Reitsema, V. (Vera) (2013) Lung injury in in vivo cooling and potential treatments through activation of the endogenous production of H2S in rat. thesis, Medicine.
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Abstract
Hypothermia is commonly used to prevent organ injury during major surgery, but causes adverse effects as inflammation and cellular injury in the lung as well. Hibernators are capable to survive hypothermia without organ injury. Hydrogen sulfide (H2S) is identified as a key compound in natural and pharmacological torpor and can be endogenously produced by cystathionine β synthase (CBS). Dopamine is known to stimulate endogenous H2S production by allosteric activation and upregulation of CBS. H2S can protect against ischemia/reperfusion injury and modulates the immune system. In T-cells, H2S plays an important regulating role as co-regulatory signal. Furthermore, activated T-cells have enhanced levels of CBS. CBS domains are not only found in the CBS protein, but also in adenosine monophosphate (AMP)-activated protein kinase (AMPK). AMPK is activated when cellular energy is depleted and quickly after T-cell activation. AMPK activation signals toward an energy-conserving state. Due to its regulatory role in metabolism and the molecular structure of AMPK, we hypothesized that AMPK is an upstream protein of the CBS/H2S pathway. We investigated the interaction between AMPK and CBS/H2S and their effects on T-cell activation in vitro in a Jurkat cell line. Naïve Jurkat cells were treated with dopamine, H2S or the specific AMPK activator A769662 and subsequently activated. Dopamine and H2S did not lead to any changes in the activation status of the Jurkat cells. Phosphorylation of AMPK inhibited the activation levels of naïve T-cells, but pretreatment with the AMPK-activator A769662 boosted CD69 levels after activation. The effects seen on the activation status did not correlate with any changes in CBS expression. In this study we show there is no link between AMPK activation and CBS expression in T-cells, but they seem to have a similar function in parallel pathways. We investigated in vivo in our rat model of forced hypothermia whether an increase in endogenous H2S by dopamine might protect against hypothermic pulmonary injury. Rats were cooled to 15⁰C and rewarmed up to 37⁰C under ketamine anesthesia with either dopamine (125 µg/kg/min) or NaCl (vehicle). There were no significant differences in lung morphology, damage or inflammation markers between the rats cooled under ketamine anaesthesia and the dopamine treated rats. However, dopamine treatment increased the number of macrophages in lung tissue. Here, we provide clues that in vivo administration of dopamine during hypothermia does not protect lungs from inflammation due to cold ischemia in an early stage. This study contributes to the understanding of the mechanisms by which H2S production affects the immune system and might lead to the development of new treatments in major surgery.
| Item Type: | Thesis (Thesis) |
|---|---|
| Supervisor name: | Henning, R.H. |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Jun 2020 11:05 |
| Last Modified: | 25 Jun 2020 11:05 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/2537 |
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