Lung Fibroses Research Articles

The effects of using halloysite nano-clay in concrete on human health and environments: An overview study

Halloysite nano-clay (HNC), which is a natural, non-toxic nanomaterial falling under the kaolin subgroup of clay minerals, has a unique nanostructure. Its external layer consists of silica (Si-O-Si), and its internal tube core is alumina (Al-OH) with an internal monolayer of water molecules. HNC is around 1 µm long, and its external and inner diameters range from 40 to 70 nm and 10 to 20 nm, respectively. It is used in the pharmaceutical industry because its unique nanostructure allows for controllable, sustained drug release. It has also been employed to capture cancer cells in the blood and purify water, remove oil spills and reduce water pollution. HNC is considered safe in low and medium doses. In the construction industry, it can be used to produce low-carbon concrete and reduce carbon dioxide (CO2) emissions, where CO2 is the main cause of global warming. However, incorporating it into concrete to improve the mechanical properties and durability of the material has led to concerns regarding environmental effects and the health of construction workers. In consideration of these issues, the principal objective of this overview study was to investigate the effects of such HNC usage on human health and environments. The results showed that inhaling or ingesting high doses of HNC can cause lung fibroses in animals and humans. Although it does not irritate the skin, it may cause eye irritation.

Understanding idiopathic pulmonary fibrosis - Clinical features, molecular mechanism and therapies.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung fibrosing disease with high prevalence that has a prognosis worse than many cancers. There has been a recent influx of new observations aimed at explaining the mechanisms responsible for the initiation and progression of pulmonary fibrosis. However, despite this, the pathogenesis of the disease is largely unclear. Recent progress has been made in the characterization of specific pathologic and clinical features that have enhanced the understanding of pathologically activated molecular pathways during the onset and progression of IPF. This review highlights several of the advances that have been made and focus on the pathobiology of IPF. The work also details the different factors that are responsible for the disposition of the disease - these may be internal factors such as cellular mechanisms and genetic alterations, or they may be external factors from the environment. The changes that primarily occur in epithelial cells and fibroblasts that lead to the activation of profibrotic pathways are discussed in depth. Finally, a complete repertoire of the treatment therapies that have been used in the past as well as future medications and therapies is provided.

Endothelial-Mesenchymal Transition in COVID-19 lung lesions

Sars-Cov-2 infection is still a healthcare emergency and acute respiratory distress failure with Diffuse Alveolar Damage (DAD) features is the main causes of patients’ death. Pathogenic mechanisms of the disease are not clear yet, but new insights are necessary to improve therapeutic management, to prevent fatal irreversible multi-organ damage and to adequately follow up those patients who survive. Here we investigated, by histochemistry and immunohistochemistry, a wide number of mapped lung specimens taken from whole body autopsies of 7 patients dead of COVID-19 disease. Our data confirm morphological data of other authors, and enlarge recent reports of the literature suggesting that Endothelial–Mesenchymal Transition might be central to COVID-19 lung fibrosing lesions. Furthermore, based upon recent acquisition of new roles in immunity and vascular pathology of the CD31 molecule, we hypothesize that this molecule might be important in the development and treatment of COVID-19 pulmonary lesions. These preliminary findings need further investigations to shed light on the complexity of Sars-Cov-2 disease.

Effectiveness and safety of rituximab for the treatment of refractory systemic sclerosis associated calcinosis: A case series and systematic review of the literature.

To analyze the effectiveness and safety of rituximab (RTX) for the treatment of refractory systemic sclerosis (SSc)-associated calcinosis. We undertook an observational study of patients with this complication treated with 1 or more cycles of RTX (1 g × 2 weeks) and evaluated for at least 12 months after RTX treatment in a single center. The primary outcome measures of the study were the improvement of calcinosis symptoms (pain, signs of local inflammation, and new episodes of skin ulceration) and the radiologic evolution of the calcification(s). We treated 8 patients with refractory SSc-related calcinosis with RTX (off-label use). The main indications for RTX were complicated calcinosis unresponsive to previous therapies with concomitant arthritis in 2 patients and refractory arthritis or interstitial lung fibrosing disease in the remaining 6 patients. The mean number of RTX cycles administered was 3.12 ± 2.1 (range, 1-7), the median duration of RTX treatment was 9 months (interquartile range [IQR], 7.5-36 months), and the median follow-up after the first infusion of RTX dose was 19 months (IQR, http://catsalut.gencat.cat/web/.content/minisite/catsalut/proveidors_professionals/medicaments_farmacia/phf_mhda/informes_camse/esclerosi_sistemica/Dictamen-CAMS_-ES_-web.pdf (n.d.) 5-45 months). Four patients (50%) had a significant improvement in clinical symptoms (sustained improvement in the visual analog scale for pain of at least 50% and no new episodes of local inflammation or skin ulceration). Two of these patients (25%) also had a complete resolution or significant reduction in the size of the calcification(s) on X-ray, according with the radiographical scoring system for calcinosis developed by the Scleroderma Clinical Trials Consortium. In the remaining 4 patients (50%), RTX did not provide any significant clinical or radiologic benefit for calcinosis. The frequency of adverse effects was low, occurring in only 1 patient (12.5%), who developed upper respiratory tract infections not requiring hospitalization. Our preliminary data suggest that RTX may be helpful as a rescue therapy in selected cases of severe and refractory SSc-related calcinosis.

Morphologic and molecular study of lung cancers associated with idiopathic pulmonary fibrosis and other pulmonary fibroses

BackgroundPrimitive lung cancers developed on lung fibroses are both diagnostic and therapeutic challenges. Their incidence may increase with new more efficient lung fibrosis treatments. Our aim was to describe a cohort of lung cancers associated with idiopathic pulmonary fibrosis (IPF) and other lung fibrotic disorders (non-IPF), and to characterize their molecular alterations using immunohistochemistry and next-generation sequencing (NGS).MethodsThirty-one cancer samples were collected from 2001 to 2016 in two French reference centers for pulmonary fibrosis - 18 for IPF group and 13 for non-IPF group. NGS was performed using an ampliseq panel to analyze hotspots and targeted regions in 22 cancer-associated genes. ALK, ROS1 and PD-L1 expressions were assessed by immunohistochemistry.ResultsSquamous cell carcinoma was the most frequent histologic subtype in the IPF group (44%), adenocarcinoma was the most frequent subtype in the non-IPF group (62%). Forty-one mutations in 13 genes and one EGFR amplification were identified in 25 samples. Two samples had no mutation in the selected panel. Mutations were identified in TP53 (n = 20), MET (n = 4), BRAF (n = 3), FGFR3, PIK3CA, PTEN, STK11 (n = 2), SMAD4, CTNNB1, DDR2, ERBB4, FBXW7 and KRAS (n = 1) genes. No ALK and ROS1 expressions were identified. PD-L1 was expressed in 10 cases (62%) with only one (6%) case >50%.ConclusionsThis extensive characterization of lung fibrosis-associated cancers evidenced molecular alterations which could represent either potential therapeutic targets either clues to the pathophysiology of these particular tumors. These findings support the relevance of large molecular characterization of every lung fibrosis-associated cancer.

Autotaxin signaling, purinergic receptors and lung damage

ATX is a secreted enzyme that produces lysophosphatindic acid (LPA) in plasma. For several years investigators have characterize endogenous factors that regulate ATX expression and compartmentalization. However many questions remain unanswered and this article highlights our recent finding that autotaxin (ATX) is readily induced by toxic environmental chemicals. LPA binds G-protein coupled receptors that affect basic cell functions. The interest in the ATX-LPA axis stems from its role in embryogenesis and its association to diseases such as allergic asthma, idiopathic lung fibroses, rheumatoid arthritis, wound healing and several common types of cancer. In our study we used toluene diisocyanate (TDI) and other diisocyanates. Diisocyanates are low-molecular weight industrial chemicals notorious for being respiratory sensitizers and lung toxicants. Mechanisms behind these effects are not sufficiently characterized. We mainly used TDI and found that TDI in the nM range induced a rapid secretion of ATX from respiratory epithelial cells. Two purinergic recptors, P2X4 and P2X7, were implicated in this effect of TDI, suggesting that there is a “P2X-ATX axis” in bronchial epithelium that is sensitive to diisocyanates. We also showed associations between TDI exposures, LPA levels in plasma and symptoms reported by exposed individuals. Thus, our data support a role for the ATX-LPA axis in TDI toxicity. Furthermore, they suggest novel ways to study the regulation of ATX expression. Of particular interest is to understand how ATX expression is affected by purinergic receptors, and to investigate a possible involvement of ATX in asthma induced by diisocyanates and perhaps other low-molecular weight environmental chemicals. Our study also raises questions about current occupational exposure limits for diisocyanates.

Asbestosis and other pulmonary fibrosis in asbestos-exposed workers: high-resolution CT features with pathological correlations.

The purpose was to identify distinguishing CT features of pathologically diagnosed asbestosis, and correlate diagnostic confidence with asbestos body burden. Thirty-three workers (mean age at CT: 73years) with clinical diagnoses of asbestosis, who were autopsied (n = 30) or underwent lobectomy (n = 3), were collected. Two radiologists independently scored high-resolution CT images for various CT findings and the likelihood of asbestosis was scored. Two pathologists reviewed the pathology specimens and scored the confidence of their diagnoses. Asbestos body count was correlated with CT and pathology scores. Pathologically, 15 cases were diagnosed as asbestosis and 18 cases with various lung fibroses other than asbestosis. On CT, only the score of the subpleural curvilinear lines was significantly higher in asbestosis (p = 0.03). Accuracy of CT diagnosis of asbestosis with a high confidence ranged from 0.73 to 0.79. Asbestos body count positively correlated with CT likelihood of asbestosis (r = 0.503, p = 0.003), and with the confidence level of pathological diagnosis (r = 0.637, p < 0.001). Subpleural curvilinear lines were the only clue for the diagnosis of asbestosis. However, this was complicated by other lung fibrosis, especially at low asbestos body burden. • Various patterns of pulmonary fibrosis occurred in asbestos-exposed workers. • The fibre burden in lungs paralleled confident CT diagnosis of asbestosis. • The fibre burden in lungs paralleled confident pathological diagnosis of asbestosis. • Subpleural curvilinear lines were an important CT finding favouring asbestosis.

Oxidative Stress Markers in Exhaled Breath Condensate in Lung Fibroses Are Not Significantly Affected by Systemic Diseases

Exhaled breath condensate (EBC) is assumed to reflect processes in the lungs, yet it is unknown whether oxidative stress markers in EBC are affected by systemic disorders (atherosclerosis, hypertension, diabetes) or whether lung diseases increase markers in plasma and urine. 8-isoprostane, 4-hydroxy-trans-2-nonenale (HNE) and malondialdehyde (MDA) were measured using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS) in EBC, plasma and urine in 82 patients (45 with asbestosis and hyalinosis, and 37 with silicosis) and in 29 control subjects. 8-isoprostane and HNE in EBC, and HNE in urine were higher in both groups of patients. In addition, 8-isoprostane in plasma and urine, and MDA in urine were higher in asbestos-exposed patients and MDA in plasma in silicotics, with this marker in plasma correlated with the grade of silicosis. In all subjects, 8-isoprostane in EBC correlated with urine (r=0.38, p<0.001) and plasma levels (r=0.28, p=0.003), and HNE and MDA with urine levels (r=0.31, p<0.001; r=0.23, p=0.016, respectively). Most markers positively correlated with lung function impairment, EBC markers negatively with vitamin E supplementation. To conclude: The influence of satisfactorily controlled systemic disorders on markers in EBC in patients with pneumoconioses is not significant. In addition to oxidative stress markers in EBC, lung fibroses may increase oxidative stress markers in plasma and urine.

Fibre-years, pulmonary asbestos burden and asbestosis

AbstractThe relations between cumulative asbestos fibre doses at the work-places and asbestos burden of the lung evaluated by lung dust analyses have been tested on 3 different groups of patients of the German Mesothelioma Register: 1. total collective (n=366), 2. collective without elevated asbestos burden of the lungs (n=193), 3. collective with asbestoses/minimal asbestoses (n=64). The relations between the above mentioned parameters are in general only weak. The limit value of >25 fibre-years is found in 19.65% of persons without increased pulmonary asbestos burden. In spite of reaching or exceeding the cumulative doses of 25 fibre-years, 245% of the whole collective also show no elevated asbestos-concentrations in their lung tissues. By contrast, 425% of patients with asbestos-associated lung fibroses do not attain 25 fibre-years at their work-places. Considering our data it is doubtful that the postulated limit value of 25 fibre-years can be an adequate parameter for the evaluation of asbestos-associated lung fibroses.

Malignant mesothelioma--German mesothelioma register 1987-1999.

The study group comprised a collective of 1,605 patients with malignant mesotheliomas and with lung tissue available for lung dust analyses. Clinical features, occupational histories, expositions and individual data were evaluated, and the asbestos bodies concentrations (asbestos bodies/cm3 lung tissue or g wet tissue) were determined. Mesotheliomas developed mainly in men (94.5%). Of the cases, 96.4% were of pleural origin and only 3.3% were peritoneal mesotheliomas. The biphasic subtype predominated (61.3%), followed by the epithelioid type (29.3%). The sarcomatoid subtype was rarely developed (9.4%). Mean age at first diagnosis was 60.4 years. The mean survival time from time of symptom onset was 13.5 months. Patients with epithelioid subtypes had a longer survival time (16.9 months) than those with biphasic (13.1 months) and sarcomatoid subtypes (5.5 months). Of the patients, 73% presented pleural effusions as initial symptoms of the disease. An increased asbestos burden was identified by light microscopy in 84.8% of the patients. There was no association between histological subtypes and the asbestos burden of the lungs. Patients with peritoneal mesotheliomas had distinctly higher asbestos burdens in the lungs than patients with pleural mesotheliomas. There exists no association between lung asbestos burdens and survival times. The mean latency period was 37.8 years. A trend: higher asbestos burden of the lung/shorter latency periods was suggested. About 70% of the patients had a history of occupational exposure to asbestos dust. Most patients worked in the building trade, the locksmith and machine building industries and in the steel and blast-furnace industries. Of the patients, 25.6% had asbestos-associated lung fibroses, in 40.7% of the cases pleural plaques were identified. The most important causal factor for development of mesotheliomas is still asbestos, primarily amphibole asbestos. The recurring occurrence of mesotheliomas in younger people without known asbestos exposure needs the urgent investigation of other inducing factors for mesotheliomas.

Inhibitory effects of the dietary antioxidants butylated hydroxyanisole and butylated hydroxytoluene on bronchioloalveolar cell proliferation during the bleomycin-induced pulmonary fibrosing process in hamsters

The effects of dietary antioxidants on bleomycin (BLM)-induced pulmonary fibrosis were investigated in Syrian golden hamsters. In addition, the influence on cell proliferative activity in bronchioloalveolar hyperplastic lesions during the lung fibrosing process was evaluated in terms of argyrophil nucleolar organizer regions (AgNORs) and proliferating cell nuclear antigen (PCNA). Male 6-wk-old hamsters were divided into six groups. Groups 1–3 were intratracheally instilled with BLM at a dose of 2.5 U/kg body weight on days 0 and 14, and then given a diet supplemented with 1% butylated hydroxyanisole (BHA), or 1% butylated hydroxytoluene (BHT), or basal diet alone for the following 41 days. Groups 4–6 were given 1% BHA, 1% BHT or basal diet without BLM treatment for the same time period as that of groups 1–3. The mortality rate of animals in group 1 (BLM/BHA) (one in 20; 5%) was lower than in those of groups 2 (BLM/BHT) (three in 20; 15%) and 3 (BLM alone) (four in 20; 20%). BHA and BHT treatments significantly inhibited lung weight gains by BLM ( P < 0.05). Histopathologically, both BHA and BHT reduced BLM-induced pulmonary histopathological changes such as fibrosis, macrophage aggregation and epithelial proliferation, with a tendency for correlation with accumulation of type III collagen. In addition, antioxidant treatment significantly lowered the mean numbers of AgNORs ( P < 0.01) and PCNA-labelling indices ( P < 0.05) in the hyperplastic bronchioloalveolar lesions. The results thus indicate that these antioxidants exert inhibitory effects on proliferation of hyperplastic lesions associated with lung fibrosis.

Alpha-2-macroglobulin, monomeric and polymeric immunoglobulin A, and immunoglobulin M in bronchoalveolar lavage.

The concentrations of alpha 2-macroglobulin (alpha 2M), IgM, and the various molecular forms of IgA were measured in unconcentrated bronchoalveolar lavage (BAL) of normal subjects and in that of patients with interstitial lung disease. In BAL of control subjects, as previously observed in other external secretions, orosomucoid-coefficient of excretion relative to albumin (RCE) = 1.1 (albumin RCE = 1)-IgG (RCE = 0.7 in nonsmokers), and alpha 2M (RCE = 0.04) appeared to be secreted mainly by seepage from plasma according to molecular size. The secretion of p-IgA (RCE = 22), IgM (RCE = 0.09), and transferrin (RCE = 1.2) was selective, suggesting either local lung synthesis of these components or their active transepithelial transport. Concentrations of p-IgA, alpha 2M, and IgM in BAL displayed RCE at least 10 times lower than in other external secretions, reflecting the unsignificant local synthesis of these components in alveolar septa. In interstitial lung diseases, including sarcoidosis, hypersensitivity pneumonitis, and other lung fibroses, all protein concentrations in BAL were raised. Increased seepage of plasma proteins across the blood-gas barrier accounted for the elevation of orosomucoid and p-IgA (RCE unchanged). It probably accounted for the appearance in BAL of a characteristic peak of serum type dimeric IgA unbound to secretory component (SC), for the reduced percentage of free SC (5% versus 27% in control subjects), and for part of the increased percentage of m-IgA (52% versus 28% in control subjects). Contribution of local synthesis, presumably by cells infiltrating the alveolar tissue, was indirectly demonstrated for m-IgA and IgG, which were selectively secreted, more than 2-fold greater than albumin.(ABSTRACT TRUNCATED AT 250 WORDS)

Disorders of oxygen transport in the lung in lung fibroses with special reference to the O-2 diffusion capacity

Bei neun Patienten mit diffuser idiopathischer Lungenfibrose und bei neun Patienten mit einer diffusen Fibrosierung der Lunge im Gefolge ciner Sarcoidose (Stadium III), wurden in Ruhe ventilatorische und blutgasanalytische Untersuchungen einschlieslich der Berechnung der O2-Diffusionskapazitat der Lunge durchgefuhrt. Alle Patienten zeigten eine Steigerung des Atemminutenvolumens und der spezifischen Ventilation. Trotz einer starken Erhohung der Totraumventilation, die mit einer Steigerung der Atemfrequenz einherging, war eine normale alveolare Ventilation gewahrleistet: Das effektive alveolare Ventilationsvolumen war mit Ausnahme weniger Falle normal, der alveolare Saucrstoffdruck war nicht erniedrigt, der arterielle CO2-Druck war nicht erhoht. Die bei ausgepragten Fallen einer Lungenfibrose in der Regel vorhandene Verminderung der arteriellen Sauerstoffspannung, sowie die Vergroserung der alveolar-arteriellen O2-Druck-Differenz, sind vorwiegend die Folge einer O2-Diffusionsstorung, welche das vorherrschende Symptom einer Lungenfibrose darstellt. Entsprechend ist die alveolar-endcapillare O2-Druck-Differenz wahrend Hypoxieatmung vergrosert, die O2-Diffusionskapazitat der Lunge ist vermindert.