RARE DISEASE
Asbestos intoxication
Asbestos intoxication
Asbestos intoxication
Synonyms: Asbestosis
Synonyms: Asbestosis
Synonyms: Asbestosis
Drug discovery
0
drugs
With orphan designations
Overview
Asbestos intoxication refers to lung damage from inhaling asbestos fibers, causing inflammation, fibrosis, and irreversible scarring (asbestosis). Clinical features include progressive dyspnea, dry cough, and chest pain, with a latency period of 20–30 years post-exposure [1][3][16]. Complications include respiratory failure, pulmonary hypertension, and increased risk of lung cancer/mesothelioma [16][17]. Diagnosis relies on exposure history, imaging, and pulmonary function tests. Management focuses on symptom relief, slowing progression, and preventing secondary complications [3][8][13].
Burden
Global: ~255,000 annual deaths, with 91% linked to occupational exposure [4][5][14].
U.S.: ~1,300 asbestos-related deaths/year; asbestosis contributes to ~613 annual fatalities [2][7][9].
Economic impact: High costs from chronic care, lost productivity, and disability-adjusted life years (DALYs) [5][14].
Categories: rare respiratory diseases, rare transplant-related disorders
Research Papers
390 drug discovery papers about Asbestos intoxication, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
390 drug discovery papers about Asbestos intoxication, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-10 | CURRENT STATUS OF GLOBAL AEROMICROBIOLOGY STUDIES
Abstract:Climate change when it had commenced due to anthropogenic activities is currently alsoinfluencing cells, propagules, environment aerosol borne, bioaerosol borne dispersal ofmicroorganisms (modes like the annual dust storms, urban and metropolitan suspended dustby vehicle plying on roads, desert storms, volcanic eruptions, silica- asbestosis, cement dustfrom building construction and industries, etc) are the major factors elevating problems likecontact dermatitis, respiratory diseases, allergies, occupational hazards (lung cancers, etc) tohumans and mammals. Thus, aeromicrobiology is concerned with health status andsocioeconomic progress of humans globally. Several species of aspergillus spores cause skinand respiratory tract infection. A. niger and A. fumigatus is the cause of otomycosis due toinfections of outer ear canal. Defeacating in open, dessication, and dispersion of faecalcontaminated soil carry airborne microorganisms (fungi, bacteria, viruses etc.,) far and wide.Tuberculosis, diphtheria, meningitis, pertusis, Streptococcus pneumonia as well as anthrax;Pandemic of Covid-19 and other virus infections spread through air. This is throughbioaerosol - aerosol transition facilitated by moisture, heat, temperature and air currents.Moreover, both natural and unnatural factors alter aeromicrobiology impact on humans. A‘solar aeromicrobiology model’ to purify air at any place have been proposed to eradicate orreducepathogenic and non-pathogenic microorganism (proposed by D.R.Saxena).The rapid Zooplane are "Machzooplane" such as birds, bats, and insects spread all types ofmicroorganisms intracontinentally if they are migratory (also fishes), if not intercontinently.The intracontinental zooplane include above stated animals as well as rodents, reptiles, etc.,that daily move in search of food, mate, etc. The slowest but ecologically significant zooplaneare bugs, ants, soil worms that disseminate the nonpathogenic and pathogenic microorganismsoccurring in air, water as well as soil borne medium.Scavengers also disseminatemicroorganisms (using various media-animal/human microbial cycle as proposed by theauthor) due to their feeding– defaecation and locomotory behaviour.Use of AI fabricated and controlled universal solar aeromicrobiology model also minidomestic models in everyresidence / flat has been hypothesized. The Prions may be a discarded protein particleofafaulty gene that is quiescent and may be accidently switched on. Now such genes maymetabolically synthesize materials such as DNA, RNA, Proteins, etc., in the bodies ofmicroorganisms, invertebrates and vertebrates including humans. This mechanism may be forslow or rapid evolution of self and non self infectious agents( this unwanted DNA, RNA,Proteins that are accidently synthesized and are not degraded and now cause diseases ),theirproduction may be accelerated manifolds triggered by continuous current climate as well asclimate changes in future and that will be the cause of global human deaths.
2026-05-11 | PREVENTIVE DIETARY NUTRITION FOR PATIENTS WITH ASBESTOSIS
This article provides a detailed overview of the basic principles of preventive dietary nutrition, the role of nutrients, and practical recommendations for patients suffering from asbestosis. A proper diet plays a crucial role in combating the progression of the disease. The article examines the role of foods rich in antioxidants, vitamins, minerals, and fiber in protecting lung tissue, based on scientific evidence.
2026-05-01 | B19-04 Pulmonary Osteoclast-like Cells in Asbestos-induced Pulmonary Fibrosis
Abstract Rationale Chrysotile asbestos inhalation drives a progressive fibrotic response in the lung, yet the cellular programs that mediate injury progression remain incompletely defined. Recent work has identified pulmonary osteoclast-like cells (POLCs) as rare, macrophage-derived effector cells that emerge in particulate lung injury and promote matrix remodeling. Whether POLCs are induced by asbestos and contribute to asbestosis pathogenesis has not been established. Here, we combined single-cell transcriptomics with histologic, molecular, and physiologic readouts to define asbestos-induced POLCs and test whether their modulation alters disease severity. Methods C57BL/6J mice received intratracheal instillation of chrysotile asbestos, and replicate whole lungs were collected at follow-up timepoints from Day 0 (control) to Day 56 post-instillation. Pulmonary function testing, lung histology, and qPCR for osteoclast-associated genes were performed in parallel. Whole-lung single-nucleus RNA sequencing was used to model longitudinal transcriptional dynamics across the injury time course. In a separate cohort, whole-lung single-cell RNA sequencing was performed to characterize cell-specific responses to treatment with zoledronic acid, a bisphosphonate that inhibits osteoclast activity. Monocle3 supported dimensionality reduction, cell state annotation, pathway analysis, and pseudotime modeling, and a beta-binomial model quantified relative changes in cell type proportions. Results Asbestos exposure results in a progressive decline in pulmonary function and produces histologic evidence of early inflammatory infiltration and fibrotic deposition by Day 28. scRNA-seq identifies more than 30 lung cell states, with strong early expansion of myeloid populations. Alveolar macrophages show increased expression of canonical osteoclast-associated genes, including Acp5, Ctsk, and Atp6v0d2, which rise sharply by Day 7 and persist through later timepoints. qPCR confirms upregulation of osteoclast-related transcripts, acquisition of capacity for bone pitting and protein staining for TRAP5b and CTSK demonstrates robust induction of osteoclast programs. TRAP+ multinucleated cells are significantly increased in BALF from asbestos-exposed mice. Pseudotime analyses indicate differentiation of POLCs along a trajectory marked by acquisition of bone-resorption, matrix-remodeling, and catabolic signatures. Intraperitoneal (i.p.) treatment with the bisphosphonate, zoledronic acid, reduced POLC abundance, and attenuated parenchymal fibrosis due to asbestos based on multiple gene expression, histologic, and physiologic measures relative to i.p. vehicle control, supporting a functional role for POLCs in disease progression. Conclusions Chrysotile asbestos induces the emergence of pulmonary osteoclast-like cells that arise from macrophage lineages and display robust osteoclast gene programs. Pharmacologic inhibition of POLCs reduces lung fibrosis, identifying POLCs as a potential therapeutic target in asbestosis. This abstract is funded by: I01 BX005128-01a (VA Merit)
2026-05-01 | REVIEW OF CURRENT AND EMERGING ANTIFIBROTIC THERAPY FOR ASBESTOSIS AND SILICOSIS
Asbestosis and silicosis are progressive occupational lung diseases driven by asbestos fiber and respirable crystalline silica inhalation, resulting in chronic inflammation and irreversible pulmonary fibrosis. While prevention and early diagnosis remain paramount due to the lack of curative options, current supportive therapies offer limited efficacy. This review examines their pathogenesis, immune mechanisms, and management strategies, with emphasis on antifibrotic agents like pirfenidone and nintedanib, alongside emerging therapies such as PDE4B inhibitors (e.g., nerandomilast) and stem cell approaches. Recent clinical data suggest slowed fibrosis progression, but occupational-specific RCTs are needed to optimize safety, efficacy, and biomarkers in high-risk cohorts like construction workers.
2025-10-01 | 8286874 Impact of interventions to prevent asbestos-related respiratory disease in an exposed worker registry using a simplified G-computation
The Ontario Asbestos Workers Registry is a regulatory exposure registry obligating employers to report the number of work hours with asbestos containing materials for each of their workers. Currently, each worker is notified of the need for a medical examination once they have accrued 2,000 reported hours of work with asbestos. However, recent research showed a substantial excess of asbestos-related respiratory disease among workers in the registry indicating that the notification policy requires revision. We sought to evaluate the impact on disease prevention of alternative policies limiting asbestos work hours among registry participants using a novel application of parametric G-computation we term ‘G-POSH’. A cohort of 26,164 asbestos registry workers were followed for cancer and non-malignant disease diagnoses in Ontario from 1986 through 2019. G-POSH was used to estimate decreases in disease risk under five hypothetical exposure reduction interventions. Inverse probability of censoring weighting was used to adjust for time-varying confounding due to healthy worker survivor bias. Standard Poisson regression analyses of the association between cumulative asbestos work hours and respiratory disease incidence rates showed substantially elevated rates well before reaching 2,000 asbestos work hours. Using G-POSH, limiting cumulative asbestos work hours to 100 hours would have reduced the risk of asbestosis by half (Risk Ratio, RR: 0.52, 95% CI 0.43-0.63) and lung cancer by 15% (RR: 0.85, 95% CI 0.78-0.92) compared to the observed natural course in the cohort. Limiting exposure to 2,000 asbestos work hours had a smaller but still substantial impact on prevention of asbestosis (RR 0.77, 95% CI: 0.70-0.86). Inverse probability weighted estimates showed a minor influence of healthy worker bias. G-POSH is a simplified tool for estimating intervention effects in occupational cohorts. Regulatory agencies should intervene sooner to prevent respiratory disease among workers in the registry.
proteins
2026-02-19 | Asbestos Disease Initiation.
A model is developed of disease initiation and progression for asbestos related plaque deposition and mesothelioma based on prior models of wound healing and asbestos transport. The model includes short term processes such as macrophage polarization and immune system response, extending the time frame to that of detectable disease. Model results were in a biologically reasonable range. Cancer development and plaque deposition are shown to be dependent on total exposure (intensity * duration). Plaque deposition was sensitive to many systemic parameters, suggesting that assays could be developed to identify individuals with higher risk. Tumor development was sensitive only to a few parameters describing exposure and T-cell levels, indicating potential for immune system intervention.
1999-08-01 | Role of Transcription Factor NF-κB in Asbestos-Induced TNFα Response from Macrophages
Asbestos exposure in humans is associated with inflammatory, fibrotic, and malignant diseases in the lung. Increasing evidence supports the hypothesis that the production of proinflammatory cytokines such as tumor necrosis factor-α (TNFα) is an important mediator of the pathologic responses of asbestosis. In this study, we examine the role of nuclear transcription factor-κB (NF-κB) and free oxygen radicals in asbestos-induced TNFα gene and protein expression in lung macrophages. Exposure of the cells to crocidolite asbestos caused a parallel increase in TNFα production and NF-κB activation, as analyzed by enzyme-linked immunosorbent assay and electrophoretic mobility shift assay. Inhibition of NF-κB by SN50, an inhibitor of NF-κB nuclear translocation, or by sequence-specific oligonucleotides directed against the NF-κB binding site of TNFα promoter attenuated the asbestos effect on TNFα production. Gene transfection assays using an expression plasmid containing a luciferase reporter gene and a TNFα-derived NF-κB gene promoter further indicated the dependence of NF-κB activation on asbestos-induced gene expression. The effects of asbestos on NF-κB and TNFα activation were inhibited by oxygen radical scavengers and were enhanced by antioxidant enzyme inhibitors. These results indicate that asbestos-induced TNFα gene expression is mediated through a process that involves NF-κB activation and free radical reactions.
1993-09-01 | Asbestos directly increases lung epithelial permeability
Asbestos causes the fibrotic lung disease asbestosis, but the biologic basis for this is unknown. Lung epithelial dysfunction including increased permeability is hypothesized to contribute to lung scarring in other forms of pulmonary fibrosis. Lung epithelial permeability is increased in both animals and humans exposed to asbestos. It is not known whether the increased epithelial permeability results from direct effects of asbestos or occurs as a result of the inflammatory reaction to asbestos fibers. To address this question we used a cultured human lung epithelial model, and we measured the direct effect of asbestos on lung epithelial barrier integrity as measured by mannitol permeability. We exposed the monolayer to chryogenically ground, respirable-sized chrysotile asbestos particles. This chrysotile asbestos caused a dose- and time-dependent increase in mannitol permeability across the epithelial monolayer. Increased mannitol permeability occurred both in the presence and in the absence of serum, was not due to cytotoxicity as measured by lactate dehydrogenase release, and was not associated with altered actin cytoskeleton at the light microscopic level. Permeability to 70 kDa neutral dextran also increased after asbestos exposure; however, the absolute permeability to dextran was less than mannitol permeability. Neither latex beads nor tantalum caused any change in permeability, suggesting that our findings are not explained by nonspecific effects of particles. Increased permeability did not reverse in the continued presence of asbestos and persisted even after removing the asbestos. Finally, surface-bound iron did not appear to be necessary for this effect because neither chelating iron with deferoxamine nor iron-loading the asbestos altered the effect on mannitol permeability. These results show that asbestos has direct effects on lung epithelial permeability. Together with the recent observation that asbestos directly increases epithelial fibrinolytic activity, our results suggest a novel mechanism for asbestos-induced lung injury.
1992-12-01 | New perspectives on basic mechanisms in lung disease. 1. Lung injury, inflammatory mediators, and fibroblast activation in fibrosing alveolitis.
It is over 25 years since Scadding first defined the term fibrosing alveolitis. It has since been established that complex mechanisms underlie its pathogenesis, including epithelial and endothelial injury, vascular leakage, production of inflammatory cells and their mediators, and fibroblast activation. Only through a detailed knowledge of how these cellular and molecular events are interlinked will we learn how to combat this disease, which is notoriously resistant to present treatments. So far the only therapeutic advances have been refinements in immunosuppression, and even these treatments are frequently disappointing. We believe that future advances in treatment will come from the development of agents that protect endothelial and epithelial cells from further injury and agents that can inhibit release of inflammatory mediators. A better knowledge of the mechanisms of collagen gene activation and the biochemical pathways of collagen production may also allow the identification of vulnerable sites at which new treatments may be directed. A combined approach to modifying appropriate parts of both the inflammatory component and the fibroblast/collagen component should provide a new stimulus to research. Further epidemiological studies are also needed to identify the environmental causes of lung injury that initiate the cascade of events leading to interstitial fibrosis.
1989-04-01 | Asbestos and Cancer: Human Natural Killer Cell Activity is Suppressed by Asbestos Fibers but Can Be Restored by Recombinant lnterleukin-2
Inhalation of asbestos fibers is associated with a marked increase in the risk of developing pulmonary malignancy, particularly bronchogenic carcinoma. As natural killer (NK) cells are specialized lymphocytes that are considered to have an important in vivo role in the recognition and destruction of malignant cells, we examined the capacity of asbestos fibers (chrysotile, amosite, and crocidolite) to interfere with the NK activity of nylon wool-nonadherent, human blood lymphocytes (51Cr-release assay, K562 target cells, 14 h effector-to-target ratio = 50:1). Final asbestos concentrations used were 1 to 1,000 micrograms/ml. None of the fibers altered spontaneous target cell lysis or lymphocyte viability. All types of asbestos suppressed NK activity in a dose-dependent fashion. This effect was most marked with chrysotile, which exerted a profound inhibitory effect on blood NK cell activity; at 100 micrograms/ml, NK activity was inhibited 84 +/- 2% (p less than 0.001). The suppressive effects of asbestos were exerted directly on the NK cells (large granular lymphocytes, 91 +/- 2% inhibition at 100 micrograms/ml; p less than 0.001). Exposure of lymphocytes to recombinant interleukin-2 (IL-2, 150 units/ml) for 24 h prior to exposure to asbestos restored the level of activity to 99 +/- 6% of the original value (p less than 0.001), and lung lymphocytes that were exposed to IL-2 in vivo (active sarcoidosis) were resistant to suppression by asbestos. Similar results were observed in a group of patients with asbestosis. This suppression of NK activity may contribute to the increased susceptibility of asbestos-exposed persons to the development of pulmonary malignancy.
antibodies
2025-09-27 | Pulmonary Osteoclast-Like Cells Contribute to Asbestos-Induced Pulmonary Fibrosis
Rationale: Asbestos exposure causes pulmonary fibrosis, but mechanisms remain unclear and no effective therapy exists. We recently reported that osteoclast-like transformation of pulmonary myeloid cells occurs in pulmonary alveolar microlithiasis and silicosis, producing acid and proteolytic enzymes that harm lung tissue. Here, we investigated whether asbestos drives a similar pathological process. Methods: Chrysotile or crocidolite fibers were delivered intratracheally to C57BL/6 mice. Lung sections from mice and asbestosis patients were analyzed. RANKL levels in BAL cells, alveolar macrophages, and type II pneumocytes were measured by ELISA. Results: TRAP and CTSK positive osteoclast-like multinucleated giant cells (OLMNGC) are present in the lungs of human asbestosis patients. Pulmonary fibrosis in the asbestos-challenged mouse lung is accompanied by the osteoclastic transformation of pulmonary myeloid cells, as assessed by histology, immunohistochemistry, and gene expression profiles. Asbestos-induced OLMNGC are embedded in fibrotic parenchymal lesions and comprise approximately 5% of BAL cells, which when plated on bone slices confer the capacity to pit the bone surface and release collagen 1 (CTX-1) fragments into the media. Asbestos exposure induces RANKL expression in BAL cells. Conclusion: Asbestos induces osteoclast-like transformation of pulmonary myeloid cells or recruits osteoclast precursors, resulting in sustained production of matrix-degrading enzymes and acid. These cells fail to degrade tough asbestos fibers, causing collateral lung damage and progressive fibrosis. Targeting such osteoclast-like cells could mitigate lung scarring in asbestos-exposed individuals.
2019-01-03 | Epithelial to Mesenchymal Transition in Human Mesothelial Cells Exposed to Asbestos Fibers: Role of TGF-β as Mediator of Malignant Mesothelioma Development or Metastasis via EMT Event
Asbestos exposure increases the risk of asbestosis and malignant mesothelioma (MM). Both fibrosis and cancer have been correlated with the Epithelial to Mesenchymal Transition (EMT)—an event involved in fibrotic development and cancer progression. During EMT, epithelial cells acquire a mesenchymal phenotype by modulating some proteins. Different factors can induce EMT, but Transforming Growth Factor β (TGF-β) plays a crucial role in promoting EMT. In this work, we verified if EMT could be associated with MM development. We explored EMT in human mesothelial cells (MeT-5A) exposed to chrysotile asbestos: we demonstrated that asbestos induces EMT in MeT-5A cells by downregulating epithelial markers E-cadherin, β-catenin, and occludin, and contemporarily, by upregulating mesenchymal markers fibronectin, α-SMA, and vimentin, thus promoting EMT. In these cells, this mechanism is mediated by increased TGF-β secretion, which in turn downregulates E-cadherin and increases fibronectin. These events are reverted in the presence of TGF-β antibody, via a Small Mother Against Decapentaplegic (SMAD)-dependent pathway and its downstream effectors, such as Zinc finger protein SNAI1 (SNAIL-1), Twist-related protein (Twist), and Zinc Finger E-Box Binding Homeobox 1 (ZEB-1), which downregulate the E-cadherin gene. Since SNAIL-1, Twist, and ZEB-1 have been shown to be overexpressed in MM, these genes could be considered possible predictive or diagnostic markers of MM development.
2018-01-24 | Therapeutic potential of targeting S100A11 in malignant pleural mesothelioma
Abstract Malignant pleural mesothelioma (MPM) is an aggressive tumor with an unfavorable prognosis. The standard therapeutic approaches are limited to surgery, chemotherapy, and radiotherapy. Because the consequent clinical outcome is often unsatisfactory, a different approach in MPM treatment is required. S100A11, a Ca 2+ -binding small protein with two EF-hands, is frequently upregulated in various human cancers. Interestingly, it has been found that intracellular and extracellular S100A11 have different functions in cell viability. In this study, we focused on the impact of extracellular S100A11 in MPM and explored the therapeutic potential of an S100A11-targeting strategy. We examined the secretion level of S100A11 in various kinds of cell lines by enzyme-linked immunosorbent assay. Among them, six out of seven MPM cell lines actively secreted S100A11, whereas normal mesothelial cell lines did not secrete it. To investigate the role of secreted S100A11 in MPM, we inhibited its function by neutralizing S100A11 with an anti-S100A11 antibody. Interestingly, the antibody significantly inhibited the proliferation of S100A11-secreting MPM cells in vitro and in vivo. Microarray analysis revealed that several pathways including genes involved in cell proliferation were negatively enriched in the antibody-treated cell lines. In addition, we examined the secretion level of S100A11 in various types of pleural effusions. We found that the secretion of S100A11 was significantly higher in MPM pleural effusions, compared to others, suggesting the possibility for the use of S100A11 as a biomarker. In conclusion, our results indicate that extracellular S100A11 plays important roles in MPM and may be a therapeutic target in S100A11-secreting MPM.
2017-03-20 | Pleural mesothelioma in household members of asbestos-exposed workers in Friuli Venezia Giulia, Italy
Objectives: Malignant mesothelioma is closely associated to asbestos exposure.One such exposure may occur through contact with occupationally exposed household members and their belongings.This study examines the features of pleural mesothelioma attributable only to asbestos brought home by another family member.Material and Methods: The data sources were 1063 mesothelioma cases diagnosed between 1995 and 2014, from the Friuli Venezia Giulia Mesothelioma Register.In all cases the diagnosis of mesothelioma was based on the pathology report.Exposure information and demographic data were acquired by an occupational medical standardized questionnaire/interview. Results: Household-exposure mesothelioma cases included 33 women and 2 men.Relationships were: wives (N = 22), daughters (N = 9), sons (N = 2), and mothers (N = 2).Asbestos exposure in the workers predominantly occurred in shipyards.Out of the 35 pleural cases, 19 were epithelial, 9 biphasic, 3 sarcomatoid, and 4 not specified.The mean age at diagnosis was 77 years old.The mean latency was 59 years, with wives having a significant shorter latency than offspring.Latency was not significantly related to morphology and asbestosis.The overall mean survival was 16 months (median 11 months) but treatment was beneficial (mean 16 months vs. 7 months).Biphasic/sarcomatoid histology and presence of asbestosis were associated with a decreased survival, although not with statistical significance.Conclusions: Our data confirms that household exposure increases the risk for pleural mesothelioma amongst women with no history of occupational asbestos exposure.This is an ongoing problem in many countries, as well as in Italy, where the evaluation of a framework for the compensation of these cases is under debate.
2016-06-22 | [Asbestos and respiratory diseases].
Previous occupational asbestos exposure (more rarely environmental or domestic exposure) may induce various pleural and/or pulmonary, benign or malignant diseases, sometimes with a very long latency for malignant mesothelioma (MM). Asbestos has been widely extracted and used in Western countries and in emerging or developing countries, resulting in a peak of MM incidence in France around 2020 and likely in a world pandemic of asbestos-induced diseases. These patients have mostly benign respiratory diseases (pleural plugs) but may also be diagnosed with lung cancer or malignant pleural mesothelioma, and have a global poor outcome. New therapeutic tools (targeted therapies, immunotherapy…) with first promising results are developed. However, it is crucial to obtain a full ban of asbestos use worldwide, and to do a regular follow-up of asbestos-exposed subjects, mostly if they are already diagnosed with benign respiratory diseases. Finally, new cancers (larynx and ovary) were recently added to the list of asbestos-induced tumors.
gene therapies
2025-05-01 | System Resolution of Spp1+ Macrophage Heterogeneities Identifies Disease-potentiating Crosstalk Between Macrophage and Alveolar Epithelium in Pulmonary Fibrosis
Abstract RATIONALE. Macrophages regulate the development of fibrosis. Multiple scRNAseq studies of fibrotic diseases have identified a pro-fibrotic osteopontin (SPP1)-expressing macrophage population, but the functional heterogeneity of this population and their role in different disease contexts remains poorly defined. Additionally, the effects of various therapeutic interventions on the Spp1+ macrophages are not yet understood. METHODS. We performed a meta-analysis of Spp1+ macrophages from scRNAseq of murine fibrotic models across tissues (heart, kidney, and lungs), encompassing 16 datasets and 112,014 macrophage cells. For pulmonary fibrosis, we evaluated distinct injury models, including bleomycin, silica, asbestosis, and radiation, characterizing the functional heterogeneity of the Spp1+ macrophages throughout disease progression. In the lungs, we identified novel interactions between this population and the alveolar epithelial cells, further validated by in vitro studies. Finally, we posited this work as a scRNA-seq atlas to explore the effect of different anti-fibrotic interventions on the Spp1+ macrophage, achieved through the integration of external single cell datasets to the atlas via reference-based methods. RESULTS. We uncovered two functionally distinct Spp1+ macrophages (Spp1+ Arg1+ Fn1+ and Spp1+ Cd36+ Mmp12+). In silico, both populations are ECM-remodeling, with one being metabolically driven (Cd36+ Mmp12+) and the other secretory (Arg1+ Fn1+). Cd36+ Mmp12+ appears later in the injury response, while Arg1+ Fn1+ peaks early and mediates pathological intercellular crosstalk. Development trajectory analysis suggests Cd36+ Mmp12+ may arise from the Arg1+ Fn1+ macrophages. In the lungs, Arg1+ Fn1+ secretion of fibronectin may disrupt the trans-differentiation of AT2 to AT1 cells by potentiating the Krt8+ intermediate cell state, thereby impairing alveolar re-epithelization. Late-stage Spp1 cytokine secretion by Cd36+ Mmp12+ further augments the epithelial-mesenchymal transition of AT2 cells, leading to irreversible ECM deposition. Using the Spp1+ macrophage atlas, we examined the effects of Nintedanib and Ccr2 by integrating scRNAseq data from the lungs of mice with Ccr2-KO and post-Nintedanib treatment. While Nintedanib did not affect the Spp1+ populations, Ccr2-KO selectively depleted the Arg1+ Fn1+ subtype and its associated crosstalk with the AT2 cells. CONCLUSION. This study highlights previously unappreciated functional diversity within the Spp1+ macrophage population and disease-potentiating crosstalk between macrophage and epithelial cells in pulmonary fibrosis. We further provide a platform to investigate how distinct pro-fibrotic factors may influence this diverse population.
2021-04-22 | Role of CCR2+ Myeloid Cells in Inflammation Responses Driven by Expression of a Surfactant Protein-C Mutant in the Alveolar Epithelium
Acute inflammatory exacerbations (AIE) represent precipitous deteriorations of a number of chronic lung conditions, including pulmonary fibrosis (PF), chronic obstructive pulmonary disease and asthma. AIEs are marked by diffuse and persistent polycellular alveolitis that profoundly accelerate lung function decline and mortality. In particular, excess monocyte mobilization during AIE and their persistence in the lung have been linked to poor disease outcome. The etiology of AIEs remains quite uncertain, but environmental exposure and genetic predisposition/mutations have been identified as two contributing factors. Guided by clinical evidence, we have developed a mutant model of pulmonary fibrosis leveraging the PF-linked missense isoleucine to threonine substitution at position 73 [I73T] in the alveolar type-2 cell-restricted Surfactant Protein-C [SP-C] gene [ SFTPC ]. With this toolbox at hand, the present work investigates the role of peripheral monocytes during the initiation and progression of AIE-PF. Genetic ablation of CCR2 + monocytes (SP-C I73T CCR2 KO ) resulted in improved lung histology, mouse survival, and reduced inflammation compared to SP-C I73T CCR2 WT cohorts. FACS analysis of CD11b + CD64 - Ly6C hi monocytes isolated 3 d and 14 d after SP-C I73T induced injury reveals dynamic transcriptional changes associated with “Innate Immunity’ and ‘Extracellular Matrix Organization’ signaling. While immunohistochemical and in situ hybridization analysis revealed comparable levels of tgfb1 mRNA expression localized primarily in parenchymal cells found nearby foci of injury we found reduced effector cell activation (C1q, iNOS, Arg1) in SP-C I73T CCR2 KO lungs as well as partial colocalization of tgfb1 mRNA expression in Arg1 + cells. These results provide a detailed picture of the role of resident macrophages and recruited monocytes in the context of AIE-PF driven by alveolar epithelial dysfunction.
small molecules
2026-06-10 | CURRENT STATUS OF GLOBAL AEROMICROBIOLOGY STUDIES
Abstract:Climate change when it had commenced due to anthropogenic activities is currently alsoinfluencing cells, propagules, environment aerosol borne, bioaerosol borne dispersal ofmicroorganisms (modes like the annual dust storms, urban and metropolitan suspended dustby vehicle plying on roads, desert storms, volcanic eruptions, silica- asbestosis, cement dustfrom building construction and industries, etc) are the major factors elevating problems likecontact dermatitis, respiratory diseases, allergies, occupational hazards (lung cancers, etc) tohumans and mammals. Thus, aeromicrobiology is concerned with health status andsocioeconomic progress of humans globally. Several species of aspergillus spores cause skinand respiratory tract infection. A. niger and A. fumigatus is the cause of otomycosis due toinfections of outer ear canal. Defeacating in open, dessication, and dispersion of faecalcontaminated soil carry airborne microorganisms (fungi, bacteria, viruses etc.,) far and wide.Tuberculosis, diphtheria, meningitis, pertusis, Streptococcus pneumonia as well as anthrax;Pandemic of Covid-19 and other virus infections spread through air. This is throughbioaerosol - aerosol transition facilitated by moisture, heat, temperature and air currents.Moreover, both natural and unnatural factors alter aeromicrobiology impact on humans. A‘solar aeromicrobiology model’ to purify air at any place have been proposed to eradicate orreducepathogenic and non-pathogenic microorganism (proposed by D.R.Saxena).The rapid Zooplane are "Machzooplane" such as birds, bats, and insects spread all types ofmicroorganisms intracontinentally if they are migratory (also fishes), if not intercontinently.The intracontinental zooplane include above stated animals as well as rodents, reptiles, etc.,that daily move in search of food, mate, etc. The slowest but ecologically significant zooplaneare bugs, ants, soil worms that disseminate the nonpathogenic and pathogenic microorganismsoccurring in air, water as well as soil borne medium.Scavengers also disseminatemicroorganisms (using various media-animal/human microbial cycle as proposed by theauthor) due to their feeding– defaecation and locomotory behaviour.Use of AI fabricated and controlled universal solar aeromicrobiology model also minidomestic models in everyresidence / flat has been hypothesized. The Prions may be a discarded protein particleofafaulty gene that is quiescent and may be accidently switched on. Now such genes maymetabolically synthesize materials such as DNA, RNA, Proteins, etc., in the bodies ofmicroorganisms, invertebrates and vertebrates including humans. This mechanism may be forslow or rapid evolution of self and non self infectious agents( this unwanted DNA, RNA,Proteins that are accidently synthesized and are not degraded and now cause diseases ),theirproduction may be accelerated manifolds triggered by continuous current climate as well asclimate changes in future and that will be the cause of global human deaths.
2026-05-11 | PREVENTIVE DIETARY NUTRITION FOR PATIENTS WITH ASBESTOSIS
This article provides a detailed overview of the basic principles of preventive dietary nutrition, the role of nutrients, and practical recommendations for patients suffering from asbestosis. A proper diet plays a crucial role in combating the progression of the disease. The article examines the role of foods rich in antioxidants, vitamins, minerals, and fiber in protecting lung tissue, based on scientific evidence.
2026-05-01 | B19-04 Pulmonary Osteoclast-like Cells in Asbestos-induced Pulmonary Fibrosis
Abstract Rationale Chrysotile asbestos inhalation drives a progressive fibrotic response in the lung, yet the cellular programs that mediate injury progression remain incompletely defined. Recent work has identified pulmonary osteoclast-like cells (POLCs) as rare, macrophage-derived effector cells that emerge in particulate lung injury and promote matrix remodeling. Whether POLCs are induced by asbestos and contribute to asbestosis pathogenesis has not been established. Here, we combined single-cell transcriptomics with histologic, molecular, and physiologic readouts to define asbestos-induced POLCs and test whether their modulation alters disease severity. Methods C57BL/6J mice received intratracheal instillation of chrysotile asbestos, and replicate whole lungs were collected at follow-up timepoints from Day 0 (control) to Day 56 post-instillation. Pulmonary function testing, lung histology, and qPCR for osteoclast-associated genes were performed in parallel. Whole-lung single-nucleus RNA sequencing was used to model longitudinal transcriptional dynamics across the injury time course. In a separate cohort, whole-lung single-cell RNA sequencing was performed to characterize cell-specific responses to treatment with zoledronic acid, a bisphosphonate that inhibits osteoclast activity. Monocle3 supported dimensionality reduction, cell state annotation, pathway analysis, and pseudotime modeling, and a beta-binomial model quantified relative changes in cell type proportions. Results Asbestos exposure results in a progressive decline in pulmonary function and produces histologic evidence of early inflammatory infiltration and fibrotic deposition by Day 28. scRNA-seq identifies more than 30 lung cell states, with strong early expansion of myeloid populations. Alveolar macrophages show increased expression of canonical osteoclast-associated genes, including Acp5, Ctsk, and Atp6v0d2, which rise sharply by Day 7 and persist through later timepoints. qPCR confirms upregulation of osteoclast-related transcripts, acquisition of capacity for bone pitting and protein staining for TRAP5b and CTSK demonstrates robust induction of osteoclast programs. TRAP+ multinucleated cells are significantly increased in BALF from asbestos-exposed mice. Pseudotime analyses indicate differentiation of POLCs along a trajectory marked by acquisition of bone-resorption, matrix-remodeling, and catabolic signatures. Intraperitoneal (i.p.) treatment with the bisphosphonate, zoledronic acid, reduced POLC abundance, and attenuated parenchymal fibrosis due to asbestos based on multiple gene expression, histologic, and physiologic measures relative to i.p. vehicle control, supporting a functional role for POLCs in disease progression. Conclusions Chrysotile asbestos induces the emergence of pulmonary osteoclast-like cells that arise from macrophage lineages and display robust osteoclast gene programs. Pharmacologic inhibition of POLCs reduces lung fibrosis, identifying POLCs as a potential therapeutic target in asbestosis. This abstract is funded by: I01 BX005128-01a (VA Merit)
2026-05-01 | REVIEW OF CURRENT AND EMERGING ANTIFIBROTIC THERAPY FOR ASBESTOSIS AND SILICOSIS
Asbestosis and silicosis are progressive occupational lung diseases driven by asbestos fiber and respirable crystalline silica inhalation, resulting in chronic inflammation and irreversible pulmonary fibrosis. While prevention and early diagnosis remain paramount due to the lack of curative options, current supportive therapies offer limited efficacy. This review examines their pathogenesis, immune mechanisms, and management strategies, with emphasis on antifibrotic agents like pirfenidone and nintedanib, alongside emerging therapies such as PDE4B inhibitors (e.g., nerandomilast) and stem cell approaches. Recent clinical data suggest slowed fibrosis progression, but occupational-specific RCTs are needed to optimize safety, efficacy, and biomarkers in high-risk cohorts like construction workers.
2025-10-01 | 8286874 Impact of interventions to prevent asbestos-related respiratory disease in an exposed worker registry using a simplified G-computation
The Ontario Asbestos Workers Registry is a regulatory exposure registry obligating employers to report the number of work hours with asbestos containing materials for each of their workers. Currently, each worker is notified of the need for a medical examination once they have accrued 2,000 reported hours of work with asbestos. However, recent research showed a substantial excess of asbestos-related respiratory disease among workers in the registry indicating that the notification policy requires revision. We sought to evaluate the impact on disease prevention of alternative policies limiting asbestos work hours among registry participants using a novel application of parametric G-computation we term ‘G-POSH’. A cohort of 26,164 asbestos registry workers were followed for cancer and non-malignant disease diagnoses in Ontario from 1986 through 2019. G-POSH was used to estimate decreases in disease risk under five hypothetical exposure reduction interventions. Inverse probability of censoring weighting was used to adjust for time-varying confounding due to healthy worker survivor bias. Standard Poisson regression analyses of the association between cumulative asbestos work hours and respiratory disease incidence rates showed substantially elevated rates well before reaching 2,000 asbestos work hours. Using G-POSH, limiting cumulative asbestos work hours to 100 hours would have reduced the risk of asbestosis by half (Risk Ratio, RR: 0.52, 95% CI 0.43-0.63) and lung cancer by 15% (RR: 0.85, 95% CI 0.78-0.92) compared to the observed natural course in the cohort. Limiting exposure to 2,000 asbestos work hours had a smaller but still substantial impact on prevention of asbestosis (RR 0.77, 95% CI: 0.70-0.86). Inverse probability weighted estimates showed a minor influence of healthy worker bias. G-POSH is a simplified tool for estimating intervention effects in occupational cohorts. Regulatory agencies should intervene sooner to prevent respiratory disease among workers in the registry.
proteins
2026-02-19 | Asbestos Disease Initiation.
A model is developed of disease initiation and progression for asbestos related plaque deposition and mesothelioma based on prior models of wound healing and asbestos transport. The model includes short term processes such as macrophage polarization and immune system response, extending the time frame to that of detectable disease. Model results were in a biologically reasonable range. Cancer development and plaque deposition are shown to be dependent on total exposure (intensity * duration). Plaque deposition was sensitive to many systemic parameters, suggesting that assays could be developed to identify individuals with higher risk. Tumor development was sensitive only to a few parameters describing exposure and T-cell levels, indicating potential for immune system intervention.
1999-08-01 | Role of Transcription Factor NF-κB in Asbestos-Induced TNFα Response from Macrophages
Asbestos exposure in humans is associated with inflammatory, fibrotic, and malignant diseases in the lung. Increasing evidence supports the hypothesis that the production of proinflammatory cytokines such as tumor necrosis factor-α (TNFα) is an important mediator of the pathologic responses of asbestosis. In this study, we examine the role of nuclear transcription factor-κB (NF-κB) and free oxygen radicals in asbestos-induced TNFα gene and protein expression in lung macrophages. Exposure of the cells to crocidolite asbestos caused a parallel increase in TNFα production and NF-κB activation, as analyzed by enzyme-linked immunosorbent assay and electrophoretic mobility shift assay. Inhibition of NF-κB by SN50, an inhibitor of NF-κB nuclear translocation, or by sequence-specific oligonucleotides directed against the NF-κB binding site of TNFα promoter attenuated the asbestos effect on TNFα production. Gene transfection assays using an expression plasmid containing a luciferase reporter gene and a TNFα-derived NF-κB gene promoter further indicated the dependence of NF-κB activation on asbestos-induced gene expression. The effects of asbestos on NF-κB and TNFα activation were inhibited by oxygen radical scavengers and were enhanced by antioxidant enzyme inhibitors. These results indicate that asbestos-induced TNFα gene expression is mediated through a process that involves NF-κB activation and free radical reactions.
1993-09-01 | Asbestos directly increases lung epithelial permeability
Asbestos causes the fibrotic lung disease asbestosis, but the biologic basis for this is unknown. Lung epithelial dysfunction including increased permeability is hypothesized to contribute to lung scarring in other forms of pulmonary fibrosis. Lung epithelial permeability is increased in both animals and humans exposed to asbestos. It is not known whether the increased epithelial permeability results from direct effects of asbestos or occurs as a result of the inflammatory reaction to asbestos fibers. To address this question we used a cultured human lung epithelial model, and we measured the direct effect of asbestos on lung epithelial barrier integrity as measured by mannitol permeability. We exposed the monolayer to chryogenically ground, respirable-sized chrysotile asbestos particles. This chrysotile asbestos caused a dose- and time-dependent increase in mannitol permeability across the epithelial monolayer. Increased mannitol permeability occurred both in the presence and in the absence of serum, was not due to cytotoxicity as measured by lactate dehydrogenase release, and was not associated with altered actin cytoskeleton at the light microscopic level. Permeability to 70 kDa neutral dextran also increased after asbestos exposure; however, the absolute permeability to dextran was less than mannitol permeability. Neither latex beads nor tantalum caused any change in permeability, suggesting that our findings are not explained by nonspecific effects of particles. Increased permeability did not reverse in the continued presence of asbestos and persisted even after removing the asbestos. Finally, surface-bound iron did not appear to be necessary for this effect because neither chelating iron with deferoxamine nor iron-loading the asbestos altered the effect on mannitol permeability. These results show that asbestos has direct effects on lung epithelial permeability. Together with the recent observation that asbestos directly increases epithelial fibrinolytic activity, our results suggest a novel mechanism for asbestos-induced lung injury.
1992-12-01 | New perspectives on basic mechanisms in lung disease. 1. Lung injury, inflammatory mediators, and fibroblast activation in fibrosing alveolitis.
It is over 25 years since Scadding first defined the term fibrosing alveolitis. It has since been established that complex mechanisms underlie its pathogenesis, including epithelial and endothelial injury, vascular leakage, production of inflammatory cells and their mediators, and fibroblast activation. Only through a detailed knowledge of how these cellular and molecular events are interlinked will we learn how to combat this disease, which is notoriously resistant to present treatments. So far the only therapeutic advances have been refinements in immunosuppression, and even these treatments are frequently disappointing. We believe that future advances in treatment will come from the development of agents that protect endothelial and epithelial cells from further injury and agents that can inhibit release of inflammatory mediators. A better knowledge of the mechanisms of collagen gene activation and the biochemical pathways of collagen production may also allow the identification of vulnerable sites at which new treatments may be directed. A combined approach to modifying appropriate parts of both the inflammatory component and the fibroblast/collagen component should provide a new stimulus to research. Further epidemiological studies are also needed to identify the environmental causes of lung injury that initiate the cascade of events leading to interstitial fibrosis.
1989-04-01 | Asbestos and Cancer: Human Natural Killer Cell Activity is Suppressed by Asbestos Fibers but Can Be Restored by Recombinant lnterleukin-2
Inhalation of asbestos fibers is associated with a marked increase in the risk of developing pulmonary malignancy, particularly bronchogenic carcinoma. As natural killer (NK) cells are specialized lymphocytes that are considered to have an important in vivo role in the recognition and destruction of malignant cells, we examined the capacity of asbestos fibers (chrysotile, amosite, and crocidolite) to interfere with the NK activity of nylon wool-nonadherent, human blood lymphocytes (51Cr-release assay, K562 target cells, 14 h effector-to-target ratio = 50:1). Final asbestos concentrations used were 1 to 1,000 micrograms/ml. None of the fibers altered spontaneous target cell lysis or lymphocyte viability. All types of asbestos suppressed NK activity in a dose-dependent fashion. This effect was most marked with chrysotile, which exerted a profound inhibitory effect on blood NK cell activity; at 100 micrograms/ml, NK activity was inhibited 84 +/- 2% (p less than 0.001). The suppressive effects of asbestos were exerted directly on the NK cells (large granular lymphocytes, 91 +/- 2% inhibition at 100 micrograms/ml; p less than 0.001). Exposure of lymphocytes to recombinant interleukin-2 (IL-2, 150 units/ml) for 24 h prior to exposure to asbestos restored the level of activity to 99 +/- 6% of the original value (p less than 0.001), and lung lymphocytes that were exposed to IL-2 in vivo (active sarcoidosis) were resistant to suppression by asbestos. Similar results were observed in a group of patients with asbestosis. This suppression of NK activity may contribute to the increased susceptibility of asbestos-exposed persons to the development of pulmonary malignancy.
antibodies
2025-09-27 | Pulmonary Osteoclast-Like Cells Contribute to Asbestos-Induced Pulmonary Fibrosis
Rationale: Asbestos exposure causes pulmonary fibrosis, but mechanisms remain unclear and no effective therapy exists. We recently reported that osteoclast-like transformation of pulmonary myeloid cells occurs in pulmonary alveolar microlithiasis and silicosis, producing acid and proteolytic enzymes that harm lung tissue. Here, we investigated whether asbestos drives a similar pathological process. Methods: Chrysotile or crocidolite fibers were delivered intratracheally to C57BL/6 mice. Lung sections from mice and asbestosis patients were analyzed. RANKL levels in BAL cells, alveolar macrophages, and type II pneumocytes were measured by ELISA. Results: TRAP and CTSK positive osteoclast-like multinucleated giant cells (OLMNGC) are present in the lungs of human asbestosis patients. Pulmonary fibrosis in the asbestos-challenged mouse lung is accompanied by the osteoclastic transformation of pulmonary myeloid cells, as assessed by histology, immunohistochemistry, and gene expression profiles. Asbestos-induced OLMNGC are embedded in fibrotic parenchymal lesions and comprise approximately 5% of BAL cells, which when plated on bone slices confer the capacity to pit the bone surface and release collagen 1 (CTX-1) fragments into the media. Asbestos exposure induces RANKL expression in BAL cells. Conclusion: Asbestos induces osteoclast-like transformation of pulmonary myeloid cells or recruits osteoclast precursors, resulting in sustained production of matrix-degrading enzymes and acid. These cells fail to degrade tough asbestos fibers, causing collateral lung damage and progressive fibrosis. Targeting such osteoclast-like cells could mitigate lung scarring in asbestos-exposed individuals.
2019-01-03 | Epithelial to Mesenchymal Transition in Human Mesothelial Cells Exposed to Asbestos Fibers: Role of TGF-β as Mediator of Malignant Mesothelioma Development or Metastasis via EMT Event
Asbestos exposure increases the risk of asbestosis and malignant mesothelioma (MM). Both fibrosis and cancer have been correlated with the Epithelial to Mesenchymal Transition (EMT)—an event involved in fibrotic development and cancer progression. During EMT, epithelial cells acquire a mesenchymal phenotype by modulating some proteins. Different factors can induce EMT, but Transforming Growth Factor β (TGF-β) plays a crucial role in promoting EMT. In this work, we verified if EMT could be associated with MM development. We explored EMT in human mesothelial cells (MeT-5A) exposed to chrysotile asbestos: we demonstrated that asbestos induces EMT in MeT-5A cells by downregulating epithelial markers E-cadherin, β-catenin, and occludin, and contemporarily, by upregulating mesenchymal markers fibronectin, α-SMA, and vimentin, thus promoting EMT. In these cells, this mechanism is mediated by increased TGF-β secretion, which in turn downregulates E-cadherin and increases fibronectin. These events are reverted in the presence of TGF-β antibody, via a Small Mother Against Decapentaplegic (SMAD)-dependent pathway and its downstream effectors, such as Zinc finger protein SNAI1 (SNAIL-1), Twist-related protein (Twist), and Zinc Finger E-Box Binding Homeobox 1 (ZEB-1), which downregulate the E-cadherin gene. Since SNAIL-1, Twist, and ZEB-1 have been shown to be overexpressed in MM, these genes could be considered possible predictive or diagnostic markers of MM development.
2018-01-24 | Therapeutic potential of targeting S100A11 in malignant pleural mesothelioma
Abstract Malignant pleural mesothelioma (MPM) is an aggressive tumor with an unfavorable prognosis. The standard therapeutic approaches are limited to surgery, chemotherapy, and radiotherapy. Because the consequent clinical outcome is often unsatisfactory, a different approach in MPM treatment is required. S100A11, a Ca 2+ -binding small protein with two EF-hands, is frequently upregulated in various human cancers. Interestingly, it has been found that intracellular and extracellular S100A11 have different functions in cell viability. In this study, we focused on the impact of extracellular S100A11 in MPM and explored the therapeutic potential of an S100A11-targeting strategy. We examined the secretion level of S100A11 in various kinds of cell lines by enzyme-linked immunosorbent assay. Among them, six out of seven MPM cell lines actively secreted S100A11, whereas normal mesothelial cell lines did not secrete it. To investigate the role of secreted S100A11 in MPM, we inhibited its function by neutralizing S100A11 with an anti-S100A11 antibody. Interestingly, the antibody significantly inhibited the proliferation of S100A11-secreting MPM cells in vitro and in vivo. Microarray analysis revealed that several pathways including genes involved in cell proliferation were negatively enriched in the antibody-treated cell lines. In addition, we examined the secretion level of S100A11 in various types of pleural effusions. We found that the secretion of S100A11 was significantly higher in MPM pleural effusions, compared to others, suggesting the possibility for the use of S100A11 as a biomarker. In conclusion, our results indicate that extracellular S100A11 plays important roles in MPM and may be a therapeutic target in S100A11-secreting MPM.
2017-03-20 | Pleural mesothelioma in household members of asbestos-exposed workers in Friuli Venezia Giulia, Italy
Objectives: Malignant mesothelioma is closely associated to asbestos exposure.One such exposure may occur through contact with occupationally exposed household members and their belongings.This study examines the features of pleural mesothelioma attributable only to asbestos brought home by another family member.Material and Methods: The data sources were 1063 mesothelioma cases diagnosed between 1995 and 2014, from the Friuli Venezia Giulia Mesothelioma Register.In all cases the diagnosis of mesothelioma was based on the pathology report.Exposure information and demographic data were acquired by an occupational medical standardized questionnaire/interview. Results: Household-exposure mesothelioma cases included 33 women and 2 men.Relationships were: wives (N = 22), daughters (N = 9), sons (N = 2), and mothers (N = 2).Asbestos exposure in the workers predominantly occurred in shipyards.Out of the 35 pleural cases, 19 were epithelial, 9 biphasic, 3 sarcomatoid, and 4 not specified.The mean age at diagnosis was 77 years old.The mean latency was 59 years, with wives having a significant shorter latency than offspring.Latency was not significantly related to morphology and asbestosis.The overall mean survival was 16 months (median 11 months) but treatment was beneficial (mean 16 months vs. 7 months).Biphasic/sarcomatoid histology and presence of asbestosis were associated with a decreased survival, although not with statistical significance.Conclusions: Our data confirms that household exposure increases the risk for pleural mesothelioma amongst women with no history of occupational asbestos exposure.This is an ongoing problem in many countries, as well as in Italy, where the evaluation of a framework for the compensation of these cases is under debate.
2016-06-22 | [Asbestos and respiratory diseases].
Previous occupational asbestos exposure (more rarely environmental or domestic exposure) may induce various pleural and/or pulmonary, benign or malignant diseases, sometimes with a very long latency for malignant mesothelioma (MM). Asbestos has been widely extracted and used in Western countries and in emerging or developing countries, resulting in a peak of MM incidence in France around 2020 and likely in a world pandemic of asbestos-induced diseases. These patients have mostly benign respiratory diseases (pleural plugs) but may also be diagnosed with lung cancer or malignant pleural mesothelioma, and have a global poor outcome. New therapeutic tools (targeted therapies, immunotherapy…) with first promising results are developed. However, it is crucial to obtain a full ban of asbestos use worldwide, and to do a regular follow-up of asbestos-exposed subjects, mostly if they are already diagnosed with benign respiratory diseases. Finally, new cancers (larynx and ovary) were recently added to the list of asbestos-induced tumors.
gene therapies
2025-05-01 | System Resolution of Spp1+ Macrophage Heterogeneities Identifies Disease-potentiating Crosstalk Between Macrophage and Alveolar Epithelium in Pulmonary Fibrosis
Abstract RATIONALE. Macrophages regulate the development of fibrosis. Multiple scRNAseq studies of fibrotic diseases have identified a pro-fibrotic osteopontin (SPP1)-expressing macrophage population, but the functional heterogeneity of this population and their role in different disease contexts remains poorly defined. Additionally, the effects of various therapeutic interventions on the Spp1+ macrophages are not yet understood. METHODS. We performed a meta-analysis of Spp1+ macrophages from scRNAseq of murine fibrotic models across tissues (heart, kidney, and lungs), encompassing 16 datasets and 112,014 macrophage cells. For pulmonary fibrosis, we evaluated distinct injury models, including bleomycin, silica, asbestosis, and radiation, characterizing the functional heterogeneity of the Spp1+ macrophages throughout disease progression. In the lungs, we identified novel interactions between this population and the alveolar epithelial cells, further validated by in vitro studies. Finally, we posited this work as a scRNA-seq atlas to explore the effect of different anti-fibrotic interventions on the Spp1+ macrophage, achieved through the integration of external single cell datasets to the atlas via reference-based methods. RESULTS. We uncovered two functionally distinct Spp1+ macrophages (Spp1+ Arg1+ Fn1+ and Spp1+ Cd36+ Mmp12+). In silico, both populations are ECM-remodeling, with one being metabolically driven (Cd36+ Mmp12+) and the other secretory (Arg1+ Fn1+). Cd36+ Mmp12+ appears later in the injury response, while Arg1+ Fn1+ peaks early and mediates pathological intercellular crosstalk. Development trajectory analysis suggests Cd36+ Mmp12+ may arise from the Arg1+ Fn1+ macrophages. In the lungs, Arg1+ Fn1+ secretion of fibronectin may disrupt the trans-differentiation of AT2 to AT1 cells by potentiating the Krt8+ intermediate cell state, thereby impairing alveolar re-epithelization. Late-stage Spp1 cytokine secretion by Cd36+ Mmp12+ further augments the epithelial-mesenchymal transition of AT2 cells, leading to irreversible ECM deposition. Using the Spp1+ macrophage atlas, we examined the effects of Nintedanib and Ccr2 by integrating scRNAseq data from the lungs of mice with Ccr2-KO and post-Nintedanib treatment. While Nintedanib did not affect the Spp1+ populations, Ccr2-KO selectively depleted the Arg1+ Fn1+ subtype and its associated crosstalk with the AT2 cells. CONCLUSION. This study highlights previously unappreciated functional diversity within the Spp1+ macrophage population and disease-potentiating crosstalk between macrophage and epithelial cells in pulmonary fibrosis. We further provide a platform to investigate how distinct pro-fibrotic factors may influence this diverse population.
2021-04-22 | Role of CCR2+ Myeloid Cells in Inflammation Responses Driven by Expression of a Surfactant Protein-C Mutant in the Alveolar Epithelium
Acute inflammatory exacerbations (AIE) represent precipitous deteriorations of a number of chronic lung conditions, including pulmonary fibrosis (PF), chronic obstructive pulmonary disease and asthma. AIEs are marked by diffuse and persistent polycellular alveolitis that profoundly accelerate lung function decline and mortality. In particular, excess monocyte mobilization during AIE and their persistence in the lung have been linked to poor disease outcome. The etiology of AIEs remains quite uncertain, but environmental exposure and genetic predisposition/mutations have been identified as two contributing factors. Guided by clinical evidence, we have developed a mutant model of pulmonary fibrosis leveraging the PF-linked missense isoleucine to threonine substitution at position 73 [I73T] in the alveolar type-2 cell-restricted Surfactant Protein-C [SP-C] gene [ SFTPC ]. With this toolbox at hand, the present work investigates the role of peripheral monocytes during the initiation and progression of AIE-PF. Genetic ablation of CCR2 + monocytes (SP-C I73T CCR2 KO ) resulted in improved lung histology, mouse survival, and reduced inflammation compared to SP-C I73T CCR2 WT cohorts. FACS analysis of CD11b + CD64 - Ly6C hi monocytes isolated 3 d and 14 d after SP-C I73T induced injury reveals dynamic transcriptional changes associated with “Innate Immunity’ and ‘Extracellular Matrix Organization’ signaling. While immunohistochemical and in situ hybridization analysis revealed comparable levels of tgfb1 mRNA expression localized primarily in parenchymal cells found nearby foci of injury we found reduced effector cell activation (C1q, iNOS, Arg1) in SP-C I73T CCR2 KO lungs as well as partial colocalization of tgfb1 mRNA expression in Arg1 + cells. These results provide a detailed picture of the role of resident macrophages and recruited monocytes in the context of AIE-PF driven by alveolar epithelial dysfunction.
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