Health Hazard Evaluation Determination Report No. 74-97-286: Blaw Knox Foundry and Mill Machinery, Inc., Warwood Plant: Wheeling, West Virginia

Based on the results of environmental and medical studies by NIOSH, a toxic exposure to crystalline free silica (7631869) is determined to exist among foundry workers in the Blaw Knox Foundry and Mill Machinery (SIC-3313), Incorporated, Warwood Plant, (SIC-331) Wheeling, West Virginia. The workroom air concentrations of crystalline free silica are found to exceed the current NIOSH standard of 0.05 milligram per cubic meter. Employees are also found to be transiently exposed to phosphine (7803512) generated in the machining of nodular iron rolls. The possibility of metal fumes and calcium-oxide (1305788) transiently exceeding the current safety limits during tapping operations is suspected because of the episodic and transient symptoms of mucous membrane and skin irritation noted by cranemen and pitmen. Recommendations include use of low silica containing sand, good housekeeping, better exhaust ventilation, regular wetting of foundry sand with water, mechanizing the shake out procedures, use of breathing apparatus, long sleeve shirts and gloves by cranemen, and repairing the seal on the crane cabs. [Description provided by NIOSH

Integrating Clinical Probability into the Diagnostic Approach to Idiopathic Pulmonary Fibrosis: An International Working Group Perspective

Background. When considering the diagnosis of idiopathic pulmonary fibrosis (IPF), experienced clinicians integrate clinical features that help to differentiate IPF from other fibrosing interstitial lung diseases, thus generating a “pre-test” probability of IPF. The aim of this international working group perspective was to summarize these features using a tabulated approach similar to chest HRCT and histopathologic patterns reported in the international guidelines for the diagnosis of IPF, and to help formally incorporate these clinical likelihoods into diagnostic reasoning to facilitate the diagnosis of IPF. Methods. The committee group identified factors that influence the clinical likelihood of a diagnosis of IPF, which was categorized as a pre-test clinical probability of IPF into “high” (70-100%), “intermediate” (30-70%), or “low” (0-30%). After integration of radiological and histopathological features, the post-test probability of diagnosis was categorized into “definite” (90-100%), “high confidence” (70-89%), “low confidence” (51-69%), or “low” (0-50%) probability of IPF. Findings. A conceptual Bayesian framework was created, integrating the clinical likelihood of IPF (“pre-test probability of IPF”) with the HRCT pattern, the histopathology pattern when available, and/or the pattern of observed disease behavior into a “post-test probability of IPF”. The diagnostic probability of IPF was expressed using an adapted diagnostic ontology for fibrotic interstitial lung diseases. Interpretation. The present approach will help incorporate the clinical judgement into the diagnosis of IPF, thus facilitating the application of IPF diagnostic guidelines and, ultimately improving diagnostic confidence and reducing the need for invasive diagnostic techniques

Disparities Between Asbestosis and Silicosis Claims Generated by Litigation Screenings and Clinical Studies

In 2005, U.S. District Court Judge Janis Jack, presiding over an MDL proceeding involving 10,000 claims of silicosis, issued a 264 page opinion rejecting the reliability of thousands of medical reports generated by litigation screenings. In that report, she documented in great detail the existence of a fraudulent scheme to create bogus medical evidence that lead her to conclude that it is apparent that truth and justice had very little to do with these diagnoses. . . . [Indeed] it is clear that lawyers, doctors and screening companies were all willing participants in a scheme to manufacture. . . [diagnoses] for money. In this article, I consider whether hundreds of thousands of medical reports generated by asbestos screenings also have been manufactured for money. While both plaintiffs\u27 lawyers and the litigation doctors they hire have steadfastly refused to disclose the percentage of those screened that are found to have asbestosis, I have been able to determine the percentages of positive diagnoses and to compare that to the results of a review of 80 clinical studies. Based on my research, I conclude that for every 1000 occupationally exposed workers screened, litigation screenings generate approximately 500-600 diagnoses of asbestosis. In a clinical setting, however, the number diagnosed with asbestosis would be 30-50. The excess diagnoses of asbestosis in litigation screenings produced over $25 billion in payments to claimants of which approximately$10 billion was paid to the lawyers. I also review clinical studies in which X-rays read by litigation doctors were re-read by independent medical experts. These re-readings found error rates that ranged from 62% to 97.5%. My review of the pandemic of nonmalignant asbestos-related disease claims which were filed in the 1990-2004 period in the tort system and with asbestos bankruptcy trusts and comparison with the number of hospitalizations primarily for asbestosis in that period shows similar disparities. The conclusion I draw from the data and evidence presented is that Judge Jack\u27s findings with regard to the medical reports in the silica MDL applies with at least equal force to nonmalignant asbestos litigation: the medical reports are mostly manufactured for money

Rodent models of cardiopulmonary disease: their potential applicability in studies of air pollutant susceptibility.

The mechanisms by which increased mortality and morbidity occur in individuals with preexistent cardiopulmonary disease following acute episodes of air pollution are unknown. Studies involving air pollution effects on animal models of human cardiopulmonary diseases are both infrequent and difficult to interpret. Such models are, however, extensively used in studies of disease pathogenesis. Primarily they comprise those developed by genetic, pharmacologic, or surgical manipulations of the cardiopulmonary system. This review attempts a comprehensive description of rodent cardiopulmonary disease models in the context of their potential application to susceptibility studies of air pollutants regardless of whether the models have been previously used for such studies. The pulmonary disease models include bronchitis, emphysema, asthma/allergy, chronic obstructive pulmonary disease, interstitial fibrosis, and infection. The models of systemic hypertension and congestive heart failure include: those derived by genetics (spontaneously hypertensive, Dahl S. renin transgenic, and other rodent models); congestive heart failure models derived by surgical manipulations; viral myocarditis; and cardiomyopathy induced by adriamycin. The characteristic pathogenic features critical to understanding the susceptibility to inhaled toxicants are described. It is anticipated that this review will provide a ready reference for the selection of appropriate rodent models of cardiopulmonary diseases and identify not only their pathobiologic similarities and/or differences to humans but also their potential usefulness in susceptibility studies

The updated evidence of pirfenidone treated silicosis based on network pharmacology, molecular docking and experimental validation

ObjectiveSilicosis remains a debilitating occupational lung disease with limited therapeutic options, despite emerging evidence supporting pirfenidone’s (PFD) anti-fibrotic efficacy in clinical practice. However, the molecular circuitry governing PFD’s therapeutic actions in silicosis remains incompletely mapped, hindering mechanism-driven therapeutic optimization. To bridge this knowledge gap, we executed network pharmacology to replenish its molecular mechanisms and potential therapeutic targets.Materials and methodsWe replicated a silicosis C57BL6/J mouse model and evaluated inflammation and fibrosis using HE, Masson, and Sirius Red staining assays. The expression of fibrotic markers α-SMA and Fibronectin were determined by immunofluorescence assay. Network pharmacology and molecular docking were used to predict potential therapeutic mechanisms and targets. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunofluorescence experiments were verified as the key predicted targets.ResultsPFD alleviated the level of inflammation and collagen deposition and fibrotic markers α-SMA and Fibronectin expression in silicosis lung. Network pharmacology analysis predicted three potential target proteins, including TNF, MMP9, and NF-κB1, as well as ten possible signaling pathways. Molecular docking showed a good binding activity between PFD and hub genes. qRT-PCR and immunofluorescence confirmed that PFD inhibited TNF, MMP9, and NF-κB activation. Additionally, we found increased expression of TLR2, a key upstream gene of NF-κB.ConclusionIn conclusion, we identified TNF, MMP9, NF-κB1 and TLR2, that contribute to the therapeutic effects of PFD in silicosis. Mechanistically, PFD appears to mitigate silicosis pathogenesis through suppression of epithelial TLR2/NF-κB pathway activation

Analysis of airway secretions in a model of sulfur dioxide induced chronic obstructive pulmonary disease (COPD)

Hypersecretion and chronic phlegm are major symptoms of chronic obstructive pulmonary disease (COPD) but animal models of COPD with a defined functional hypersecretion have not been established so far. To identify an animal model of combined morphological signs of airway inflammation and functional hypersecretion, rats were continuously exposed to different levels of sulfur dioxide (SO2, 5 ppm, 10 ppm, 20 ppm, 40 ppm, 80 ppm) for 3 (short-term) or 20–25 (long-term) days. Histology revealed a dose-dependent increase in edema formation and inflammatory cell infiltration in short-term-exposed animals. The submucosal edema was replaced by fibrosis after long-term-exposure. The basal secretory activity was only significantly increased in the 20 ppm group. Also, stimulated secretion was significantly increased only after exposure to 20 ppm. BrdU-assays and AgNOR-analysis demonstrated cellular metaplasia and glandular hypertrophy rather than hyperplasia as the underlying morphological correlate of the hypersecretion. In summary, SO2-exposure can lead to characteristic airway remodeling and changes in mucus secretion in rats. As only long-term exposure to 20 ppm leads to a combination of hypersecretion and airway inflammation, only this mode of exposure should be used to mimic human COPD. Concentrations less or higher than 20 ppm or short term exposure do not induce the respiratory symptom of hypersecretion. The present model may be used to characterize the effects of new compounds on mucus secretion in the background of experimental COPD

Multi-walled carbon nanotube instillation impairs pulmonary function in C57BL/6 mice

<p>Abstract</p> <p>Background</p> <p>Multi-walled carbon nanotubes (MWCNTs) are widely used in many disciplines due to their unique physical and chemical properties. Therefore, some concerns about the possible human health and environmental impacts of manufactured MWCNTs are rising. We hypothesized that instillation of MWCNTs impairs pulmonary function in C57BL/6 mice due to development of lung inflammation and fibrosis.</p> <p>Methods</p> <p>MWCNTs were administered to C57BL/6 mice by oropharyngeal aspiration (1, 2, and 4 mg/kg) and we assessed lung inflammation and fibrosis by inflammatory cell infiltration, collagen content, and histological assessment. Pulmonary function was assessed using a FlexiVent system and levels of Ccl3, Ccl11, Mmp13 and IL-33 were measured by RT-PCR and ELISA.</p> <p>Results</p> <p>Mice administered MWCNTs exhibited increased inflammatory cell infiltration, collagen deposition and granuloma formation in lung tissue, which correlated with impaired pulmonary function as assessed by increased resistance, tissue damping, and decreased lung compliance. Pulmonary exposure to MWCNTs induced an inflammatory signature marked by cytokine (IL-33), chemokine (Ccl3 and Ccl11), and protease production (Mmp13) that promoted the inflammatory and fibrotic changes observed within the lung.</p> <p>Conclusions</p> <p>These results further highlight the potential adverse health effects that may occur following MWCNT exposure and therefore we suggest these materials may pose a significant risk leading to impaired lung function following environmental and occupational exposures.</p

Investigating the role of the respiratory microbiome and metabolome in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease of unknown aetiology. There is growing evidence that the lung microbiota may play a role in IPF. However, no study has investigated the functional impact of the short-chain fatty acids (SCFAs) on disease pathogenesis. The aim of this thesis was to characterise the respiratory microbiome and metabolome in healthy controls and subjects with IPF and to investigate the influence of the SCFAs on human primary bronchial epithelial cells (PBECs) and human lung fibroblasts (HLFs) from these individuals. Subjects diagnosed with IPF (n=201) and healthy controls (n=40) were prospectively recruited and underwent bronchoscopy. Bacterial DNA was isolated and 16S rRNA gene sequencing undertaken to characterise bacterial communities. Untargeted 1H nuclear magnetic resonance spectroscopybased metabolomics and targeted gas chromatography-mass spectrometry captured the metabolic profile of these samples. PBECs, differentiated at air-liquid interface, and HLF from healthy controls and subjects with IPF were either left untreated or exposed to the SCFAs. Compared to healthy controls, the IPF microbiota was less diverse (P<0.01), and had increased proportions of Firmicutes (P<0.01), Streptococcus and Staphylococcus (P<0.05). Relative concentrations of the SCFAs were increased in IPF compared to healthy controls, and in IPF, propionate positively correlated with the bacterial burden (rho=0.47, P=8 x 10-5). Treatment of PBECs from IPF subjects but not healthy controls with the SCFAs led to morphological changes, a dose-dependent release of pro-inflammatory mediators in the cell supernatant, and a decrease in transepithelial electrical resistance (TEER) over time. Compared to baseline, exposure of IPF PBECs to 1 mM of propionate led to a 40% reduction in TEER and a significant increase (P<0.05) in the secretion of IL-6. Treatment of HLFs with 5 mM of propionate or butyrate was found to increase cell proliferation at 72 hours. Subjects with IPF display an altered microbiome which is associated with a distinct metabolic signature in the lower airways. Differences in bacterial genera and an increased bacterial burden in IPF results in changes in the SCFAs in the airways. In vitro work demonstrates the potential of these SCFAs to shape immunological responses in the lung, mediating the pathogenesis of fibrosis.Open Acces

Endothelial and innate immune cross-talk in the time pathogenesis of pulmonary fibrosis in mice

Thesis (Ph.D.)--Boston UniversitySystemic Sclerosis (SSc) is a progressive autoimmune disease characterized by vasculopathy, immune dysfunction and fibrosis of skin and internal organs. Pulmonary fibrosis is the most severe complication. Although pathogenesis of SSc is not completely understood, it is believed to be initiated by early and persistent damage to endothelial cells (ECs), which may initiate inflammation and activation of fibroblasts. In this study we used subcutaneous instillation of bleomycin (BLM), which induces skin and lung fibrosis similar to SSC. ECs are targeted by BLM, however, the extent of EC contribution to pulmonary inflammation and fibrosis, and the degree of vasculopathy in this model are not fully understood. The core hypothesis of this work is that BLM induced injury to ECs contributes to pathogenic processes, resulting in pulmonary fibrosis. Through a unique method of cell sorting and gene expression analysis, we demonstrated EC injury (Matrix Metalloproteinase 12, von Willebrand Factor) and activation in response to BLM. Activation of ECs was demonstrated by expression of selectins, chemokines, and cytokines, contributing to inflammation and macrophage recruitment. Direct contribution of ECs to fibrosis was demonstrated by up-regulation of pro-fibrotic cytokines (Osteopontin, Connective Tissue Growth Factor, Plasminogen Activation Inhibitor-1), activation of collagen production by fibroblasts, and expression of Endothelial to Mesenchymal Transition (EndoMT) markers (Fibronectin, Fibroblast Specific Protein-1). Importantly, responses were sustained, suggesting that ECs perpetuate damage and repair mechanisms that promote fibrosis. Previous work from our lab has shown that transcription factor Friend Leukemia Virus Integration-1 (Fli1) is down-regulated in fibroblasts and ECs in SSc, contributing to fibrosis and vasculopathy in the skin. Intriguingly, Fli1 is also down-regulated in the lung during BLM induced fibrosis, but not in ECs. Further studies demonstrated that Fli1 was down-regulated in macrophages, where it is regulated by inflammatory signals. Fli1 was also down-regulated in mesenchymal cells, which includes fibroblasts. Previous in vitro studies have shown that Fli1 regulates fibrosis through regulation of collagen and other extracellular matrix proteins. In this study, we identified Tissue Inhibitor of Metalloproteinase-3, an important molecule in collagen degradation, as a novel Fli1 target, revealing another mechanism by which Fli1 contributes to development of fibrosis

Sarcoidosis - a multisystem disease.

Sarcoidosis is a systemic inflammatory disease, characterised by granuloma formation upon an unknown trigger in genetically predisposed individuals. The inflammation is characterised by an activation of both the innate immune system, with macrophages differentiating into epitheloid cells and dendritic cells, and the adaptive immune system, particularly T helper (Th) 1 and Th17 cells. Since all organs can be affected to varying extents, clinical presentation is often diverse. Most commonly, the lungs, lymph nodes, skin and eyes are involved, whereas cardiac, renal and neurological manifestations are less common but associated with higher morbidity. Depending on the clinical symptoms, a detailed evaluation including thorough clinical examination, imaging and laboratory tests should explore all possible organ involvements. In some patients, fatigue manifests as a para-sarcoidosis symptom impacting quality of life, even if sarcoidosis is in remission. Some acute syndromic presentations, such as Löfgren's syndrome, have a good prognosis and are commonly self-limiting. If possible, a topical treatment, for example for cutaneous sarcoidosis or bronchial involvement, should be applied. Treatment of severe cases with persisting disease activity necessitates long-term immunosuppressive drugs, with glucocorticoids as the first-line option. Steroid-sparing and second-line drugs include methotrexate, azathioprine, mycophenolate mofetil and immunomodulators such hydroxychloroquine, with the latter being first-line therapy in cutaneous sarcoidosis. Tumour necrosis factor-alpha inhibitors (particularly adalimumab and infliximab) are used as third-line agents but are administered earlier in cases of persistent disease activity, severe organ-involvement or intolerance to conventional drugs. Treatment decisions should be based on a multidisciplinary approach, depending on organ involvement and treatment tolerability. Para-sarcoidosis manifestations, particularly fatigue, should also be carefully addressed, where the patient could also be enrolled in multidimensional rehabilitation programmes. With various organ involvement and different phenotypes, larger studies including real-world data from registries are necessary to evaluate different sarcoidosis endotypes and preferential treatment pathways