Mast Cells Play a Critical Role in the Systemic Inflammatory Response and End-Organ Injury Resulting from Trauma

Abstract

Background Much of the morbidity following trauma results from excessive activation of the innate immune system. This is manifested as a systemic inflammatory response and associated end-organ damage. Although mast cells are known to be important in many immune responses, their role in the systemic response to severe trauma is unknown. Study Design C57BL/6J-KitW-sh/BsmJ (mast cell deficient) and wild type mice were subjected to 1.5h of hemorrhagic shock plus bilateral femur fracture and soft tissue injury (HS/T), followed by resuscitation at 4.5h. Blood withdrawal volumes, mean arterial pressures; circulating cytokine, chemokine, High Mobility Group Box-1 (HMGB-1), double strain DNA (dsDNA), transaminase levels, and histology in liver and lung were compared between groups. Results Mast cell deficient mice exhibited greater hemodynamic stability than wild type mice. At baseline, the mast cell deficient mice exhibited no difference in any of the organ injury or inflammatory markers measured. As expected, wild type mice subjected to HS/T exhibited end organ damage manifested by marked increases in circulating Alanine transaminase (ALT), aspartate aminotransferase (AST), and double-strain DNA (dsDNA) levels, as well as histological evidence of tissue necrosis. In clear contrast, mast cell deficient mice exhibited almost no tissue damage. Similarly, the magnitude of increased circulating cytokine and chemokine induced by HS/T was much less in the mast cell deficient mice than in the wild type group. Conclusions Mast cell deficiency resulted in a damped systemic inflammatory response, greatly attenuated multiple organ injury, and more stable hemodynamics in HS/T. Thus, mast cells appear to be a critical component of the initial host response to severe injury.

Delayed Neutralization of Interleukin 6 Reduces Organ Injury, Selectively Suppresses Inflammatory Mediator, and Partially Normalizes Immune Dysfunction Following Trauma and Hemorrhagic Shock

“…Consistent with our previous reports (20), we found that both lung injury (Figure 2, A–L) and liver injury (Figure 2, M–X) were maximal between 6 and 24h. Lung injury was assessed by histology and lung injury score (Figure 3, A–C) while liver damage was assessed histologically and by circulating levels of ALT (Figure 3, D–F).…”

“…were given as necessary throughout the course of the experiment. Bilateral Pseudofracture (PF) and hemorrhagic shock (HS) were performed as previously described by our group (19, 20). Briefly, donor mice were euthanized via overdose of pentobarbital and the femurs and tibias were removed from both hind limbs and crushed using a sterile mortar and pestle in the biohazard hood.…”

Defective Bone Repair in C57Bl6 Mice With Acute Systemic Inflammation

“…Similar macrophage-induced increases in fibrous tissue formation leading to defective healing of skin wounds have been associated with LPS-induced systemic inflammation [37]. In addition to macrophages, mast cells have been implicated in the immune response to trauma in a mouse model of acute systemic inflammation [9]. The systemic inflammatory response and end organ (liver, lung) damage 6 hours after being subjected to hemorrhagic shock and femoral fracture were less severe in mast cell-deficient KitW-sh mice compared with wild type mice.…”

“…The systemic inflammatory response and end organ (liver, lung) damage 6 hours after being subjected to hemorrhagic shock and femoral fracture were less severe in mast cell-deficient KitW-sh mice compared with wild type mice. Cai et al [9] concluded from their data that mast cells play a key role in the systemic inflammatory response. In previous work we characterized healing of the femoral bone defect used in the current study in mast cell-deficient KitW-sh mice [6].…”

Transient Regional Hypothermia Applied to a Traumatic Limb Attenuates Distant Lung Injury Following Blast Limb Trauma

“…The consequence is distant organ injury, predominantly affecting the lungs (3)(4)(5). Limb trauma followed by injury to distant organs is likely responsible for the high morbidity and mortality observed (6)(7)(8). Therefore, therapeutic interventions to treat or block these "cascade" consequences are needed to improve outcomes of such patients (9,10).…”