Abstract：
:In present study, the apoptosis induction and proliferation suppression effects of l-phenylalanine (l-Phe) on fibroblasts were confirmed. The action sites of l-Phe on fibroblasts suppression were deduced to be calcium sensitive receptor (CaSR) which could cause the release of endoplasmic reticulum (ER) Ca2+ stores; disruption of intracellular Ca2+ homeostasis triggers cell apoptosis via the ER or mitochondrial pathways. The down-regulation of CaSR were observed after the application of l-Phe, and the results those l-Phe triggered the increasing of intracellular Ca2+ concentration and calcineurin expression, and then the apoptosis and increasing G1 fraction of fibroblasts have verified our deduction. Hence, l-Phe could be seen as a kind of anti-fibrotic drugs for the crucial participation of fibroblast in the occurrence of fibrosis. And then, poly(p-dioxanone-co-l-phenylalanine) (PDPA) which could prolong the in-vivo anti-fibrotic effect of l-Phe for the sustained release of l-Phe during its degradation could be treated as anti-fibrotic polymer prodrugs. Based on the above, the in vivo anti-fibrotic function of PDPA was evaluated in rabbit ear scarring, rat peritoneum lipopolysaccharide, and rat sidewall defect/cecum abrasion models. PDPA reduced skin scarring and suppressed peritoneal fibrosis and post operation adhesion as well as secretion of transforming growth factor-β1 in injured tissue. These results indicate that PDPA is an effective agent for preventing fibrosis following tissue injury. STATEMENT OF SIGNIFICANCE:We have previously demonstrated that poly(p-dioxanone-co-l-phenylalanine) (PDPA) could induce apoptosis to fibroblast and deduced that the inhibitory effect comes from l-phenylalanine. In present study, the inhibition mechanism of l-phenylalanine on fibroblast proliferation was demonstrated. The calcium sensitive receptor (CaSR) was found to be the action site. The CaSR was downregulated after the application of l-phenylalanine, and then the ER Ca2+ stores were released. The released Ca2+ can simultaneously activate Ca2+/calcineurin and then trigger apoptosis and G1 arrest of fibroblast. Hence, l-phenylalanine could be seen as anti-fibrosis drug and PDPA which conjugate l-phenylalanine by hydrolytic covalent bonds could be seen as l-phenylalanine polymer prodrug. Based above, the in vivo anti-fibrotic function of PDPA were verified in three different animal models.
journal_name
Acta Biomaterjournal_title
Acta biomaterialiaauthors
Wang B,Wen A,Feng C,Niu L,Xiao X,Luo L,Shen C,Zhu J,Lei J,Zhang Xdoi
10.1016/j.actbio.2018.04.018subject
Has Abstractpub_date
2018-06-01 00:00:00pages
180-189eissn
1742-7061issn
1878-7568pii
S1742-7061(18)30221-6journal_volume
73pub_type
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journal_title：Acta biomaterialia
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journal_title：Acta biomaterialia
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journal_title：Acta biomaterialia
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doi：10.1016/j.actbio.2012.11.001
更新日期：2013-03-01 00:00:00
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journal_title：Acta biomaterialia
pub_type： 杂志文章
doi：10.1016/j.actbio.2010.01.019
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journal_title：Acta biomaterialia
pub_type： 杂志文章,评审
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更新日期：2018-06-01 00:00:00
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更新日期：2018-07-15 00:00:00
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journal_title：Acta biomaterialia
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更新日期：2019-05-01 00:00:00
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更新日期：2013-02-01 00:00:00
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journal_title：Acta biomaterialia
pub_type： 杂志文章
doi：10.1016/j.actbio.2012.04.025
更新日期：2012-08-01 00:00:00
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更新日期：2019-12-01 00:00:00
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更新日期：2009-10-01 00:00:00
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journal_title：Acta biomaterialia
pub_type： 杂志文章
doi：10.1016/j.actbio.2016.12.053
更新日期：2017-03-01 00:00:00
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pub_type： 杂志文章
doi：10.1016/j.actbio.2015.05.014
更新日期：2015-09-01 00:00:00
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journal_title：Acta biomaterialia
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更新日期：2009-09-01 00:00:00
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journal_title：Acta biomaterialia
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更新日期：2019-12-01 00:00:00
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journal_title：Acta biomaterialia
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更新日期：2017-03-15 00:00:00
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journal_title：Acta biomaterialia
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更新日期：2016-03-01 00:00:00
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journal_title：Acta biomaterialia
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更新日期：2007-07-01 00:00:00
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journal_title：Acta biomaterialia
pub_type： 杂志文章
doi：10.1016/j.actbio.2018.05.005
更新日期：2018-07-01 00:00:00
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journal_title：Acta biomaterialia
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更新日期：2011-01-01 00:00:00
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更新日期：2018-02-01 00:00:00
