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Anti-Apoptotic Effects of 3,3',5-Triiodo-L-Thyronine in the Liver of Brain-Dead Rats.

Rebolledo RA, Van Erp AC, Ottens PJ, Wiersema-Buist J, Leuvenink HG, Romanque P - PLoS ONE (2015)

Bottom Line: T3 pre-conditioning leads to anti-apoptotic and pro-mitotic effects in liver tissue following ischemia/reperfusion injury.Interestingly, no differences in the expression of inflammatory genes (IL-6, MCP-1, IL-1β) or the presence of pro-mitotic markers (Cyclin-D and Ki-67) were found in brain-dead animals treated with T3 compared to vehicle-treated animals.T3 pre-conditioning leads to beneficial effects in the liver of brain-dead rats as seen by lower cellular injury and reduced apoptosis, and supports the suggested role of T3 hormone therapy in the management of brain-dead donors.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands; Physiopathology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.

ABSTRACT

Background: Thyroid hormone treatment in brain-dead organ donors has been extensively studied and applied in the clinical setting. However, its clinical applicability remains controversial due to a varying degree of success and a lack of mechanistic understanding about the therapeutic effects of 3,3',5-Triiodo-L-thyronine (T3). T3 pre-conditioning leads to anti-apoptotic and pro-mitotic effects in liver tissue following ischemia/reperfusion injury. Therefore, we aimed to study the effects of T3 pre-conditioning in the liver of brain-dead rats.

Methods: Brain death (BD) was induced in mechanically ventilated rats by inflation of a Fogarty catheter in the epidural space. T3 (0.1 mg/kg) or vehicle was administered intraperitoneally 2 h prior to BD induction. After 4 h of BD, serum and liver tissue were collected. RT-qPCR, routine biochemistry, and immunohistochemistry were performed.

Results: Brain-dead animals treated with T3 had lower plasma levels of AST and ALT, reduced Bax gene expression, and less hepatic cleaved Caspase-3 activation compared to brain-dead animals treated with vehicle. Interestingly, no differences in the expression of inflammatory genes (IL-6, MCP-1, IL-1β) or the presence of pro-mitotic markers (Cyclin-D and Ki-67) were found in brain-dead animals treated with T3 compared to vehicle-treated animals.

Conclusion: T3 pre-conditioning leads to beneficial effects in the liver of brain-dead rats as seen by lower cellular injury and reduced apoptosis, and supports the suggested role of T3 hormone therapy in the management of brain-dead donors.

No MeSH data available.


Related in: MedlinePlus

T3 pre-treatment did not give rise to mitotic effects in the liver.Analyses performed following 4 h of BD in the BD groups and 0.5 h of ventilation in the sham groups. (A), (B), (C), and (D) Immunohistochemistry staining of cellular proliferation marker Ki-67 at 100 x original magnification in the liver from (A) sham + vehicle, (B) sham + T3, (C) BD + vehicle, and (D) BD + T3-treated rats. The sections are representative of 7 independent rats per group. (E) Ki-67 protein quantification in the liver, shown as the number of positive cells in the liver per field at 20 x original magnification, counted twice in a blinded fashion. Black arrows show examples of positive cells. (F) Hepatic, relative mRNA expression of pro-mitotic gene Cyclin-D was analyzed by real-time PCR. Data are presented as mean ± SD, n = 7 per group (* p < 0.05).
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pone.0138749.g005: T3 pre-treatment did not give rise to mitotic effects in the liver.Analyses performed following 4 h of BD in the BD groups and 0.5 h of ventilation in the sham groups. (A), (B), (C), and (D) Immunohistochemistry staining of cellular proliferation marker Ki-67 at 100 x original magnification in the liver from (A) sham + vehicle, (B) sham + T3, (C) BD + vehicle, and (D) BD + T3-treated rats. The sections are representative of 7 independent rats per group. (E) Ki-67 protein quantification in the liver, shown as the number of positive cells in the liver per field at 20 x original magnification, counted twice in a blinded fashion. Black arrows show examples of positive cells. (F) Hepatic, relative mRNA expression of pro-mitotic gene Cyclin-D was analyzed by real-time PCR. Data are presented as mean ± SD, n = 7 per group (* p < 0.05).

Mentions: To determine whether T3 treatment also resulted in pro-mitotic effects, the relative expression of Cyclin-D and presence of Ki-67 positive cells were analyzed. Cyclin D is involved in cell cycle progression and Ki-67 is a marker of proliferation as it is present in all proliferating cells [38]. The number of Ki-67 positive liver cells did not change following BD or T3 treatment (Fig 5A–5E). Relative expression of Cyclin-D in liver tissue was significantly lower in brain-dead compared to sham animals (p < 0.001), but did not change following T3 treatment (Fig 5F).


Anti-Apoptotic Effects of 3,3',5-Triiodo-L-Thyronine in the Liver of Brain-Dead Rats.

Rebolledo RA, Van Erp AC, Ottens PJ, Wiersema-Buist J, Leuvenink HG, Romanque P - PLoS ONE (2015)

T3 pre-treatment did not give rise to mitotic effects in the liver.Analyses performed following 4 h of BD in the BD groups and 0.5 h of ventilation in the sham groups. (A), (B), (C), and (D) Immunohistochemistry staining of cellular proliferation marker Ki-67 at 100 x original magnification in the liver from (A) sham + vehicle, (B) sham + T3, (C) BD + vehicle, and (D) BD + T3-treated rats. The sections are representative of 7 independent rats per group. (E) Ki-67 protein quantification in the liver, shown as the number of positive cells in the liver per field at 20 x original magnification, counted twice in a blinded fashion. Black arrows show examples of positive cells. (F) Hepatic, relative mRNA expression of pro-mitotic gene Cyclin-D was analyzed by real-time PCR. Data are presented as mean ± SD, n = 7 per group (* p < 0.05).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4593580&req=5

pone.0138749.g005: T3 pre-treatment did not give rise to mitotic effects in the liver.Analyses performed following 4 h of BD in the BD groups and 0.5 h of ventilation in the sham groups. (A), (B), (C), and (D) Immunohistochemistry staining of cellular proliferation marker Ki-67 at 100 x original magnification in the liver from (A) sham + vehicle, (B) sham + T3, (C) BD + vehicle, and (D) BD + T3-treated rats. The sections are representative of 7 independent rats per group. (E) Ki-67 protein quantification in the liver, shown as the number of positive cells in the liver per field at 20 x original magnification, counted twice in a blinded fashion. Black arrows show examples of positive cells. (F) Hepatic, relative mRNA expression of pro-mitotic gene Cyclin-D was analyzed by real-time PCR. Data are presented as mean ± SD, n = 7 per group (* p < 0.05).
Mentions: To determine whether T3 treatment also resulted in pro-mitotic effects, the relative expression of Cyclin-D and presence of Ki-67 positive cells were analyzed. Cyclin D is involved in cell cycle progression and Ki-67 is a marker of proliferation as it is present in all proliferating cells [38]. The number of Ki-67 positive liver cells did not change following BD or T3 treatment (Fig 5A–5E). Relative expression of Cyclin-D in liver tissue was significantly lower in brain-dead compared to sham animals (p < 0.001), but did not change following T3 treatment (Fig 5F).

Bottom Line: T3 pre-conditioning leads to anti-apoptotic and pro-mitotic effects in liver tissue following ischemia/reperfusion injury.Interestingly, no differences in the expression of inflammatory genes (IL-6, MCP-1, IL-1β) or the presence of pro-mitotic markers (Cyclin-D and Ki-67) were found in brain-dead animals treated with T3 compared to vehicle-treated animals.T3 pre-conditioning leads to beneficial effects in the liver of brain-dead rats as seen by lower cellular injury and reduced apoptosis, and supports the suggested role of T3 hormone therapy in the management of brain-dead donors.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands; Physiopathology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.

ABSTRACT

Background: Thyroid hormone treatment in brain-dead organ donors has been extensively studied and applied in the clinical setting. However, its clinical applicability remains controversial due to a varying degree of success and a lack of mechanistic understanding about the therapeutic effects of 3,3',5-Triiodo-L-thyronine (T3). T3 pre-conditioning leads to anti-apoptotic and pro-mitotic effects in liver tissue following ischemia/reperfusion injury. Therefore, we aimed to study the effects of T3 pre-conditioning in the liver of brain-dead rats.

Methods: Brain death (BD) was induced in mechanically ventilated rats by inflation of a Fogarty catheter in the epidural space. T3 (0.1 mg/kg) or vehicle was administered intraperitoneally 2 h prior to BD induction. After 4 h of BD, serum and liver tissue were collected. RT-qPCR, routine biochemistry, and immunohistochemistry were performed.

Results: Brain-dead animals treated with T3 had lower plasma levels of AST and ALT, reduced Bax gene expression, and less hepatic cleaved Caspase-3 activation compared to brain-dead animals treated with vehicle. Interestingly, no differences in the expression of inflammatory genes (IL-6, MCP-1, IL-1β) or the presence of pro-mitotic markers (Cyclin-D and Ki-67) were found in brain-dead animals treated with T3 compared to vehicle-treated animals.

Conclusion: T3 pre-conditioning leads to beneficial effects in the liver of brain-dead rats as seen by lower cellular injury and reduced apoptosis, and supports the suggested role of T3 hormone therapy in the management of brain-dead donors.

No MeSH data available.


Related in: MedlinePlus