Role of hemorrhage in the induction of systemic inflammation and remote organ damage: Analysis of combined pseudo‐fracture and hemorrhagic shock

This study was performed to analyze the role of hemorrhage‐induced hypotension in the induction of systemic inflammation and remote organ dysfunction. Male C57/BL6 mice (6‐ to 10‐week old and 20–30 g) were used. Animals were either subjected to pseudo‐fracture [PF; standardized soft‐tissue injury and injection of crushed bone, PF group: n = 9], or PF combined with hemorrhagic shock (HS + PF group: n = 6). Endpoint was 6 h. Systemic inflammation was assessed by IL‐6 and IL‐10 levels. Myeloperoxidase (MPO) and NF‐κB activity in the lung and liver tissue were obtained to assess remote organ damage. The increases of systemic cytokines are similar for animals subjected to PF and PF + HS (IL‐6: 189 pg/ml ± 32.5 vs. 160 pg/ml ± 5.3; IL‐10: 60.3 pg/ml ± 15.8 vs. 88 pg/ml ± 32.4). Furthermore, the features (ALT; NF‐κB) of liver injury are equally elevated in mice subjected to PF (76.9 U/L ± 4.5) and HS + PF (80 U/L ± 5.5). Lung injury, addressed by MPO activity was more severe in group HS + PF (2.95 ng/ml ± 0.32) than in group PF (1.21 ng/ml ± 0.2). Both PF and additional HS cause a systemic inflammatory response. In addition, hemorrhage seems to be associated with remote affects on the lung. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:270–274, 2011

[1]  Y. Vodovotz,et al.  LOCAL EXPOSURE OF BONE COMPONENTS TO INJURED SOFT TISSUE INDUCES TOLL-LIKE RECEPTOR 4-DEPENDENT SYSTEMIC INFLAMMATION WITH ACUTE LUNG INJURY , 2008, Shock.

[2]  Y. Vodovotz,et al.  PATTERNS OF CYTOKINE RELEASE AND EVOLUTION OF REMOTE ORGAN DYSFUNCTION AFTER BILATERAL FEMUR FRACTURE , 2008, Shock.

[3]  Y. Vodovotz,et al.  The Role of Fracture-Associated Soft Tissue Injury in the Induction of Systemic Inflammation and Remote Organ Dysfunction After Bilateral Femur Fracture , 2008, Journal of orthopaedic trauma.

[4]  Timothy R Billiar,et al.  Systemic inflammation and end organ damage following trauma involves functional TLR4 signaling in both bone marrow‐derived cells and parenchymal cells , 2008, Journal of leukocyte biology.

[5]  G. Franklin,et al.  Systemic inflammation after trauma. , 2007, Injury.

[6]  H. Özgüç,et al.  Relationships between markers of inflammation, severity of injury, and clinical outcomes in hemorrhagic shock , 2007, Advances in therapy.

[7]  K. Willett,et al.  Mortality in patients with bilateral femoral fractures , 2007 .

[8]  A. Sauaia,et al.  Decreased progression of postinjury lung dysfunction to the acute respiratory distress syndrome and multiple organ failure. , 2006, Surgery.

[9]  L. Ware Pathophysiology of acute lung injury and the acute respiratory distress syndrome. , 2006, Seminars in respiratory and critical care medicine.

[10]  Timothy R Billiar,et al.  Systemic inflammation and remote organ damage following bilateral femur fracture requires Toll-like receptor 4. , 2006, American journal of physiology. Regulatory, integrative and comparative physiology.

[11]  Y. Vodovotz,et al.  Toll-like receptor-4 signaling mediates hepatic injury and systemic inflammation in hemorrhagic shock. , 2006, Journal of the American College of Surgeons.

[12]  H. Pape,et al.  Die Bedeutung der Zytokine in der posttraumatischen Entzündungsreaktion , 2005, Der Unfallchirurg.

[13]  A. Sauaia,et al.  The role of the lung in postinjury multiple organ failure. , 2005, Surgery.

[14]  M. Keel,et al.  Pathophysiology of polytrauma. , 2005, Injury.

[15]  C. Born,et al.  Cytokines in patients with polytrauma. , 2004, Clinical orthopaedics and related research.

[16]  W. Mills,et al.  Mortality After Reamed Intramedullary Nailing of Bilateral Femur Fractures , 2003, Clinical orthopaedics and related research.

[17]  R. Bellamy Workers' compensation: the patient, the physician, and the system. , 2001, Journal of Bone and Joint Surgery. American volume.

[18]  Y. Vodovotz,et al.  Hepatocyte toll-like receptor 2 expression in vivo and in vitro: role of cytokines in induction of rat TLR2 gene expression by lipopolysaccharide. , 2000, Shock.

[19]  L. Kinzl,et al.  Is interleukin 6 an early marker of injury severity following major trauma in humans? , 2000, Archives of surgery.

[20]  P. Wang,et al.  Organ dysfunction following hemorrhage and sepsis: mechanisms and therapeutic approaches (Review). , 1999, International journal of molecular medicine.

[21]  I. Marzi,et al.  Mediators in polytrauma – pathophysiological significance and clinical relevance , 1998, Langenbeck's Archives of Surgery.

[22]  I. Chaudry,et al.  Severe depression of host immune functions following closed-bone fracture, soft-tissue trauma, and hemorrhagic shock. , 1998, Critical care medicine.

[23]  E. Faist,et al.  SYSTEMIC INFLAMMATORY RESPONSE SYNDROME (SIRS), MULTIPLE ORGAN DYSFUNCTION SYNDROME (MODS), MULTIPLE ORGAN FAILURE (MOF): ARE WE WINNING THE BATTLE? , 1998, Shock.

[24]  I. Chaudry,et al.  Do different rates of fluid resuscitation adversely or beneficially influence immune responses after trauma-hemorrhage? , 1998, The Journal of trauma.

[25]  J. Mege,et al.  Patterns of cytokine evolution (tumor necrosis factor-alpha and interleukin-6) after septic shock, hemorrhagic shock, and severe trauma. , 1997, Critical care medicine.

[26]  U. Steckholzer,et al.  Relationship of interleukin-10 plasma levels to severity of injury and clinical outcome in injured patients. , 1997, The Journal of trauma.

[27]  A. Sauaia,et al.  The inflammatory profile of interleukin-6, interleukin-8, and soluble intercellular adhesion molecule-1 in postinjury multiple organ failure , 1996 .

[28]  E. Moore,et al.  Interleukin-6 in the injured patient. Marker of injury or mediator of inflammation? , 1996, Annals of surgery.

[29]  I. Chaudry,et al.  Immune function is more compromised after closed bone fracture and hemorrhagic shock than hemorrhage alone. , 1996, Archives of surgery.

[30]  G. Regel,et al.  Pattern of Organ Failure following Severe Trauma , 1996, World Journal of Surgery.

[31]  R. Sauerwein,et al.  Cytokine Patterns in Patients After Major Vascular Surgery, Hemorrhagic Shock, and Severe Blunt Trauma Relation with Subsequent Adult Respiratory Distress Syndrome and Multiple Organ Failure , 1993, Annals of surgery.

[32]  I. Chaudry,et al.  Interferon-gamma attenuates hemorrhage-induced suppression of macrophage and splenocyte functions and decreases susceptibility to sepsis. , 1992, Surgery.

[33]  K. Johnson,et al.  Incidence of adult respiratory distress syndrome in patients with multiple musculoskeletal injuries: effect of early operative stabilization of fractures. , 1985, The Journal of trauma.

[34]  C. Krettek,et al.  [The importance of cytokines in the posttraumatic inflammatory reaction]. , 2005, Der Unfallchirurg.

[35]  I. Pallister Current concepts of respiratory insufficiency syndromes after fracture. , 2002, The Journal of bone and joint surgery. British volume.

[36]  P. Giannoudis,et al.  Simultaneous bilateral femoral fractures: systemic complications in 14 cases , 2000, International Orthopaedics.

[37]  I. Chaudry,et al.  Chloroquine attenuates hemorrhagic shock-induced immunosuppression and decreases susceptibility to sepsis. , 1992, Archives of surgery.

[38]  D. Livingston,et al.  Hemorrhagic shock inhibits lipopolysaccharide-induced myelopoiesis in both germ-free and conventional rats. , 1992, Surgery.

[39]  Z. Ba,et al.  Differential alterations in plasma IL-6 and TNF levels after trauma and hemorrhage. , 1991, The American journal of physiology.