Chrysotile Stimulated UPA Activity and Mesothelioma Disease

One interesting study is called, "Expression and Activity of Urokinase and Its Receptor in Endothelial and Pulmonary Epithelial Cells Exposed to Asbestos" by Aaron Barchowsky, Robert R. Roussel, Ronald J. Krieser, Brooke T. Mossman and Melinda D. Treadwell - Toxicology and Applied Pharmacology - Volume 152, Issue 2, October 1998, Pages 388-396. Here is an excerpt: "Abstract - An elongated endothelial cell phenotype, which demonstrated increased ICAM-1-dependent neutrophil adherence, was induced when these cells were exposed to noncytotoxic concentrations of asbestos (Treadwellet al., Toxicol. Appl. Pharmacol.139, 62-70, 1996). The present study examined mechanisms underlying this phenotypic change by investigating the effects of asbestos on transcription factor activation and expression of urokinase-type plasminogen activator (uPA) and its receptor uPAR.In situzymography was used to compare the effects of these fibers on the activity of uPA. Cultures incubated with chrysotile or crocidolite asbestos, but not refractory ceramic fiber 1 (RCF-1), demonstrate localized cleavage of plasminogen, which was inhibited by amiloride. Immunocytochemistry showed that chrysotile-stimulated uPA activity was associated with a time-dependent augmentation of uPAR protein levels. RT-PCR analysis was used to investigate molecular mechanisms for these increases. Chrysotile asbestos, but not RCF-1, increased endothelial cell uPA message, relative to changes in β-actin mRNA. This response to asbestos was not limited to endothelial cells, since both uPA and uPAR mRNA levels increase in human bronchial epithelial BEAS-2B cells exposed to chrysotile fibers. Finally, both types of asbestos, but not RCF-1, increased nuclear levels of nuclear factor-kappaB (NF-κB), a transcription factor common to increased expression of ICAM-1 and uPA. These data demonstrate that asbestos caused fiber-specific activation of endothelial and pulmonary epithelial cells, resulting in phenotypes capable of facilitating tissue remodeling."

Another interesting study is called, "Transfection of a manganese-containing superoxide dismutase gene into hamster tracheal epithelial cells ameliorates asbestos-mediated cytotoxicity" by Brooke T. Mossman, Piyawan Surinrut, Bradford T. Brinton, Joanne P. Marsh, Nicholas H. Heintz, Barbara Lindau-Shepard and Jacquelin B. Shaffer - Free Radical Biology and Medicine - Volume 21, Issue 2, 1996, Pages 125-131. Here is an excerpt: "Abstract - To determine if overexpression of manganese-containing SOD (MnSOD) alters cell sensitivity to asbestos, an expression cassette containing murine MnSOD cDNA was cotransfected with pSV2neo, a plasmid conferring resistance to the antibiotic G418, into a diploid cell line of hamster tracheal epithelial (HTE) cells. Pools of G418-resistant transfectants were characterized by Southern and Northern blot analyses and enzyme activity assays. Although increases in MnSOD gene copies in individual cell pools ranged from approximately 7- to 86-fold in comparison to cells transfected with pSV2neo alone, steady-state levels of MnSOD mRNA were increased only by 1.4-to 2.3-fold. Despite modest increases in MnSOD mRNA, significant elevations in MnSOD enzyme activity were observed in pools of G418-resistant cells. MnSOD-transfected cell lines were more resistant to the cytotoxic effects of crocidolite asbestos using a sensitive colony-forming efficiency (CFE) assay. These data show that MnSOD has a direct role in cell defense against asbestos-induced cytotoxicity, an oxidant-dependent process."

Another interesting study is called, "A study of the short-term retention and clearance of inhaled asbestos by rats, using U.I.C.C. standard reference samples." By Middleton AP, Beckett ST, Davis JM. - Inhaled Part. 1975 Sep;4 Pt 1:247-58. Here is an excerpt: "Abstract - Rats have been dosed over a 6-week period with U.I.C.C. standard reference samples of amosite, crocidolite and chrysotile A, each at three concentrations: 1,5 and 10 mg/m3. Mass concentrations in the exposure chambers were monitored daily. Because the M.R.E. gravimetric sampler was found to undersample some of these dusts at high concentrations, a sampler with a vertical elutriator was developed. Data on other physical parameters of the dust clouds were also obtained and it was found that the fibre number (greater than 5 micron in length) vs. mass correlation varied markedly between asbestos varieties. After dusting, the rats were sacrificed in five batches over a period of 4 months. The lungs of some animals were retained for pathological examination. This did not reveal any fibrosis although large numbers of fibres were visible, mostly within alveolar macrophages. The remaining lungs were analysed for their asbestos contents by a method based upon infrared spectrophotometry. The clearance data confirm earlier published reports that for rats dosed at similar mass concentrations of chrysotile and amphibole, those dosed with chrysotile retain considerably less dust in their lungs. The data also suggest that the retention and clearance of amphibole abestos may be dose related. Some mathematical treatment of the clearance data has been undertaken."

We all owe a debt of gratitude to these fine researchers. If you found any of these excerpts interesting, please read them in their entirety.


Monty Wrobleski is the author of this article, for more information please click on the following links:

Depuy ASR Recall

Depuy ASR Recall

Mesothelioma Lawyer