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Relationship: 2652

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increased cellular proliferation and differentiation leads to Accumulation, Collagen

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increased cellular proliferation and differentiation

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Accumulation, Collagen

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Substance interaction with the pulmonary resident cell membrane components leading to pulmonary fibrosis	adjacent	High	High	Sabina Halappanavar (send email)	Under development: Not open for comment. Do not cite	WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

When activated, fibroblasts migrate to the site of tissue injury and build a provisional extracellular matrix (ECM), which is then used as a scaffold for tissue regeneration. Activated fibroblasts in turn produce Interleukin (IL)-13, IL-6, IL-1β and Transforming growth factor beta (TGF-β), propagating the response. In the second phase, which is the proliferative phase, angiogenesis is stimulated to provide vascular perfusion to the wound. During this phase more fibroblasts are proliferated and they acquire Alpha-smooth muscle actin (α-SMA) expression and become myofibroblasts. Thus, myofibroblasts exhibit features of both fibroblasts and smooth muscle cells. The myofibroblasts synthesise and deposit ECM components that eventually replace the provisional ECM. Because of their contractile properties, they play a major role in contraction and closure of the wound tissue (Darby et al., 2014). Apart from secreting ECM components, myofibroblasts also secrete proteolytic enzymes such as metalloproteinases and their inhibitors tissue inhibitor of metalloproteinases, which play a role in the final phase of the wound healing which is scar formation phase or tissue remodelling.

During this final phase, new synthesis of ECM is suppressed to allow remodelling. The wound is resolved with the secretion of procollagen type 1 and elastin, and infiltrated cells including inflammatory cells, fibroblasts and myofibroblasts are efficiently removed by cellular apoptosis. However, in the presence of continuous stimulus resulting in excessive tissue damage, uncontrolled healing process is initiated involving exaggerated expression of pro-fibrotic cytokines and growth factors such as TGF-β, excessive proliferation of fibroblasts and myofibroblasts, increased synthesis and deposition of ECM components, inhibition of reepithelialisation, all of which lead to replacement of the normal architecture of the alveoli and fibrosis (Ueha et al., 2012; Wallace et al., 2007).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The biological plausibility of this KER is high. There is an accepted mechanistic relationship between activated myofibroblasts, and the capacity to secrete collagen (Hinz, 2016a; Hinz, 2016b; Hu and Phan, 2013).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

The empirical evidence to support this KER is high. It is generally accepted knowledge that activated myofibroblasts are collagen secreting cells (Blaauboer et al., 2014; Hinz, 2016a; Li et al., 2017; For additional references see Table 1).

Mice infused subcutaneously with bleomycin showed pronounced lung fibrosis, characterised by elevated levels of TGF-β1 and collagen genes (Hoyt and Lazo, 1988). Radiation induced lung fibrosis was shown to precede high levels of TGF-β1 expression (Yi et al., 1996). Mice lacking TGF-β-receptor II showed resistance to bleomycin induced lung fibrosis (Li et al., 2011). Inhibition of fibroblast proliferation and differentiation by counteracting the activity of TGF-β attenuates bleomycin-induced lung fibrosis (Chen et al., 2013; Guan et al., 2016). Adenoviral vector-mediated gene transfer based transient overexpression of TGF-β1 in lungs of mice induced progressive lung fibrosis (Bonniaud et al., 2004). Targeted inhibition of Wnt/β-catenin signalling by a small molecule drug inhibited the mesenchymal-myofibroblast transition and repressed matrix gene expression leading to attenuated lung fibrosis (Cao et al., 2018).

Dose-Response Relationship:

There are a number of in vitro and in vivo studies that indicate a dose-response relationship in this KER. At a higher dose of the stressor, an increased in fibroblast proliferation and myofibroblast differentiation leads to increases in ECM deposition.

Ma et al. (2017) studied the role of epithelial-mesenchymal transition (EMT) in cerium oxide (CeO₂) induced fibrosis. Male Sprague-Dawley rats were exposed to 0.15-7 mg/kg CeO₂ via intratracheal instillation and sacrificed at various times post-exposure. At 28 days post-exposure there was a dose-dependent increase in hydroxyproline content in lung tissue. Mice exposed to 3.5 mg/kg showed an increase in soluble collagen levels in bronchoalveolar lavage fluid (BALF) at day 3 and day 28 and an increase in α-SMA expression levels in lung tissue with a peak at day 1 post-exposure. From CeO₂-exposed rats (3.5 mg/kg), macrophages, fibroblast, and alveolar epithelial cells type II (AEC2s) cells were isolated. Macrophages produced TGF-β1 with peaks at day 3 and 10 post-exposure. Fibroblast proliferation decreased in a dose-dependent manner, and an increase in the levels of α-SMA in fibroblasts and AEC2s at day 28 post-exposure. They concluded that CeO₂ exposure affects fibroblast function and induces EMT in AEC2s cells.

Blaauboer et al. (2014) studied the expression of elastin (ELN), type V collagen, and tenascin C (TNC) during the development of lung fibrosis and the effect of myofibroblast differentiation on this expression. Female C57Bl/6 mice were exposed to a single intratracheal instillation bleomycin 30 µl (1.25 U/ml in PBS). Seven days before sacrifice, mice received 35 µl deuterated water (D₂O)/g via intraperitoneal injection to label new collagen. Mice were sacrificed 1, 3, 4 or 5 weeks post-exposure. An increase in the level of α-SMA protein level in histological staining was observed, with a peak after 2 weeks. ECM proteins levels increased (histological staining). Elastin increased in a time-dependent manner with a peak after 4 weeks. Type V collagen and TNC increased after 1 week and decreased over time. They found that gene expression of ELN, type V collagen and TNC highly correlated to new collagen formation. Primary normal human lung fibroblast and human fetal lung fibroblast were exposed to different concentrations of TGF-β1. The expression of Actin assembly-inducing protein (ACTA), Collagen alpha-1(I) chain (COL1A1), ELN, Collagen type V alpha 1 chain (COL5A1) and TNC increased in a dose-response relationship after 24 h. Fibroblast cultured in ELN coatings and stimulated with 10 ng/ml TGF-β1 for 48 h, showed an increase in the levels of ACTA2, COL1A1, and ELN. The In vitro study demonstrated that fibrotic changes in the composition of the ECM have a regulatory role during fibrosis development.

Judge et al. (2015) determined that the Lactate dehydrogenase-A (LDHA) enzyme was upregulated in radiation and that lactate is required for radiation-induced myofibroblast differentiation. In lung biopsies obtained from patients who received thoracic radiation for cancer treatment, an overexpression of LDHA and α-SMA by immunostaining was seen, as well as the accumulation of collagen fibers. Mice C57BL/6mice were exposed to 5 Gray (Gy) total body plus 10 Gy thoracic radiation. They found that LDHA overexpressed in lungs at 26 week, and LDHA mRNA increased over time at 16-26 weeks (post-radiation). Primary human lung fibroblasts were exposed to 3, and 7 Gy. At the highest dose 5 days post-radiation, an increase in the levels of LDHA protein expression, extracellular acidification, lactate levels in supernatants, α-SMA protein expression, soluble collagen I, Col1A1, and Collagen type III alpha 1 chain (Col3A1) mRNA levels, and TGF-β1 bioactivity was seen. LDHA siRNA and an LDH inhibitor, inhibits radiation-induced myofibroblast differentiation.

Lai et al. (2018) studied whether copper oxide (CuO) nanoparticles (NPs) could induce epithelial cell injury, pulmonary inflammation, and fibrosis in C57BL/6 mice. Animals were nasally instilled with 1, 2.5, 5, and 10 mg/kg of CuO NPs, and responses were evaluated at 7, 14, and 28 days post-exposure. In a dose-dependent manner, authors found increased mRNA levels of proinflammatory genes such as C-C motif chemokine ligand (CCL)-2, CCL-3, IL-4, IL-10, Interferon gamma (IFN-α), and TGF-β1 in lung tissue. Cell apoptosis was also increased in a dose-dependent manner at 1, 2.5, and 5 mg/Kg. Also, the increase of TGF-β1 in BALF at day 14 and the increase of α-SMA at day 28 in lung tissue followed a dose-response relationship at 2.5 and 5 mg/Kg. After 28 days of exposure, there was an increase in collagen-I and hydroxyproline content at 2.5 and 5 mg/Kg.

Temporal Relationship:

In vitro and in vivo studies highlight the temporal relationship between the two KEs in this KER.

Osterholzer et al. (2013) evaluated local inflammation and fibrosis after a targeted epithelial insult. Wild type (WT) C57BL/6 and transgenic mice expressing the diphtheria toxin (DT) receptor were intraperitoneally injected with DT once daily for 14 days at a dose of 10.0 µg/kg in 100 µl of PBS. Observations were evaluated at various days post-DT initiation. At day 7 and 14, an accumulation of exudate macrophages and Ly-6C^high monocytes was observed. The immunophenotype of ExM and Ly-6C^high monocytes at day 14 showed an expression of arginase, inducible nitric oxide synthase (iNOs), IL-13, TGF-β, CD45+, Type 1 collagen (Col1)+, and C-C motif chemokine-receptor (CCR)4. CCR2 deficient mice (CCR2-/-) did not show an accumulation of inflammatory cells and fibrosis. Finally, at day 21, lung collagen deposition was evident, as measured by hydroxyproline content.

Fang et al. (2018) studied the EMT characterized by the loss of endothelial specific markers (Cadherine 5 [Cdh5], Platelet and endothelial cell adhesion molecule 1 [PECAM1]), the acquisition of the mesenchymal markers (Col1A1, Acta 2), and the expression of α-SMA and Collagen I and III. Stock TEK-Green fluorescent protein (GFP) 287 Sato/JNiu Tie2-GFP mice were administered with 0.5 g/Kg silicon dioxide (SiO₂) instilled intratracheally in one dose. After 28 days of treatment GFP were localized with α-SMA/Acta2 and the amount of Sirius red (collagen I and III) increased. Mouse microvascular lung cells were exposed to 50 µg/cm² for 0, 6, 12, 24, and 48 h. An increase in the level of mesenchymal markers, a decrease in the level of endothelial markers, and an increase in cell proliferation and migration were observed after 12 h in a time-dependent manner. The exposure to SiO₂ increased the expression of circHECTD1 (a circular RNA which regulates the SiO₂-induced EMT) after 1, 3 and 24 h of exposure, and decrease the expression of HECTD1 12, 24 and 48 h post-exposure.

Activated macrophages secrete Metalloproteinase inhibitor 1 (TIMP1) into the ECM to inhibit matrix metalloproteinases and this could promote cell proliferation and inhibit fibroblast apoptosis through CD63/integrin β1 ERK signaling. Dong et al. (2017) characterized TiMP1 expression after multi-walled carbon nanotube (MWCNT) exposure. Male C57BL/6J WT and B6.129S4-Timp1tm1Pds/J (Timp1 Knockout [KO]) mice were administered with MWCNTs at 40 µg per mouse by pharyngeal aspiration. Lungs were harvested at 1, 3, 7- and 14-days post-exposure. TIMP1 mRNA and protein levels increased in lung, BALF and serum at day 1, and then decreased over time. A similar behavior was observed for Fibronectin 1 (FN1), Fibroblast-specific protein-1 (FSP), Ki67 and Proliferating cell nuclear antigen (PCNA) expression, which are markers of proliferation, with a peak at 7 and 14 days post-exposure. Collagen deposition was observed at 1 day post-exposure with a peak at day 7. At day 7 they also observed an increase in the expression of Heat shock protein (Hsp)47, vimentin, α-SMA, Platelet derived growth factor receptor beta (PDGFR-β), and genes involved in cell cycle regulation (Mitotic checkpoint serine/threonine-protein kinase BUB1 beta [Bub1β], Macrophage-capping protein [Capg], Histone H3-like centromeric protein A [Cenpa], Kinesin-like protein Kif2c, Kinesin-like protein Kif22, Minichromosome maintenance complex component 5 [Mcm5], Polo like kinase 1 [Plk1] and Tubulin alpha-6 chain [Tuba 6]). TIMP1 KO mice displayed reduced responses. The formation of TIMP1/CD63/integrin b1 complex on the cell surface lead to an activation of the extracellular signal-regulated kinases (Erk)1/3 pathway.

Hu et al. (2015) studied the effects of conditional mesenchymal-specific deletion of Neurogenic locus notch homolog protein 1 (Notch1) on pulmonary fibrosis. A conditional KO of Notch1 (CKO) in collagen I-expressing mesenchymal cells was generated (Notch1fl/fl, Col1a2-cre-ER(T)+/0). Col1a2-cre-ER(T)+/0 with WT Notch1 mice and CKO were given daily intraperitoneal injections of tamoxifen for 8 days to induce mesenchymal cell-specific expression of the Cre-ER(T) recombinase and the removal of the floxed Notch1 (Notch1 CKO Mice). Control mice and Notch1 CKO were injected endotracheally with 2 U/Kg Bleomycin. Mice were sacrificed after 7, 14, and 21 days. Jagged1 (Jag-1) and Notch1 protein expression increased with a peak at 7- and 14-days post-exposure. After 14 days of the treatment, an increase in the levels of mRNA and protein of α-SMA and Col1 was seen, as well as an increase in the percentage of α-SMA+ lung fibroblasts. 28 days post-exposure there was an increase in the content of hydroxyproline in lungs. CKO mice showed a significant attenuation of collagen deposition and myofibroblast differentiation.

Li et al. (2017) evaluated whether low-dose cadmium exposure induces peribronchiolar fibrosis through site-specific phosphorylation of vimentin. C57BL/6 mice were exposed to 0.009 or 0.018 mg/kg cadmium chloride (CdCl₂) via non-surgical intratracheal instillation in saline every other day for eight weeks. On weeks 1, 2, 4, and 8, mice were sacrificed, and lungs were removed for histology. At week 4, the expression of α-SMA and collagen-I increased. Also, subepithelial thickness and airway resistance increased at this time point. Collagen content was also raised in a time-dependent manner. In a parallel experiment, primary human fibroblasts were incubated with CdCl₂ at 5, 10, and 20 μM for 3 h and then allowed to recover for 3, 24, 48, and 72 h. α-SMA protein expression and soluble collagen increased in a dose-dependent manner; meanwhile, α-SMA, fibronectin, and collagen-I increased in a time-dependent manner. These results demonstrated that cadmium induces myofibroblast differentiation and ECM deposition around small airways.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Several studies have shown that inhibition of TGF-β involved in fibroblast activation and collagen deposition results in attenuated fibrotic response in lungs; however, results are inconsistent. More studies are required to support the quantitative KER.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

List of the literature that was cited for this KER description. More help

Blaauboer ME, Boeijen FR, Emson CL, Turner SM, Zandieh-Doulabi B, Hanemaaijer R, Smit TH, Stoop R, Everts V. Extracellular matrix proteins: a positive feedback loop in lung fibrosis? Matrix Biol. 2014 Feb;34:170-8. doi: 10.1016/j.matbio.2013.11.002.
Bonniaud P, Kolb M, Galt T, Robertson J, Robbins C, Stampfli M, Lavery C, Margetts PJ, Roberts AB, Gauldie J. Smad3 null mice develop airspace enlargement and are resistant to TGF-beta-mediated pulmonary fibrosis. J Immunol. 2004 Aug 1;173(3):2099-108. doi: 10.4049/jimmunol.173.3.2099.
Cao H, Wang C, Chen X, Hou J, Xiang Z, Shen Y, Han X. Inhibition of Wnt/β-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis. Sci Rep. 2018 Sep 11;8(1):13644. doi: 10.1038/s41598-018-28968-9.
Chen YL, Zhang X, Bai J, Gai L, Ye XL, Zhang L, Xu Q, Zhang YX, Xu L, Li HP, Ding X. Sorafenib ameliorates bleomycin-induced pulmonary fibrosis: potential roles in the inhibition of epithelial-mesenchymal transition and fibroblast activation. Cell Death Dis. 2013 Jun 13;4(6):e665. doi: 10.1038/cddis.2013.154.
Dong J, Ma Q. TIMP1 promotes multi-walled carbon nanotube-induced lung fibrosis by stimulating fibroblast activation and proliferation. Nanotoxicology. 2017 Feb;11(1):41-51. doi: 10.1080/17435390.2016.1262919.
Fang S, Guo H, Cheng Y, Zhou Z, Zhang W, Han B, Luo W, Wang J, Xie W, Chao J. circHECTD1 promotes the silica-induced pulmonary endothelial-mesenchymal transition via HECTD1. Cell Death Dis. 2018 Mar 14;9(3):396. doi: 10.1038/s41419-018-0432-1.
Guan R, Wang X, Zhao X, Song N, Zhu J, Wang J, Wang J, Xia C, Chen Y, Zhu D, Shen L. Emodin ameliorates bleomycin-induced pulmonary fibrosis in rats by suppressing epithelial-mesenchymal transition and fibroblast activation. Sci Rep. 2016 Oct 24;6:35696. doi: 10.1038/srep35696.
Hinz B. Myofibroblasts. Exp Eye Res. 2016a Jan;142:56-70. doi: 10.1016/j.exer.2015.07.009.
Hinz B. The role of myofibroblasts in wound healing. Curr Res Transl Med. 2016b Oct-Dec;64(4):171-177. doi: 10.1016/j.retram.2016.09.003.
Hoyt DG, Lazo JS. Alterations in pulmonary mRNA encoding procollagens, fibronectin and transforming growth factor-beta precede bleomycin-induced pulmonary fibrosis in mice. J Pharmacol Exp Ther. 1988 Aug;246(2):765-71.
Hu B, Phan SH. Myofibroblasts. Curr Opin Rheumatol. 2013 Jan;25(1):71-7. doi: 10.1097/BOR.0b013e32835b1352.
Hu B, Wu Z, Bai D, Liu T, Ullenbruch MR, Phan SH. Mesenchymal deficiency of Notch1 attenuates bleomycin-induced pulmonary fibrosis. Am J Pathol. 2015 Nov;185(11):3066-75. doi: 10.1016/j.ajpath.2015.07.014.
Judge JL, Owens KM, Pollock SJ, Woeller CF, Thatcher TH, Williams JP, Phipps RP, Sime PJ, Kottmann RM. Ionizing radiation induces myofibroblast differentiation via lactate dehydrogenase. Am J Physiol Lung Cell Mol Physiol. 2015 Oct 15;309(8):L879-87. doi: 10.1152/ajplung.00153.2015.
Lai X, Zhao H, Zhang Y, Guo K, Xu Y, Chen S, Zhang J. Intranasal Delivery of Copper Oxide Nanoparticles Induces Pulmonary Toxicity and Fibrosis in C57BL/6 mice. Sci Rep. 2018 Mar 14;8(1):4499. doi: 10.1038/s41598-018-22556-7.
Li M, Krishnaveni MS, Li C, Zhou B, Xing Y, Banfalvi A, Li A, Lombardi V, Akbari O, Borok Z, Minoo P. Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis. J Clin Invest. 2011 Jan;121(1):277-87. doi: 10.1172/JCI42090.
Li FJ, Surolia R, Li H, Wang Z, Liu G, Liu RM, Mirov SB, Athar M, Thannickal VJ, Antony VB. Low-dose cadmium exposure induces peribronchiolar fibrosis through site-specific phosphorylation of vimentin. Am J Physiol Lung Cell Mol Physiol. 2017 Jul 1;313(1):L80-L91. doi: 10.1152/ajplung.00087.2017.
Ma J, Bishoff B, Mercer RR, Barger M, Schwegler-Berry D, Castranova V. Role of epithelial-mesenchymal transition (EMT) and fibroblast function in cerium oxide nanoparticles-induced lung fibrosis. Toxicol Appl Pharmacol. 2017 May 15;323:16-25. doi: 10.1016/j.taap.2017.03.015.
Osterholzer JJ, Olszewski MA, Murdock BJ, Chen GH, Erb-Downward JR, Subbotina N, Browning K, Lin Y, Morey RE, Dayrit JK, Horowitz JC, Simon RH, Sisson TH. Implicating exudate macrophages and Ly-6C(high) monocytes in CCR2-dependent lung fibrosis following gene-targeted alveolar injury. J Immunol. 2013 Apr 1;190(7):3447-57. doi: 10.4049/jimmunol.1200604.
Ueha S, Shand FH, Matsushima K. Cellular and molecular mechanisms of chronic inflammation-associated organ fibrosis. Front Immunol. 2012 Apr 10;3:71. doi: 10.3389/fimmu.2012.00071.
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.
Yi ES, Bedoya A, Lee H, Chin E, Saunders W, Kim SJ, Danielpour D, Remick DG, Yin S, Ulich TR. Radiation-induced lung injury in vivo: expression of transforming growth factor-beta precedes fibrosis. Inflammation. 1996 Aug;20(4):339-52. doi: 10.1007/BF01486737.