No abstract

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. These features can reoccur following external neurolysis, currently the most common surgical treatment for peripheral nerve scarring, 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. We therefore developed a reliable rat model that 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 that is known to cause nerve injury in humans. After a 3-week contact period with the sciatic nerve in female Sprague Dawley rats, we could demonstrate severe intra- and perineural scarring that resulted in grade 3 adhesions and major impairments in the electrophysiological peak amplitude compared with sham control (P=0.0478). Immunohistochemical analysis of the nerve structure revealed vigorous nerve inflammation and recruitment of T cells and macrophages. Also, distinct nerve degeneration was determined by immunostaining. These pathological alterations were further reflected in significant functional deficiencies, as determined by the analysis of relevant gait parameters as well as the quantification of the sciatic functional index starting at week 1 post-operation (P<0.01). Moreover, with this model we could, for the first time, demonstrate not only the primary formation, but also the recurrence, of severe adhesions 1 week after glue removal, imitating a major clinical challenge. As a comparison, we tested a published model for generating perineural fibrotic adhesions, which did not result in significant pathological changes. Taken together, we established an easily reproducible and reliable rat model for peripheral nerve scarring that allows for the effective testing of new therapeutic strategies.

Our findings indicate that ED has already occurred during HS without reperfusion; intensity is strongly related to the severity of HS and consecutive SAA; and severity may appropriately be targeted and standardized in a HS model controlled by biological endpoints such as BD and/or lactate.

Inorganic nitrite (NO2 −) 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 NO2 − reduced to NO in RBCs predominantly influences the heart rate, while myoglobin (Mb) and mitochondria-derived 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 NO2 − mediated regulation of hemodynamics. Oxygen tension and hematocrit define the activity of specific NRs.

Our data suggest that the ASC-secretome supplemented resuscitation following HTS, in the 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.