Hypothesis: Compartmentalization of cytokines in intraabdominal infection

We investigated the immunopathophysiologic responses during sepsis induced by cecal ligation and puncture (CLP) in CD4-deficient (CD14 knockout [CD14KO]) mice. Our studies were designed to specifically test the role of CD14 in the inflammatory response to sepsis and to ascertain if alterations would improve morbidity or mortality. Sepsis was induced using the CLP model with appropriate antibiotic treatment. The severity of sepsis increased in the CD14KO mice with increasing puncture size (18 gauge [18G], 21G, and 25G). Following CLP, body temperature (at 12 h) and gross motor activity levels of the sham and 25G CLP groups recovered to normal, while the 21G and 18G CLP groups exhibited severe hypothermia coupled with decreased gross motor activity and body weight. There were no significant differences in survival, temperature, body weight, or activity levels between CD14KO and control mice after 21G CLP. However, CD14KO mice expressed two-to fourfold less pro-inflammatory (interleukin-1␤ [IL-1␤], tumor necrosis factor [TNF], and IL-6) and antiinflammatory (IL-10, IL-1 receptor antagonist, and TNF receptors I and II) cytokines in the blood after 21G CLP. Plasma levels of the chemokines macrophage inflammatory protein 2␣ and KC were similarly reduced in CD14KO mice. A similar trend of decreased cytokine and cytokine inhibitor levels was observed in the peritoneal cavity of CD14KO mice. Our results indicate that the CD14 pathway of activation plays a critical role in the production of both pro-inflammatory cytokines and cytokine inhibitors but has minimal impact on the morbidity or mortality induced by the CLP model of sepsis.Surgery, trauma, or other sources of inflammation can ultimately lead to sepsis, a common cause of morbidity and mortality. Temperature alterations, inflammation, and elevated cytokine levels are some characteristics of sepsis (6). While the etiology of sepsis is multifactorial, endotoxin (lipopolysaccharide [LPS]), a major component of the outer membrane of gram-negative bacteria (39, 43), is capable of inducing a sepsislike picture. Although endotoxin in appropriate amounts can activate favorable responses by increasing the ability of macrophages to mount antimicrobial activities (35, 43), large amounts of LPS can be toxic, ultimately leading to endotoxic shock (6, 39). Appropriate host recognition and responses to LPS therefore represent a key event in determining the level and type of available protection (43).CD14 is an LPS receptor (54) and is anchored to the monocyte/macrophage cell membrane via glycosylphosphatidyl inositol (18,20). In vitro studies have shown that cells bearing the CD14 receptor bind LPS in the presence of LPS-binding protein (44) and are activated to produce pro-and anti-inflammatory cytokines and chemokines and a variety of other molecules active in the innate immune response. Recently, it has been shown that signal transduction via membrane CD14 requires a signaling complex which appears to include, at a minimum, the expression of Toll 4 (9, 24, 32, 36), MD2 (47), a...

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“…This phenomenon has been termed the "tip of the iceberg" (8,30,41). Interestingly, no clear pattern emerges from our present study.…”

Section: Discussioncontrasting

confidence: 75%

Critical Role of CD14 for Production of Proinflammatory Cytokines and Cytokine Inhibitors during Sepsis with Failure To Alter Morbidity or Mortality

et al. 2001

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“…The more likely explanation for the protective effects of anti-TNF-␣ antibody in D-galsensitized, E. faecalis-infected mice is that localized TNF-␣ production, perhaps within the peritoneal cavity, contributes substantially to mortality. Recent publications support the concept of a potentially lethal compartmentalized cytokine response following intraabdominal infection (30,39). For E. faecalis K9, mean peritoneal TNF-␣ levels approximated 200 pg per peritoneum at 3 h postchallenge with 10 9 bacteria.…”

Section: Discussionmentioning

confidence: 87%

Anomalous Role of Tumor Necrosis Factor Alpha in Experimental Enterococcal Infection

Papasian¹,

Silverstein

Gao³

et al. 2002

Infect Immun

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The murine D-galactosamine (D-gal) model of tumor necrosis factor alpha (TNF-␣) hypersensitization was used as an initial tool to investigate the potential contribution of TNF-␣ to lethal intraperitoneal (i.p.) infection with Enterococcus faecalis. D-gal sensitized mice to lethal E. faecalis infection, whereas dexamethasone and neutralizing anti-TNF-␣ antibody protected D-gal-treated, E. faecalis-infected mice, implicating TNF-␣ in the lethal response to E. faecalis infection in D-gal-treated mice. Circulating TNF-␣ was undetectable for at least 8 h following i.p. E. faecalis infection, although low peritoneal levels of TNF-␣ were detected within 3 h, suggesting that localized TNF-␣ production contributed to the lethal response to E. faecalis infection in D-gal-treated mice. Although i.p. E. faecalis infection failed to induce a detectable systemic TNF-␣ response, circulating Interleukin-6 (IL-6) was detected within 3 h of infection. IL-6 was also detected in the peritoneum within an hour of infection, prior to the appearance of peritoneal TNF-␣. In striking contrast to in vivo results, E. faecalis induced a potent and rapid TNF-␣ response from both mouse peritoneal macrophages and the RAW 264.7 cell line in vitro. This led us to hypothesize that TNF-␣ production in response to E. faecalis infection is suppressed by IL-6 in vivo. In vitro experiments demonstrated a statistically significant, but modest, inhibitory effect of IL-6 on TNF-␣ production by RAW cells stimulated with E. faecalis. Collectively, these data indicate that acute, lethal E. faecalis infection appears to induce an unusual cytokine response that differs in character from that previously described for most other gram-positive and gram-negative bacteria.

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“…If the host is healthy or bacteremia is not massive, it will be controlled without any other systemic repercussion. If, on the contrary, the host is jeopardized or bacteremia is very great, a systemic inflammatory response with commitment of the patient (sepsis) can be produced [16,17].…”

Section: Anatomy and Physiology Of The Peritoneummentioning

confidence: 99%