Experimental Lung Research

Our medical research library holds 31 studies published in Experimental Lung Research (1983–2021). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 31 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: Informa Healthcare
• Published: 1980 to the present, England
• Language: English
• ISSN: 0190-2148 (print), 1521-0499 (electronic)
• Its record in the NLM Catalog

2020s

• Ponatinib is a potential therapeutic approach for malignant pleural mesothelioma. Y.W. Yang, A. Marrufo, J. Chase, et al. 2021;47(1):9-25. PubMed · Publisher

  Abstract

  Purpose: Malignant pleural mesothelioma (MPM) is a rare and deadly malignancy. Current MPM therapies remain inadequate, and outcomes are often disappointing. New meaningful therapeutic approaches are urgently needed. Accumulating evidence indicates that the cAbl pathway promotes various tumor-stimulating processes in MPM. In this study, we sought to determine ponatinib's potential utility, a clinically approved and potent cAbl inhibitor, in MPM treatment.

  Material And Methods: Four MPM lines (MSTO211H, H28, H2452, H2052) were treated with ponatinib in vitro, and their growth was assessed. Scratch wound assay was used to investigate the ponatinib effect on cell migration. The expression levels of pAbl and its downstream effectors pCrkL, pAKT, and pSTAT5 were characterized. The in vivo ponatinib effect was evaluated in human MPM cells derived tumor model.

  Results: In all four MPM lines, significant expression levels of phosphorylated cAbl/Arg and pCrkl were observed. Differentially but strongly, ponatinib inhibited the in vitro cell growth and migration of all four MPM line. Western blot analysis showed that the activation of Abl signaling was blocked in the ponatinib-treated MMP lines. In keeping, the cellular levels of pAbl and its downstream effector pCrkL, pAKT, and pSTAT5 were markedly decrease following ponatinib treatment. Moreover, ponatinib treatment amplified the levels of γH2AX in cells denoting increased double-strand DNA breaks levels. Notably, ponatinib treatment reduced in vivo tumor growth and reduced pCrkl and pSTAT5 levels in tumor samples.

  Conclusion: Ponatinib may offer a new therapeutic strategy for MPM patients based on cAbl signaling pathway inhibition.

2010s

• Comparison of functional, biochemical, and morphometric alterations in the lungs of 4 rat strains and hamsters following repeated intratracheal instillation of crocidolite asbestos. D.J. Padilla-Carlin, D.L. Costa. 2011;37(4):212-26. PubMed · Publisher

  Abstract

  Four rat strains and hamsters were exposed to 0.7 mg crocidolite asbestos/g lung once/week for 3 weeks by intratracheal instillation (IT). Pulmonary function, biochemistry, and morphometry were evaluated at 3 and 6 months after IT. Each rat strain, but not the hamster, exhibited elevated lung volumes. Quasistatic compliance in rats and hamsters was reduced 15%-40% and 25%-50%, respectively. Diffusing capacity for carbon monoxide was elevated in the rats, but in hamsters, it was reduced at both time points. Hydroxyproline was increased in the rat strains but not in hamsters. Lung protein/dry weight was not altered in most of the rat strains and in hamsters at both time points. The linear mean intercept value was increased in Fischer 344 (F344) rats (3 and 6 months) and Long Evans rats (6 months), whereas in hamsters only at 6 months. Surface area was unchanged in both species. Specific density for parenchymal tissue was reduced for F344 rats at both time points, but alveolar density values did not change overall relative to species and time. The correlated functional and morphological changes in the hamster appeared more consistent with human asbestosis. Divergent lung responses in different species and strains should be considered when selecting laboratory animal models for studies related to asbestos exposure.

2000s

• Imatinib mesylate inhibits fibrogenesis in asbestos-induced interstitial pneumonia. K. Vuorinen, F. Gao, T.D. Oury, et al. 2007;33(7):357-73. PubMed · Publisher · Free full text

  Abstract

  Profibrogeneic cytokines contribute to the accumulation of myofibroblasts in the lung interstitium in idiopathic pulmonary fibrosis (IPF). Imatinib mesylate, a tyrosine kinase inhibitor specific for Abl, platelet-derived growth factor receptor (PDGFR) and c-Kit tyrosine kinases, has been shown to inhibit fibrosis and profibrotic signaling in mouse models of inflammation-mediated lung reactions. The authors tested imatinib mesylate in vivo in a mouse model of crocidolite asbestos-induced progressive fibrosis. The ability of imatinib mesylate to inhibit profibrogeneic cytokine-induced human pulmonary fibroblast migration was tested in vitro and the expression of its target protein tyrosine kinases was assessed with immunofluorescence. In vivo, 10 mg/kg/day imatinib mesylate inhibited histological parenchymal fibrosis and led to a decrease in collagen deposition, but had no significant effect on asbestos-induced neutrophilia. However, 50 mg/kg/day imatinib mesylate did not inhibit collagen deposition. In vitro, IPF fibroblasts expressed Abl, PDGFR-alpha, PDGF-beta, but not c-Kit, and 1 microM imatinib mesylate inhibited profibrogeneic cytokine-induced IPF fibroblast migration. These results suggest that imatinib mesylate is a potential and specific inhibitor of fibroblast accumulation in asbestos-induced pulmonary fibrosis.

• Asbestos-induced activation of cell signaling pathways in human bronchial epithelial cells. X. Wang, J.M. Samet, A.J. Ghio. 2006;32(6):229-43. PubMed · Publisher

  Abstract

  Using respiratory epithelial cells transfected with either superoxide dismutase (SOD) or catalase, the authors tested the hypothesis that the activation of the epidermal growth factor (EGF) receptor signal pathway after asbestos exposure involves an oxidative stress. Western blotting using phospho-specific antibodies demonstrated that the EGF receptor kinase inhibitor PD153035 decreased both the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and its upstream signal pathway, including mitogen-activate protein kinase/ERK kinase (MEK)1/2. Similarly, the MEK1/2 kinase inhibitor PD98059 also demonstrated the ability to decrease phosphorylation of ERK1/2. Crocidolite-induced phosphorylation of EGF receptor, ERK1/2, and MEK1/2 was reduced by transfection of BEAS-2B cells with a catalase vector, supporting a participation of oxidative stress in this pathway. These results show that crocidolite can activate the phosphorylation of EGF receptor and its downstream cell signal pathway in BEAS-2B cells and this is associated with the oxidative stress presented by the fibers.

• Inhibition of malignant mesothelioma cell matrix metalloproteinase production and invasion by a novel nutrient mixture. M.W. Roomi, V. Ivanov, T. Kalinovsky, et al. 2006;32(3-4):69-79. PubMed · Publisher

  Abstract

  Malignant mesothelioma (MM), an asbestos-associated cancer with no known cure, is a highly aggressive tumor causing profound morbidity and nearly universal mortality. Extracellular matrix (ECM) matrix metalloproteinases (MMPs) produced by tumor and stromal cells play a key role in tumor invasion and metastasis. Prevention of ECM degradation by MMP inhibition has been shown to be a promising therapeutic approach to inhibition of cancer development. Based on reported anticancer properties, the authors investigated the effect of a mixture (NM) containing lysine, proline, ascorbic acid, and green tea extract on MM cell line MSTO-211 H proliferation (by [MTT] [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay), MMP secretion (by gelatinase zymography), invasion (through Matrigel), and morphology (by hematoxylin and eosin [H&E] staining). MMP-2 and phorbol 12-myristate 13-acetate (PMA)-induced MMP-9 secretion were inhibited by NM in a dose-dependent fashion, with virtual total inhibition at 500 microg/ml NM. Invasion through Matrigel was inhibited at 50, 100, and 500 microg/ml by 27%, 36%, and 100%, respectively. NM was not toxic to the MM cell line, and H&E staining did not indicate any changes at and below 100 microg/ml concentration. In conclusion, NM significantly inhibited MM cell MMP secretion and invasion-both important parameters for cancer prevention, suggesting NM is an effective treatment strategy for MM.

• A comparison of asbestos and urban particulate matter in the in vitro modification of human alveolar macrophage antigen-presenting cell function. R.F. Hamilton, A. Holian, M.T. Morandi. 2004;30(2):147-62. PubMed · Publisher

  Abstract

  The mechanism for how inhaled particles cause or exacerbate human diseases is not known. It is clear, however, that some particles are more bioactive than others. One possible mechanism may involve a modification of antigen-presenting cell function. In this study, 2 forms of asbestos (crocidolite and Libby amphibole) and PM(2.5) (an urban particle) were cultured with human alveolar macrophages (HAMs) to determine whether antigen-presenting cell (APC) function was altered. HAMs were exposed to the bioactive particles, asbestos and PM(2.5), for 24 hours, then isolated free of extracellular particulates and nonviable cells. Isolated HAMs were then cultured with autologous lymphocytes in an 11-day APC assay using tetanous toxoid as the antigen and the resulting culture supernatants were assayed for lymphocyte-derived cytokines. Asbestos exposure, regardless of type, up-regulated a TH1 lymphocyte-derived cytokine, interferon gamma (IFNgamma), and the TH2 lymphocyte-derived cytokines interleukin-4 (IL-4) and interleukin-13 (IL-13). PM(2.5) exposure up-regulated all 3 cytokines also. Although cytokine production levels were significantly higher for the treatment compared to control cultures as a group, there was extreme variability in the responses between subjects. In addition, there was no correlation between an individual's cells' response to asbestos verses PM, suggesting that more than one possible mechanism exists for a particle-induced APC effect and individual differential sensitivities to inhaled bioactive particles. This work supports the hypothesis that some inhaled particles can modify immune function by directly affecting APCs thus up-regulating the normal lymphocyte response to antigens in the lung.

• Soluble ICAM-1, MCP-1, and MIP-2 protein secretion by rat pleural mesothelial cells following exposure to amosite asbestos. G.D. Hill, J.B. Mangum, O.R. Moss, et al. 2003;29(5):277-90. PubMed · Publisher

  Abstract

  Pleural inflammation is a sequela of exposure to toxic mineral fibers such as amosite asbestos. This inflammatory response involves the influx of leukocytes from the vasculature into the pleural space. Adhesion molecules such as intercellular adhesion molecule-1 (ICAM)-1 and chemokines such as monocyte chemoattractant protein-1 (MCP)-1 and macrophage inhibitory protein-2 (MIP)-2 are known to be important in pulmonary inflammation following inhalation of particulate matter. However, little is known about their role in pleural inflammation secondary to amosite asbestos exposure. Because the pleural mesothelial cell is believed to be a key target cell of asbestos exposure, the purpose of this study was to determine if ICAM-1, MCP-1, and MIP-2 proteins were secreted by these mesothelial cells following in vitro and in vivo exposure to amosite asbestos. Increased levels of ICAM-1 and MCP-1 protein were measured following 24 or 48 hours exposure of cultured rat pleural mesothelial cells to amosite fibers (1.5 to 5.0 micro g/cm(2)). Increased levels of ICAM-1, MCP-1, and MIP-2 protein were found in pleural lavage fluid from Fischer-344 rats exposed to amosite asbestos for 4 and 12 weeks and after a 12-week recovery period (following the 12-week exposure period). These findings suggest that the secretion of ICAM-1, MCP-1, and MIP-2 by rat pleural mesothelial cells may contribute to amosite-induced pleural inflammation.

• KGF and HGF are growth factors for mesothelial cells in pleural lavage fluid after intratracheal asbestos. I.Y. Adamson, J. Bakowska. 2001;27(7):605-16. PubMed · Publisher

  Abstract

  Mesothelial cells proliferate soon after asbestos deposition in the lung. The present study investigates whether the known mesothelial cell mitogens keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF) are present in the lung and specifically in the pleural cavity during the phase of mesothelial cell growth. Rats received 1 mg crocidolite asbestos in 0.5 mL water by intratracheal instillation and were killed up to 2 weeks later; tritiated thymidine was injected 1 hour before death. Bronchoalveolar lavage (BAL) and pleural lavage (PLL) were performed. Increased inflammatory cell numbers and protein levels were found in BAL but also in PLL at 1 day after asbestos deposition. In lung sections, labeling of mesothelial cells increased > 10-fold at day 1 and stayed above normal for 1 week. During this period, the levels of HGF and KGF were significantly raised in both BAL and PLL fluids. The PLL fluid had mitogenic activity for mesothelial cells in culture and this effect was significantly reduced by antibodies to HGF and KGF. The results indicate that fiber deposition in the airspaces rapidly induces lung injury and inflammation, in which growth factors for mesothelial cells KGF and HGF are secreted. These factors reach the pleural cavity at the time when mesothelial cell proliferation occurs. It is possible that the activated, dividing mesothelial population may then be more susceptible to DNA damage by any translocated fibers.

• Primary lung fibroblasts from the 129 mouse strain exhibit reduced growth factor responsiveness in vitro. D.M. Brass, S.Y. Tsai, A.R. Brody. 2001;27(8):639-53. PubMed · Publisher

  Abstract

  Lung fibroblasts are activated to proliferate and produce connective tissue during the development of lung fibrosis. The 129 mouse strain does not develop asbestos-induced fibrogenesis, whereas several other inbred strains rapidly respond to inhaled fibers. Thus, in the experiments presented here, we have compared the responses of primary lung fibroblasts isolated from 129 and C57BL/6 mice. The 129 and C57BL/6 mouse lung fibroblasts (MLFs) proliferated similarly in 10% fetal bovine serum (FBS), but after quiescence, the 129 MLFs grew more slowly in serum and responded less to the BB isoform of platelet-derived growth factor. This is consistent with our finding that the mRNA for the PDGF-a receptor exhibits reduced expression by the 129 MLFs compared to those from C57BL/6 mice. Fibroblasts from the SJL mouse strain, from a C57BL/6-129 hybrid, and from the 3T3 cell line all proliferated more vigorously than MLFs from the 129 mice. In addition, the 129 MLFs exhibited reduced expression of alpha1 procollagen mRNA consequent to treatment with tumor necrosisfactor alpha. Based on these new findings, we suggest that the reduced fibrogenesis in asbestos-exposed 129 mice is due to an intrinsic difference in the ability of the lung fibroblasts to respond to peptide growth factors.

• Asbestos exposure induces MCP-1 secretion by pleural mesothelial cells. S. Tanaka, N. Choe, A. Iwagaki, et al. 2000;26(4):241-55. PubMed · Publisher

  Abstract

  We showed previously that both crocidolite and chrysotile asbestos inhalation induced a persistent macrophage inflammatory response within the pleural space of the rat. We postulated that the stimulus for pleural macrophage recruitment after asbestos exposure was the induction of monocyte chemoattractant protein-1 (MCP-1) synthesis by pleural mesothelial cells. To test this hypothesis, rat pleural mesothelial cells (RPMC) were cultured with or without chrysotile or crocidolite asbestos fibers (8 micrograms/cm2) in the presence (50 ng/mL) or absence of either tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 beta (IL-1 beta). MCP-1 mRNA expression was assessed by RT-PCR in RPMC cultured for 2 to 24 hours, and MCP-1 protein secretion was measured by ELISA in conditioned medium from 24-hour and 48-hour cultures. Crocidolite and chrysotile fibers induced MCP-1 mRNA expression in RPMC which was maximal after 12 hours in the absence of cytokines, but which peaked after 2 hours when RPMC were challenged with asbestos + TNF-alpha or IL-1 beta. Both types of asbestos also significantly increased MCP-1 protein secretion after 24 and 48 hours (P < .0001), an effect that was potentiated by cytokine stimulation. Rats exposed by inhalation to either chrysotile or crocidolite asbestos fibers also had greater amounts of MCP-1 protein in their pleural lavage fluid than did sham-exposed rats. These findings suggest that MCP-1 secretion by RPMC may have a role in the initiation and/or potentiation of asbestos-induced pleural injury.

• Asbestos stimulation triggers differential cytokine release from human monocytes and alveolar macrophages. L.J. Geist, L.S. Powers, M.M. Monick, et al. 2000;26(1):41-56. PubMed · Publisher

  Abstract

  Inhalation of asbestos fibers results in a variety of lung diseases, including pulmonary fibrosis. Various animal models have demonstrated the importance of cytokines in the pathogenesis of pulmonary fibrosis. Alveolar macrophages from patients exposed to asbestos spontaneously release increased amounts of cytokines. The purpose of these studies was to determine whether asbestos directly stimulates cytokine release from human alveolar macrophages after in vitro exposure. We demonstrate that, although asbestos triggers cytokine release from blood monocytes, normal alveolar macrophages do not respond to asbestos stimulation with cytokine release. However, normal alveolar macrophages are activated by asbestos particles, in vitro, as determined by the upregulation of mRNAs for cytokines, and activation of the p38 kinase, which has been shown to be important in the translation of cytokine message into protein. These studies demonstrate that asbestos stimulates both normal blood monocytes and normal alveolar macrophages, but that there is a block in translation of cytokine mRNAs in the macrophages.

1990s

• Chrysotile asbestos and H2O2 increase permeability of alveolar epithelium. S.Y. Gardner, A.R. Brody, J.B. Mangum, et al. 1997;23(1):1-16. PubMed · Publisher

  Abstract

  The alveolar epithelium contains tight junctions and provides a barrier to passage of potentially injurious substances into the pulmonary interstitium. Alveolar epithelial injury is hypothesized to be an important early event in the pathogenesis of asbestosis. Mechanisms that may contribute to alveolar epithelial cell injury following asbestos exposure include the physicochemical interactions between asbestos fibers and cells, and the generation of reactive oxygen species such as hydrogen peroxide (H2O2). The present study examined changes in transepithelial resistance (Rt) (a measure of barrier function) and permeability of alveolar epithelium after chrysotile asbestos and H2O2 exposure. Alveolar epithelial cell monolayers, obtained from isolation of rat alveolar type II cells and grown on porous supports, were exposed to chrysotile asbestos or polystyrene beads (control) at concentrations of 5, 10, and 25 micrograms/cm2 for 24 h. In separate experiments, monolayers were exposed to H2O2 at concentrations of 50, 75, and 100 microM for 1 h Rt was measured using a voltohmmeter. Prior to treatment, monolayers had a high Rt (> 2000 ohms.cm2). Permeability was assessed by measuring flux of [3H]sucrose from apical to basolateral compartments. Cytotoxicity was evaluated by lactate dehydrogenase (LDH) and preincorporated [14C]adenine release. The morphological integrity of the monolayers was evaluated by scanning electron microscopy. Chrysotile asbestos and H2O2 exposure resulted in dose-dependent decrease in alveolar epithelial Rt and increases in permeability under conditions that did not result in over cytotoxicity. These results demonstrate that both chrysotile asbestos and H2O2 have effects on alveolar epithelial Rt and permeability and suggest a potential role for the alveolar epithelium in mediation of asbestos-induced pulmonary interstitial disease.

• Enhancement of the macrophage oxidative burst by immunoglobulin coating of respirable fibers: fiber-specific differences between asbestos and man-made fibers. I.M. Hill, P.H. Beswick, K. Donaldson. 1996;22(2):133-48. PubMed · Publisher

  Abstract

  The ability of long amosite asbestos fibers (LFA), vitreous fibers (MMVF 21 and CODE 100/475), and ceramic fibers (silicon carbide and RCF 1) to stimulate superoxide production in isolated rat alveolar macrophages is examined. The cells were exposed to both naked fibers (uncoated) and fibers coated with rat immunoglobulin (IgG), a normal component of lung lining fluid. The affinity for IgG of the various fibers was assessed by quantifying the binding of 125I-labeled IgG onto the fiber surface. Naked fibers stimulated a modest release of superoxide anion from alveolar macrophages, which was not obviously dose dependent. When IgG was adsorbed onto fibers of MMVF 21 and RCF 1, there was a dramatic increase in superoxide release, which correlated well with their high affinity for IgG.IgG-adsorbed code 100/475 and silicon carbide whiskers (SiCW) stimulated only modest superoxide release, and the fibers showed a correspondingly poor affinity for the opsonin. Conversely, the adsorbed fibers of LFA, generated a dramatic increase in superoxide release from the macrophages, despite a relatively poor adsorption of IgG. This study demonstrates the potential for components of the lung lining fluid to modify the response of alveolar macrophages to respirable natural and man-made fibers. It also draws attention to fiber-specific differences in adsorptive capacity and subsequent biological activity between these fiber types in vitro and, by implication, in vivo.

• Human alveolar macrophage cytokine release in response to in vitro and in vivo asbestos exposure. R.C. Perkins, R.K. Scheule, R. Hamilton, et al. 1993;19(1):55-65. PubMed · Publisher

  Abstract

  The lung macrophage is proposed to be involved in the development of asbestos-induced pulmonary fibrosis. Knowledge of the effects of long-term asbestos exposure on lung macrophage cytokine release should better define the role of the macrophage in fibrogenesis. This study examines the effects of acute in vitro asbestos exposure and chronic in vivo asbestos exposure on human alveolar macrophage cytokine release. As indicators of asbestos-induced macrophage activation, the cellular release of IL-1 beta, TNF-alpha, IL-6, GM-CSF, and PGE2 was measured during a 24-h in vitro culture. Alveolar macrophages from normal volunteers were cultured in vitro with chrysotile asbestos. Of the factors measured, only TNF-alpha was elevated in response to asbestos exposure. Alveolar macrophages from asbestos-exposed individuals were placed into one of two groups based on their exposure history. These two groups were matched for age, smoking history, and diagnosis; none met the criteria for asbestosis. Cells isolated from subjects that had been exposed to asbestos for more than 10 years secreted enhanced basal amounts of IL-1 beta, TNF-alpha, IL-6, and PGE2, while those who had been exposed for less than 10 years did not. The results indicate that while asbestos had minimal acute effects on cytokine production by the human alveolar macrophage, intense, chronic exposure to asbestos leads to the enhanced basal release of significant amounts of several cytokines that have activity for the fibroblast, even in the absence of overt fibrosis.

• Collagen synthesis and degradation during the development of asbestos-induced pulmonary fibrosis. M.G. Arden, I.Y. Adamson. 1992;18(1):9-20. PubMed · Publisher

  Abstract

  Although pulmonary fibrosis results from exposure to a high level of asbestos, the relative contributions of increased synthesis and/or reduced degradation of total collagen and of any specific type of collagen are not clear. To examine collagen turnover, rats were instilled with crocidolite fibers via the trachea and killed at 1, 2, 4, 6, and 8 weeks. The left lobe was used to determine collagen synthesis by incubating lung pieces with [3H]proline and subsequently measuring 3-hydroxyproline (HYP). Collagenolytic activity was estimated from the release of soluble HYP after incubation of lung homogenates for 48 h. Ratios of collagen types I and III were assayed by gel electrophoresis, both on whole lung and on the labeled homogenate. As fibrosis develops, both total HYP and HYP per dry weight increase at 2 weeks and continue to rise over the experimental period with no differences in the ratio of total types I:III collagens. However, newly synthesized collagen showed an increase in type III at 2 weeks and later a higher proportion of type I collagen when compared with the control. Total collagenolytic activity of asbestos-treated lungs was the same as controls when expressed per dry weight, but was reduced when calculated per unit of collagen. However, active collagenolytic activity was lower than control values when expressed by HYP content and per dry weight at all times after asbestos. The results suggest that reduced degradation of collagen contributes to the fibrotic process in addition to the progressive increase in collagen synthesis, particularly the type I form.

• Intratracheal injection of crocidolite asbestos depresses the secretion of tumor necrosis factor by pleural leukocytes in vitro. X.Y. Li, D. Lamb, K. Donaldson. 1992;18(3):359-72. PubMed · Publisher

  Abstract

  Tumor necrosis factor (TNF) is a cytokine released predominantly by monocytes/macrophages that has been shown to modulate a variety of different immune and metabolic functions. To understand the regulatory mechanisms of TNF in governing responses in the pleural cavity following deposition of fibrous dust in the airspace of the lung, we studied the capability of leukocytes, lavaged from the pleural cavity, to release TNF in culture. TNF production by lavaged pleural leukocytes was measured using the L-929 TNF-sensitive cell line, after intratracheal instillation of crocidolite asbestos. A high level of TNF activity was found in the supernatants of normal, unstimulated pleural leukocytes; the addition of 100 ng/ml lipopolysaccharide to the culture increased the activity up to threefold. Following intratracheal instillation of 5 mg crocidolite asbestos, the pleural leukocytes secreted less TNF than the control. With increasing mass of intratracheally instilled asbestos, there was a dose-dependent reduction in TNF release. Changes in the population of the pleural leukocytes or their number could not be related to variation in TNF activity. These results suggest that exposure of rat lungs to crocidolite asbestos by intratracheal instillation affects the response of pleural leukocytes without causing changes in the population. Such changes in the bronchoalveolar space may be related to the pleural pathology found in asbestos-exposed individuals.

• Immunologic aspects of pneumoconiosis. R.K. Scheule, A. Holian. 1991;17(4):661-85. Review PubMed · Publisher

  Abstract

  This review summarizes recent research bearing on the role played by cells of the immune system in the development of pneumoconiosis. Findings related to the cellular and humoral immune responses to silica and asbestos are highlighted. Experimental results from humans and animal models are integrated into our current understandings of cellular and cytokine-mediated pathways leading to the generation of immune responses that may contribute to fibrogenesis and fibrosis. Potential mechanisms leading to the generation of an immune response by particulates are discussed, together with the indirect effects of particulates on fibroblasts by way of the cytokine network in the lung. Finally, suggestions are given for future research to help further elucidate the relationships between the cellular components of the immune system of the lung and the fibroblast that lead to fibrosis.

• Influence of continued asbestos exposure on the outcome of asbestosis in sheep. R. Bégin, A. Cantin, S. Massé. 1991;17(5):971-84. PubMed · Publisher

  Abstract

  Clinical recognition of asbestosis is generally followed by exclusion of the worker from the active workforce and appropriate compensation. Given the better industrial hygiene conditions of the 1990s, and a recent report suggesting that low-level asbestos exposure may not affect progression of asbestosis, the medical rationale to pension asbestos workers with early asbestosis has been questioned in the legal courts. To study the influence of asbestos exposure after established asbestosis, we enrolled 25 sheep. Ten were normal controls (group A) and 15 had asbestosis, after 2 years of repeated 10-day interval, 100-mg chrysotile exposure (Eur Respir J 3:81-90, 1990). The asbestotic sheep were divided into a group of five without further asbestos exposure (group B), a group of five with continued exposure at induction doses (group C), and a group of five with continued exposure of 10% induction doses (group D). All were followed by chest radiography, lung function, and lung lavage at 3-month intervals and histopathology when appropriate. During the 12-month study, mortality occurred only in groups C and D (40% in both, P less than .02). Chest radiograph and lung function were worse in groups C and D. The enhanced macrophagic and neutrophilic alveolitis observed on lung lavage and the pathological findings in the deceased sheep suggested progression of asbestosis and bacterial infections as the major contributors to the higher mortality of sheep in groups C and D. In conclusion, asbestos exposure after disease recognition was associated with increased mortality in our sheep and this was largely associated with progression of asbestosis and added lung infection.

• Inorganic particles induce secretion of a macrophage homologue of platelet-derived growth factor in a density-and time-dependent manner in vitro. R.M. Schapira, A.R. Osornio-Vargas, A.R. Brody. 1991;17(6):1011-24. PubMed · Publisher

  Abstract

  The inhalation of inorganic dust can lead to the development of interstitial pulmonary fibrosis, characterized by the accumulation of fibroblasts and connective tissue matrix in the lung interstitium. The fibrosis causes alterations in the architecture of the lung parenchyma, resulting in abnormal gas exchange and hypoxemia. In a rat model of asbestos exposure, inhaled fibers are deposited on alveolar duct bifurcations, followed by an accumulation of alveolar macrophages at the sites of dust deposition. The alveolar macrophage is thought to be a major mediator of the pulmonary inflammatory response to inhaled dust. Platelet-derived growth factor (PDGF) is a cytokine that has potent chemotactic and mitogenic effects on mesenchymal cells, such as fibroblasts and smooth muscle cells. We studied the secretion of an alveolar macrophage-derived homologue of PDGF in response to carbonyl iron spheres or chrysotile asbestos fibers in vitro. We demonstrate here that rat alveolar macrophages attached to a plastic substrate produce 69 +/- 79 picograms (pg) of PDGF per 10 million macrophages. This is similar to amounts recovered from human platelets. In contrast, macrophages exposed to iron spheres secrete 429 +/- 177 pg of PDGF/10(6) macrophages after 24 h in culture. Exposure to asbestos fibers increased the PDGF production to 628 +/- 213 pg/10(6) cells. PDGF secretion was influenced by the particles in a density- and time-dependent manner. We hypothesize that PDGF and other cytokines secreted by macrophages mediate the development of dust-induced lung disease.

• Asbestos-induced release of a human alveolar macrophage-derived neutrophil chemotactic factor. A.A. Hayes, T.J. Venaille, A.H. Rose, et al. 1990;16(2):121-30. PubMed · Publisher

  Abstract

  Neutrophils accumulate in the alveoli of asbestos-exposed individuals. In determining whether asbestos fibers induce the release of neutrophil chemotactic factor (NCF) from human alveolar macrophages, alveolar macrophages (10(6) cell/mL) obtained by bronchoalveolar lavage from six non-asbestos-exposed control subjects were exposed to crocidolite (0.1 and 1 mg/mL), chrysotile (1 mg/mL), or medium alone for 4 h, and NCF activity was measured in the supernatants in a 48-well microchemotaxis chamber with polycarbonate membrane filters (pore size, 3 microns) and purified human neutrophils. Alveolar macrophages in medium alone released negligible amounts of NCF (4 +/- 1 neutrophils per high-power field [N/HPF]). When macrophages were exposed to crocidolite (0.1 and 1 mg/mL), significant NCF release occurred (43 +/- 9 and 105 +/- 32 N/HPF, respectively; p less than 0.01 for each amount compare to alveolar macrophages cultured in medium alone). Chrysotile (1 mg/mL) induced similar NCF release (96 +/- 14 N/HPF; p less than 0.01 compared to unstimulated alveolar macrophages). Partial characterization of the NCF by Sephadex G-25 fine gel filtration demonstrated a molecular size of less than 1,000 daltons. These results show that human alveolar macrophages release NCF after exposure to asbestos. Release of NCF by alveolar macrophages in asbestos-exposed individuals may play a central role in the pathogenesis of asbestosis.

1980s

• Secretion of fibronectin by mineral dust-derived alveolar macrophages and activated peritoneal macrophages. R. Davies, G. Erdogdu. 1989;15(2):285-97. PubMed · Publisher

  Abstract

  The in vitro secretion of fibronectin by rat alveolar macrophages recovered following the intratracheal instillation of various mineral dusts was examined using a competitive enzyme-linked immunoassay (CELIA) method. Cells derived with the fibrogenic dusts DQ12 quartz and UICC crocidolite asbestos had elevated rates of fibronectin secretion when compared ith those derived from titanium dioxide or saline. The in vitro culture of alveolar macrophages with dusts did not lead to elevated rates of fibronectin secretion, suggesting that mechanisms other than the direct interaction between dusts and macrophages may be responsible for elevated rates of fibronectin secretion by cells exposed to fibrogenic dusts. This suggests that fibronectin deposition seen in pneumoconiotic lesions in immunohistochemical studies may in part have been derived from macrophages. Thioglycollate-induced activated mouse peritoneal macrophages secreted significantly less fibronectin than resident peritoneal macrophages, a finding contrasting with those of Tsukamoto et al. [7].

• The distribution of amosite asbestos fibers in the lungs of workers with mesothelioma or carcinoma. A. Churg, B. Wiggs. 1989;15(5):771-83. PubMed · Publisher

  Abstract

  We have previously shown that there are differences in the sizes of fibers of amosite asbestos in different parts of the lung in workers with relatively high asbestos exposure and malignant pleural mesothelioma. To determine whether this distribution pattern is specific to cases of mesothelioma, we compared the fiber distribution in the lungs of 20 cases of mesothelioma and 10 cases of carcinoma of the lung. The two test groups were statistically identical in terms of age, and exposure period, and overall both groups had very similar mean fiber concentrations and mean fiber sizes. When individual sampling sites within the lung were considered, neither group showed preferential fiber concentration in any area. However, there were definite differences in the intrapulmonary fiber size distribution both within and between the two groups: Cases of mesothelioma showed accumulation of lung fibers in the peripheral upper lobe with shorter central upper lobe fibers. The lung cancer cases demonstrated a reverse pattern, with shorter fibers in the peripheral compared to central upper lobe, but accumulations of long fibers in the peripheral lower lobe. Fiber surfaces and masses showed similar differences among sample sites. We conclude that (1) there is no evidence for fiber concentration variations in different portions of the lung; (2) there is strong evidence for variations in fiber sizes in different portions of the lung, and these differences are most clearly related to fiber length, surface area, and mass; (3) contrary to data from experimental animals, there are no clear gravitational effects on fiber distribution in humans; and (4) there are reproducible differences in intrapulmonary fiber size distribution between mesothelioma and lung cancer cases. These differences may be a manifestation of individual handling of mineral particles because of structural variations in individual lungs.

• Cigarette smoke potentiates asbestos-induced airflow abnormalities. J.L. Wright, V. Tron, B. Wiggs, et al. 1988;14(4):537-48. PubMed · Publisher

  Abstract

  It has been suggested that exposure to both asbestos and cigarette smoke can produce worse parenchymal lung disease than exposure to asbestos alone. Using a guinea pig model of asbestos administration that produces primarily airway disease and associated airflow abnormalities, we showed previously that the combination of asbestos and smoke acts synergistically to produce more marked increases in tissue collagen, fibrosis of airway walls, and early interstitial fibrosis than are seen with asbestos alone. To investigate the functional effects of these morphological and biochemical abnormalities, pulmonary function tests for volumes and flows, including lung volumes, pressure-volume curves, and flow-volume curves, were performed. By themselves, both smoke and asbestos produced increases in total lung capacity (TLC), residual volume (RV), and functional residual capacity (FRC); the two agents together made all these changes worse than either one alone. Both smoking and asbestos moved the pressure-volume curve upward, and the effects of the two agents together were again greater than either alone. Similarly, both smoke and asbestos decreased flows, and the two agents produced more severe impairment than either one by itself. The changes in volumes, pressure-volume curve, and flows correlated with both increased thickness of small airway walls and increases in airspace size. These observations indicate that, at least in this guinea pig model, cigarette smoke can potentiate the functional consequences of asbestos exposure.

• Clearance of chrysotile asbestos from human lung. A. Churg, L. DePaoli. 1988;14(5):567-74. PubMed · Publisher

  Abstract

  In contrast to amphibole asbestos, chrysotile asbestos fails to accumulate in human lungs. The reason for this phenomenon is not known. To examine this problem, we extracted chrysotile and tremolite fibers from the lungs of 11 chrysotile miners and millers whose last exposure was within 2 years of death and 12 chrysotile miners and millers whose last exposure was greater than 12 years (7 with last exposure 12-15 years and 5 with last exposure 22-25 years) before death. Fibers were extracted by bleach digestion, and concentrations, compositions, and sizes were determined by analytical electron microscopy. Native UICC Canadian chrysotile was used as a composition standard. Compared to the standard, there was minor loss of magnesium at 2 years and additional very slight loss after 12 years. The ratio of chrysotile to tremolite concentration did not change with time. There was also no evidence of increasing fiber length with time from last exposure. These data indicate that accumulation of amphibole compared to chrysotile in human lungs does not reflect either long-term dissolution of chrysotile or long-term preferential clearance of chrysotile compared to amphibole. Contrary to results of animal studies, fiber length in humans does not increase with time since last exposure. These findings imply that the failure of chrysotile to accumulate in human lungs reflects events that occur early after exposure rather than long-term clearance mechanisms.

• Pulmonary macrophages are attracted to inhaled particles through complement activation. D.B. Warheit, L.H. Overby, G. George, et al. 1988;14(1):51-66. PubMed · Publisher

  Abstract

  Pulmonary macrophages play a central role in clearing inhaled particles from the lung. Previously, we showed that inhaled asbestos fibers activate complement-dependent chemotactic factors on alveolar surfaces to facilitate macrophage recruitment to sites of fiber deposition. In the studies presented here, we have tested a variety of inorganic particles for complement activation in vitro and correlated these data with results on particle-induced macrophage accumulation in vivo. We found that significant chemotactic activity was activated in rat serum and concentrated lavaged proteins by chrysotile and crocidolite asbestos, iron-coated chrysotile asbestos, fiberglass, and wollastonite fibers, as well as by carbonyl iron and zymosan particles. Ash from the Mt. St. Helens volcano did not induce chemotactic activity in either the serum or lavaged proteins. Rats were exposed to brief aerosols of each of the particles listed above (except zymosan). All the particle types studied were deposited primarily at first alveolar duct bifurcations. In addition, all of the particles, except Mt. St. Helens ash, induced at 48 h postexposure significant accumulations of macrophages at these sites. Time-course studies of carbonyl iron particle exposure demonstrated that iron induced a rapid macrophage response, but both particles and phagocytic macrophages were cleared from alveolar surfaces within 8 days after exposure. The Mt. St. Helens ash induced no macrophage accumulation at any time postexposure. We conclude that particles with a wide variety of physical characteristics are capable of activating complement and consequently attracting macrophages, both in vitro and in vivo. We suggest that complement activation is a mechanism through which pulmonary macrophages can detect inhaled particles on alveolar surfaces.

• Asbestos-induced fibrosis in rats: increase in lung mast cells and autacoid contents. I. Keith, R. Day, S. Lemaire, et al. 1987;13(3):311-27. PubMed · Publisher

  Abstract

  Adult male Wistar rats were treated with one tracheal instillation of 5 or 10 mg chrysotile B asbestos fibers in 0.5 ml saline, or 0.5 ml saline only (controls). Rats were killed at 1, 3, and 6 months postinstillation. Serotonin and histamine were quantitated in lung tissue homogenate using high-performance liquid chromatography with electrochemical and fluorometric detection, respectively. Serotonin was also quantitated in the cytoplasm of grouped (NEB) and individual (NEC) neuroendocrine cells and in mast cells using formaldehyde vapor-induced fluorescence and microspectrofluorometry, and density indices of NEBs, NECs, and mast cells were determined. Tissue edema, fibrotic lesions, and medial hypertrophy of pulmonary arterioles were assessed morphometrically. Test rats had higher pulmonary serotonin and histamine levels than controls at 1, 3, and 6 months. They also had higher cellular serotonin in NEBs at 1 month, but not in NECs, and tended to have higher serotonin levels in mast cells at 6 months. Mast cell numbers were higher among tests at 1 and 3 months, whereas NEBs and NECs were unchanged by asbestos. There was no difference between tests and controls in the amount of tissue edema at any time. However, all test rats had distinct lung lesions characterized by peribronchiolar fibrosis and bronchiolitis obliterans. No such lesions were present among control rats. Typically, mast cells were located immediately beneath the epithelial basal lamina of the bronchiolar fibrotic projections and at their stalks, whereas no mast cells were noted beneath normal epithelium, indicating a role of mast cells in asbestos-induced peribronchiolar fibrosis. Moreover, arteriolar medial hypertrophy at all three ages in conjunction with the increased levels of serotonin was an index of putative chronic pulmonary hypertension. Our results suggest that asbestos-induced rises in serotonin and histamine are due primarily to increased numbers of mast cells.

• Pathophysiologic correlations in asbestos-induced airway disease in the guinea pig. J.L. Wright, V. Tron, D. Filipenko, et al. 1986;11(4):307-17. PubMed · Publisher

  Abstract

  To determine whether asbestos-induced changes in the structure of the walls of small airways might be associated with abnormalities of pulmonary function, guinea pigs were given 10 mg of amosite asbestos (test group) or saline (control group) by intratracheal instillation. Pulmonary function tests performed 6 months later revealed significant increases in FRC, RV, and TLC in the test group. Measurement of airway wall thickness showed that both membranous and respiratory bronchioles were significantly thickened in the test group; this group also had airways of smaller internal diameter than the controls. Analysis for lung collagen content as hydroxyproline showed a 50% increase in the asbestos exposed animals. There was, however, only minimal and very focal interstitial fibrosis (asbestosis) in the lung parenchyma. Analysis of fiber size indicated that the fibers obtained by digestion of the tissue or from the lavage fluid were significantly longer and wider than those in the original asbestos sample; however, the tissue contained considerably larger fibers than the lavage fluid. We conclude that: Asbestos can produce airway fibrosis and narrowing causing air trapping on pulmonary function examination; this process occurs in the absence of significant interstitial fibrosis of the parenchyma (asbestosis), implying that abnormalities of pulmonary function which are consistent with airflow obstruction in asbestos exposed animals can be caused by pathologic changes in the small airways alone; long asbestos fibers are preferentially retained in the lung, and the longest fibers appear to be in a compartment inaccessible to lavage, presumably, in this model, in airway walls. Enhanced penetration of long fibers into tissue may be one reason why long fibers are more pathogenic than short ones.

• Pulmonary bombesin in experimentally induced asbestosis in rats. R. Day, I. Lemaire, S. Masse, et al. 1985;8(1):1-13. PubMed · Publisher

  Abstract

  The pulmonary levels of immunoreactive bombesin in normal rat lungs and rat lungs exposed to asbestos were determined. Experimental asbestosis was induced in rats by a single intratracheal injection of 5 mg or 10 mg UICC standard Canadian Chrysotile B while sham-operated control rats received only the saline carrier. At 1, 3, 6, and 9 months following instillation, 5 animals of each group were sacrificed and the lungs removed. A section was kept for morphologic analysis, while the remaining portion was submitted to acid extraction and later measured for bombesin content by radioimmunoassay (RIA). The Chrysotile B-exposed tissues displayed the characteristic features typical of the fibrotic state associated with asbestosis one month following exposure and thereafter. The pulmonary bombesinlike immunoreactivity ranged from 4.5-7.5 pmoles/g tissue in normal rat lung, and these levels remained unchanged at 1 and 3 months after asbestos exposure. However at 6 and 9 months, significant increases ranging between 2 and 2.5 fold were observed. The initial increases in bombesin levels occurred at a later time (6 months) than those already observed for vasoactive intestinal peptide (VIP) (3 months). However, VIP levels plateaued at 9 months, while those of bombesin were still increasing. High-pressure liquid chromatography (HPLC) coupled with RIA demonstrates the presence of two bombesin-immunoreactive peaks in normal rat lung, the major one coeluting with the mammalian bombesinlike peptide gastrin-releasing peptide (GRP) and the other one being presumably a C-terminal portion of GRP. These data indicate that immunoreactive bombesin and VIP are selectively increased at different times following asbestos instillation and that these changes occur after the onset of fibrosis and the appearance of well-defined fibrotic lesions.

• Changes in numbers and dimensions of chrysotile asbestos fibers in lungs of rats following short-term exposure. V.L. Roggli, A.R. Brody. 1984;7(2):133-47. PubMed · Publisher

  Abstract

  Previous studies from this laboratory have demonstrated that in rats exposed briefly to aerosolized chrysotile asbestos, fibers initially deposited in the distal lung impact primarily at bifurcations of alveolar ducts. Subsequently, there is a progressive decrease in the numbers of fibers seen by scanning electron microscopy at the bifurcations with increasing time from initial exposure. The purpose of the present study was to assess the number and dimensions of fibers deposited in the lungs of these rats and to determine how these parameters changed at various intervals after the termination of exposure. This was accomplished using a sodium hypochlorite digestion-concentration technique to recover the fibers on a membrane filter. The numbers and dimensions of the fibers were then assessed using scanning electron microscopy. Utilizing these data, the mass of asbestos retained in the lung was calculated with a newly developed formula. Twenty-three percent of the respirable fraction was deposited in the lungs, and 19% of this amount was still present 31 days after exposure. Over the 31 days, there was a progressive increase (p less than 0.05) in mean fiber length and a significant decrease (p less than 0.05) in the diameter of the population of fibers retained in the lung. Such data should prove useful in attempting to understand the progressive pathogenesis of asbestos-induced interstitial lung disease, which seems to be related, at least in part, to the dimensions of the inhaled fibers.

• Surface morphology and correlated phagocytic capacity of pulmonary macrophages lavaged from the lungs of rats. D.B. Warheit, L.H. Hill, A.R. Brody. 1984;6(1):71-82. PubMed · Publisher

  Abstract

  The morphology and phagocytic capacities of pulmonary macrophages recovered by lavage from normal rats were studied in vitro after incubation under various culture conditions. Most adherent macrophages (73 +/- 6%) were flat and exhibited ruffled surfaces. Phagocytosis of carbonyl iron beads by pulmonary macrophages was quantitated using secondary and backscattered electron microscopic techniques. Our results show that macrophage surface features correlate with the phagocytic capacity of the cells, that is, macrophages with ruffled membranes phagocytose a significantly greater number of iron beads than do smooth, unruffled cells (P less than or equal to 0.001). Moreover, an enhanced percentage of smooth cells (48%) was found in populations of tracheobronchial macrophages; this finding correlated with a reduced phagocytic potential. When the percentages of smooth cells were increased experimentally by incubating cells with silica or varying pH conditions, the number of macrophages devoid of carbonyl iron beads was enhanced. The results show that smooth macrophages are functionally impaired compared with ruffled cells. These studies form the basis for assessing functional alterations of macrophages exposed in vivo to inhaled toxic particulates such as chrysotile asbestos and silica.

• Reaction of rat lungs to inhaled chrysotile asbestos following acute and subchronic exposures. B.E. Barry, K.C. Wong, A.R. Brody, et al. 1983;5(1):1-21. PubMed · Publisher

  Abstract

  Inhalation of asbestos fibers can cause fibrotic and neoplastic diseases in the lung. The early in vivo interactions between fibers and lung tissue that initiate these diseases have received little study. Male and female Fischer 344 rats were placed in inhalation chambers and exposed to 9.06 +/- 1.83 mg/m3 (average respirable mass) of chrysotile asbestos for 1 hr, 1 day, 7 hr/day for 5 days, or 5 days/week for 3 months. Qualitative examination of the tissue showed that, after 1 day, fibers were found not only in the alveolar macrophages, but also in the epithelium and interstitium of the alveolar region. After 3 months, numerous fibers were present in the epithelium and interstitium. Morphometric analysis of this tissue showed that these compartments were also the most significantly changed as a result of asbestos exposure. The majority of epithelial changes were attributable to a 57% increase in the number of type II cells and a 90% increase in their average cell volume. The interstitial cell population increased 58% with a 40% increase in the average cell volume. There was no significant increase in the volume of noncellular interstitium. A morphologic characterization of the interstitial cells showed that interstitial macrophages accounted for almost the entire increase in this population and that 88% of the fiber-containing cells were macrophages. Several interstitial macrophages contained membrane-bound inclusions which were shown by x-ray energy spectrometry to be microcalcifications. They were composed of rings of calcium phosphate granules around asbestos fibers. These microcalcifications may indicate sublethal cell injury caused by the presence of asbestos fibers in the cell cytoplasm. Fibers which enter but do not kil alveolar cells may be an essential component for the pathogenesis of lung disease caused by asbestos inhalation.

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