Systemic inflammation relates to neuroaxonal damage associated with long-term cognitive dysfunction in COVID-19 patients.

BACKGROUND AND OBJECTIVES: Cognitive deficits are increasingly recognized as a long-term sequela of severe COVID-19. The underlying processes and molecular signatures associated with these long-term neurological sequalae of COVID-19 remain largely unclear, but may be related to systemic inflammation-induced effects on the brain. We studied the systemic inflammation-brain interplay and its relation to development of long-term cognitive impairment in patients who survived severe COVID-19. Trajectories of systemic inflammation and neuroaxonal damage blood biomarkers during ICU admission were analyzed and related to long-term cognitive outcomes. METHODS: Prospective longitudinal cohort study of patients with severe COVID-19 surviving ICU admission. During admission, blood was sampled consecutively to assess levels of inflammatory cytokines and neurofilament light chain (NfL) using an ultrasensitive multiplex Luminex assay and single molecule array technique (Simoa). Cognitive functioning was evaluated using a comprehensive neuropsychological assessment six months after ICU-discharge. RESULTS: Ninety-six patients (median [IQR] age 61 [55-69] years) were enrolled from March 2020 to June 2021 and divided into two cohorts: those who received no COVID-19-related immunotherapy (n = 28) and those treated with either dexamethasone or dexamethasone and tocilizumab (n = 68). Plasma NfL concentrations increased in 95 % of patients during their ICU stay, from median [IQR] 23 [18-38] pg/mL at admission to 250 [160-271] pg/mL after 28 days, p < 0.001. Besides age, glomerular filtration rate, immunomodulatory treatment, and C-reactive protein, more specific markers of systemic inflammation at day 14 (i.e., interleukin (IL)-8, tumour necrosis factor, and IL-1 receptor antagonist) were significant predictors of blood NfL levels at day 14 of ICU admission (R2 = 44 %, p < 0.001), illustrating the association between sustained systemic inflammation and neuroaxonal damage. Twenty-six patients (27 %) exhibited cognitive impairment six months after discharge from the ICU. NfL concentrations showed a more pronounced increase in patients that developed cognitive impairment (p = 0.03). Higher NfL predicted poorer outcome in information processing speed (Trail Making Test A, r = -0.26, p = 0.01; Letter Digit Substitution Test, r = -0.24, p = 0.02). DISCUSSION: Prolonged systemic inflammation in critically ill COVID-19 patients is related to neuroaxonal damage and subsequent long-term cognitive impairment. Moreover, our findings suggest that plasma NfL concentrations during ICU stay may possess prognostic value in predicting future long-term cognitive impairment in patients that survived severe COVID-19.

Fatigue during acute systemic inflammation is associated with reduced mental effort expenditure while task accuracy is preserved.

BACKGROUND: Earlier work within the physical domain showed that acute inflammation changes motivational prioritization and effort allocation rather than physical abilities. It is currently unclear whether a similar motivational framework accounts for the mental fatigue and cognitive symptoms of acute sickness. Accordingly, this study aimed to assess the relationship between fatigue, cytokines and mental effort-based decision making during acute systemic inflammation. METHODS: Eighty-five participants (41 males; 18-30 years (M = 23.0, SD = 2.4)) performed a mental effort-based decision-making task before, 2 h after, and 5 h after intravenous administration of 1 ng/kg bacterial lipopolysaccharide (LPS) to induce systemic inflammation. Plasma concentrations of cytokines (interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)) and fatigue levels were assessed at similar timepoints. In the task, participants decided whether they wanted to perform (i.e., 'accepted') arithmetic calculations of varying difficulty (3 levels: easy, medium, hard) in order to obtain rewards (3 levels: 5, 6 or 7 points). Acceptance rates were analyzed using a binomial generalized estimated equation (GEE) approach with effort, reward and time as independent variables. Arithmetic performance was measured per effort level prior to the decisions and included as a covariate. Associations between acceptance rates, fatigue (self-reported) and cytokine concentration levels were analyzed using partial correlation analyses. RESULTS: Plasma cytokine concentrations and fatigue were increased at 2 h post-LPS compared to baseline and 5 h post-LPS administration. Acceptance rates decreased for medium, but not for easy or hard effort levels at 2 h post-LPS versus baseline and 5 h post-LPS administration, irrespective of reward level. These reductions in acceptance rates occurred despite improved accuracy on the arithmetic calculations itself. Reduced acceptance rates for medium effort were associated with increased fatigue, but not with increased cytokine concentrations. CONCLUSION: Fatigue during acute systemic inflammation is associated with alterations in mental effort allocation, similarly as observed previously for physical effort-based choice. Specifically, willingness to exert mental effort depended on effort and not reward information, while task accuracy was preserved. These results extend the motivational account of inflammation to the mental domain and suggest that inflammation may not necessarily affect domain-specific mental abilities, but rather affects domain-general effort-allocation processes.

Hypoxemia in the presence or absence of systemic inflammation does not increase blood lactate levels in healthy volunteers.

PURPOSE: Elevated lactate levels are a sign of critical illness and may result from insufficient oxygen delivery. We investigated whether hypoxemia and/or systemic inflammation, results in increased lactate levels in healthy volunteers. MATERIALS AND METHODS: 30 healthy volunteers were exposed to either 3.5 h of hypoxemia (FiO2 ± 11.5%), normoxemic endotoxemia (FiO2 21%, administration of 2 ng/kg endotoxin), or hypoxemic endotoxemia (n = 10 per group). Blood lactate, hemoglobin, SpO2, PaO2, PaCO2, pH, and hemodynamic parameters were serially measured. RESULTS: Hypoxemic treatment resulted in lower SpO2 (81.7 ± 2.6 and 81.4 ± 2.4% in the hypoxemia and hypoxemic endotoxemia groups, respectively) and hyperventilation with a PaCO2 decrease of 0.8 ± 0.5 and 1.5 ± 0.6 kPa and an increase in pH. Arterial oxygen content (CaO2) decreased by 20.5 ± 2.9 and 23.5 ± 4.4%, respectively. Lactate levels were slightly, but significantly higher in both hypoxemic groups compared with the normoxemic endotoxemia group over time (p < 0.0001 for both groups), but remained below 2.3 mmol/L in all subjects. Whereas PaO2 and SpO2 did not correlate with lactate levels, PaCO2, pH and CaO2 did. CONCLUSIONS: Hypoxemia, in the absence or presence of inflammation does not result in relevant increases of lactate. The small increases in lactate observed are likely to be due to hyperventilation-related decreases in glycolysis.

Promotion of vascular integrity in sepsis through modulation of bioactive adrenomedullin and dipeptidyl peptidase 3.

Sepsis represents one of the major medical challenges of the 21st century. Despite substantial improvements in the knowledge on pathophysiological mechanisms, this has so far not translated into novel adjuvant treatment strategies for sepsis. In sepsis, both vascular tone and vascular integrity are compromised, and contribute to the development of shock, which is strongly related to the development of organ dysfunction and mortality. In this review, we focus on dipeptidyl peptidase 3 (DPP3) and adrenomedullin (ADM), two molecules that act on the vasculature and are involved in the pathophysiology of sepsis and septic shock. DPP3 is an ubiquitous cytosolic enzyme involved in the degradation of several important signalling molecules essential for regulation of vascular tone, including angiotensin II. ADM is a key hormone involved in the regulation of vascular tone and endothelial barrier function. Previous studies have shown that circulating concentrations of both DPP3 and ADM are independently associated with the development of organ failure and adverse outcome in sepsis. We now discuss new evidence illustrating that these molecules indeed represent two distinct pathways involved in the development of septic shock. Recently, both ADM-enhancing therapies aimed at improving endothelial barrier function and vascular tone and DPP3-blocking therapies aimed at restoring systemic angiotensin responses have been shown to improve outcome in various preclinical sepsis models. Given the current lack of effective adjuvant therapies in sepsis, additional research on the therapeutic application of these peptides in humans is highly warranted.

An add-on training program involving breathing exercises, cold exposure, and meditation attenuates inflammation and disease activity in axial spondyloarthritis - A proof of concept trial.

OBJECTIVES: The primary objective of this trial was to assess safety and anti-inflammatory effects of an add-on training program involving breathing exercises, cold exposure, and meditation in patients with axial spondyloarthritis. METHODS: This study was an open-label, randomised, one-way crossover clinical proof-of-concept trial. Twenty-four patients with moderately active axial spondyloarthritis(ASDAS >2.1) and hs-CRP ≥5mg/L were included and randomised to an intervention (n = 13) and control group (n = 11) group that additionally received the intervention after the control period. The intervention period lasted for 8 weeks. The primary endpoint was safety, secondary endpoints were change in hs-CRP, serum calprotectin levels and ESR over the 8-week period. Exploratory endpoints included disease activity measured by ASDAS-CRP and BASDAI, quality of life (SF-36, EQ-5D, EQ-5D VAS), and hospital anxiety and depression (HADS). RESULTS: We found no significant differences in adverse events between groups, with one serious adverse event occurring 8 weeks after end of the intervention and judged 'unrelated'. During the 8-week intervention period, there was a significant decline of ESR from (median [interquartile range] to 16 [9-26.5] to 9 [5-23] mm/hr, p = 0.040, whereas no effect was found in the control group (from 14 [8.3-27.3] to 16 [5-37] m/hr, p = 0.406). ASDAS-CRP declined from 3.1 [2.5-3.6] to 2.3 [1.9-3.2] in the intervention group (p = 0.044). A similar trend was observed for serum calprotectin (p = 0.064 in the intervention group versus p = 0.182 in the control group), but not for hs-CRP. CONCLUSIONS: This proof-of-concept study in axial spondyloarthritis met its primary endpoint with no safety signals during the intervention. There was a significant decrease in ESR levels and ASDAS-CRP upon the add-on training program in the intervention group. These findings warrant full-scale randomised controlled trials of this novel therapeutic approach in patients with inflammatory conditions. TRIAL REGISTRATION: ClinicalTrials.gov; NCT02744014.

Remote ischaemic preconditioning does not modulate the systemic inflammatory response or renal tubular stress biomarkers after endotoxaemia in healthy human volunteers: a single-centre, mechanistic, randomised controlled trial.

BACKGROUND: Remote ischaemic preconditioning (RIPC) consists of repeated cycles of limb ischaemia and reperfusion, which may reduce perioperative myocardial ischaemic damage and kidney injury. We hypothesised that RIPC may be beneficial by attenuating the systemic inflammatory response. We investigated whether RIPC affects the response in humans to bacterial endotoxin (lipopolysaccharide [LPS]) by measuring plasma cytokines and renal cell-cycle arrest mediators, which reflect renal tubular stress. METHODS: Healthy male volunteers were randomised to receive either daily RIPC for 6 consecutive days (RIPCmultiple, n=10) plus RIPC during the 40 min preceding i.v. LPS (2 ng kg-1), RIPC only during the 40 min before LPS (RIPCsingle, n=10), or no RIPC preceding LPS (control, n=10). As a surrogate marker of renal tubular stress, the product of urinary concentrations of two cell-cycle arrest markers was calculated (tissue inhibitor of metalloproteinases-2 [TIMP2]*insulin-like growth factor binding protein-7 [IGFBP7]). Data are presented as median (inter-quartile range). RESULTS: In both RIPC groups, RIPC alone increased [TIMP2]*[IGFBP7]. LPS administration resulted in fever, flu-like symptoms, and haemodynamic alterations. Plasma cytokine concentrations increased profoundly during endotoxaemia (control group: tumor necrosis factor alpha [TNF-α] from 14 [9-16] pg ml-1 at baseline to 480 [284-709] pg ml-1 at 1.5 h after LPS; interleukin-6 [IL-6] from 4 [4-4] pg ml-1 at baseline to 659 [505-1018] pg ml-1 at 2 h after LPS). LPS administration also increased urinary [TIMP2[*[IGFBP7]. RIPC had no effect on LPS-induced cytokine release or [TIMP2]*[IGFBP7]. CONCLUSIONS: RIPC neither modulated systemic cytokine release nor attenuated inflammation-induced tubular stress after LPS. However, RIPC alone induced renal markers of cell-cycle arrest. CLINICAL TRIAL REGISTRATION: NCT02602977.

The endotoxin-induced pulmonary inflammatory response is enhanced during the acute phase of influenza infection.

BACKGROUND: Influenza infections are often complicated by secondary infections, which are associated with high morbidity and mortality, suggesting that influenza profoundly influences the immune response towards a subsequent pathogenic challenge. However, data on the immunological interplay between influenza and secondary infections are equivocal, with some studies reporting influenza-induced augmentation of the immune response, whereas others demonstrate that influenza suppresses the immune response towards a subsequent challenge. These contrasting results may be due to the use of various types of live bacteria as secondary challenges, which impedes clear interpretation of causal relations, and to differences in timing of the secondary challenge relative to influenza infection. Herein, we investigated whether influenza infection results in an enhanced or suppressed innate immune response upon a secondary challenge with bacterial lipopolysaccharide (LPS) in either the acute or the recovery phase of infection. METHODS: Male C57BL/6J mice were intranasally inoculated with 5 × 103 PFU influenza virus (pH1N1, strain A/Netherlands/602/2009) or mock treated. After 4 (acute phase) or 10 (recovery phase) days, 5 mg/kg LPS or saline was administered intravenously, and mice were sacrificed 90 min later. Cytokine levels in plasma and lung tissue, and lung myeloperoxidase (MPO) content were determined. RESULTS: LPS administration 4 days after influenza infection resulted in a synergistic increase in TNF-α, IL-1ß, and IL-6 concentrations in lung tissue, but not in plasma. This effect was also observed 10 days after influenza infection, albeit to a lesser extent. LPS-induced plasma levels of the anti-inflammatory cytokine IL-10 were enhanced 4 days after influenza infection, whereas a trend towards increased pulmonary IL-10 concentrations was found. LPS-induced increases in pulmonary MPO content tended to be enhanced as well, but only at 4 days post-infection. CONCLUSIONS: An LPS challenge in the acute phase of influenza infection results in an enhanced pulmonary pro-inflammatory innate immune response. These data increase our insight on influenza-bacterial interplay. Combing data of the present study with previous findings, it appears that this enhanced response is not beneficial in terms of protection against secondary infections, but rather damaging by increasing immunopathology.

Characterization of a model of systemic inflammation in humans in vivo elicited by continuous infusion of endotoxin.

Investigating the systemic inflammatory response in patients with critical illness such as sepsis, trauma and burns is complicated due to uncertainties about the onset, duration and severity of the insult. Therefore, in vivo models of inflammation are essential to study the pathophysiology and to evaluate immunomodulatory therapies. Intravenous bolus administration of endotoxin to healthy volunteers is a well-established model of a short-lived systemic inflammatory response, characterized by increased plasma cytokine levels, flu-like symptoms and fever. In contrast, patients suffering from systemic inflammation are often exposed to inflammatory stimuli for an extended period of time. Therefore, continuous infusion of endotoxin may better reflect the kinetics of the inflammatory response encountered in these patients. Herein, we characterize a novel model of systemic inflammation elicited by a bolus infusion of 1 ng/kg, followed by a 3hr continuous infusion of 1 ng/kg/h of endotoxin in healthy volunteers, and compared it with models of bolus administrations of 1 and 2 ng/kg of endotoxin. The novel model was well-tolerated and resulted in a more pronounced increase in plasma cytokine levels with different kinetics and more prolonged symptoms and fever compared with the bolus-only models. Therefore, the continuous endotoxin infusion model provides novel insights into kinetics of the inflammatory response during continuous inflammatory stimuli and accommodates a larger time window to evaluate immunomodulating therapies.

Crew Resource Management in the Intensive Care Unit: a prospective 3-year cohort study.

BACKGROUND: Human factors account for the majority of adverse events in both aviation and medicine. Human factors awareness training entitled "Crew Resource Management (CRM)" is associated with improved aviation safety. We determined whether implementation of CRM impacts outcome in critically ill patients. METHODS: We performed a prospective 3-year cohort study in a 32-bed ICU, admitting 2500-3000 patients yearly. At the end of the baseline year, all personnel received CRM training, followed by 1 year of implementation. The third year was defined as the clinical effect year. All 7271 patients admitted to the ICU in the study period were included. The primary outcome measure was ICU complication rate. Secondary outcome measures were ICU and hospital length of stay, and standardized mortality ratio. RESULTS: Occurrence of serious complications was 67.1/1000 patients and 66.4/1000 patients during the baseline and implementation year respectively, decreasing to 50.9/1000 patients in the post-implementation year (P = 0.03). Adjusted odds ratios for occurrence of complications were 0.92 (95% CI 0.71-1.19, P = 0.52) and 0.66 (95% CI 0.51-0.87, P = 0.003) in the implementation and post-implementation year. The incidence of cardiac arrests was 9.2/1000 patients and 8.3/1000 patients during the baseline and implementation year, decreasing to 3.5/1000 patients (P = 0.04) in the post-implementation year, while cardiopulmonary resuscitation success rate increased from 19% to 55% and 67% (P = 0.02). Standardized mortality ratio decreased from 0.72 (95% CI 0.63-0.81) in the baseline year to 0.60 (95% CI 0.53-0.67) in the post-implementation year (P = 0.04). CONCLUSION: Our data indicate an association between CRM implementation and reduction in serious complications and lower mortality in critically ill patients.

Lidocaine increases the anti-inflammatory cytokine IL-10 following mechanical ventilation in healthy mice.

BACKGROUND: Mechanical ventilation (MV) induces an inflammatory response that may result in (acute) lung injury. Lidocaine, an amide local anesthetic, has anti-inflammatory properties in vitro and in vivo, possibly due to an attenuation of pro-inflammatory cytokines, intracellular adhesion molecule-1 (ICAM-1), and reduction of neutrophils influx. We hypothesized an attenuation of MV-induced inflammatory response with intravenously administered lidocaine. METHODS: Lidocaine (Lido) (2, 4, and 8 mg/kg/h) was intravenously administered during 4 h of MV with a tidal volume of 8 ml/kg, positive end expiratory pressure 1,5 cmH2O and FiO2 0.4. We used one ventilated control (CON) group receiving vehicle. After MV, mice were euthanized, and lungs and blood were immediately harvested, and cytokine levels and ICAM-1 levels were measured in plasma and lung homogenates. Pulmonary neutrophils influx was determined in LEDER-stained slices of lungs. Anesthetic need was determined by painful hind paw stimulation. RESULTS: Lidocaine-treated animals (Lido 2, 4 and 8 mg/kg/h) showed higher interleukin (IL)-10 plasma levels compared to control animals. Lidocaine treatment with 8 mg/kg/h (Lido 8) resulted in higher IL-10 in lung homogenates. No differences were observed in pro-inflammatory cytokines, ICAM-1, and pulmonary influx between the different ventilated groups. CONCLUSIONS: Intravenously administered lidocaine increases levels of plasma IL-10 with infusion from 2, 4, and 8 mg/kg/h and pulmonary levels of IL-10 with 8 mg/kg/h in a murine mechanical ventilation model. Intravenously administered lidocaine appears to reduce anesthetic need in mice.

Sepsis-induced immunoparalysis: mechanisms, markers, and treatment options.

Sepsis remains the leading cause of death in the ICU. Considering the key role of the immune system in sepsis, immunomodulation represents an attractive target for adjunctive therapy. Until recently, clinical trials focused on suppression of the immune system, but this approach failed to improve sepsis outcome. Recent advances in the understanding of sepsis have led to the view that not the initial hyperinflammatory state, but rather a profoundly suppressed state of the immune system, called sepsis-induced immunoparalysis, accounts for the majority of sepsis-related deaths. Immunoparalysis results in ineffective clearance of septic foci, and renders the septic patient more vulnerable to secondary infections, as well as reactivation of latent infections. Several mechanisms behind immunoparalysis have been recognised. Furthermore, due to recognition of the importance of immunoparalysis, immunostimulatory treatment is emerging as a possible adjunctive treatment for sepsis. As such, identification of patients suffering from immunoparalysis using biomarkers is of utmost importance to guide immunostimulatory treatment. In this review, an short overview of the concept of immunoparalysis is presented, while the main focus is on potential biological markers of immunoparalysis and promising immunostimulatory therapeutic agents. The challenging heterogeneity of septic patients in respect to immunomodulatory advances will be discussed, and recommendations for future research are provided.

Resveratrol attenuates NF-κB-binding activity but not cytokine production in mechanically ventilated mice.

BACKGROUND: Mechanical ventilation (MV) can result in inflammation and subsequent lung injury. Toll-like receptor (TLR)4 and NF-κB are proposed to play a crucial role in the MV-induced inflammatory response. Resveratrol (RVT) exhibits anti-inflammatory effects in vitro and in vivo supposedly by interfering with TLR4 signaling and NF-κB. In the present study, we investigated the role of RVT in MV-induced inflammation in mice. METHODS: RVT (10 mg/kg, 20 mg/kg and 40 mg/kg) or vehicle was intraperitoneally administered 1 h before start of MV (4 h, tidal volume 8 ml/kg, positive end-expiratory pressure 1,5 cmH2 O and FiO2 0.4). Blood and lungs were harvested for cytokine analysis. DNA binding activity of transcription factor NF-κB was measured in lung homogenates. RESULTS: MV resulted in elevated pulmonary concentrations of IL-1ß, IL-6, keratinocyte-derived chemokine (KC) and NF-κB DNA-binding activity. RVT at 10, 20 and 40 mg/kg reduced NF-κB's DNA-binding activity following MV compared with ventilated controls. However, no differences in cytokine release were found between RVT-treated and control ventilated mice. Similarly, in plasma, MV resulted in elevated concentrations of TNF-α, KC and IL-6, but RVT did not affect cytokine levels. CONCLUSIONS: RVT abrogates the MV-induced increase in pulmonary NF-κB activity but does not attenuate cytokine levels. This implies a less prominent role for NF-κB in MV-induced inflammation than previously assumed.

Vitamin D status is not associated with inflammatory cytokine levels during experimental human endotoxaemia.

Vitamin D has been shown to modulate innate immune responses in vitro and ex vivo; however, human in-vivo data are lacking. At high latitudes, seasonal vitamin D deficiency is common due to alternating ultraviolet (UV)-B radiation exposure. In the present study, we investigated whether levels of 25 hydroxyvitamin D(3) [25(OH)D(3) ] and its active metabolite 1,25 dihydroxyvitamin D(3) [1,25(OH)(2) D(3) ] are subject to seasonal variation and whether plasma levels of these vitamin D metabolites correlate with the in-vivo cytokine response during experimental human endotoxaemia [administration of lipopolysaccharide (LPS) in healthy volunteers]. Plasma levels of 25(OH)D(3) and 1,25(OH)(2) D(3) were determined in samples obtained just prior to administration of an intravenous bolus of 2 ng/kg LPS (derived from Escherichia coli O:113) in 112 healthy male volunteers. In the same subjects, plasma levels of the inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10 were analysed serially after endotoxin administration. Plasma levels of 1,25(OH)(2) D(3) , but not 25(OH)D(3) , were subject to significant seasonal variation, with lower levels in autumn and winter. 25(OH)D(3) and 1,25(OH)(2) D(3) levels did not correlate with plasma cytokine responses. Furthermore, 25(OH)D(3) deficient subjects (< 50 nmol/l) displayed an identical cytokine response compared with sufficient subjects. In conclusion, plasma levels of vitamin D are not correlated with the LPS-induced TNF, IL-6 and IL-10 cytokine response in humans in vivo. These findings question the direct role of vitamin D in modulation of the innate immune response.

α7 nicotinic acetylcholine receptor agonist GTS-21 attenuates ventilator-induced tumour necrosis factor-α production and lung injury.

BACKGROUND: Mechanical ventilation (MV) induces an inflammatory response that can lead to lung injury. The vagus nerve can limit the inflammatory response through the cholinergic anti-inflammatory pathway. We evaluated the effects of stimulation of the cholinergic anti-inflammatory pathway with the selective partial α7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 on inflammation and lung injury induced by MV using clinically relevant ventilator settings. Furthermore, we investigated whether altering endogenous cholinergic signalling, by administration of the non-specific nAChR antagonist mecamylamine and the peripherally acting acetylcholinesterase inhibitor neostigmine, modulates the MV-induced inflammatory response. METHODS: C57BL6 mice were injected i.p. with either the selective α7nAChR agonist GTS-21 (8 mg kg(-1)), the acetylcholinesterase inhibitor neostigmine (80 µg kg(-1)), the nAChR antagonist mecamylamine (1 mg kg(-1)), or a placebo; followed by 4 h of MV (8 ml kg(-1), 1.5 cm H(2)O PEEP). RESULTS: MV resulted in release of cytokines in plasma and lungs compared with unventilated mice. Lung and plasma levels of tumour necrosis factor (TNF)-α, but not of interleukin-10, were lower in GTS-21-treated animals compared with placebo (P<0.05). In addition, GTS-21 lowered the alveolar-arterial gradient, indicating improved lung function (P=0.04). Neither neostigmine nor mecamylamine had an effect on MV-induced inflammation or lung function. CONCLUSIONS: MV with clinically relevant ventilator settings results in pulmonary and systemic inflammation. Stimulation of the cholinergic anti-inflammatory pathway with GTS-21 attenuates MV-induced release of TNF-α, which was associated with reduced lung injury. Modulation of endogenous cholinergic signalling did not affect the MV-induced inflammatory response. Selective stimulation of the cholinergic anti-inflammatory pathway may represent new treatment options for MV-induced lung injury.

Increased vagal tone accounts for the observed immune paralysis in patients with traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of death and disability, especially in the younger population. In the acute phase after TBI, patients are more vulnerable to infection, associated with a decreased immune response in vitro. The cause of this immune paralysis is poorly understood. Apart from other neurologic dysfunction, TBI also results in an increase in vagal activity. Recently, the vagus nerve has been demonstrated to exert an anti-inflammatory effect, termed the cholinergic anti-inflammatory pathway. The anti-inflammatory effects of the vagus nerve are mediated by the alpha 7 nicotinic acetylcholine receptor present on macrophages and other cytokine-producing cells. From these observations, we hypothesize that the immune paralysis observed in patients with TBI may, at least in part, result from augmented vagal activity and subsequent sustained effects of the cholinergic anti-inflammatory pathway. This pathway may counteract systemic proinflammation caused by the release of endogenous compounds termed alarmins as a result of tissue trauma. However, sustained activity of this pathway may severely impair the body's ability to combat infection. Since the cholinergic anti-inflammatory pathway can be pharmacologically modulated in humans, it could represent a novel approach to prevent infections in patients with TBI.