LAUSR

Sepsis is a deadly syndrome characterized by organ dysfunction and failure following an infection. The body’s response to infection is designed to limit the spread of pathogens and to facilitate clearance of the invading microorganisms. In most instances, this process is successful and the patient recovers. In some patients, the response to infection results in severe damage to the infected tissue and initiates a cascade that leads to multiple organ dysfunction and death. The incidence of sepsis is increasing and it represents a significant health burden worldwide.1 Despite decades of research into the pathophysiology of this syndrome, supportive care with antibiotics, intravenous fluids, and vasopressors is the mainstay of therapy. Currently, there are no therapies that prevent or reverse organ damage that occurs in the setting of sepsis and the basic approach is to provide supportive care to enable the body to heal. Traditionally, studies of sepsis therapeutics focus on targeting a single molecule or pathway. Although this approach allows for elegant dissection of the molecular mechanisms of inflammation and organ injury, it is possible that the response to infection is multifaceted and that targeting a single molecule is not adequate to limit or reverse organ injury. An alternative approach is to target pathways that regulate gene transcription of multiple proinflammatory pathways and immune cell recruitment. Previous work has demonstrated that high mobility group A1 (HMGA1), a chromatin associated protein that regulates gene transcription by modifying DNA structure and recruiting transcription factors,2 may function in this manner. Drugs that inhibit HMGA1, such as Netropsin and distamycin A, have been shown to improve survival in murine endotoxemia by disrupting transcription factor binding to the promoter regions of proinflammatory and leukocyte trafficking genes.3,4 In the current issue of The Journal of Leukocyte Biology, Baron et al. expand upon their prior findings and examine the role of HMGA1 in murinemodel of endotoxemia and Escherichia coli sepsis using a genetic approach.5 Because HMGA1 knockout mice develop cardiac abnormalities and hematologicmalignancies,6 the authors designed amouse that expresses a dominant negative form of HMGA1 (dnHMGA1) that inhibits HMGA1 biological activity in vascular smooth muscle cells.7 To determine the effect of the dnHMGA1 in regulating inflammation, vascular smooth muscle cells were isolated from dnHMGA1 transgenic and wild-type mice and stimulated in vitro with proinflammatory cytokines. The authors demonstrate that overexpression of dnHMGA1 suppressed NOS2 promoter activity resulting in reduced NOS2 expression when stimulated with IL-1β . Interestingly, there was an increased interaction of the dnHMGA1 with the p50 subunit of NF-κB suggesting that formation of the p50/RelA heterodimer may be impaired. Previous work showed that dnHMGA1 does not bind to DNA,2 and these results suggest a DNA-independent role of HMGA1 in regulating gene expression. To investigate the impact of vascular smooth muscle cell-restricted dnHMGA1 regulation of organ injury following sepsis, the authors determine both local and systemic immunological responses. The authors measured blood pressure at serial time points following E. coli endotoxin administration and determined that dnHMGA1 mice had reduced hypotension beginning at 8 h. These data suggest an early and direct effect of dnHMGA1 on vascular tone. To examine mortality, a fibrin clotmodel was employed inwhich E. coli is released into the peritoneum to induce sepsis. These data demonstrated that the dnHMGA1 transgenic mice had significantly higher survival compared to wildtype control mice. Interestingly, the mortality effect did not depend on the ability to control the primary infection as there was no difference in cellular recruitment, bacterial load, or neutrophil phagocytosis in the peritoneal cavity between the groups. These data indicate that the dnHMGA1 blunts the inflammatory response without disarming innate host defenses. To investigate how expression of the dnHMGA1 improved mortality, the authors found reduced macrophage and neutrophil recruitment into the spleenand the lungsof thednHMG1transgenic mice as measured by immunostaining of histologic sections. The authors hypothesize that the reduced cellular recruitment to these organs was due to diminished production of the macrophage and neutrophil chemokines. They measured CXCL2/Mip2 and CCL2/MCP1 produced in vitro by cytokine stimulated smooth muscle cells and in vivo from E.coli infected spleen and plasma samples and found decreased levels in dnHMGA1mice compared to control mice. This study highlights the multiple phases of sepsis that are associated with sequential activation of the proand anti-inflammatory pathways. The initial phase of sepsis is typically characterized by a hyperinflammatory response that leads to vascular dysfunction and shock. The later phase of sepsis is characterized by immune suppression, susceptibility to superinfections, and multiple organ failure. Interestingly, it appears that the dnHMGA1 transgenic mice are protected from both the hyperinflammatory response, as demonstrated by reduced hypotension early after exposure to E. coli LPS, and the later phase, as demonstrated by increased survival following the E. coli fibrin clot-induced sepsis model. These data suggest a unique mechanism by which HMGA1-depedenent inhibition of DNA binding