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postgraduate thesis: Protective effects of IL-11 on experimental intracerebral hemorrhage
Title | Protective effects of IL-11 on experimental intracerebral hemorrhage |
---|---|
Authors | |
Advisors | Advisor(s):Cheung, RTF |
Issue Date | 2023 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Du, S. [杜斯琪]. (2023). Protective effects of IL-11 on experimental intracerebral hemorrhage. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Intracerebral hemorrhage (ICH) accounts for 20% of all strokes. It carries a poor prognosis with a high mortality rate and a big chance of permanent neurological deficits. Experimental ICH models are instrumental in elucidating the underlying pathophysiological processes and evaluating novel therapies for ICH. Inflammation and apoptosis are two crucial factors contributing to ICH-induced secondary injury. Interleukins (ILs) are cytokines which play essential roles in activation, differentiation and functioning of inflammatory cells. IL-11 is an anti-inflammatory cytokine previously found to be increased in plasma of ICH patients. However, its roles during ICH remain unknown.
First, autologous blood injection was made into the brain at one of three different injection rates to establish a stable and reproducible rat ICH model. Using this model, the effects of ICH on neurological functions, brain edema and both the level and cellular expression of IL-11 were measured. Before investigating the effect of injected IL-11 on ICH, two doses of recombinant IL-11 (rIL-11) were injected individually and compared with each other to find out the optimal injection dose. Using the optimal dose, the neurological function, hematoma volume, brain edema, levels of inflammatory mediators, including tumor necrosis factor alpha (TNF-α) and IL-1β, as well as apoptosis indicators, including terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X (Bax) and neurogenesis markers after rIL-11 injection were measured. Next, an in vitro ICH model was established by exposing differentiated SH-SY5Y cells to hemin. Upon rIL-11 administration, cell viability, apoptosis, and both signal transducer and activator of transcription 3 (STAT3)/Bcl-2 expression were evaluated.
A rat ICH model with unilateral hematoma formation, associated brain edema and contralateral neurological deficits were successfully established. ICH led to increased unilateral IL-11 expression mainly in peri-hematomal neurons on day 1. ICH also induced neuronal apoptosis and expression of pro-inflammatory mediators. Following a stereotaxic injection of rIL-11, there was reduction in neurological deficits and brain edema despite no change in the hematoma volume. There was also a decrease in ICH-induced neuronal apoptosis and expression of pro-inflammatory factors, as well as improvement in neurogenesis. In the in vitro experiments using differentiated SH-SY5Y cells, rIL-11 treatment improved the viability whilst reduced the apoptosis. Phosphorylated STAT3 (p-STAT3)/STAT3 and Bcl-2 expression were also increased.
In summary, ICH induces IL-11 production. IL-11 treatment protects against ICH injury partly via reducing neuronal apoptosis and inflammation as well as by promoting neurogenesis. The anti-apoptotic effect may be mediated partly via the STAT3/Bcl-2 pathway. |
Degree | Doctor of Philosophy |
Subject | Interleukins Brain - Hemorrhage - Treatment |
Dept/Program | Medicine |
Persistent Identifier | http://hdl.handle.net/10722/335916 |
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | Cheung, RTF | - |
dc.contributor.author | Du, Siqi | - |
dc.contributor.author | 杜斯琪 | - |
dc.date.accessioned | 2023-12-29T04:04:49Z | - |
dc.date.available | 2023-12-29T04:04:49Z | - |
dc.date.issued | 2023 | - |
dc.identifier.citation | Du, S. [杜斯琪]. (2023). Protective effects of IL-11 on experimental intracerebral hemorrhage. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/335916 | - |
dc.description.abstract | Intracerebral hemorrhage (ICH) accounts for 20% of all strokes. It carries a poor prognosis with a high mortality rate and a big chance of permanent neurological deficits. Experimental ICH models are instrumental in elucidating the underlying pathophysiological processes and evaluating novel therapies for ICH. Inflammation and apoptosis are two crucial factors contributing to ICH-induced secondary injury. Interleukins (ILs) are cytokines which play essential roles in activation, differentiation and functioning of inflammatory cells. IL-11 is an anti-inflammatory cytokine previously found to be increased in plasma of ICH patients. However, its roles during ICH remain unknown. First, autologous blood injection was made into the brain at one of three different injection rates to establish a stable and reproducible rat ICH model. Using this model, the effects of ICH on neurological functions, brain edema and both the level and cellular expression of IL-11 were measured. Before investigating the effect of injected IL-11 on ICH, two doses of recombinant IL-11 (rIL-11) were injected individually and compared with each other to find out the optimal injection dose. Using the optimal dose, the neurological function, hematoma volume, brain edema, levels of inflammatory mediators, including tumor necrosis factor alpha (TNF-α) and IL-1β, as well as apoptosis indicators, including terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X (Bax) and neurogenesis markers after rIL-11 injection were measured. Next, an in vitro ICH model was established by exposing differentiated SH-SY5Y cells to hemin. Upon rIL-11 administration, cell viability, apoptosis, and both signal transducer and activator of transcription 3 (STAT3)/Bcl-2 expression were evaluated. A rat ICH model with unilateral hematoma formation, associated brain edema and contralateral neurological deficits were successfully established. ICH led to increased unilateral IL-11 expression mainly in peri-hematomal neurons on day 1. ICH also induced neuronal apoptosis and expression of pro-inflammatory mediators. Following a stereotaxic injection of rIL-11, there was reduction in neurological deficits and brain edema despite no change in the hematoma volume. There was also a decrease in ICH-induced neuronal apoptosis and expression of pro-inflammatory factors, as well as improvement in neurogenesis. In the in vitro experiments using differentiated SH-SY5Y cells, rIL-11 treatment improved the viability whilst reduced the apoptosis. Phosphorylated STAT3 (p-STAT3)/STAT3 and Bcl-2 expression were also increased. In summary, ICH induces IL-11 production. IL-11 treatment protects against ICH injury partly via reducing neuronal apoptosis and inflammation as well as by promoting neurogenesis. The anti-apoptotic effect may be mediated partly via the STAT3/Bcl-2 pathway. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Interleukins | - |
dc.subject.lcsh | Brain - Hemorrhage - Treatment | - |
dc.title | Protective effects of IL-11 on experimental intracerebral hemorrhage | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Medicine | - |
dc.description.nature | published_or_final_version | - |
dc.date.hkucongregation | 2023 | - |
dc.identifier.mmsid | 991044634607003414 | - |