive Fibrosis

Abstract 17019: The Missense W792R Mutation in C6 Domain of Cardiac Myosin Binding Protein-C Alters Morphology and Contractility in Mouse Myocardium

Background: Mutations in cardiac myosin binding protein C (cMyBP-C) are a common cause of hypertrophic cardiomyopathy (HCM) in humans. While many known cMyBP-C mutations lead to haploinsufficiency, others lead to amino acid substitutions which may impact protein function in unique ways The W792R mutation introduces a charge change and is known to be pathogenic in humans. This mutation, located remotely from both the regulatory amino terminus, and the C-terminus, has an unknown impact on the final protein structure and function. Goal: Generate a murine knock-in model to fully characterize the impact of the W792R mutation on cardiac morphology and function in vivo. Methods: We generated a W792R knock-in (KI) mouse and produced heterozygous (HT) and homozygous (KI) offspring, and wild-type (WT) littermate controls. We performed histology, RNA and protein expression analyses, and mechanics on isolated trabeculae at postnatal day 12 (KI n=5; HT n=3; and LC n=4). One-way ANOVA used to compare KI and HT to WT samples, with p-values &lt; ; 0.05 as significant. Results: The KI mice did not live past ~20 days old with massive hypertrophy, dilated atrium, myofibrillar disarray and fibrosis. Full-length mutant protein was expressed and incorporated into the sarcomere. Survival and morphology in the HT was similar to WT. Post-natal day 10 KI mice demonstrated severely enlarged atria and ventricles, interstitial fibrosis, a trend towards increased Ca 2+ sensitivity (pCA 50 KI 5.8 vs HT 5.65 vs LC 5.67 mM; p &gt; 0.05), a trend towards increased cross-bridge cycling kinetics (k tr KI 24.00 + 2.42 vs HT 24.33 + 1.08 vs LC 21.25 + 0.87; p &gt; 0.05) and increased levels of β-myosin heavy chain expression compared to both LC and HT mice. Conclusions: In our mouse HCM model, homozygous expression of the W792R-cMyBP-C mutation recapitulates severe human HCM and provides mechanistic insights into the pathology of this mutation. The trend towards accelerated crossbridge kinetics suggest that the W792R mutation disrupts the inhibitory effects of cMyBP-C on myosin-actin binding implicating the potential application of current myosin ATPase inhibitors in the treatment of patients carrying this mutation. Ongoing work will expand sample sizes to evaluate significance of findings.

Pathologic Findings in Severe Coal Workers' Pneumoconiosis in Contemporary US Coal Miners.

The pathology of coal workers' pneumoconiosis (CWP) and its most severe form-progressive massive fibrosis (PMF)-in US coal miners has changed in recent years. Severe disease is occurring in younger miners and has been linked to an increase in silica dust exposure. To update the description of the pathologic features of CWP in contemporary miners compared to historical miners. This study is a retrospective expert classification of lung tissue from 85 historical and contemporary coal miners with PMF. Significant pathologic features were scored by using a standardized instrument with consensus achieved for major findings, including newly defined categories of PMF as coal-type, mixed-type, and silica-type. Pathologic features associated with silica dust exposure, including silica-type PMF, mineral dust alveolar proteinosis (MDAP), and immature (early stage) silicotic nodules, were increased in contemporary miners. Detailed descriptions of the pathology of contemporary CWP with illustrative figures are provided. Silica-related pathologies are more common in contemporary miners. Severe forms of CWP can be detected by subtyping PMF lesions (if present) or by identification of mature and immature silicotic nodules, coal mine dust-related alveolar proteinosis, and severe inflammation in coal miners' lungs. Silica-type PMF cases showed significantly higher levels of MDAP than either mixed- or coal-type PMF (P < .001). High profusion of birefringent silica/silicate particles was observed more frequently in cases with immature (early stage) silicotic nodules (P = .04). Severe inflammation was also significantly increased in contemporary miners (P = .03). Our findings underscore the urgent need to revise current exposure limits and monitoring of respirable crystalline silica in US coal mines.

Erasmus Syndrome: A Rare Case Report of Systemic Sclerosis with Silicosis and Progressive Massive Fibrosis

Erasmus Syndrome is a rare disorder that is characterized by the development of systemic sclerosis after significantly prolonged exposure to silica with or without silicosis. Systemic Sclerosis is a multisystem autoimmune disease with vascular changes, inflammation, and diffuse tissue fibrosis. We report a case of Erasmus syndrome in a 45-year-old male who worked in the marble industry. The patient presented with difficulty in breathing, skin tightening, joint pain, Raynaud’s phenomenon, microstomia, and progressive massive fibrosis. Keywords: Erasmus Syndrome, Systemic Sclerosis, Silicosis, Progressive Massive Fibrosis

Tetrandrine slows the radiographic progression of progressive massive fibrosis in pneumoconiosis: a retrospective cohort study

ObjectiveThis study aims to explore the clinical effect of Tetrandrine (Tet) on progressive massive fibrosis (PMF) of pneumoconiosis.MethodsThis retrospective study collected 344 pneumoconiosis patients with PMF, and 127 were eligible for the final analysis, including 57 patients in the Tet group and 70 patients in the control group. The progress of imaging and lung function were compared between the two groups.ResultsAfter 13 months (median) of treatment, the size of PMF was smaller in the Tet group than that in the control group (1526 vs. 2306, p=0.001), and the size was stable in the Tet group (1568 vs. 1526, p= 0.381), while progressed significantly in the control group (2055 vs. 2306, p=0.000). The small nodule profusion and emphysema were also milder than that in the control group (6.0 vs. 7.5, p=0.046 and 8.0 vs. 12, p=0.016 respectively). Pulmonary ventilation function parameters FVC and FEV1 improved in the Tet group (3222 vs. 3301, p=0.021; 2202 vs. 2259, p=0.025 respectively) and decreased in the control group (3272 vs. 3185, p= 0.00; 2094 vs. 1981, p=0.00 respectively). FEV1/FVC was also significantly higher in the Tet group than that in the control group (68.45vs. 60.74, p=0.001). However, similar result was failed to observed for DLco%, which showed a significant decrease in both groups.ConclusionTet has shown great potential in the treatment of PMF by slowing the progression of pulmonary fibrosis and the decline of lung function.

Effects of direct acting antiviral therapy on liver stiffness measured by using fibro scan in Egyptian patients with chronic hepatitis C.

Aim Egypt has the highest incidence of hepatitis C virus (HCV) infection in the world. Fibrosis development is common in HCV cases, and it is important in disease prediction. The aim of this study was to demonstrate the role of fibro scan in assessment of changes in hepatic stiffness in patients with chronic HCV infection following direct acting antiviral treatment (DAAT). Methods This prospective observational research included 120 patients with compensated HCV infection. All patients were subjected to fibro scan before and after receiving DAAT. Patients' history, clinical examination, laboratory parameters (red - RBCs, and white blood cells - WBCs, hepatic function test, renal function test, coagulation profile, HBsAg, AFP - alpha feto protein, HbA1C, HCVAb) and fibro scan were done for all patients. Results Stiffness may differentiate F0-2 minimal fibrosis from F3-4 massive fibrosis using ROC-curve analysis, with 77.5% sensitivity, 90% specificity, 88.57% positive predictive value (PPV), and 80% negative predictive value (NPV). With sensitivity, specificity, PPV, and NPV of 71.4%, 44.5%, 43.48%, and 71.43%, respectively, the APRI-score can discriminate F0-2 from F3-4 at cutoff of 0.314. At a cutoff of 1.18, Fib4 calculation can discriminate F0-2 from F3-4, with sensitivity, specificity, PPV, and NPV of 78.6%, 64.1%, 63.04%, and 78.57%, respectively. Conclusion Hepatic fibrosis measurements such as fibro scan and non-invasive fibrosis scores (FIB-4) and aspartate aminotransferase (AST) to platelet ratio index (APRI) showed a significant improvement after direct-acting antiviral therapy. Improvements in hepatic function tests, serum creatinine level, and platelet count are also seen.

Silicosis Among Immigrant Engineered Stone (Quartz) Countertop Fabrication Workers in California

Silicosis associated with inhalation of respirable crystalline silica among engineered stone countertop fabrication workers is an emerging health concern. To describe clinical, socioeconomic, and occupational characteristics of patients diagnosed with silicosis associated with engineered stone in California. This case series included reported cases of silicosis associated with fabrication of engineered stone countertops, as identified by statewide surveillance by the California Department of Public Health (2019-2022). Data analysis was performed from October 2022 to March 2023. Patient interviews and medical record abstractions were used to assess occupational exposure to respirable crystalline silica, including duration of work tenure and preventive measures undertaken. Demographics, clinical characteristics, health care utilization, and clinical outcomes were obtained, including vital status, hypoxia, and lung transplant. This case series identified 52 male patients meeting inclusion criteria; median (IQR) age was 45 (40-49) years, and 51 were Latino immigrants. Ten (19%) were uninsured, and 20 (39%) had restricted-scope Medi-Cal; 25 (48%) presented initially to an emergency department. A delay in diagnosis occurred in 30 (58%) patients, most commonly due to alternative initial diagnoses of bacterial pneumonia (9 [30%]) or tuberculosis (8 [27%]). At diagnosis, 20 (38%) patients had advanced disease (progressive massive fibrosis) with severely or very severely reduced forced expiratory volume in 1 second in 8 (18%) and 5 (11%), respectively. Of the cases, 10 (19%) were fatal; median (IQR) age at death was 46 (38-51) years, and 6 patients (12%) were alive with chronic resting hypoxia. Eleven were referred for lung transplant: 3 underwent transplant with 1 fatality; 7 were declined transplant, with 6 fatalities; and 1 died prior to listing. Median (IQR) work tenure was 15 (10-20) years; 23 (45%) reported use of water suppression for dust mitigation, and 25 (48%) continued to fabricate stone after being diagnosed with silicosis. In this case series performed in California, silicosis associated with occupational exposure to dust from engineered stone primarily occurred among young Latino immigrant men. Many patients presented with severe disease, and some cases were fatal.