Why a second look might be worth it: immuno-modulatory therapies in the critically ill patient

Siegler, Benedikt Hermann; Brenner, Thorsten; Uhle, Florian; Weiterer, Sebastian; Weigand, Markus A.; Hofer, Stefan

doi:10.21037/jtd.2016.04.37

Cited by 5 publications

(4 citation statements)

References 57 publications

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“…In accordance with the literature [ 17 , 18 ], endotoxemia in the present model was characterized by cardiovascular and hemodynamic impairment. In addition, we demonstrated that injecting LPS in rodents produces a pronounced systemic inflammatory reaction in the form of markedly increased expression and concentration of proinflammatory cytokines, as also shown previously by other studies [ 19 , 20 , 21 , 22 ].…”

Section: Discussionsupporting

confidence: 89%

Ablation of the Right Cardiac Vagus Nerve Reduces Acetylcholine Content without Changing the Inflammatory Response during Endotoxemia

Plaschke

Monica

Uhle

et al. 2018

IJMS

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Acetylcholine is the main transmitter of the parasympathetic vagus nerve. According to the cholinergic anti-inflammatory pathway (CAP) concept, acetylcholine has been shown to be important for signal transmission within the immune system and also for a variety of other functions throughout the organism. The spleen is thought to play an important role in regulating the CAP. In contrast, the existence of a “non-neuronal cardiac cholinergic system” that influences cardiac innervation during inflammation has been hypothesized, with recent publications introducing the heart instead of the spleen as a possible interface between the immune and nervous systems. To prove this hypothesis, we investigated whether selectively disrupting vagal stimulation of the right ventricle plays an important role in rat CAP regulation during endotoxemia. We performed a selective resection of the right cardiac branch of the Nervus vagus (VGX) with a corresponding sham resection in vehicle-injected and endotoxemic rats. Rats were injected with lipopolysaccharide (LPS, 1 mg/kg body weight, intravenously) and observed for 4 h. Intraoperative blood gas analysis was performed, and hemodynamic parameters were assessed using a left ventricular pressure-volume catheter. Rat hearts and blood were collected, and the expression and concentration of proinflammatory cytokines using quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were measured, respectively. Four hours after injection, LPS induced a marked deterioration in rat blood gas parameters such as pH value, potassium, base excess, glucose, and lactate. The mean arterial blood pressure and the end-diastolic volume had decreased significantly. Further, significant increases in blood cholinesterases and in proinflammatory (IL-1β, IL-6, TNF-α) cytokine concentration and gene expression were obtained. Right cardiac vagus nerve resection (VGX) led to a marked decrease in heart acetylcholine concentration and an increase in cardiac acetylcholinesterase activity. Without LPS, VGX changed rat hemodynamic parameters, including heart frequency, cardiac output, and end-diastolic volume. In contrast, VGX during endotoxemia did not significantly change the concentration and expression of proinflammatory cytokines in the heart. In conclusion we demonstrate that right cardiac vagal innervation regulates cardiac acetylcholine content but neither improves nor worsens systemic inflammation.

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Section: Discussionsupporting

confidence: 89%

Ablation of the Right Cardiac Vagus Nerve Reduces Acetylcholine Content without Changing the Inflammatory Response during Endotoxemia

Plaschke

Monica

Uhle

et al. 2018

IJMS

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“…However, further studies are required to validate the use of theophylline for the treatment of sepsis. Future studies should investigate epigenetic heterogeneity and explore strategies to avoid potentially harmful effects of candidate drugs such as theophylline [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 2 (HDAC2) attenuates lipopolysaccharide (LPS)-induced inflammation by regulating PAI-1 expression

et al. 2018

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BackgroundSepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection, and is primarily characterized by an uncontrolled systemic inflammatory response. In the present study, we developed an effective adjunct therapy mediated by a novel mechanism, to attenuate overt inflammation. LPS-treated macrophages were adopted as an in vitro model of endotoxin-induced inflammation during sepsis. Experiments were carried out using primary mouse peritoneal macrophages and the murine macrophage cell line RAW264.7, to elucidate the mechanisms by which HDAC2 modulates endotoxin-induced inflammation.ResultsResults revealed that PAI-1, TNF, and MIP-2 expression were inhibited by theophylline, an HDAC2 enhancer, in a RAW macrophage cell line, following LPS-induced inflammation. Thus, HDAC2 plays an important role in immune defense by regulating the expression of inflammatory genes via the c-Jun/PAI-1 pathway. During LPS-induced inflammation, overexpression of HDAC2 was found to inhibit PAI-1, TNF, and MIP-2 expression. Following LPS stimulation, HDAC2 knockdown increased nuclear translocation and DNA binding of c-Jun to the PAI-1 gene promoter, thereby activating PAI-1 gene transcription. Furthermore, inhibition of PAI-1 by TM5275 alone or in combination with theophylline notably suppressed TNF and MIP-2 expression.ConclusionHDAC2 can attenuate lipopolysaccharide-induced inflammation by regulating c-Jun and PAI-1 expression in macrophages.

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“…Blocking systemic inflammation by targeting specific cytokines through antibody-mediated neutralization have so far yielded mixed results in clinical settings [135][136][137][138] or effectiveness in selected subgroups.…”

Section: Covid-19 For Avenues Therapeuticmentioning

confidence: 99%

Cytokine storm and COVID-19: a chronicle of pro-inflammatory cytokines

et al. 2020

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Coronavirus disease 2019 (COVID-19) has swept the world, unlike any other pandemic in the last 50 years. Our understanding of the disease has evolved rapidly since the outbreak; disease prognosis is influenced mainly by multi-organ involvement. Acute respiratory distress syndrome, heart failure, renal failure, liver damage, shock and multi-organ failure are strongly associated with morbidity and mortality. The COVID-19 disease pathology is plausibly linked to the hyperinflammatory response of the body characterized by pathological cytokine levels. The term ‘cytokine storm syndrome’ is perhaps one of the critical hallmarks of COVID-19 disease severity. In this review, we highlight prominent cytokine families and their potential role in COVID-19, the type I and II interferons, tumour necrosis factor and members of the Interleukin family. We address various changes in cellular components of the immune response corroborating with changes in cytokine levels while discussing cytokine sources and biological functions. Finally, we discuss in brief potential therapies attempting to modulate the cytokine storm.

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Why a second look might be worth it: immuno-modulatory therapies in the critically ill patient

Cited by 5 publications

References 57 publications

Ablation of the Right Cardiac Vagus Nerve Reduces Acetylcholine Content without Changing the Inflammatory Response during Endotoxemia

Ablation of the Right Cardiac Vagus Nerve Reduces Acetylcholine Content without Changing the Inflammatory Response during Endotoxemia

Histone deacetylase 2 (HDAC2) attenuates lipopolysaccharide (LPS)-induced inflammation by regulating PAI-1 expression

Cytokine storm and COVID-19: a chronicle of pro-inflammatory cytokines

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