carina penzenstadler - Academia.edu (original) (raw)

Papers by carina penzenstadler

SHOCK, 2018

Background: Hemorrhagic shock (HS) followed by resuscitation is often associated with sympathoadr... more Background: Hemorrhagic shock (HS) followed by resuscitation is often associated with sympathoadrenal activation (SAA) and endothelial damage (ED). Objective: We aimed to evaluate the impact of HS alone on the magnitude of SAA and consecutive ED, and to characterize potential targets for a standardized and reproducible model of HS-induced endotheliopathy in rats. Methods: Rats were subjected either to a volume-controlled HS (40% of total blood volume: v-HS group) or to a laboratory-guided HS (l-HS) targeting base deficit (BD) more than 5.5 mmol/L and/or lactate more than 2.2 mmol/L using a pressure-controlled volume loss. Results: At the end of shock, mean arterial pressure was significantly higher in the v-HS than the l-HS group (36 ± 5.6 vs. 30 ± 3.0 mmHg; P < 0.01). Base deficit and lactate were higher in l-HS than the v-HS group (BD: 9.5 ± 2.5 vs. 3.0 ± 1.0 mmol/L; P < 0.001; lactate: 4.1 ± 1.3 vs. 1.6 ± 0.6 mmol/L; P < 0.001). sVEGFR-1 and syndecan-1 were approximately...

Background Blood loss and resuscitation after trauma are associated with decreased hematocrit and... more Background Blood loss and resuscitation after trauma are associated with decreased hematocrit and hypoxia. Previously we showed that nitric oxide (NO) supplemented resuscitation (Sobhian et al., Am. J. Surg. (2011)), despite a transient decrease in mean arterial pressure, significantly enhanced perfusion in various organs with a strong trend to improve survival. Recently nitrite was identified as a potent NO-source under hypoxia. The aim of this study was to investigate the hemodynamic effects of nitrite under hypoxic conditions in a volume replacement model in rats. Methods Anesthetized rats were bled (0.5 min/ml) and Ringer’s solution was infused simultaneously (1.5 ml/min) to reduce hematocrit from 41 ± 2% to 20 ± 2%. Animals were randomly assigned to normoxia (NOX, PO2 > 80 mm Hg) or hypoxia (HOX, PO2 approx. 55 mm Hg). Hypoxia was induced by inhalation of nitrogen/air containing 15% O2. After 10 min of hypoxia or equal normoxic period, animals received a bolus dose of nitrit...

Inflammation, fibrosis and perineural adhesions with the surrounding tissue are common pathologic... more Inflammation, fibrosis and perineural adhesions with the surrounding tissue are common pathological processes following nerve injury and surgical interventions on peripheral nerves in human patients. Furthermore, these signs can reoccur following external neurolysis, currently the most common surgical treatment, thus leading to renewed nerve function impairment and chronic pain. To enable a successful evaluation of new therapeutic approaches, it is crucial to use a reproducible animal model that mimics the main clinical symptoms occurring in human patients. However, a clinically relevant model combining both histological and functional alterations has not been published to date. For this reason, we developed a reliable rat model, which exhibits the essential pathological processes of peripheral nerve scarring. In our study, we present a novel method for the induction of nerve scarring by applying glutaraldehyde-containing glue, known to cause nerve injury in humans. After a three-we...

Shock

We tested whether resuscitation supplemented with a) rat adipose-derived stem cells (ASCs) or b) ... more We tested whether resuscitation supplemented with a) rat adipose-derived stem cells (ASCs) or b) secretome (conditioned media) of ASCs can ameliorate inflammation, cell/organ injury, and/or improve outcome after Hemorrhagic traumatic shock (HTS). Rats were subjected to HTS and a resuscitation protocol that mimics pre-hospital restrictive reperfusion followed by an adequate reperfusion phase. 20 minutes into the restrictive reperfusion, animals received an intravenous bolus of 2x10 cells (ASC group) or the secretome produced by 2x10 ASCs/24 h (ASC-Secretome group). Controls received the vehicle (Vehicle group). All rats were observed for 28-day survival. HTS-induced inflammation represented by IL-6 was inhibited in the ASC (80%, p &amp;amp;amp;amp;amp;amp;amp;lt; 0.001) and in ASC-Secretome (59%, p &amp;amp;amp;amp;amp;amp;amp;lt; 0.01) group at 48 h compared to Vehicle group. At 24 h, HTS-induced liver injury reflected in plasma alanine aminotransferase was ameliorated by 36% (p &amp;amp;amp;amp;amp;amp;amp;lt; 0.001) in both the ASC and ASC-Secretome groups when compared to the Vehicle. There was no effect on kidney function and/or general cell injury markers. HTS-induced a moderate 28-day mortality (18%) that was prevented (p = 0.08) in the ASC but not in the ASC-Secretome group (12%). Our data suggest that the ASC-secretome supplemented resuscitation following HTS, in absence of the stem cells, exerts anti-inflammatory and liver protective effects. Given its ease of preparation, storage, availability and application (in contrast to the stem cells) we believe that the cell free secretome has a better therapeutic potential in the early phase of an acute hemorrhagic shock scenario.

Molecules

Background aim: Reperfusion after hemorrhagic traumatic shock (HTS) is often associated with comp... more Background aim: Reperfusion after hemorrhagic traumatic shock (HTS) is often associated with complications that are partly ascribed to the formation of reactive oxygen species (ROS). The aim of our study was to compare the effects of restrictive reperfusion (RR) to rapid full reperfusion (FR) on ROS formation and/or oxidative events. Materials and methods: Anesthetized male rats were randomly subjected to HTS followed by FR (75 mL/kg/h) or RR (30 mL/kg/h for 40 min, followed by 75 mL/kg/h) with Ringer’s solution (n = 8/group). Compartment-specific ROS formation was determined by infusion of ROS scavenger 1-hydroxy-3-carboxy-2,2,5,5-tetramethyl-pyrrolidine hydrochloride (CP-H) during resuscitation, followed by electron paramagnetic resonance spectroscopy. Sham-operated animals (n = 8) served as controls. The experiment was terminated 100 min post-shock. Results: Mean arterial pressure was significantly higher in the FR compared to the RR group during early reperfusion. Only RR animal...

Acta Biomaterialia

Peripheral nerve fibrosis and painful adhesions are common, recurring pathological sequelae follo... more Peripheral nerve fibrosis and painful adhesions are common, recurring pathological sequelae following injury. In this study, vital human amnion (hAM), an increasingly interesting biomaterial for regenerative medicine, was investigated as a novel therapy. hAM was first analyzed in vitro regarding its anti-adhesive characteristics. Then, the reflected region of hAM which was identified as more suitable, was transplanted into female Sprague Dawley rats with recurring sciatic nerve scarring (n = 24) and compared with untreated controls (n = 30) at one, four and twelve weeks. Immune response and fibrosis was investigated by (immuno)histochemical analysis. Nerve structure was examined and function determined using electrophysiology and gait analysis. Here we identified strongly reduced adhesions in the hAM-treated rats, displaying a significant difference at four weeks post transplantation compared to untreated controls (p = 0.0052). This correlated with the in vitro cell attachment test on hAM explants, which demonstrated a distinctly limited ability of fibroblasts to adhere to amniotic epithelial cells. Upon hAM transplantation, significantly less intraneural fibrosis was identified at the later time points. Moreover, hAM-treated rats exhibited a significantly higher sciatic functional index (SFI) after four weeks compared to controls (p &amp;amp;amp;amp;amp;lt; 0.05), which indicated a potentially pro-regenerative effect of hAM. As a possible explanation, an impact of hAM on the endogenous immune response, including T cell and macrophage subsets, was indicated. We conclude that hAM is strongly effective against recurring nerve scarring and induces an anti-fibrotic and pro-regenerative effect, making it highly promising for treating adhesion-related disorders. Abnormal fibrotic bonding of tissues, frequently involving peripheral nerves, affects millions of people worldwide. These so-called adhesions usually cause severe pain and drastically reduce quality of life. To date, no adequate treatment exists and none is routinely used in the clinical practice. In this study, vital human amnion, a part of the placenta, was transplanted in a rat model of peripheral nerve scarring and recurring adhesions as novel therapeutic approach. Amniotic cells have already demonstrated to feature stem-cell like properties and produce pro-regenerative factors, which makes the amnion an increasingly promising biomaterial for regenerative medicine. We identified that its transplantation was very effective against peripheral nerve scarring and distinctly reduced recurring adhesions. Moreover, we identified a pro-regenerative effect. This study showed that the amnion is a highly promising novel therapeutic approach for adhesion-related disorders.

Scientific Reports

Inorganic nitrite (NO 2 −) can be reduced back to nitric oxide (NO) by several heme proteins call... more Inorganic nitrite (NO 2 −) can be reduced back to nitric oxide (NO) by several heme proteins called nitrite reductases (NR) which affect both the vascular tonus and hemodynamics. The objective of this study was to clarify the impact of several NRs on the regulation of hemodynamics, for which hemodynamic parameters such as heart rate, blood pressure, arterial stiffness, peripheral resistance and myocardial contractility were characterized by pulse wave analysis. We have demonstrated that NO 2 − reduced to NO in RBCs predominantly influences the heart rate, while myoglobin (Mb) and mitochondriaderived NO regulates arterial stiffness, peripheral resistance and myocardial contractility. Using ex vivo on-line NO-detection, we showed that Mb is the strongest NR occurring in heart, which operates sufficiently only at very low oxygen levels. In contrast, mitochondrial NR operates under both hypoxia and normoxia. Additional experiments with cardiomyocytes suggested that only mitochondria-derived generation of NO regulates cGMP levels mediating the contractility of cardiomyocytes. Our data suggest that a network of NRs is involved in NO 2 − mediated regulation of hemodynamics. Oxygen tension and hematocrit define the activity of specific NRs. Nitric oxide (NO) is a key player in the regulation of hemodynamic parameters such as peripheral resistance 1 , arterial pressure 2,3 , aortic stiffness, myocardial contractility 4,5 , heart rate, cardiac index 6,7 , and as a consequence tissue perfusion 8. Various isoforms of NO synthase (NOS) are the main sources of NO under normoxic conditions. However, NOS become inefficient under hypoxic conditions 9 , due to the fact that this enzyme family is oxygen dependent 10. Nitrite, the second major source of NO, becomes relevant exclusively under hypoxic conditions. Hypoxia has been shown to facilitate the reduction of nitrite to NO, a process catalyzed by so called nitrite reductases (NR) complementary to oxygen-dependent NO synthases 11. For this reason, nitrite administration has already been suggested for therapeutic treatment of diseases associated with impaired oxygen delivery 12,13. Both dietary nitrate and nitrate have also been shown to regulate blood pressure 14,15. Several reports suggest that hemodynamic effects of nitrite occur not only under hypoxic but also under normoxic conditions. In healthy volunteers under normoxic conditions circulating nitrite concentrations have been shown to correlate with systolic and diastolic blood pressure 16,17 and the administration of nitrite resulted in the dilation of conduit arteries 18. These data suggest that nitrite-mediated NO release may not only contribute to improve hemodynamics under hypoxic/ischemic conditions but also to physiological regulation of hemodynamics. There are three major sources of nitrite in the body (i) oxidation of NO formed by different NOS, (ii) absorption from food and (iii) the release from specific drugs, such as nitroglycerin. Hobbs et al. showed that beetroot bread, containing large amount of nitrate, which is reduced to nitrite in the gastrointestinal tract, increased endothelium-independent vasodilation and decreased diastolic blood pressure and arterial stiffness in healthy men 19. Several groups reported that diverse NRs regulate hemodynamics, from which two were found in red blood cells (RBC). Gladwin and co-authors suggested hemoglobin (Hb) in RBC as a key regulator of hemodynamics 20,21 , while Ahluwalia and coworkers presented evidence that blood pressure is regulated predominantly by xanthine oxidoreductase (XOR) which is also localized in RBCs 22. In contrast Rassaf 's group reported that Mb located in blood vessels, not Hb or XOR, is the major NR responsible for hemodynamic effects of nitrite 23,24. In addition, Zweier and coauthors suggested that cytoglobin is the key NR responsible for nitrite effects in aorta ring assays 25. In our previous studies we established the mitochondrial electron transport chain as a potent NR 26 , in particular,

Disease models & mechanisms, Aug 26, 2017

Inflammation, fibrosis and perineural adhesions with the surrounding tissue are common pathologic... more Inflammation, fibrosis and perineural adhesions with the surrounding tissue are common pathological processes following nerve injury and surgical interventions on peripheral nerves in human patients. Furthermore, these signs can reoccur following external neurolysis, currently the most common surgical treatment, thus leading to renewed nerve function impairment and chronic pain. To enable a successful evaluation of new therapeutic approaches, it is crucial to use a reproducible animal model that mimics the main clinical symptoms occurring in human patients. However, a clinically relevant model combining both histological and functional alterations has not been published to date. For this reason, we developed a reliable rat model, which exhibits the essential pathological processes of peripheral nerve scarring.In our study, we present a novel method for the induction of nerve scarring by applying glutaraldehyde-containing glue, known to cause nerve injury in humans. After a three-wee...

SHOCK, 2018

Shock

Molecules

Acta Biomaterialia

Scientific Reports

Disease models & mechanisms, Aug 26, 2017

Inflammation, fibrosis and perineural adhesions with the surrounding tissue are common pathologic... more Inflammation, fibrosis and perineural adhesions with the surrounding tissue are common pathological processes following nerve injury and surgical interventions on peripheral nerves in human patients. Furthermore, these signs can reoccur following external neurolysis, currently the most common surgical treatment, thus leading to renewed nerve function impairment and chronic pain. To enable a successful evaluation of new therapeutic approaches, it is crucial to use a reproducible animal model that mimics the main clinical symptoms occurring in human patients. However, a clinically relevant model combining both histological and functional alterations has not been published to date. For this reason, we developed a reliable rat model, which exhibits the essential pathological processes of peripheral nerve scarring.In our study, we present a novel method for the induction of nerve scarring by applying glutaraldehyde-containing glue, known to cause nerve injury in humans. After a three-wee...