Histone Deacetylation Inhibitors as Therapy Concept in Sepsis.
Andreas von KnethenBernhard BrünePublished in: International journal of molecular sciences (2019)
Sepsis is characterized by dysregulated gene expression, provoking a hyper-inflammatory response occurring in parallel to a hypo-inflammatory reaction. This is often associated with multi-organ failure, leading to the patient's death. Therefore, reprogramming of these pro- and anti-inflammatory, as well as immune-response genes which are involved in acute systemic inflammation, is a therapy approach to prevent organ failure and to improve sepsis outcomes. Considering epigenetic, i.e., reversible, modifications of chromatin, not altering the DNA sequence as one tool to adapt the expression profile, inhibition of factors mediating these changes is important. Acetylation of histones by histone acetyltransferases (HATs) and initiating an open-chromatin structure leading to its active transcription is counteracted by histone deacetylases (HDACs). Histone deacetylation triggers a compact nucleosome structure preventing active transcription. Hence, inhibiting the activity of HDACs by specific inhibitors can be used to restore the expression profile of the cells. It can be assumed that HDAC inhibitors will reduce the expression of pro-, as well as anti-inflammatory mediators, which blocks sepsis progression. However, decreased cytokine expression might also be unfavorable, because it can be associated with decreased bacterial clearance.
Keyphrases
- dna methylation
- anti inflammatory
- gene expression
- genome wide
- septic shock
- acute kidney injury
- intensive care unit
- inflammatory response
- transcription factor
- poor prognosis
- immune response
- dna damage
- induced apoptosis
- oxidative stress
- liver failure
- toll like receptor
- binding protein
- type diabetes
- cell cycle arrest
- lipopolysaccharide induced
- cell proliferation
- single molecule
- lps induced
- drug induced
- adipose tissue
- mesenchymal stem cells
- histone deacetylase
- low cost
- aortic dissection
- nucleic acid
- pi k akt
- metabolic syndrome