Toll-like receptor 4 activation

11056-06-7

Bleomycin

Bleo Bleocin Blenamax Bleo-Kyowa Bleomycins NSC 125066

DTXSID1030862

D048031

MESH JNK Mitogen-Activated Protein Kinases

PR:000000046

PR TGF-beta

FMA:66768

FMA Epithelial cell

GO:0023052

GO signaling

GO:0001837

GO epithelial to mesenchymal transition

WIKI increased

WIKI occurrence

Bleomycin Bleomycin is a potent anti-tumour drug, routinely used for treating various types of human cancers (Umezawa et al., 1967; Adamson, 1976). Lung injury and lung fibrosis are the major adverse effects of this drug in humans (Hay J et al., 1991). Bleomycin is shown to induce lung fibrosis in experimental animals - in dogs (Fleischman et al., 1971), mice (Adamson IY and Bowden DH, 1974), hamsters (Snider GL et al., 1978) and is widely used as a model chemical to study the mechanisms of fibrosis in humans (reviewed in Moeller et al., 2008; Gilhodes et al., 2017). <ol> <li>Adamson, I. (1976). Pulmonary Toxicity of Bleomycin. Environmental Health Perspectives, 16, p.119.</li> <li>Adamson, IYR. and Bowden, DH. (1974). The Pathogenesis of Bleomycin-Induced Pulmonary Fibrosis in Mice. The American Journal of Pathology. 77(2), pp185-198.</li> <li>Fleischman, R., Baker, J., Thompson, G., Schaeppi, U., Illievski, V., Cooney, D. and Davis, R. (1971). Bleomycin-induced interstitial pneumonia in dogs. Thorax, 26(6), pp.675-682.</li> <li>Gilhodes, J., Julé, Y., Kreuz, S., Stierstorfer, B., Stiller, D. and Wollin, L. (2017). Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis. PLOS ONE, 12(1), p.e0170561.</li> <li>Hay, J., Shahzeidi, S. and Laurent, G. (1991). Mechanisms of bleomycin-induced lung damage. Archives of Toxicology, 65(2), pp.81-94.</li> <li>Moeller, A., Ask, K., Warburton, D., Gauldie, J. and Kolb, M. (2008). The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?. The International Journal of Biochemistry & Cell Biology, 40(3), pp.362-382.</li> <li>Snider GL., Celli, BR., Goldstein, RH., O'Brien, JJ. and Lucey, EC. (1978). Chronic interstitial pulmonary fibrosis produced in hamsters by endotracheal bleomycin. Lung volumes, volume-pressure relations, carbon monoxide uptake, and arterial blood gas studied. Am Rev Respir Dis. Feb; 117(2). pp289-97.</li> <li>Umezawa, H., Ishizuka, M., Maeda, K. and Takeuchi, T. (1967). Studies on bleomycin. Cancer, 20(5), pp.891-895.</li> </ol>

2018-01-01T16:45:53

2019-10-29T13:08:19

Carbon nanotubes, Multi-walled carbon nanotubes, single-walled carbon nanotubes, carbon nanofibres   Julie Mullera, Franc¸ois Huauxa, Nicolas Moreaub, Pierre Missona, Jean-Franc¸ois Heiliera, Monique Delosc, Mohammed Arrasa, Antonio Fonsecab, Janos B. Nagyb, Dominique Lison Julie Mullera, Franc¸ois Huauxa, Nicolas Moreaub, Pierre Missona, Jean-Franc¸ois Heiliera, Monique Delosc, Mohammed Arrasa, Antonio Fonsecab, Janos B. Nagyb, Dominique Lison

2018-01-01T17:51:04

2018-01-01T17:52:30

WCS_9606

common toxicological species humans

10090

NCBI mouse

10116

NCBI rat

Toll-like receptor 4 activation

TLR4 activation

Molecular

AOPWiki 2020-07-09T02:59:35

2020-07-09T02:59:35

Inactivation of PPARγ

Molecular

Following pulmonary exposure, the stressor interacts with cellular membranes of alveolar macrophages, other inflammatory cells, epithelial cells and proteins (lung surfactants) in the lung space. The stressor acts as an antagonist of PPARγ of epithelial and inflammatory cells in the lung.

AOPWiki 2017-02-15T02:43:41

2017-12-26T02:12:06

Activation, JNK

Cellular

CL:0000255

CL eukaryotic cell

AOPWiki 2017-02-15T04:43:20

2017-09-16T10:17:47

Activator protein 1 activation

AP-1 activation

Cellular

AOPWiki 2020-07-09T03:07:53

2020-07-09T03:07:53

Pin-1 activation

Cellular

AOPWiki 2020-07-09T03:10:16

2020-07-09T03:10:16

Latent Transforming growth Factor beta expression

TGFbeta expression

Cellular

AOPWiki 2020-07-09T03:14:13

2020-07-09T03:14:13

Activation, TGF-beta pathway

Cellular

CL:0000255

CL eukaryotic cell

AOPWiki 2017-02-15T03:51:12

2017-09-16T10:17:45

Epithelial Mesenchymal Transition

EMT

Cellular

Epithelial-mesenchymal transition (EMT) is a phenomenon in which the cells transit from epithelial-like into mesenchymal-like phenotypes (Huan et al., 2022; Tanabe, 2017; Tanabe et al., 2015). In cancer, cells exhibiting EMT features contribute to metastasis and drug resistance. It is known that D-2-hydroxyglurate induces EMT (Guerra et al., 2017; Jia et al., 2018; Mishra et al., 2018; Sciacovelli & Frezza, 2017). D-2-hydroxyglurate, an inhibitor of Jumonji-family histone demethylase, increased the trimethylation of histone H3 lysine 4 (H3K4) in the promoter region of the zinc finger E-box-binding homeobox 1 (ZEB1), followed by the induction of EMT (Colvin et al., 2016). Wnt5a induces EMT and metastasis in non-small-cell lung cancer (Wang et al., 2017). EMT is related to Wnt/beta-catenin signaling and is important for treatment-resistant cancer (Tanabe et al., 2016). TGFbeta induces EMT (Wendt et al., 2010). ZEB is one of the critical transcription factors for EMT regulation (Zhang et al., 2015). SNAI1 (Snail) is an important transcription factor for cell differentiation and survival. The phosphorylation and nuclear localization of Snail1 induced by Wnt signaling pathways are critical for the regulation of EMT (Kaufhold & Bonavida, 2014). Transcription factors SNAI1 and TWIST1 induce EMT (Hodge et al., 2018) (Mani et al., 2008). It is suggested that Sp1, a transcription factor involved in cell growth and metastasis, is induced by cytochrome P450 1B1 (CYP1B1), and promotes EMT, which leads to cell proliferation and metastasis (Kwon et al., 2016). <table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none; width:601px"> <tbody> <tr> <td style="background-color:#eaf1dd; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:601px"> Biological state   An epithelial-mesenchymal transition (EMT) is a biologic process in which epithelial cells are polarized, interact through their basal surface with basement membrane, and undergo biochemical changes to assume a mesenchymal cell phenotype. This phenotypic transformation has various characters such as enhanced migratory capacity, high invasiveness, elevated resistance to apoptosis, and greatly increased production of ECM components (Kalluri,  R.,  and  Neilson,  E.G.  2003). The completion of an EMT is signalled by the degradation of the underlying basement membrane and the formation of a mesenchymal cell that can migrate away from the epithelial layer in which it originated.    EMT has a number of distinct molecular processes like activation of transcription factors, expression of specific cell surface proteins, reorganization and expression of cytoskeletal proteins, production of ECM-degrading enzymes, and changes in the expression of specific microRNAs. These factors are used as biomarkers to demonstrate the passage of a  cell through an EMT.   Biological compartment Cellular Role in General Biology: Excessive proliferation of epithelial cells and angiogenesis mark the initiation and early growth of primary epithelial cancers. (Hanahan, D., and Weinberg, R.A. 2000). The subsequent acquisition of invasiveness, initially manifest by invasion through the basement membrane, is thought  to herald the onset of the last stages of the multi-step process that  leads eventually to metastatic dissemination, with life-threatening  consequences.  There has been an intense research going on in the genetic controls and biochemical mechanisms underlying the acquisition of the invasive phenotype and the subsequent systemic spread of the cancer cell.  Activation of an EMT program has been proposed as the critical mechanism for the acquisition of malignant phenotypes by epithelial cancer cells (Thiery, J.P. 2002).  Pre-clinical experiments such as mice models and cell culture experiments  has demonstrated  that carcinoma cells can acquire a mesenchymal phenotype and express mesenchymal markers such as α-SMA, FSP1, vimentin,  and desmin (Yang,  J.,  and  Weinberg,  R.A.  2008). These cells  are seen at the invasive front  of primary tumors and are considered to be the cells that eventually  enter into subsequent steps of the invasion-metastasis cascade, i.e.,  intravasation, transport through the circulation, extravasation, formation of micro metastases, and ultimately colonization (the growth  of small colonies into macroscopic metastases) (Thiery, J.P. 2002, Fidler, I.J., and Poste, G. 2008, Brabletz, T., et al. 2001). An  apparent  paradox  comes  from  the  observation  that  the  EMT-derived migratory cancer cells typically establish secondary colonies at distant sites that resemble, at the histopathological  level, the primary tumor from which they arose; accordingly,  they no longer exhibit the mesenchymal phenotypes ascribed to  metastasizing  carcinoma  cells.  Reconciling this behaviour with the proposed role of EMT as a facilitator of metastatic dissemination requires the additional notion that metastasizing cancer cells must shed their mesenchymal phenotype via a MET during  the course of secondary tumor formation (Zeisberg, M et al 2005). The tendency of  disseminated cancer cells to undergo EMT likely reflects the local  microenvironments that they encounter after extravasation into  the parenchyma of a distant organ, quite possibly the absence of  the heterotypic signals they experienced in the primary tumor that  were responsible for inducing the EMT in the first place (Thiery, J.P. 2002, Jechlinger, M et al 2002, Bissell, M.J et al 2002). These evidences indicate that induction of an EMT is likely to be a centrally important mechanism for the progression of carcinomas to a metastatic stage and implicates MET during the subsequent colonization process. However, many steps of this mechanistic model still require direct experimental validation. It remains unclear at present whether these phenomena and molecular mechanisms relate to and explain the metastatic dissemination of non-epithelial cancer cells. The entire spectrum of signaling agents that contribute to EMTs of carcinoma cells remains unclear. One  theory suggests that  the genetic and epigenetic alterations undergone by cancer cells during the course of primary tumor formation render them especially responsive to EMT-inducing heterotypic signals originating in the tumor-associated stroma. Oncogenes induce senescence, and recent studies suggest that cancer cell EMTs may also play a role in preventing senescence induced by oncogenes, thereby facilitating subsequent aggressive dissemination (Smit, M.A., and Peeper, D.S. 2008, Ansieau, S., et al. 2008, Weinberg, R.A. 2008).  In  the case of many carcinomas, EMT-inducing signals emanating  from the tumor-associated stroma, notably HGF, EGF, PDGF,  and TGF-β, appear to be responsible for the induction or functional  activation  in  cancer  cells  of  a  series  of  EMT-inducing  transcription factors, notably Snail, Slug, zinc finger E-box binding homeobox 1 (ZEB1), Twist, Goosecoid, and FOXC2 (Thiery, J.P. 2002, Jechlinger, M  et al 2002, Shi, Y., and Massague, J. 2003, Niessen, K., et al. 2008, Medici, D et al 2008, Kokudo,  T.,  et  al.  2008). Once expressed and activated, each of these transcription factors can act pleiotropically to choreograph the complex EMT program, more often than not with the help of other members of this cohort of transcription factors. The actual implementation by these cells of their EMT program depends on a series of  intracellular signaling networks involving, among other signal- transducing  proteins,  ERK,  MAPK,  PI3K,  Akt,  Smads,  RhoB,  β-catenin, lymphoid enhancer binding factor (LEF), Ras, and c-Fos  as well as cell surface proteins such as β4 integrins, α5β1 integrin, and αVβ6 integrin (Tse,  J.C.,  and  Kalluri,  R.  2007). Activation of EMT programs is also facilitated by the disruption of cell-cell adherens junctions and the cell-ECM adhesions mediated by integrins (Yang,  J.,  and  Weinberg,  R.A.  2008, Weinberg, R.A. 2008, Gupta, P.B  et al 2005, Yang,  J et al 2006, Mani, S.A., et al. 2007, Mani, S.A., et al. 2008, Hartwell, K.A., et al. 2006, Taki, M et al 2006)..   </td> </tr> </tbody> </table>

Loss of <a href="https://en.wikipedia.org/wiki/E-cadherin">E-cadherin</a> and cell polarity is considered to be a fundamental event in epithelial-mesenchymal transition. The simultaneous expression of epithelial (e.g. E-cadherin) and mesenchymal markers (e.g. N-cadherin and vimentin) within the airway epithelium are indicative for ongoing transition (Borthwick et al. 2009, 2010). <table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none; width:586px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:58px">   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:155px"> Method/ measurement referenc </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:73px"> Reliability   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:68px"> Strength of evidence   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:63px"> Assay fit for purpose   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:102px"> Repeatability/ reproducibility   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:67px"> Direct measure </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:58px"> Human cell line </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:155px"> qRT-PCR,cell viability assay, Western blotting,EdU incorporation assay </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:73px"> + </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:68px"> Strong </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:63px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:67px"> Yes </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:58px"> Human </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:155px"> IHC,micro array,qPCR, SNP array </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:73px"> + </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:68px"> Moderate </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:63px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px"> Yes </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:67px"> Yes </td> </tr> </tbody> </table> <ul> <li style="text-align:left">EMT can be detected by immunostaining with pro-surfactant protein-C (pro-SPC) and N-cadherin in idiopathic pulmonary fibrosis (IPF) lung in vivo (Kim et al., 2006).</li> <li style="text-align:left">EMT can be detected by immunostaining with vimentin in lung alveola in vivo (Kim et al., 2006).</li> <li style="text-align:left">EMT can be detected as the increased level of the transcription factors, zinc finger E-box-binding homeobox (ZEB), Twist and Snail (Huang et al., 2022).</li> </ul>

The key event is applicaple in Homo sapiens: <ul> <li style="text-align:left">Wnt5a expression leads to epithelial-mesenchymal transition (EMT) and metastasis in non-small-cell lung cancer in Homo sapiens (Wang et al., 2017).</li> <li style="text-align:left">WNT2 expression lead to EMT induction in Homo sapiens (Zhou et al., 2016).</li> <li style="text-align:left">EMT is induced in cancer and involved in cancer metastasis in Homo sapiens (Suarez-Carmona, Lesage, Cataldo, & Gilles, 2017) (Du & Shim, 2016).</li> </ul> Regulation of miRNA expression by DNA replication,damage and repair responses,transcription and translation has been proved in animals like mice,canine and cell line experiments.

UBERON:0000062

UBERON organ

CL:0000066

CL epithelial cell

Not Specified Unspecific

Not Specified

Not Otherwise Specified

High

Borthwick, L. A., Parker, S. M., Brougham, K. A., Johnson, G. E., Gorowiec, M. R., Ward, C., … Fisher, A. J. (2009). Epithelial to mesenchymal transition (EMT) and airway remodelling after human lung transplantation. Thorax, 64(9), 770–777. <a href="https://doi.org/10.1136/thx.2008.104133">https://doi.org/10.1136/thx.2008.104133</a> Borthwick, L. A., McIlroy, E. I., Gorowiec, M. R., Brodlie, M., Johnson, G. E., Ward, C., … Fisher, A. J. (2010). Inflammation and epithelial to mesenchymal transition in lung transplant recipients: Role in dysregulated epithelial wound repair. American Journal of Transplantation, 10(3), 498–509. <a href="https://doi.org/10.1111/j.1600-6143.2009.02953.x">https://doi.org/10.1111/j.1600-6143.2009.02953.x</a> Al Saleh, S., Al Mulla, F., & Luqmani, Y. A. (2011). Estrogen receptor silencing induces epithelial to mesenchymal transition in human breast cancer cells. PloS one, 6(6), e20610. Bissell, M. J., Radisky, D. C., Rizki, A., Weaver, V. M., & Petersen, O. W. (2002). The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation, 70(9-10), 537-546. Bouris, P., Skandalis, S. S., Piperigkou, Z., Afratis, N., Karamanou, K., Aletras, A. J., ... & Karamanos, N. K. (2015). Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells. Matrix Biology, 43, 42-60. Brabletz, T., Jung, A., Reu, S., Porzner, M., Hlubek, F., Kunz-Schughart, L. A., ... & Kirchner, T. (2001). Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proceedings of the National Academy of Sciences, 98(18), 10356-10361. Brabletz, T., Jung, A., Reu, S., Porzner, M., Hlubek, F., Kunz-Schughart, L. A., ... & Kirchner, T. (2001). Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proceedings of the National Academy of Sciences, 98(18), 10356-10361. Colvin, H., Nishida, N., Konno, M., Haraguchi, N., Takahashi, H., Nishimura, J., . . . Ishii, H. (2016). Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer. Sci Rep, 6, 36289. doi:10.1038/srep36289 Du, B., & Shim, J. S. (2016). Targeting Epithelial-Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer. Molecules, 21(7). doi:10.3390/molecules21070965 Fang, C. X., Ma, C. M., Jiang, L., Wang, X. M., Zhang, N., Ma, J. N., . . . Zhao, Y. D. (2018). p38 MAPK is Crucial for Wnt1- and LiCl-Induced Epithelial Mesenchymal Transition. Curr Med Sci, 38(3), 473-481. doi:10.1007/s11596-018-1903-4 Fidler, I. J., & Poste, G. (2008). The “seed and soil” hypothesis revisited. The lancet oncology, 9(8), 808. Guerra, F., Guaragnella, N., Arbini, A. A., Bucci, C., Giannattasio, S., & Moro, L. (2017). Mitochondrial Dysfunction: A Novel Potential Driver of Epithelial-to-Mesenchymal Transition in Cancer. Front Oncol, 7, 295. doi:10.3389/fonc.2017.00295 Gupta, P. B., Mani, S., Yang, J., Hartwell, K., & Weinberg, R. A. (2005, January). The evolving portrait of cancer metastasis. In Cold Spring Harbor symposia on quantitative biology (Vol. 70, pp. 291-297). Cold Spring Harbor Laboratory Press. Hanahan, D., and Weinberg, R.A. (2000). The hall- marks of cancer. Cell. 100:57–70. Hartwell, K. A., Muir, B., Reinhardt, F., Carpenter, A. E., Sgroi, D. C., & Weinberg, R. A. (2006). The Spemann organizer gene, Goosecoid, promotes tumor metastasis. Proceedings of the National Academy of Sciences, 103(50), 18969-18974. Jechlinger, M., Grünert, S., & Beug, H. (2002). Mechanisms in epithelial plasticity and metastasis: insights from 3D cultures and expression profiling. Journal of mammary gland biology and neoplasia, 7(4), 415-432. Hodge, D. Q., Cui, J., Gamble, M. J., & Guo, W. (2018). Histone Variant MacroH2A1 Plays an Isoform-Specific Role in Suppressing Epithelial-Mesenchymal Transition. Sci Rep, 8(1), 841. doi:10.1038/s41598-018-19364-4 Huan, Z., Zhang, Z., Zhou, C., Liu, L., Huang, C. (2022). Epithelial-mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities. MedComm. 2022 May 18;3(2):e144. doi: 10.1002/mco2.144 Jia, D., Park, J. H., Jung, K. H., Levine, H., & Kaipparettu, B. A. (2018). Elucidating the Metabolic Plasticity of Cancer: Mitochondrial Reprogramming and Hybrid Metabolic States. Cells, 7(3). doi:10.3390/cells7030021 Kalluri, R., & Neilson, E. G. (2003). Epithelial-mesenchymal transition and its implications for fibrosis. The Journal of clinical investigation, 112(12), 1776-1784. Kaufhold, S., & Bonavida, B. (2014). Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention. J Exp Clin Cancer Res, 33, 62. doi:10.1186/s13046-014-0062-0 Kim, K. K., Kugler, M. C., Wolters, P. J., Robillard, L., Galvez, M. G., Brumwell, A. N., . . . Chapman, H. A. (2006). Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. PNAS, 103(35), 13180-13185. doi:10.1073/pnas.0605669103 Kwon, Y. J., Baek, H. S., Ye, D. J., Shin, S., Kim, D., & Chun, Y. J. (2016). CYP1B1 Enhances Cell Proliferation and Metastasis through Induction of EMT and Activation of Wnt/beta-Catenin Signaling via Sp1 Upregulation. PLoS One, 11(3), e0151598. doi:10.1371/journal.pone.0151598 Kokudo, T., Suzuki, Y., Yoshimatsu, Y., Yamazaki, T., Watabe, T., & Miyazono, K. (2008). Snail is required for TGFβ-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells. Journal of cell science, 121(20), 3317-3324. Lin, H. Y., Liang, Y. K., Dou, X. W., Chen, C. F., Wei, X. L., Zeng, D., ... & Zhang, G. J. (2018). Notch3 inhibits epithelial–mesenchymal transition in breast cancer via a novel mechanism, upregulation of GATA-3 expression. Oncogenesis, 7(8), 1-15. Liu, Y., Liu, R., Fu, P., Du, F., Hong, Y., Yao, M., ... & Zheng, S. (2015). N1-Guanyl-1, 7-diaminoheptane sensitizes estrogen receptor negative breast cancer cells to doxorubicin by preventing epithelial-mesenchymal transition through inhibition of eukaryotic translation initiation factor 5A2 activation. Cellular Physiology and Biochemistry, 36(6), 2494-2503. Mani, S. A., Yang, J., Brooks, M., Schwaninger, G., Zhou, A., Miura, N., ... & Weinberg, R. A. (2007). Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proceedings of the National Academy of Sciences, 104(24), 10069-10074. Mani, S. A., Guo, W., Liao, M. J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., ... & Weinberg, R. A. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133(4), 704-715. Medici, D., Hay, E. D., & Olsen, B. R. (2008). Snail and Slug promote epithelial-mesenchymal transition through β-catenin–T-cell factor-4-dependent expression of transforming growth factor-β3. Molecular biology of the cell, 19(11), 4875-4887. Mishra, P., Tang, W., Putluri, V., Dorsey, T. H., Jin, F., Wang, F., . . . Ambs, S. (2018). ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming. J Clin Invest, 128(1), 323-340. doi:10.1172/JCI93815 Niessen, K., Fu, Y., Chang, L., Hoodless, P. A., McFadden, D., & Karsan, A. (2008). Slug is a direct Notch target required for initiation of cardiac cushion cellularization. The Journal of cell biology, 182(2), 315-325. Sciacovelli, M., & Frezza, C. (2017). Metabolic reprogramming and epithelial-to-mesenchymal transition in cancer. FEBS J, 284(19), 3132-3144. doi:10.1111/febs.14090 Shi, Y., & Massagué, J. (2003). Mechanisms of TGF-β signaling from cell membrane to the nucleus. cell, 113(6), 685-700. Smit, M. A., & Peeper, D. S. (2008). Deregulating EMT and senescence: double impact by a single twist. Cancer cell, 14(1), 5-7. Suarez-Carmona, M., Lesage, J., Cataldo, D., & Gilles, C. (2017). EMT and inflammation: inseparable actors of cancer progression. Mol Oncol, 11(7), 805-823. doi:10.1002/1878-0261.12095 Sun, J., Yang, X., Zhang, R., Liu, S., Gan, X., Xi, X., . . . Sun, Y. (2017). GOLPH3 induces epithelial-mesenchymal transition via Wnt/beta-catenin signaling pathway in epithelial ovarian cancer. Cancer Med, 6(4), 834-844. doi:10.1002/cam4.1040 Taki, M., Verschueren, K., Yokoyama, K., Nagayama, M., & Kamata, N. (2006). Involvement of Ets-1 transcription factor in inducing matrix metalloproteinase-2 expression by epithelial-mesenchymal transition in human squamous carcinoma cells. International journal of oncology, 28(2), 487-496. Tanabe, S. (2017). Molecular markers and networks for cancer and stem cells. J Embryol Stem Cell Res, 1(1). Tanabe, S., Kawabata, T., Aoyagi, K., Yokozaki, H., & Sasaki, H. (2016). Gene expression and pathway analysis of CTNNB1 in cancer and stem cells. World J Stem Cells, 8(11), 384-395. doi:10.4252/wjsc.v8.i11.384 Tanabe, S., Komatsu, M., Kazuhiko, A., Yokozaki, H., & Sasaki, H. (2015). Implications of epithelial-mesenchymal transition in gastric cancer. Translational Gastrointestinal Cancer, 4(4), 258-264 Thiery, J. P. (2002). Epithelial–mesenchymal transitions in tumour progression. Nature reviews cancer, 2(6), 442-454. Tse, J. C., & Kalluri, R. (2007). Mechanisms of metastasis: epithelial‐to‐mesenchymal transition and contribution of tumor microenvironment. Journal of cellular biochemistry, 101(4), 816-829. Wang, B., Tang, Z., Gong, H., Zhu, L., & Liu, X. (2017). Wnt5a promotes epithelial-to-mesenchymal transition and metastasis in non-small-cell lung cancer. Biosci Rep, 37(6). doi:10.1042/BSR20171092 Weinberg, R. A. (2008). Twisted epithelial–mesenchymal transition blocks senescence. Nature cell biology, 10(9), 1021-1023. Wendt, M. K., Smith, J. A., & Schiemann, W. P. (2010). Transforming growth factor-beta-induced epithelial-mesenchymal transition facilitates epidermal growth factor-dependent breast cancer progression. Oncogene, 29(49), 6485-6498. doi:10.1038/onc.2010.377 Wik, E., Ræder, M. B., Krakstad, C., Trovik, J., Birkeland, E., Hoivik, E. A., ... & Salvesen, H. B. (2013). Lack of estrogen receptor-α is associated with epithelial–mesenchymal transition and PI3K alterations in endometrial carcinoma. Clinical Cancer Research, 19(5), 1094-1105. Yang, J., & Weinberg, R. A. (2008). Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Developmental cell, 14(6), 818-829. Yang, J., Mani, S. A., & Weinberg, R. A. (2006). Exploring a new twist on tumor metastasis. Cancer research, 66(9), 4549-4552. Ye, Y., Xiao, Y., Wang, W., Yearsley, K., Gao, J. X., Shetuni, B., & Barsky, S. H. (2010). ERα signaling through slug regulates E-cadherin and EMT. Oncogene, 29(10), 1451-1462. Zeisberg, M., Shah, A. A., & Kalluri, R. (2005). Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. Journal of Biological Chemistry, 280(9), 8094-8100. Zeng, Q., Zhang, P., Wu, Z., Xue, P., Lu, D., Ye, Z., ... & Yan, X. (2014). Quantitative proteomics reveals ER-α involvement in CD146-induced epithelial-mesenchymal transition in breast cancer cells. Journal of proteomics, 103, 153-169. Zhang, P., Sun, Y., & Ma, L. (2015). ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell Cycle, 14(4), 481-487. doi:10.1080/15384101.2015.1006048 Zhou, Y., Huang, Y., Cao, X., Xu, J., Zhang, L., Wang, J., . . . Zheng, M. (2016). WNT2 Promotes Cervical Carcinoma Metastasis and Induction of Epithelial-Mesenchymal Transition. PLoS One, 11(8), e0160414. doi:10.1371/journal.pone.0160414 AOPWiki 2017-07-26T19:11:33

2024-04-24T00:44:46

Pulmonary fibrosis

Organ

Pulmonary fibrosis is broadly defined as the thickening or scarring of lung tissue, due to excessive deposition of extracellular matrix. In the normal human lung, the nasopharynx and the conducting airways are mainly covered by epithelium composed of ciliated, mucous secreting cells in direct contact with the basement membrane with submucosal glands containing goblet, duct, and serous cells also contributing to the fluid balance and mucous production (Koval and Sidhaye, 2017). Within this epithelium, basal cells are found which are stimulated to proliferate and differentiate in response to injury (Koval and Sidhaye, 2017). Further down the lung, in the terminal bronchiole region, the epithelium does not contain submucosal glands, but instead contains club cells which produce pulmonary surfactant and can differentiate into bronchiolar or alveolar epithelial cells (AECs). Finally, in the terminal airspaces, the epithelium is made up entirely of type I and type II AECs. In between the two adjacent alveoli are two layers of alveolar epithelium resting on basement membrane, which consists of interstitial space, pulmonary capillaries, elastin and collagen fibres. Thus, the alveolar capillary membrane (ACM), where gas exchange takes place, is made up of the alveolar epithelium and alveolar endothelium (Gracey et al, 1968). In pulmonary fibrosis, damage to the pulmonary epithelium results in excessive deposition of collagen by constitutively activated myofibroblasts during the wound healing response. This causes a pronounced decrease in the number of capillaries within the alveolar septa with asymmetric deposition of collagen and cells between part of the surface of a capillary and the nearby alveolar lining. In areas where capillaries are not present, the ACM is occupied with collagen and cells.

In vivo, histopathological analysis is used for assessing fibrotic lung disease. Morphometric analysis of the diseased area versus total lung area is used to quantitatively stage the fibrotic disease. Although, some inconsistencies can be introduced during the analysis due to the experience of the individual scoring the disease, the histological stain, etc., a numerical scale with grades from 0 to 8, originally developed by Ashcroft et al., 1988 is assigned to indicate the amount of fibrotic tissue in histological samples. This scale is applied to diagnose lung fibrosis in both human and animal samples. Modifications to this scoring system were proposed (Hubner et al., 2008), which enables morphological distinctions thus enabling a better grading of the disease. Using the modified scoring system, bleomycin induced lung fibrosis in rats was scored as follows: Grade 0 – normal lung, Grade 1 – isolated alveolar septa with gentle fibrotic changes, Grade 2 – knot like formation in fibrotic areas in alveolar septa, Grade 3 – contiguous fibrotic walls of alveolar septa, Grade 4 – single fibrotic masses, Grade 5 – confluent fibrotic masses, Grade 6 – large contiguous fibrotic masses, Grade 7 – air bubbles and Grade 8 – fibrotic obliteration. Further morphometric analysis can be conducted to quantify the total disease area (Nikota et al., 2017). Lungs are formalin fixed and paraffin embedded such that an entire cross section of lung can be presented on a slide. The entire cross section is captured in a series of images using wide field light microscope. Areas of alveolar epithelium thickening and consolidated air space are identified. ImageJ software (freely available) is used to trace the total area (green line) and the diseased area (red line) imaged and quantified. The diseased area is equal to disease area/total area (Nikota et al., 2017). In vitro, there is no single assay that can measure the alveolar thickness. However, a combination of assays spanning various KEs described above provide a measure of the extent of fibrogenesis potential of tested substances. Real-time reverse transcription-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assays (ELISA) measuring increased collagen, Transforming growth factor beta 1 (TGF-β1) and various pro-inflammatory mediators are used as sensitive markers of potential of substances to induce the adverse outcome of lung fibrosis.

UBERON:0002048

UBERON lung

High Unspecific

High

Adults

High High High 1. Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol. 1988 Apr;41(4):467-70. doi: 10.1136/jcp.41.4.467. 2. Gracey DR, Divertie MB, Brown AL Jr. Alveolar-capillary membrane in idiopathic interstitial pulmonary fibrosis. Electron microscopic study of 14 cases. Am Rev Respir Dis. 1968 Jul;98(1):16-21. doi: 10.1164/arrd.1968.98.1.16. 3. Hübner RH, Gitter W, El Mokhtari NE, Mathiak M, Both M, Bolte H, Freitag-Wolf S, Bewig B. Standardized quantification of pulmonary fibrosis in histological samples. Biotechniques. 2008 Apr;44(4):507-11, 514-7. doi: 10.2144/000112729.  4. Koval M, Sidhaye VK. Introduction: The Lung Epithelium. In: Sidhaye VK, Koval M, editors. Lung Epithelial Biology in the Pathogenesis of Pulmonary Disease. Boston: Academic Press; 2017. p. xiii-xviii. Elsevier. 5. Nikota J, Banville A, Goodwin LR, Wu D, Williams A, Yauk CL, Wallin H, Vogel U, Halappanavar S. Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework. Part Fibre Toxicol. 2017 Sep 13;14(1):37. doi: 10.1186/s12989-017-0218-0.  AOPWiki 2017-07-26T19:13:54

2023-05-12T17:09:50

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AOPWiki 2020-07-09T03:19:42

2020-07-09T03:19:42

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AOPWiki 2020-07-09T03:20:09

2020-07-09T03:20:09

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AOPWiki 2020-07-09T03:20:26

2020-07-09T03:20:26

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AOPWiki 2020-07-09T03:20:44

2020-07-09T03:20:44

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AOPWiki 2020-07-09T03:21:13

2020-07-09T03:21:13

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AOPWiki 2020-07-09T03:21:32

2020-07-09T03:21:32

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AOPWiki 2020-07-09T03:22:01

2020-07-09T03:22:01

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AOPWiki 2020-07-09T03:23:14

2020-07-09T03:23:14

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AOPWiki 2020-07-09T03:24:01

2020-07-09T03:24:01

Toll-like receptor 4 activation and peroxisome proliferator-activated receptor gamma inactivation leading to pulmonary fibrosis

TLR4 activation, PPAR gamma activation and Pulmonary fibrosis

Seokjoo Yoon

Seokjoo Yoon, Korea Institute of Toxicology, South Korea Woo-Keun Kim, Korea Institute of Toxicology, South Korea Mikyung Song, Korea Institute of Toxicology, South Korea Kyuhong Lee, Korea Institute of Toxicology, South Korea Sangwoo Lee, Korea Institute of Toxicology, South Korea Sabina Halappanavar

BY-SA

2.0

adjacent

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AOPWiki 2020-06-29T02:57:02

2023-04-29T16:03:03