Biology subjects

van der Heijden, J.

Publications and source records attributed to van der Heijden, J..

4 recordsLinked to original sources

bioRxiv2023

Fluid restrictive resuscitation with high molecular weight hyaluronan infusion in early peritonitis-sepsis

Sepsis is a condition with high morbidity and mortality. Prompt recognition and initiation of treatment is essential. Despite forming an integral part of sepsis management, fluid resuscitation may also lead to volume overload, which in turn is associated with increased mortality. The optimal fluid strategy in sepsis resuscitation is yet to be defined. Hyaluronan, an endogenous glycosaminoglycan with high affinity to water is an important constituent of the endothelial glycocalyx. We hypothesized that exogenously administered hyaluronan would contribute to endothelial glycocalyx integrity and counteract intravascular volume depletion in a fluid restrictive model of peritonitis. In a prospective, blinded model of porcine peritonitis-sepsis, we randomized animals to intervention with hyaluronan (n=8) or 0.9% saline (n=8). The animals received an infusion of 0.1% hyaluronan 6 ml/kg/h, or the same volume of saline, during the first two hours of peritonitis. Stroke volume variation and hemoconcentration were comparable in the two groups throughout the experiment. Cardiac output (p=0.008 and p=0.017) and diastolic blood pressure (p=0.015 and p=0.019) were higher in the intervention group during the infusion of hyaluronan, but these effects disappeared as the experiment proceeded. The increase in lactate was more pronounced in the intervention group (p=0.041) throughout the experiment, while concentrations of surrogate markers of glycocalyx damage; syndecan 1 (0.6 {+/-} 0.2 ng/ml vs 0.5 {+/-} 0.2 ng/ml, p=0.292), heparan sulphate (1.23 {+/-} 0.2 vs 1.4 {+/-} 0.3 ng/ml, p=0.211) and vascular adhesion protein 1 (7.0 {+/-} 4.1 vs 8.2 {+/-} 2.3 ng/ml, p=0.492) were comparable in the two groups at the end of the experiment. In conclusion, hyaluronan did not counteract intravascular volume depletion in early peritonitis sepsis. The intervention was associated with higher cardiac output and diastolic blood pressure, than placebo, during the infusion. However, the increase in lactate throughout the experiment was more pronounced in the intervention group.

pharmacology and toxicology↗

bioRxiv2021

High molecular weight hyaluronan - a potential adjuvant to fluid resuscitation in porcine abdominal sepsis

While fluid resuscitation is fundamental in the treatment of sepsis-induced tissue hypo-perfusion, a sustained positive fluid balance is associated with excess mortality. Crystalloids are the mainstay of fluid resuscitation and use of either synthetic colloids or albumin is controversial. Hyaluronan, an endogenous glycosaminoglycan with high affinity to water, has not been tested as adjuvant in fluid resuscitation. We sought to evaluate the effects of hyaluronan as an adjuvant to fluid resuscitation in peritonitis induced sepsis. In a prospective, parallel-grouped, blinded model of porcine peritonitis-sepsis, we randomized animals to intervention with adjuvant hyaluronan (add-on to standard therapy) (n=8) or 0.9% saline (n=8). After the onset of hemodynamic instability the animals received an initial bolus of 0.1 % hyaluronan 1 mg/kg/10 min or placebo (saline) followed by a continuous infusion of 0.1% hyaluronan (1 mg/kg/h) or saline during the experiment. We hypothesized that the administration of hyaluronan would reduce the volume of fluid administered (aiming at stroke volume variation <13%) and/or attenuate the inflammatory reaction. Total volumes of intravenous fluids infused were 17.5 {+/-} 11 ml/kg/h vs. 19.0 {+/-} 7 ml/kg/h in intervention and control groups, respectively (p = 0.442). Plasma IL-6 increased to 2450 (1420 - 6890) pg/ml and 3700 (1410 - 11960) pg/ml (18 hours of resuscitation) in the intervention and control groups (NS). In a post-hoc analysis, modified shock index remained lower in intervention group (p = 0.011 - 0.037). In conclusion adjuvant hyaluronan did not reduce the volume needed for fluid administration or decrease the inflammatory reaction. Adjuvant hyaluronan was, however, associated with lower modified shock index. Bearing in mind that the experiment has a limited group-size we suggest that further studies on hyaluronan in sepsis are warranted.

pharmacology and toxicology↗

bioRxiv2020

Mechanistic understanding enables the rational design of salicylanilide combination therapies for Gram-negative infections

One avenue to combat multidrug-resistant Gram-negative bacteria is the co-administration of multiple drugs (combination therapy), which can be particularly promising if drugs synergize. The identification of synergistic drug combinations, however, is challenging. Detailed understanding of antibiotic mechanisms can address this issue by facilitating the rational design of improved combination therapies. Here, using diverse biochemical and genetic assays, we reveal the molecular mechanisms of niclosamide, a clinically-approved salicylanilide compound, and demonstrate its potential for Gram-negative combination therapies. We discovered that Gram-negative bacteria possess two innate resistance mechanisms that reduce their niclosamide susceptibility: a primary mechanism mediated by multidrug efflux pumps and a secondary mechanism of nitroreduction. When efflux was compromised, niclosamide became a potent antibiotic, dissipating the proton motive force (PMF), increasing oxidative stress and reducing ATP production to cause cell death. These insights guided the identification of diverse compounds that synergized with salicylanilides when co-administered (efflux inhibitors, membrane permeabilizers, and antibiotics that are expelled by PMF-dependent efflux), thus suggesting that salicylanilide compounds may have broad utility in combination therapies. We validate these findings in vivo using a murine abscess model, where we show that niclosamide synergizes with the membrane permeabilizing antibiotic colistin against high-density infections of multidrug-resistant Gram-negative clinical isolates. We further demonstrate that enhanced nitroreductase activity is a potential route to adaptive niclosamide resistance but show that this causes collateral susceptibility to clinical nitro-prodrug antibiotics. Thus, we highlight how mechanistic understanding of mode of action, innate/adaptive resistance, and synergy can rationally guide the discovery, development and stewardship of novel combination therapies. ImportanceThere is a critical need for more effective treatments to combat multidrug-resistant Gram-negative infections. Combination therapies are a promising strategy, especially when these enable existing clinical drugs to be repurposed as antibiotics. We reveal the mechanisms of action and basis of innate Gram-negative resistance for the anthelmintic drug niclosamide, and subsequently exploit this information to demonstrate that niclosamide and analogs kill Gram-negative bacteria when combined with antibiotics that inhibit drug efflux or permeabilize membranes. We confirm the synergistic potential of niclosamide in vitro against a diverse range of recalcitrant Gram-negative clinical isolates, and in vivo in a mouse abscess model. We also demonstrate that nitroreductases can confer resistance to niclosamide, but show that evolution of these enzymes for enhanced niclosamide resistance confers a collateral sensitivity to other clinical antibiotics. Our results highlight how detailed mechanistic understanding can accelerate the evaluation and implementation of new combination therapies.

microbiology↗

bioRxiv2020

Does the Antisecretory Peptide AF-16 modulate fluid balance and inflammation in experimental peritonitis induced sepsis?

Sepsis is a life-threatening condition due to a dysregulated immunological response to infection. Apart from source control and broad-spectrum antibiotics, management is based on fluid resuscitation and vasoactive drugs. Fluid resuscitation implicates the risk of volume overload, which in turn is associated with longer stay in intensive care, prolonged use of mechanical ventilation and increased mortality. Antisecretory factor (AF), an endogenous protein, is detectable in most tissues and in plasma. The biologically active site of the protein is located in an 8-peptide sequence, contained in a synthetic 16-peptide fragment, named AF-16. The protein as well as the peptide AF-16 has multiple modulatory effects on abnormal fluid transport and edema formation/resolution as well as in a variety of inflammatory conditions. Apart from its anti-secretory and anti-inflammatory characteristics, AF is an inhibitor of capillary leakage in intestine. It is not known whether the protein AF or the peptide AF-16 can ameliorate symptoms in sepsis. We hypothesized that AF-16 decreases the degree of hemodynamic instability, the need of fluid resuscitation, vasopressor dose and tissue edema in fecal peritonitis. To test the hypothesis, we induced peritonitis and sepsis by injecting autologous fecal solution into abdominal cavity of anesthetized pigs, and randomized (in a blind manner) the animals to intervention (AF-16, n=8) or control (saline, n=8) group. After onset of hemodynamic instability (defined as mean arterial pressure < 60 mmHg maintained for > 5 minutes), resuscitation was initiated by an infusion of AF-16 or saline. We recorded respiratory and hemodynamic parameters hourly for twenty hours and collected post mortem tissue samples at the end of the experiment. No differences between the groups were observed regarding hemodynamics, fluid balance, lung mechanics, gas exchange or histology. This experimental study suggests that AF-16 does not modulate sepsis symptoms in peritonitis induced sepsis.

pathology↗