© 2004 American Thoracic Society
Balance of Inflammation in SepsisTo the Editor:
In their study, Sherwood and colleagues (1) look at mainly the proinflammatory cytokines in addition to CD8+ T cells and natural killer cell activity. Despite its expense, modulation of proinflammatory response alone in sepsis has not shown any benefit on mortality rate in septic patients (2). Compensatory antiinflammatory response leads to monocyte/macrophage hyporesponsiveness, resulting in the suppression of proinflammatory cytokines. Inflammatory cytokines, such as IFN- Although Sherwood and colleagues (1) looked at the CD8+ T cells and natural killer cells along with Th1 cytokines, it certainly would have been interesting to know the levels of IL-10, a potent immunomodulatory cytokine, and IL-4, the index cytokine of Th2 cell activity. IL-10 not only limits and halts the inflammatory response, but it also regulates the proliferation of T cells, B cells, natural killer cells, antigen-presenting cells, mast cells, and granulocytes (5).
Heidecke and colleagues (6) showed that unbalanced production of proinflammatory and antiinflammatory cytokines occur in patients with severe intraabdominal infection, with severe suppression of tumor necrosis factor-
Institute of Medical Sciences Aberdeen, Scotland, United Kingdom FOOTNOTES Conflict of Interest Statement: E.P. has no declared conflict of interest. REFERENCES
From the Authors: I read Dr. Pravinkumar's letter with great interest and appreciate his comments. Our recent article (1) examined the response of ß2 microglobulin knockout mice to acute intraabdominal sepsis. We found that ß2 microglobulin knockout mice treated with anti-asialoGM1 exhibit greater than 70% long-term survival after cecal ligation and puncture. The improved survival was associated with decreased production of proinflammatory cytokines, less hypothermia, and improved acid–base balance. The novel finding of our work is that CD8+ T and natural killer cells contribute to the proinflammatory response associated with acute peritonitis. Most prior investigations have focused on macrophage function during the early proinflammatory phase of sepsis (2). The model of sepsis used in our studies is rapidly lethal and causes mortality of wild-type mice within 24 to 30 hours. This mimics the clinical presentation of patients with severe acute peritonitis. Clinically, most patients with acute peritonitis can be effectively treated during this early inflammatory phase with fluid resuscitation, surgery, and antibiotics. However, our findings provide a better understanding of the underlying mechanisms mediating the systemic inflammatory response during acute peritonitis. There are many underlying causes of sepsis, all of which have differences in pathophysiology. Furthermore, individual patients are likely to pass through different phases of sepsis ranging from an early proinflammatory phase (systemic inflammatory response syndrome) to later immunoparalysis (compensatory antiinflammatory response) (3). Some have speculated that these phases may coexist. The factors that have been classically used to define sepsis are physiologic (4), yet much of the pathogenesis of sepsis is caused by immunologic alterations. Many investigators are working to identify markers that will define the immunologic status of the septic patient (5, 6). On the basis of immunologic conditions, targeted immunotherapy could be provided. For example, antiinflammatory therapies may be beneficial in patients exhibiting a proinflammatory phenotype, whereas they may worsen immunosuppression and increase the risk for mortality in patients with immunoparalysis. Therefore, I fully agree with Dr. Pravinkumar. The pathogenesis of sepsis is dependent on a complex interplay of proinflammatory and antiinflammatory mediators that change over time. Our study addresses factors that are important during the early proinflammatory phase of septic peritonitis. Hopefully, treatment of clinical sepsis will improve as our understanding of this complex disease process advances.
The University of Texas Medical Branch Galveston, Texas FOOTNOTES Conflict of Interest Statement: E.R.S. has no declared conflict of interest. REFERENCES
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, interleukin (IL)-12, and granulocyte colony-simulating factor, have been tried in the past to overcome this (
in nonsurvivors. Hence, there must be cautious optimism in postulating therapies in sepsis, directed either at proinflammatory or antiinflammatory cytokines alone.