Abstract
Sepsis-induced lymphopenia is a major cause of morbidities in intensive care units and in populations with chronic conditions such as renal failure, diabetes, HIV and alcohol abuse. Currently, other than supportive care and antibiotics, there are no treatments for this condition. We developed an in vitro assay to understand the role of the ER-stress-mediated apoptosis process in lymphocyte death during polymicrobial sepsis, which was reproducible in in vivo mouse models. Modulating ER stress using chemical chaperones significantly reduced the induction of the pro-apoptotic protein Bim both in vitro and in mice. Furthermore, in a ‘two-hit’ pneumonia model in mice, we have been able to demonstrate that administration of the chemical chaperone TUDCA helped to maintain lymphocyte homeostasis by significantly reducing lymphocyte apoptosis and this correlated with four-fold improvement in survival. Our results demonstrate a novel therapeutic opportunity for treating sepsis-induced lymphopenia in humans.
Highlights
In the United States alone, ∼7 50000 individuals develop sepsis, and of these ∼30% succumb to this disorder annually
This upregulation appeared to be modulated by structurally dissimilar chemical chaperones with UPR modulating ability such as Genistein[12], compound c/dorsomorphin[13] and Tauroursodeoxycholic acid (TUDCA)[14] (Fig. 3B)
Our results show that when mice were injected with either PBS or with cecal slurry followed by TUDCA, allowed to recover and challenged intra-nasally with P. aeruginosa, the mice injected with cecal slurry were more susceptible to P. aeruginosa compared to sham injected mice (Fig. 5C)
Summary
In the United States alone, ∼7 50000 individuals develop sepsis (or colloquially known as blood poisoning), and of these ∼30% succumb to this disorder annually. Improved treatment protocols have resulted in most patients surviving this stage and entering a protracted immune suppressive phase[3] The latter phase is characterized by extensive apoptosis in the cells of the adaptive immune system, i.e., B cells, and T cells[2] leading to prolonged lymphopenia. Experimental drug therapies for sepsis are currently at a crossroad with more than 30 drug trials failing in the last 25 years These include, but not limited to, Eritoran or anti-TLR4 compound (Eisai Co. Ltd, Japan), Xigris or activated protein C (Eli Lilly & Co. USA), CytoFab or anti-TNFαantibody (AstraZeneca, Sweden) and Talactoferrin alfa, an immuno-modulatory lactoferrin (Agennix, Germany) to name a few. Our study defines a novel therapeutic strategy for treating sepsis with Gram-negative bacterial infections
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