Vasopressin Impairment During Sepsis Is Associated with Hypothalamic Intrinsic Apoptotic Pathway and Microglial Activation

Abstract

Previous studies have shown that in the early phase of sepsis, the plasma concentration of arginine vasopressin (AVP) is increased, but in the late phase, its levels remain inadequately low, despite of persistent hypotension. One hypothesis suggested for this relative deficiency is apoptosis of vasopressinergic neurons. Here, we investigated apoptosis pathways in the hypothalamus during sepsis, as well as mechanisms underlying this process. Male Wistar rats were submitted to sepsis by cecal ligation and puncture (CLP) or nonmanipulated (naive) as control. After 6 and 24 h, the animals were decapitated and brain and blood were collected to assess hypothalamic apoptotic markers, IFN-γ plasma levels, and evidence for breakdown of the blood-brain barrier (BBB). Sepsis caused a decrease in mitochondrial antiapoptotic proteins (Bcl-2, Bcl-xL) in the hypothalamus, but had no effect on markers of cell death mediated by death receptors or immune cells. In the supraoptic nuclei of these animals, microglia morphology was consistent with activation, associated with an increase in plasma IFN-γ. A transitory breakdown of BBB in the hypothalamus was seen at 6 h following CLP. The results indicate that the intrinsic but not extrinsic apoptosis pathway is involved in the cell death observed in vasopressinergic neurons, and that this condition is temporally associated with microglial activation and BBB leaking.

Alterations in hypothalamic synaptophysin and death markers may be associated with vasopressin impairment in sepsis survivor rats

“…28 In previous studies, we found low amounts of Bcl-2 and high levels of cleaved caspase-3 in the hypothalamus of septic animals, associated with a deficit in AVP secretion. 15,16 In the present study, we observed a persistent alteration of these cellular death markers even after recovery from sepsis.…”

“…The present study was designed to bring together insights from previous studies conducted by our group where we had demonstrated that: (i) sepsis promotes morphological changes in hypothalamic microglial cells that are compatible with their activation; 16 (ii) the administration of an IL-1 receptor antagonist caused a decrease in hypothalamic oxidative stress, improving AVP secretion; 15,19 and (iii) there is an impairment in AVP secretion, persistent plasma inflammatory mediators and an attenuated activation of magnocellular neurones after an acute osmotic stimulus in sepsis survivor. 21 Therefore, we hypothesised that a decrease of hypothalamic synaptic density may lead to a dysfunction in the osmotic regulatory response in sepsis survivors.…”

“…They promote attenuated hypothalamic activation of osmoregulatory, volume regulatory and AVP-producing magnocellular neurones, 7,[15][16][17][18] resulting in impaired AVP synthesis and secretion. 9,19,20 Although this scenario is now reasonably well understood during sepsis, we know relatively little about whether and how these neuroendocrine abnormalities persist in sepsis survivors.…”

Baroreceptor denervation reduces inflammatory status but worsens cardiovascular collapse during systemic inflammation

“…We showed here that spleen tissue homogenates collected from rats that received LPS exhibit a significant increase of pro-inflammatory cytokines. Surprisingly, there were no significant increases in TNF-α [an essential early mediator of inflammation 2,38 ] or IFN-γ [a later inflammatory marker 39 ] levels in rats submitted to SAD during LPS-induced SI (Fig. 7).…”

Baroreceptor denervation reduces inflammatory status and worsens cardiovascular collapse during systemic inflammation

“…We showed here that spleen tissue homogenates collected from rats that received LPS exhibit a significant increase of pro-inflammatory cytokines. Surprisingly, there were no significant increases in TNF-α [an essential early mediator of inflammation (2, 40)] or IFN-γ [a later inflammatory marker (41)] levels in rats submitted to SAD during LPS-induced SI (Fig. 8 B).…”