Skip to main content

Main menu

  • Home
  • Articles
    • Current Issue
    • Next in The JI
    • Archive
    • Brief Reviews
    • Pillars of Immunology
    • Translating Immunology
    • Most Read
    • Top Downloads
    • Annual Meeting Abstracts
  • COVID-19/SARS/MERS Articles
  • Info
    • About the Journal
    • For Authors
    • Journal Policies
    • Influence Statement
    • For Advertisers
  • Editors
  • Submit
    • Submit a Manuscript
    • Instructions for Authors
    • Journal Policies
  • Subscribe
    • Journal Subscriptions
    • Email Alerts
    • RSS Feeds
    • ImmunoCasts
  • More
    • Most Read
    • Most Cited
    • ImmunoCasts
    • AAI Disclaimer
    • Feedback
    • Help
    • Accessibility Statement
  • Other Publications
    • American Association of Immunologists
    • ImmunoHorizons

User menu

  • Subscribe
  • Log in

Search

  • Advanced search
The Journal of Immunology
  • Other Publications
    • American Association of Immunologists
    • ImmunoHorizons
  • Subscribe
  • Log in
The Journal of Immunology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Next in The JI
    • Archive
    • Brief Reviews
    • Pillars of Immunology
    • Translating Immunology
    • Most Read
    • Top Downloads
    • Annual Meeting Abstracts
  • COVID-19/SARS/MERS Articles
  • Info
    • About the Journal
    • For Authors
    • Journal Policies
    • Influence Statement
    • For Advertisers
  • Editors
  • Submit
    • Submit a Manuscript
    • Instructions for Authors
    • Journal Policies
  • Subscribe
    • Journal Subscriptions
    • Email Alerts
    • RSS Feeds
    • ImmunoCasts
  • More
    • Most Read
    • Most Cited
    • ImmunoCasts
    • AAI Disclaimer
    • Feedback
    • Help
    • Accessibility Statement
  • Follow The Journal of Immunology on Twitter
  • Follow The Journal of Immunology on RSS

Splenectomy Protects against Sepsis Lethality and Reduces Serum HMGB1 Levels

Jared M. Huston, Haichao Wang, Mahendar Ochani, Kanta Ochani, Mauricio Rosas-Ballina, Margot Gallowitsch-Puerta, Mala Ashok, Lihong Yang, Kevin J. Tracey and Huan Yang
J Immunol September 1, 2008, 181 (5) 3535-3539; DOI: https://doi.org/10.4049/jimmunol.181.5.3535
Jared M. Huston
*Laboratory of Biomedical Science,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Haichao Wang
‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, NY 11030
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mahendar Ochani
*Laboratory of Biomedical Science,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kanta Ochani
*Laboratory of Biomedical Science,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mauricio Rosas-Ballina
*Laboratory of Biomedical Science,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Margot Gallowitsch-Puerta
*Laboratory of Biomedical Science,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mala Ashok
‡Department of Emergency Medicine, North Shore University Hospital, Manhasset, NY 11030
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lihong Yang
*Laboratory of Biomedical Science,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kevin J. Tracey
*Laboratory of Biomedical Science,
†Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York 11030;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Huan Yang
*Laboratory of Biomedical Science,
†Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York 11030;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

High mobility group box 1 (HMGB1) is a critical mediator of lethal sepsis. Previously, we showed that apoptotic cells can activate macrophages to release HMGB1. During sepsis, apoptosis occurs primarily in lymphoid organs, including the spleen and thymus. Currently, it is unclear whether this accelerated lymphoid organ apoptosis contributes to systemic release of HMGB1 in sepsis. In this study, we report that splenectomy significantly reduces systemic HMGB1 release and improves survival in mice with polymicrobial sepsis. Treatment with a broad-spectrum caspase inhibitor reduces systemic lymphocyte apoptosis, suppresses circulating HMGB1 concentrations, and improves survival during polymicrobial sepsis, but fails to protect septic mice following splenectomy. These findings indicate that apoptosis in the spleen is essential to the pathogenesis of HMGB1-mediated sepsis lethality.

Severe sepsis is the leading cause of death in intensive care units and accounts for 9.3% of deaths in the United States annually (1). High mobility group box 1 (HMGB1)3 is an intracellular DNA-binding protein that is a mediator in lethal sepsis (2, 3, 4, 5, 6). HMGB1 is released into the extracellular milieu during sepsis, and administration of recombinant HMGB1 to mice recapitulates many pathological signs of sepsis, including fever, intestinal barrier dysfunction, and tissue injury (2, 3, 7, 8, 9, 10). Neutralizing Abs directed against HMGB1 reverse the course of established sepsis (3, 4, 6).

We recently showed that apoptotic cells can activate macrophages to release HMGB1 (11). Administration of a broad-spectrum caspase inhibitor to mice with polymicrobial sepsis significantly reduces serum HMGB1 concentrations and suppresses apoptosis in the thymus and spleen (11). Monoclonal neutralizing Abs against HMGB1 confer significant protection against organ damage, but do not prevent apoptosis, indicating that HMGB1 release is downstream of apoptosis on a common pathway to lethal organ damage in sepsis (11).

Little is known regarding the systemic regulation of HMGB1 release during lethal sepsis. However, it has been established that peripheral lymphoid organs, such as the thymus and spleen, are sites of extensive apoptosis in sepsis (12, 13, 14, 15). Accordingly, we reasoned that regulation of apoptosis-induced systemic HMGB1 release might occur there. We therefore studied mice with lethal polymicrobial sepsis, and found that caspase-dependent apoptosis in the spleen is a specific and critical determinant of HMGB1 release, organ damage, and lethality.

Materials and Methods

Recombinant mouse TNF was obtained from R&D Systems. Tryptic soy agar was purchased from BD Biosciences. Neutral formalin solution (10%) was obtained from Sigma-Aldrich. Poly-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK) and control peptide benzyloxycarbonyl-Phe-Ala-fluoromethylketone (Z-FA-FMK) were obtained from BD Biosciences. Anti-caspase 3 Abs (Cat. no. AF835) were from R&D Systems.

Animal experiments

Male 6–8 wk old BALB/c mice were purchased from Taconic Farms and allowed to acclimate for 7 days before experiments. All animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC). Mice were housed in the animal facility of the Feinstein Institute for Medical Research under standard temperature, light, and dark cycles.

Cecal ligation and puncture (CLP)

Mice were subjected to CLP surgery as described previously (16). Following anesthesia with an i.m. injection of ketamine (75 mg/kg, Fort Dodge) and xylazine (20 mg/kg, Bohringer Ingelheim), a 15 mm midline abdominal incision was made to expose the cecum. After ligation at 5.0 mm from the cecal tip, the cecal stump was punctured once with a 22-gauge needle, and a small amount of stool (1 mm in length) was extruded. The cecum was returned to the abdominal cavity, and the incision was closed with running 6–0 prolene suture. All animals were administered normal saline resuscitation (20 ml/kg of body weight, injected subcutaneously), and a single dose of antibiotics (Primaxin, 0.5 mg/mouse in 200 μl sterile saline, injected subcutaneously, Merck) 15 min after surgery. Survival was monitored for 3 wk. To determine levels of HMGB1 and cytokines in the serum, parallel experiments were conducted and mice were euthanized 24 or 44 h after CLP to collect blood and tissues (livers, kidneys, hearts, small intestine, thymus, and spleens). In some experiments, septic mice were given caspase inhibitor (Z-VAD-FMK) or control peptide (Z-FA-FMK, 0.5 mg/mouse, i.p.) 90 min and 12 h after CLP. Animals were euthanized 24 h after CLP; spleen and thymus were collected for analyses of apoptosis. In survival experiments, caspase inhibitor or control peptide was administered 90 min after CLP and/or splenectomy surgeries, and then every 12 h for a total of 3 days. Survival was monitored for 3 wk.

Splenectomy

When mice were subjected to both CLP and splenectomy surgeries, they received splenectomy immediately before CLP. Mice were anesthetized with ketamine and xylazine as described above. The spleen was identified following a midline laparotomy incision, and removed after appropriate blood vessel ligation. Sham animals underwent laparotomy without removing the spleen.

Blood bacterial counts

Blood bacteria were recovered as previously described (3). In brief, 5 μl of whole blood was diluted with PBS and plated as 0.15 ml aliquots on tryptic soy agar plates. Colony forming units (CFU) were counted after overnight incubation at 37°C and expressed as CFU/ml blood.

Cytokine measurements

Serum HMGB1 concentrations were determined by Western immunoblotting analysis as previously described (2, 3). HMGB1 concentrations were calculated with reference to standard curves generated with purified HMGB1 as described previously (3). Serum levels of TNF, IL-2, IL-4, IL-6, IL-10, IL-12, and IFN-γ were measured using Cytometric Bead Array (BD Biosciences) according to the manufacturer’s instructions.

Analyses of tissue histology and apoptosis

Immediately after euthanasia, tissues were collected and fixed in 10% formalin, and sections were made and stained with H&E for morphologic evaluations.

For apoptosis analyses, TUNEL staining was performed by using ApoAlert DNA fragmentation assay kit (BD Biosciences) and caspase 3 expression was determined by using immunostaining kits from Vector Laboratories. Staining and analyses were performed by blinded observers. Quantifications were performed by counting a representative area of tissue section of each slide.

Statistical analysis

Data are presented as mean ± SEM. Differences between treatment groups were determined by a Student’s t test or one-way ANOVA followed by the least significant difference test or Fisher’s exact test (for survival experiments); p values <0.05 were considered statistically significant.

Results

Splenectomy protects against sepsis lethality, reduces serum HMGB1 levels, prevents liver injury, and maintains a protective Th-1 cytokine response

To investigate the relationship between systemic cytokine release, sepsis lethality, and apoptosis in the spleen, BALB/c mice were subjected to splenectomy or sham surgery immediately before CLP surgery, a standardized murine model of intra-abdominal sepsis (16). We observed that splenectomy significantly improves survival compared with sham surgery (Fig. 1⇓A). Survival of animals was monitored for 3 wk, indicating that splenectomy provides lasting protection against sepsis lethality. To examine the effects of splenectomy on systemic cytokine release, animals were subjected to splenectomy or sham surgery before CLP, and euthanized 24 or 44 h after CLP surgery. We observed that splenectomy significantly reduces serum HMGB1 levels compared with sham-operated controls (Fig. 1⇓B). In addition, tissue histology revealed that CLP sepsis causes liver damage, as demonstrated by significant cellular edema (Fig. 1⇓C). Splenectomy conferred significant protection against liver injury as revealed by near normal liver structure, with some cell edema (Fig. 1⇓C). No apparent differences were observed in tissue sections obtained from kidney and small intestine (data not shown). We also examined whether splenectomy reverses the imbalance of the Th-1 and Th-2 cytokine response seen in sepsis (12). We observed that splenectomy significantly increases serum concentrations of Th-1 cytokines such as IL-2, IL-12, and IFN-γ at 44 h after CLP, but not at 24 h (Fig. 1⇓D). In contrast, splenectomy does not significantly alter serum concentrations of Th-2 cytokines, such as IL-4 and IL-10, as compared with sham-operated controls (Fig. 1⇓D). Taken together, these findings suggest that splenectomy has protective effects in sepsis by decreasing systemic HMGB1 release, maintaining a Th-1-dependent serum cytokine response, and reducing sepsis-induced liver injury.

FIGURE 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 1.

Splenectomy (SPX) improves survival, reduces serum HMGB1 levels, and ameliorates liver injury in septic mice. A, BALB/c mice (male, 20–25 gm) underwent splenectomy or sham surgery before CLP. Survival was monitored for 3 wk. Data are shown as percent of animals surviving (n ≥ 35 per group). ∗, p < 0.01 vs CLP group as tested by Fisher’s exact test. B, BALB/c mice underwent splenectomy or sham surgery before CLP. Animals were euthanized at 44 h after surgeries and sera were collected for determination of HMGB1 levels by Western blot analysis, as described previously (3 ). Data are presented as mean ± SEM (n = 8–11 per group) ∗, p < 0.05 vs CLP group. C, BALB/c mice underwent splenectomy or sham surgery before CLP and were euthanized at 44 h after surgeries. Selected organs were collected. Tissue sections of livers from normal and septic mice were prepared by using a standard formalin-fixed, paraffin-embedded procedure. Tissues were cut in 4-μm slides, mounted on glass slides, and stained with H & E. Left, Normal liver shows a central vein (arrow) surrounded by normal hepatocytes and sinusoids. Middle, CLP causes cellular damage, as demonstrated by significant cell edema. Right, Splenectomy prevents sepsis-induced damage and maintains near-normal hepatocytes. Data are representative of 9–14 mice per group. Magnifications, ×100. D, BALB/c mice underwent splenectomy or sham surgery and CLP. Mice were euthanized at either 24 or 44 h after surgeries. Serum levels of Th-1 cytokines IL-12, IFN-γ, and IL-2, Th-2 cytokines IL-4 and IL-10, and other cytokines including TNF and IL-6, were measured by using cytometric bead array according to the manufacturer’s instructions (see Materials and Methods). Data are mean ± SEM (n = 12–14 per group). ∗, p < 0.05 vs CLP group.

Protective effects of caspase inhibitors in sepsis require the spleen

We next performed histological analyses of the spleen and thymus. Mice were subjected to CLP with or without splenectomy, treated with caspase inhibitor or control peptide, and then euthanized 24 h after surgeries. As expected, CLP induces significant apoptosis in the white pulp of the spleen, as measured by terminal nuclear DNA condensation and fragmentation (TUNEL) staining (Fig. 2⇓A) and active caspase 3 expression (data not shown). Previous studies showed that caspases are proteases that activate apoptotic cell death, and administration of agents that inhibit caspase activity improves organ function and increases survival in experimental sepsis (12, 13, 14, 15, 17). Caspase inhibitors fail to protect mice lacking functional T and B lymphocytes, indicating that lymphocytes are critical to the caspase-dependent protective effects (17). To study the role of caspases and splenectomy in sepsis, we administered a broad-spectrum caspase inhibitor, Z-VAD-FMK, or negative control peptide, Z-FA-FMK, to splenectomized or sham-operated mice during CLP sepsis. Consistent with previous studies (11, 13, 17), we found that treatment with Z-VAD-FMK significantly reduces splenic apoptosis as revealed by TUNEL staining (Fig. 2⇓A). CLP also induces significant apoptosis in the cortex of the thymus (Fig. 2⇓B). Administration of Z-VAD-FMK significantly reduces thymic apoptosis in splenectomized septic mice as shown by TUNEL (Fig. 2⇓B) and active caspase 3 staining (data not shown). As expected, extensive apoptosis is present in the thymus of splenectomized mice in a magnitude comparable to sham-operated septic mice with intact spleen (Fig. 2⇓B).

FIGURE 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 2.

Caspase inhibitor Z-VAD-FMK reduces thymic apoptosis but fails to reduce serum HMGB1 levels in splenectomized, septic mice. Male BALB/c mice underwent CLP surgery, or splenectomy (SPX) plus CLP, and were treated with Z-VAD-FMK or control peptide at 0.5 mg/mouse (injected i.p.) at 90 min and 12 h after surgeries. Mice were euthanized 24 h after surgeries for serum and tissue measurements. Tissue sections of spleen and thymus were prepared for staining of apoptosis markers. A, TUNEL staining of spleen. Normal spleen shows white and red pulp areas (arrows indicate white pulp) with minimal apoptosis. CLP induces significant apoptosis with most TUNEL positive cells in the white pulp. Treatment with Z-VAD-FMK significantly reduces apoptosis. Magnifications, ×100. B, TUNEL staining of thymus. Compared with normal mice, CLP induces significant cortical apoptosis in the thymus. Treatment with Z-VAD-FMK reduces apoptosis in CLP and CLP plus splenectomized mice. Splenectomy does not reduce thymic apoptosis in CLP mice (n = 9–11 mice per group). Magnifications, ×100. C, Serum HMGB1 levels at 24 h after CLP and/or splenectomy surgeries, or splenectomy plus Z-VAD-FMK (n = 5–16 mice per group) ∗, p < 0.05 vs CLP group. D, Blood bacterial counts at 24 h after surgeries (n = 8–16 mice per group), p = NS.

To further explore the specific role of spleen apoptosis and systemic HMGB1 release, we administered Z-VAD-FMK, or control peptide, Z-FA-FMK, to splenectomized or sham-operated mice during CLP sepsis. Consistent with our previous findings (11), administration of Z-VAD-FMK significantly reduces serum HMGB1 levels as compared with septic mice treated with control peptide (Fig. 2⇑C). In contrast, treatment of splenectomized septic mice with Z-VAD-FMK increases serum HMGB1 levels (Fig. 2⇑C) and fails to protect against sepsis lethality (survival = 40% in control group vs 25% in Z-VAD-FMK treated group, n = 11 mice per group, p = NS). Administration of Z-VAD-FMK to splenectomized, nonseptic mice does not influence serum HMGB1 levels (Fig. 2⇑C). There is no statistical difference in blood bacterial counts between caspase inhibitor or control peptide-treated splenectomized mice or sham-splenectomized controls, suggesting that these effects are not due to changes in bactericidal clearance mechanism (Fig. 2⇑D). Together, these findings indicate that caspase-dependent apoptosis in the spleen, rather than the thymus, is specifically responsible for HMGB1 release in this model of polymicrobial sepsis, and specific prevention of spleen apoptosis protects animals against HMGB1-mediated sepsis lethality.

Discussion

Apoptosis of lymphocytes during sepsis can result in maladaptive cytokine responses, including increased release of the lethal proinflammatory cytokine HMGB1 (11). Numerous studies demonstrate that prevention of excessive lymphocyte apoptosis significantly improves survival in experimental models of sepsis (12, 13, 14, 15, 17, 18). Adoptive transfer of T lymphocytes over-expressing the anti-apoptotic protein Bcl-2 into mice, and over-expression of Bcl-2 in T lymphocytes of transgenic mice, are both protective against sepsis lethality (17, 18). Administration of compounds that block proteases involved in activating programmed cell death (e.g., caspase inhibitors) can also reduce organ damage and mortality in experimental sepsis (13, 14, 15, 17).

Previous studies from our laboratory show that administration of the broad-spectrum caspase inhibitor Z-VAD-FMK inhibits lymphocyte apoptosis in the thymus and spleen, reduces systemic HMGB1 release, and improves survival in sepsis (11). Other studies indicate that HMGB1 is released during apoptotic cell death in a time-dependent manner, and this release can be reduced by Z-VAD-FMK (19, 20). In this study, we examined the relationship between lymphoid tissue apoptosis, HMGB1 release, and organ injury during murine polymicrobial sepsis. Our findings indicate that prevention of apoptosis in the spleen via splenectomy significantly inhibits systemic HMGB1 release, reduces liver injury, and protects against sepsis lethality (Fig. 3⇓). In addition, splenectomy does not decrease apoptosis in the thymus, which suggests that HMGB1 release is dependent upon organ-specific lymphoid apoptosis. Administration of Z-VAD-FMK to splenectomized, septic mice significantly inhibits thymic apoptosis, but fails to reduce systemic HMGB1 release or improve survival, further suggesting that apoptosis in the spleen, rather than in the thymus, contributes to HMGB1-mediated sepsis lethality. HMGB1 levels are elevated in splenectomized mice treated with Z-VAD-FMK, but these results are not statistically significant as compared with animals with intact spleens plus CLP (Fig. 2⇑C). It is likely that in splenectomized animals, the progression of tissue injury in other organs contributes to elevated HMGB1.

FIGURE 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 3.

Spleen apoptosis is a specific determinant of HMGB1-mediated sepsis lethality. Sepsis causes extensive apoptosis in peripheral lymphoid organs. Phagocytosis of apoptotic cells by macrophages can induce HMGB1 release. HMGB1, a proinflammatory mediator, causes tissue injury and death in sepsis. Caspase inhibitor Z-VAD-FMK inhibits lymphocyte apoptosis in both spleen and thymus. Apoptosis in the spleen, rather than in the thymus, specifically increases systemic HMGB1 release and accelerates sepsis lethality. Prevention of apoptosis in the spleen via splenectomy reduces systemic HMGB1 release and protects against polymicrobial sepsis lethality.

Excessive lymphocyte apoptosis during sepsis may result in a shift from a Th1-dependent to a Th2-dependent cytokine response, compromising the host’s ability to defend against invasive pathogens (12). In this study, we observed that elimination of splenic apoptosis via splenectomy significantly increases levels of the Th1 cytokines IL-2, IL-12, and IFN-γ 44 h after the onset of sepsis; Th-2 cytokines such as IL-4 and IL-10 remain unchanged (Fig. 1⇑D). This suggests that local splenocyte apoptosis is critical to the modulation of systemic cytokine production. Despite this potentially beneficial Th1-mediated response, we found no difference in circulating bacterial counts between splenectomized and sham-splenectomized mice 24 h after the onset of sepsis.

Our results raise important questions regarding the precise immunological role of the spleen in sepsis (21, 22, 23). Splenectomized patients are reported to be at higher risk for developing rapidly progressive, lethal septic shock due to overwhelming bacterial infection (24, 25, 26). In this study, we show, however, that splenectomy does not impair bacterial clearance or worsen survival during polymicrobial abdominal sepsis treated with antibiotics. On the contrary, prevention of apoptosis in the spleen via splenectomy significantly reduces liver damage, reduces HMGB1 release, and decreases lethality. It may be advantageous to develop pharmacological compounds that specifically protect the critical pool of lymphocytes in the spleen that regulate HMGB1 release and sepsis lethality (Fig. 3⇑). Additional studies are needed to further explore the relationship between caspase-dependent lymphocyte apoptosis in the spleen and systemic release of HMGB1 during lethal sepsis.

Disclosures

K.J.T. is a consultant to MedImmune, Inc., Gaithersburg, MD.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • ↵1 This work was supported by the Faculty Award Program and General Clinical Research Center of The Feinstein Institute for Medical Research (M01-RR018535) and the National Institute of General Medical Sciences (NIGMS) to K.J.T.

  • ↵2 Address correspondence and reprint requests to Dr. Huan Yang, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, New York 11030. E-mail address: hyang{at}nshs.edu

  • ↵3 Abbreviations used in this paper: HMGB1, high mobility group box 1; Z-VAD-FMK, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone; Z-FA-FMK, benzyloxycarbonyl-Phe-Ala-fluoromethylketone; CLP, cecal ligation and puncture.

  • Received November 27, 2007.
  • Accepted June 26, 2008.
  • Copyright © 2008 by The American Association of Immunologists

References

  1. ↵
    Angus, D. C., W. T. Linde-Zwirbleand, J. Lidicker, G. Clermont, J. Carcillo, M. R. Pinsky. 2001. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 29: 1303-1310.
    OpenUrlCrossRefPubMed
  2. ↵
    Wang, H., O. Bloom, M. Zhang, J. M. Vishnubhakat, M. Ombrellino, J. Che, A. Frazier, H. Yang, S. Ivanova, L. Borovikova, et al 1999. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285: 248-251.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    Yang, H., M. Ochani, J. Li, X. Qiang, M. Tanovic, H. E. Harris, S. M. Susarla, L. Ulloa, H. C. Wang, R. DiRaimo, C. J. Czura, et al 2004. Reversing established sepsis with antagonists of endogenous HMGB1. Proc. Natl. Acad. Sci. USA 101: 296-301.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    Yang, H., H. Wang, C. J. Czura, K. J. Tracey. 2005. The cytokine activity of HMGB1. J. Leukocyte Biol. 78: 1-8.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Wang, H., H. Liao, M. Ochani, M. Justiniani, X. Lin, L. Yang, Y. Al-Abed, H. Wang, C. Metz, E. J. Miller, et al 2004. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat. Med. 10: 1216-1221.
    OpenUrlCrossRefPubMed
  6. ↵
    Wang, H., H. Yang, K. J. Tracey. 2004. Extracellular role of HMGB1 in inflammation and sepsis. J. Intern. Med. 255: 320-331.
    OpenUrlCrossRefPubMed
  7. ↵
    Lotze, M. T., K. J. Tracey. 2005. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nature Immunol. 5: 331-342.
    OpenUrlCrossRef
  8. ↵
    O'Connor, K. A., M. K. Hansen, C. Rachal Pugh, M. M. Deak, J. C. Biedenkapp, E. D. Milligan, J. D. Johnson, H. Wang, S. F. Maier, K. J. Tracey, L. R. Watkins. 2003. Further characterization of high mobility group box 1 (HMGB1) as a proinflammatory cytokine: central nervous system effects. Cytokine 24: 254-265.
    OpenUrlCrossRefPubMed
  9. ↵
    Sappington, P. L., R. Yang, H. Yang, K. J. Tracey, R. L. Delude, M. P. Fink. 2002. HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice. Gastroenterology 123: 790-802.
    OpenUrlCrossRefPubMed
  10. ↵
    Abraham, E., J. Arcaroli, A. Carmody, H. Wang, K. J. Tracey. 2000. HMG-1 as a mediator of acute lung inflammation. J. Immunol. 165: 2950-2954.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    Qin, S., H. Wang, R. Yuan, H. Li, M. Ochani, K. Ochani, M. Rosas-Ballina, C. J. Czura, J. M. Huston, E. Miller, et al 2006. Role of HMGB1 in apoptosis-mediated sepsis lethality. J. Exp. Med. 203: 1637-1642.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Hotchkiss, R. S., I. E. Karl. 2003. The pathophysiology and treatment of sepsis. N. Engl. J. Med. 348: 138-150.
    OpenUrlCrossRefPubMed
  13. ↵
    Hotchkiss, R. S., K. W. Tinsley, P. E. Swanson, K. C. Chang, J. P. Cobb, T. G. Buchman, S. J. Korsmeyer, I. E. Karl. 1999. Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc. Nat. Acad. Sci. 96: 14541-14546.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Wesche-Soldato, D. E., R. Z. Swan, C. S. Chang, A. Ayala. 2007. The apoptotic pathway as a therapeutic target in sepsis. Curr. Drug Targets 8: 493-500.
    OpenUrlCrossRefPubMed
  15. ↵
    Wesche, D. E., J. L. Lomas-Neira, M. Perl, C. S. Chung, A. Ayala. 2005. Leukocyte apoptosis and its significance in sepsis and shock. J. Leukocyte Biol. 78: 325-337.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Wichmann, M. W., J. M. Haisken, A. Ayala, I. H. Chaudry. 1996. Melatonin administration following hemorrhagic shock decreases mortality from subsequent septic challenge. J. Surg. Res. 65: 109-114.
    OpenUrlCrossRefPubMed
  17. ↵
    Hotchkiss, R., K. C. Chang, P. E. Swanson, K. W. Tinsley, J. J. Hui, P. Klender, S. Xanthoudakis, S. Roy, C. Black, E. Grimm, et al 2000. Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat. Immunol. 1: 496-501.
    OpenUrlCrossRefPubMed
  18. ↵
    Iwata, A., V. M. Stevenson, A. Minard, M. Tasch, J. Tupper, E. Lagasse, I. Weissman, J. M. Harlan, R. K. Winn. 2003. Over-expression of Bcl-2 provides protection in septic mice by a trans effect. J. Immunol. 171: 3136-3141.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    Jiang, W., C. W. Bell, D. S. Pisetsky. 2007. The relationship between apoptosis and high-mobility group protein 1 release from murine macrophages stimulated with lipopolysaccharide or polyinosinic-polycytidylic acid. J. Immunol. 178: 6495-6503.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    Bell, C. W., W. Jiang, C. F. Reich, III, D. S. Pisetsky. 2007. The extracellular release of HMGB1 during apoptotic cell death. Am. J. Physiol. 291: C1318-C1325.
    OpenUrl
  21. ↵
    Shih-Ching, K., M. A. Choudhry, T. Matsutani, M. G. Schwacha, L. W. Rue, I. H. Chaudry. 2004. Splenectomy differentially influences immune responses in various tissue compartments of the body. Cytokine 28: 101-108.
    OpenUrlCrossRefPubMed
  22. ↵
    Baker, C. C., H. O. Gaines, A. T. Niven-Fairchild. 1984. The effect of tuftsin and splenectomy on mortality after intra-abdominal sepsis. J. Surg. Res. 36: 499-502.
    OpenUrlCrossRefPubMed
  23. ↵
    Huston, J. M., M. Ochani, M. Rosas-Ballina, H. Liao, K. Ochani, V. A. Pavlov, M. Gallowitsch-Puerta, M. Ashok, C. J. Czura, B. Foxwell, et al 2006. Splenectomy inactivates the cholinergic anti-inflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J. Exp. Med. 203: 1623-1628.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    Konigswieser, H.. 1985. Incidence of serious infections after splenectomy in childhood. Prog. Pediatr. Surg. 18: 173-181.
    OpenUrlCrossRefPubMed
  25. ↵
    Davidson, R. N., R. A. Wall. 2001. Prevention and management of infections in patients without a spleen. Clin. Microbiol. Infect. 7: 657-660.
    OpenUrlCrossRefPubMed
  26. ↵
    Waghorn, D. J., R. T. Mayon-White. 1997. A study of 42 episodes of overwhelming post-splenectomy infection: is current guidance for asplenic individuals being followed?. J. Infection 35: 289-294.
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

The Journal of Immunology: 181 (5)
The Journal of Immunology
Vol. 181, Issue 5
1 Sep 2008
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Advertising (PDF)
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about The Journal of Immunology.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Splenectomy Protects against Sepsis Lethality and Reduces Serum HMGB1 Levels
(Your Name) has forwarded a page to you from The Journal of Immunology
(Your Name) thought you would like to see this page from the The Journal of Immunology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Splenectomy Protects against Sepsis Lethality and Reduces Serum HMGB1 Levels
Jared M. Huston, Haichao Wang, Mahendar Ochani, Kanta Ochani, Mauricio Rosas-Ballina, Margot Gallowitsch-Puerta, Mala Ashok, Lihong Yang, Kevin J. Tracey, Huan Yang
The Journal of Immunology September 1, 2008, 181 (5) 3535-3539; DOI: 10.4049/jimmunol.181.5.3535

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Splenectomy Protects against Sepsis Lethality and Reduces Serum HMGB1 Levels
Jared M. Huston, Haichao Wang, Mahendar Ochani, Kanta Ochani, Mauricio Rosas-Ballina, Margot Gallowitsch-Puerta, Mala Ashok, Lihong Yang, Kevin J. Tracey, Huan Yang
The Journal of Immunology September 1, 2008, 181 (5) 3535-3539; DOI: 10.4049/jimmunol.181.5.3535
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Disclosures
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • The immunological ménage à trois promotes inflammation in Type 2 diabetes. (54.14)
  • Identification of novel small molecule inducers of endothelium-driven innate immunity (54.10)
  • Anti-inflammatory activity of Dioscoreae rhizome in macrophages by inhibition of pro-inflammatory cytokines via NF-κB signaling pathway (54.11)
Show more INFLAMMATION

Similar Articles

Navigate

  • Home
  • Current Issue
  • Next in The JI
  • Archive
  • Brief Reviews
  • Pillars of Immunology
  • Translating Immunology

For Authors

  • Submit a Manuscript
  • Instructions for Authors
  • About the Journal
  • Journal Policies
  • Editors

General Information

  • Advertisers
  • Subscribers
  • Rights and Permissions
  • Accessibility Statement
  • FAR 889
  • Privacy Policy
  • Disclaimer

Journal Services

  • Email Alerts
  • RSS Feeds
  • ImmunoCasts
  • Twitter

Copyright © 2022 by The American Association of Immunologists, Inc.

Print ISSN 0022-1767        Online ISSN 1550-6606