Christoph L. Menzel

Caspase-1 is hepatoprotective during trauma and hemorrhagic shock by reducing liver injury and inflammation.

Adaptive immune responses are induced in liver after major stresses such as hemorrhagic shock (HS) and trauma. There is emerging evidence that the inflammasome, the multiprotein platform that induces caspase-1 activation and promotes interleukin (IL)-1β and IL-18 processing, is activated in response to cellular oxidative stress, such as after hypoxia, ischemia and HS. Additionally, damage-associated molecular patterns, such as those released after injury, have been shown to activate the inflammasome and caspase-1 through the NOD-like receptor (NLR) NLRP3. However, the role of the inflammasome in organ injury after HS and trauma is unknown. We therefore investigated inflammatory responses and end-organ injury in wild-type (WT) and caspase-1−/− mice in our model of HS with bilateral femur fracture (HS/BFF). We found that caspase-1−/− mice had higher levels of systemic inflammatory cytokines than WT mice. This result corresponded to higher levels of liver damage, cell death and neutrophil influx in caspase-1−/− liver compared with WT, although there was no difference in lung damage between experimental groups. To determine if hepatoprotection also depended on NLRP3, we subjected NLRP3−/− mice to HS/BFF, but found inflammatory responses and liver damage in these mice was similar to WT. Hepatoprotection was also not due to caspase-1-dependent cytokines, IL-1β and IL-18. Altogether, these data suggest that caspase-1 is hepatoprotective, in part through regulation of cell death pathways in the liver after major trauma, and that caspase-1 activation after HS/BFF does not depend on NLRP3. These findings may have implications for the treatment of trauma patients and may lead to progress in prevention or treatment of multiple organ failure (MOF).

Complement factor 3 deficiency attenuates hemorrhagic shock-related hepatic injury and systemic inflammatory response syndrome

Although complement activation is known to occur in the setting of severe hemorrhagic shock and tissue trauma (HS/T), the extent to which complement drives the initial inflammatory response and end-organ damage is uncertain. In this study, complement factor 3-deficient (C3(-/-)) mice and wild-type control mice were subjected to 1.5-h hemorrhagic shock, bilateral femur fracture, and soft tissue injury, followed by 4.5-h resuscitation (HS/T). C57BL/6 mice were also given 15 U of cobra venom factor (CVF) or phosphate-buffered saline injected intraperitoneally, followed by HS/T 24 h later. The results showed that HS/T resulted in C3 consumption in wild-type mice and C3 deposition in injured livers. C3(-/-) mice had significantly lower serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and circulating DNA levels, together with much lower circulating interleukin (IL)-6, IL-10, and high-mobility group box 1 (HMGB1) levels. Temporary C3 depletion by CVF preconditioning also led to reduced transaminases and a blunted cytokine release. C3(-/-) mice displayed well-preserved hepatic structure. C3(-/-) mice subjected to HS/T had higher levels of heme oxygenase-1, which has been associated with tissue protection in HS models. Our data indicate that complement activation contributes to inflammatory pathways and liver damage in HS/T. This suggests that targeting complement activation in the setting of severe injury could be useful.

Inducible nitric oxide synthase contributes to immune dysfunction following trauma.

ABSTRACT Trauma results in a persistent depression in adaptive immunity, which contributes to patient morbidity and mortality. This state of immune paralysis following trauma is characterized by a change in cell-mediated immunity, specifically a depression in T-cell function and a shift toward TH2 T-cell phenotype. Upregulation of inducible nitric oxide synthase (iNOS) is well recognized after injury and contributes to the inflammatory response and organ damage early after trauma. However, it is unknown whether iNOS plays a role in adaptive immune dysfunction after trauma. This study utilized a murine model of severe peripheral tissue injury to show that iNOS is rapidly upregulated in macrophages and a (Gr-1hi–CD11bhi) myeloid-derived suppressor cell subpopulation in the spleen. Through the use of iNOS knockout mice, a specific iNOS inhibitor, and a nitric oxide (NO) scavenger, this study demonstrates that iNOS-derived NO is required for the depression in T-lymphocyte proliferation, interferon &ggr;, and interleukin 2 production within the spleen at 48 h after trauma. These findings support the hypothesis that iNOS regulates immune suppression following trauma and suggest that targeting the sustained production of NO by iNOS may attenuate posttraumatic immune depression.

Tissue engineering of bone tissue. Principles and clinical applications

Complex fractures are still a major clinical challenge. The treatment options of large bony defects either with autografts or allografts are limited in terms of material availability and tissue in-growth. Tissue engineering might offer a solution to this problem. In an interdisciplinary approach artificial bony tissue can be generated which mimics normal bone in terms of function and morphology. So far tissue engineering of bone is mainly confined to laboratory investigations whereas clinical applications are still in the beginning. This manuscript presents the most important scaffolds as well as growth factors and cell systems. Furthermore, it focuses on clinical studies for the treatment of large bony defects using tissue engineered cell-matrix constructs.

Tissue Engineering von Knochengewebe

Complex fractures are still a major clinical challenge. The treatment options of large bony defects either with autografts or allografts are limited in terms of material availability and tissue in-growth. Tissue engineering might offer a solution to this problem. In an interdisciplinary approach artificial bony tissue can be generated which mimics normal bone in terms of function and morphology. So far tissue engineering of bone is mainly confined to laboratory investigations whereas clinical applications are still in the beginning. This manuscript presents the most important scaffolds as well as growth factors and cell systems. Furthermore, it focuses on clinical studies for the treatment of large bony defects using tissue engineered cell-matrix constructs.

Tissue Engineering von Knochengewebe@@@Tissue engineering of bone tissue: Prinzipien und klinische Anwendungsmöglichkeiten@@@Principles and clinical applications

Complex fractures are still a major clinical challenge. The treatment options of large bony defects either with autografts or allografts are limited in terms of material availability and tissue in-growth. Tissue engineering might offer a solution to this problem. In an interdisciplinary approach artificial bony tissue can be generated which mimics normal bone in terms of function and morphology. So far tissue engineering of bone is mainly confined to laboratory investigations whereas clinical applications are still in the beginning. This manuscript presents the most important scaffolds as well as growth factors and cell systems. Furthermore, it focuses on clinical studies for the treatment of large bony defects using tissue engineered cell-matrix constructs.