11056-06-7BleomycinBleo
Bleocin
Blenamax
Bleo-Kyowa
Bleomycins
NSC 125066
DTXSID1030862CHEBI:3815collagenGO:0032964collagen biosynthetic process1increasedCarbon nanotubes2017-08-09T08:01:552017-08-09T08:03:46Bleomycin<p><strong>Bleomycin</strong> 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 <strong>Moeller</strong> et al., <strong>2008;</strong> Gilhodes et al., 2017).</p>
<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. <em>The American Journal of Pathology</em>. 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. <em>Am Rev Respir Dis.</em> 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>
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2018-01-01T16:45:532019-10-29T13:08:19Carbon nanotubes, Multi-walled carbon nanotubes, single-walled carbon nanotubes, carbon nanofibres<p> </p>
<p>Julie Mullera, Franc¸ois Huauxa, Nicolas Moreaub, Pierre Missona, Jean-Franc¸ois Heiliera,</p>
<p>Monique Delosc, Mohammed Arrasa, Antonio Fonsecab, Janos B. Nagyb, Dominique Lison</p>
<p>Julie Mullera, Franc¸ois Huauxa, Nicolas Moreaub, Pierre Missona, Jean-Franc¸ois Heiliera,</p>
<p>Monique Delosc, Mohammed Arrasa, Antonio Fonsecab, Janos B. Nagyb, Dominique Lison</p>
2018-01-01T17:51:042018-01-01T17:52:30WCS_9606human10116Rattus norvegicus10090mouseWCS_9606humans10116ratIncrease, Differentiation of fibroblastsDifferentiation of fibroblastsCellular2017-07-26T19:10:082017-07-26T19:10:08Induction, Epithelial Mesenchymal TransitionEMTCellular<p>Inflammatory reactions result in the release of various cytokines which in turn can stimulate the transition of epithelial cells to a mesenchymal phenotype acquiring function characteristics of fibroblasts and myofibroblasts.</p>
<p>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).</p>
<p>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. <em>Thorax</em>, <em>64</em>(9), 770–777. <a href="https://doi.org/10.1136/thx.2008.104133"><u>https://doi.org/10.1136/thx.2008.104133</u></a></p>
<p>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. <em>American Journal of Transplantation</em>, <em>10</em>(3), 498–509. <a href="https://doi.org/10.1111/j.1600-6143.2009.02953.x"><u>https://doi.org/10.1111/j.1600-6143.2009.02953.x</u></a></p>
2017-07-26T19:11:332019-01-30T10:27:22Accumulation, CollagenAccumulation, CollagenTissue<p>Collagen is mostly found in fibrous tissues such as tendons, ligaments and skin. It is also abundant in corneas, cartilage, bones, blood vessels, the gut, intervertebral discs, and the dentin in teeth. In muscle tissue, it serves as a major component of the endomysium. Collagen is the main structural protein in the extracellular space in the various connective tissues, making up from 25% to 35% of the whole-body protein content. In normal tissues, collagen provides strength, integrity, and structure. When tissues are disrupted following injury, collagen is needed to repair the defect. If too much collagen is deposited, normal anatomical structure is lost, function is compromised, and fibrosis results.</p>
<p>The fibroblast is the most common collagen producing cell. Collagen-producing cells may also arise from the process of transition of differentiated epithelial cells into mesenchymal cells. This has been observed e.g. during renal fibrosis (transformation of tubular epithelial cells into fibroblasts) and in liver injury (transdifferentiation of hepatocytes and cholangiocytes into fibroblasts) (Henderson and Iredale, 2007)<sup>.</sup></p>
<p>There are close to 20 different types of collagen found with the predominant form being type I collagen. This fibrillar form of collagen represents over 90 percent of our total collagen and is composed of three very long protein chains which are wrapped around each other to form a triple helical structure called a collagen monomer. Collagen is produced initially as a larger precursor molecule called procollagen. As the procollagen is secreted from the cell, procollagen proteinases remove the extension peptides from the ends of the molecule. The processed molecule is referred to as collagen and is involved in fiber formation. In the extracellular spaces the triple helical collagen molecules line up and begin to form fibrils and then fibers. Formation of stable crosslinks within and between the molecules is promoted by the enzyme lysyl oxidase and gives the collagen fibers tremendous strength (Diegelmann,2001)<sup>.</sup> The overall amount of collagen deposited by fibroblasts is a regulated balance between collagen synthesis and collagen catabolism. Disturbance of this balance leads to changes in the amount and composition of collagen. Changes in the composition of the extracellular matrix initiate positive feedback pathways that increase collagen production.</p>
<p>Normally, collagen in connective tissues has a slow turn over; degradating enzymes are collagenases, belonging to the family of matrix metalloproteinases. Other cells that can synthesize and release collagenase are macrophages, neutrophils, osteoclasts, and tumor cells (Di Lullo et al., 2002; Kivirikko and Risteli, 1976; Miller and Gay, 1987; Prockop and Kivirikko, 1995).</p>
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<p>Determination of the amount of collagen produced in vitro can be done in a variety of ways ranging from simple colorimetric assays to elaborate chromatographic procedures using radioactive and non-radioactive material. What most of these procedures have in common is the need to destroy the cell layer to obtain solubilized collagen from the pericellular matrix. Rishikof et al. describe several methods to assess the in vitro production of type I collagen: Western immunoblotting of intact alpha1(I) collagen using antibodies directed to alpha1(I) collagen amino and carboxyl propeptides, the measurement of alpha1(I) collagen mRNA levels using real-time polymerase chain reaction, and methods to determine the transcriptional regulation of alpha1(I) collagen using a nuclear run-on assay (Rishikof et al., 2005). </p>
<p><span style="color:red"><span style="font-family:"Arial",sans-serif">Histological staining with stains such as Masson Trichrome, Picro-sirius red are used to identify the tissue/cellular distribution of collagen, which can be quantified using morphometric analysis both in vivo and in vitro. The assays are routinely used and are quantitative.</span></span></p>
<p><em><strong><span style="color:red"><span style="font-family:"Arial",sans-serif">Sircol Collagen Assay for collagen quantification:</span></span></strong></em></p>
<p><span style="color:red"><span style="font-family:"Arial",sans-serif">The Serius dye has been used for many decades to detect collagen in histology samples. The Serius Red F3BA selectively binds to collagen and the signal can be read at 540 nm (Chen and Raghunath, 2009; Nikota et al., 2017).</span></span></p>
<p><em><strong><span style="color:red"><span style="font-family:"Arial",sans-serif">Hydroxyproline assay:</span></span></strong></em></p>
<p><span style="color:red"><span style="font-family:"Arial",sans-serif">Hydroxyproline is a non-proteinogenic amino acid formed by the prolyl-4-hydroxylase. Hydroxyproline is only found in collagen and thus, it serves as a direct measure of the amount of collagen present in cells or tissues. Colorimetric methods are readily available and have been extensively used to quantify collagen using this assay (Chen and Raghunath, 2009; Nikota et al., 2017).</span></span></p>
<p><strong><em><span style="color:red"><span style="font-family:"Arial",sans-serif">Ex vivo precision cut tissue slices</span></span></em></strong></p>
<p><span style="color:red"><span style="font-family:"Arial",sans-serif">Precision cut tissue slices mimic the whole organ response and allow histological assessment, an endpoint of interest in regulatory decision making. While this technique uses animals, the number of animals required to conduct a dose-response study can be reduced to 1/4<sup>th</sup> of what will be used in whole animal exposure studies (Rahman et al., 2020). </span></span></p>
<p> </p>
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</pre>
<p>Humans: Bataller and Brenner, 2005; Decaris et al., 2015. </p>
<p>Mice: Dalton et al., 2009; Leung et al., 2008; Nan et al., 2013.</p>
<p>Rats: Hamdy and El-Demerdash, 2012; Li, Li et al., 2012; Luckey and Petersen, 2001; Natajaran et al., 2006.</p>
<p> </p>
UBERON:0002384connective tissueNot SpecifiedUnspecificNot SpecifiedAll life stagesHighHighHigh<ol>
<li>Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005 Feb;115(2):209-18. doi: 10.1172/JCI24282. </li>
<li>Chen CZ, Raghunath M. Focus on collagen: in vitro systems to study fibrogenesis and antifibrosis state of the art. Fibrogenesis Tissue Repair. 2009 Dec 15;2:7. doi: 10.1186/1755-1536-2-7. </li>
<li>Dalton SR, Lee SM, King RN, Nanji AA, Kharbanda KK, Casey CA, McVicker BL. Carbon tetrachloride-induced liver damage in asialoglycoprotein receptor-deficient mice. Biochem Pharmacol. 2009 Apr 1;77(7):1283-90. doi: 10.1016/j.bcp.2008.12.023. </li>
<li>Decaris ML, Emson CL, Li K, Gatmaitan M, Luo F, Cattin J, Nakamura C, Holmes WE, Angel TE, Peters MG, Turner SM, Hellerstein MK. Turnover rates of hepatic collagen and circulating collagen-associated proteins in humans with chronic liver disease. PLoS One. 2015 Apr 24;10(4):e0123311. doi: 10.1371/journal.pone.0123311.</li>
<li>Di Lullo GA, Sweeney SM, Korkko J, Ala-Kokko L, San Antonio JD. Mapping the ligand-binding sites and disease-associated mutations on the most abundant protein in the human, type I collagen. J Biol Chem. 2002 Feb 8;277(6):4223-31. doi: 10.1074/jbc.M110709200.</li>
<li>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Diegelmann R. Collagen Metabolism. Wounds. 2001;13:177-82. Available at www.medscape.com/viewarticle/423231 (accessed on 20 January 2016).</span></span></p>
</li>
<li>Hamdy N, El-Demerdash E. New therapeutic aspect for carvedilol: antifibrotic effects of carvedilol in chronic carbon tetrachloride-induced liver damage. Toxicol Appl Pharmacol. 2012 Jun 15;261(3):292-9. doi: 10.1016/j.taap.2012.04.012. </li>
<li>Henderson NC, Iredale JP. Liver fibrosis: cellular mechanisms of progression and resolution. Clin Sci (Lond). 2007 Mar;112(5):265-80. doi: 10.1042/CS20060242.</li>
<li>Kivirikko KI, Risteli L. Biosynthesis of collagen and its alterations in pathological states. Med Biol. 1976 Jun;54(3):159-86.</li>
<li>Leung TM, Tipoe GL, Liong EC, Lau TY, Fung ML, Nanji AA. Endothelial nitric oxide synthase is a critical factor in experimental liver fibrosis. Int J Exp Pathol. 2008 Aug;89(4):241-50. doi: 10.1111/j.1365-2613.2008.00590.x. </li>
<li>Li L, Hu Z, Li W, Hu M, Ran J, Chen P, Sun Q. Establishment of a standardized liver fibrosis model with different pathological stages in rats. Gastroenterol Res Pract. 2012;2012:560345. doi: 10.1155/2012/560345. </li>
<li>Luckey SW, Petersen DR. Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats. Exp Mol Pathol. 2001 Dec;71(3):226-40. doi: 10.1006/exmp.2001.2399.</li>
<li>Miller EJ, Gay S. The collagens: an overview and update. Methods Enzymol. 1987;144:3-41. doi: 10.1016/0076-6879(87)44170-0. </li>
<li>Nan YM, Kong LB, Ren WG, Wang RQ, Du JH, Li WC, Zhao SX, Zhang YG, Wu WJ, Di HL, Li Y, Yu J. Activation of peroxisome proliferator activated receptor alpha ameliorates ethanol mediated liver fibrosis in mice. Lipids Health Dis. 2013 Feb 6;12:11. doi: 10.1186/1476-511X-12-11.</li>
<li>Natarajan SK, Thomas S, Ramamoorthy P, Basivireddy J, Pulimood AB, Ramachandran A, Balasubramanian KA. Oxidative stress in the development of liver cirrhosis: a comparison of two different experimental models. J Gastroenterol Hepatol. 2006 Jun;21(6):947-57. doi: 10.1111/j.1440-1746.2006.04231.x.</li>
<li>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. </li>
<li>Prockop DJ, Kivirikko KI. Collagens: molecular biology, diseases, and potentials for therapy. Annu Rev Biochem. 1995;64:403-34. doi: 10.1146/annurev.bi.64.070195.002155. </li>
<li>Rahman L, Williams A, Gelda K, Nikota J, Wu D, Vogel U, Halappanavar S. 21st Century Tools for Nanotoxicology: Transcriptomic Biomarker Panel and Precision-Cut Lung Slice Organ Mimic System for the Assessment of Nanomaterial-Induced Lung Fibrosis. Small. 2020 Sep;16(36):e2000272. doi: 10.1002/smll.202000272.</li>
<li>Rishikof DC, Kuang PP, Subramanian M, Goldstein RH. Methods for measuring type I collagen synthesis in vitro. Methods Mol Med. 2005;117:129-40. doi: 10.1385/1-59259-940-0:129. </li>
</ol>
2016-11-29T18:41:222023-04-25T11:56:49Pulmonary fibrosisPulmonary fibrosisOrgan<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><span style="color:red">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.</span> 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). <span style="color:red">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 </span>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. </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">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).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">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).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">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. </span></span><span style="font-size:12.0pt"><span style="font-family:"Arial",sans-serif">Real-time reverse transcription-polymerase chain reaction (</span></span><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">qRT-PCR) and </span></span><span style="font-size:12.0pt"><span style="font-family:"Arial",sans-serif">enzyme-linked immunosorbent assays<strong><em> </em></strong></span></span>(<span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">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.</span></span></p>
UBERON:0002048lungHighUnspecificHighAdultsHighHighHigh<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">1.</span></span>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.</p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">2. </span></span>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.</p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">3. </span></span>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. </p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><span style="color:red">4. </span>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.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">5. </span></span>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. </p>
2017-07-26T19:13:542023-04-25T11:58:40Activation, Latent Transforming Growth Factor Beta 1TGFbeta1 activationMolecular2017-08-16T07:50:372017-08-16T07:50:37Activation, Transforming Growth Factor beta pathwayTGFbeta pathway activationMolecular2017-08-16T07:55:352017-08-16T07:55:357ca7b1cb-ab02-4f86-ba15-0e438a98f63d8ee669ec-9e19-4016-aade-96224588ac5f<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Arial",sans-serif">Fibrosis by definition is the end result of a healing process. It involves a series of lung remodelling and reorganisation events leading to permanent alteration in the lung architecture and a fixed scar tissue or fibrotic lesion (Wallace WA, 2007). Excessive deposition of extracellular matrix (ECM) or collagen is the hallmark of this disease and there is ample evidence to support this KER (<span style="color:red">Fukuda 1985, Meyer 2017, Richeldi 2017, Thannickal 2004, Zisman<em> </em>2005)</span>.</span></span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Arial",sans-serif"><span style="color:red">By definition, pulmonary fibrosis is characterized by excessive deposition of ECM and destruction of native lung architecture (Fukuda 1985, Richeldi 2017, Thannickal 2004). Thus, the plausibility of this association is undisputed.</span></span></span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Arial",sans-serif"><span style="color:red">Excessive ECM deposition is the defining characteristic of pulmonary fibrosis, and the evidence to support this relationship is unequivocal. (Meyer 2017, Thannickal 2004, Zisman 2005).</span></span></span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Arial",sans-serif">Since the adverse outcome of lung fibrosis involves multiple cell types, cell - cell interactions and cell–biomolecule interactions, it is difficult to recapitulate the entire process in one model. Therefore, an integrated approach, such as one consisting of cell systems that assess individual KEs and quantitative relationships between the KEs, is needed to predict the AO in humans.</span></span></span></span></p>
HighAdultHighHighHigh<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:12.0pt"><span style="font-family:"Arial",sans-serif"><span style="color:red">Humans (Zisman 2005, Meyer 2017), rats (Williamson 2015), mice (Williamson 2015).</span></span></span></span></span></p>
<ol>
<li>Fukuda Y, Ferrans VJ, Schoenberger CI, Rennard SI, Crystal RG. Patterns of pulmonary structural remodeling after experimental paraquat toxicity. The morphogenesis of intraalveolar fibrosis. Am J Pathol. 1985 Mar;118(3):452-75.</li>
<li>Meyer KC. Pulmonary fibrosis, part I: epidemiology, pathogenesis, and diagnosis. Expert Rev Respir Med. 2017 May;11(5):343-359. doi: 10.1080/17476348.2017.1312346.</li>
<li>Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet. 2017 May 13;389(10082):1941-1952. doi: 10.1016/S0140-6736(17)30866-8. </li>
<li>Thannickal VJ, Toews GB, White ES, Lynch JP 3rd, Martinez FJ. Mechanisms of pulmonary fibrosis. Annu Rev Med. 2004;55:395-417. doi: 10.1146/annurev.med.55.091902.103810.</li>
<li>Wallace WA, Fitch PM, Simpson AJ, Howie SE. Inflammation-associated remodelling and fibrosis in the lung - a process and an end point. Int J Exp Pathol. 2007 Apr;88(2):103-10. doi: 10.1111/j.1365-2613.2006.00515.x.</li>
<li>Williamson JD, Sadofsky LR, Hart SP. The pathogenesis of bleomycin-induced lung injury in animals and its applicability to human idiopathic pulmonary fibrosis. Exp Lung Res. 2015 Mar;41(2):57-73. doi: 10.3109/01902148.2014.979516. </li>
<li>Zisman DA, Keane MP, Belperio JA, Strieter RM, Lynch JP 3rd. Pulmonary fibrosis. Methods Mol Med. 2005;117:3-44. doi: 10.1385/1-59259-940-0:003. </li>
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2017-07-26T19:19:192023-04-22T14:58:06dac6b67f-34f7-4b75-ab67-cfe0477304ed73b37ecd-7fc4-452d-9f16-52fcc6e295c82017-08-16T07:56:282017-08-16T07:56:2873b37ecd-7fc4-452d-9f16-52fcc6e295c81c08caaf-0d6b-4e81-aa17-c8973ede11fc2017-08-16T07:57:352017-08-16T07:57:3573b37ecd-7fc4-452d-9f16-52fcc6e295c8fa1a94e2-a588-4971-b245-dafa93ea650f2017-08-16T07:58:462017-08-16T07:58:461c08caaf-0d6b-4e81-aa17-c8973ede11fc7ca7b1cb-ab02-4f86-ba15-0e438a98f63d2017-08-16T07:59:152017-08-16T07:59:15fa1a94e2-a588-4971-b245-dafa93ea650f7ca7b1cb-ab02-4f86-ba15-0e438a98f63d2017-08-16T07:59:462017-08-16T07:59:46Latent Transforming Growth Factor beta1 activation leads to pulmonary fibrosisLatent TGFbeta1 activation leads to pulmonary fibrosisUnder development: Not open for comment. Do not citeadjacentNot SpecifiedHighadjacentNot SpecifiedHighadjacentNot SpecifiedHighadjacentNot SpecifiedHighadjacentNot SpecifiedHighadjacentNot SpecifiedHighHigh<p>[1] Ehrhart F, Nymark P, Rieswijk L, Hanspers K, Mélius J: Lung fibrosis (Homo sapiens), http://wikipathways.org/index.php/Pathway:WP3624</p>
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<p>[3] Labib, S., Williams, A., Yauk, C. L., Nikota, J. K., Wallin, H., Vogel, U., & Halappanavar, S. (n.d.). Nano-risk Science: application of toxicogenomics in an adverse outcome pathway framework for risk assessment of multi-walled carbon nanotubes. https://doi.org/10.1186/s12989-016-0125-9</p>
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