Zinc deficiency increases organ damage and mortality in a murine model of polymicrobial sepsis

Daren L Knoell, Mark W. Julian, Shengying Bao, Beth Besecker, Jennifer E. MacRe, George D. Leikauf, Robert A. Disilvestro, Elliott D. Crouser

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE: Zinc deficiency is common among populations at high risk for sepsis mortality, including elderly, alcoholic, and hospitalized patients. Zinc deficiency causes exaggerated inflammatory responses to endotoxin but has not been evaluated during bacterial sepsis. We hypothesized that subacute zinc deficiency would amplify immune responses and oxidant stress during bacterial sepsis {lsqb;i.e., cecal ligation and puncture (CLP){rsqb; resulting in increased mortality and that acute nutritional repletion of zinc would be beneficial. DESIGN: Prospective, randomized, controlled animal study. SETTING: University medical center research laboratory. SUBJECTS: Adult male C57BL/6 mice. INTERVENTIONS: Ten-week-old, male, C57BL/6 mice were randomized into three dietary groups: 1) control diet, 2) zinc-deficient diet for 3 weeks, and 3) zinc-deficient diet for 3 weeks followed by oral zinc supplementation for 3 days (n = 35 per diet). Mice were then assigned to receive either CLP or sham operation (n = 15 each per diet). CLP and sham-operated treatment groups were further assigned to a 7-day survival study (n = 10 per treatment per diet) or were evaluated at 24 hours (n = 5 per treatment per diet) for signs of vital organ damage. MEASUREMENTS AND MAIN RESULTS: Sepsis mortality was significantly increased with zinc deficiency (90% vs. 30% on control diet). Zinc-deficient animals subject to CLP had higher plasma cytokines, more severe organ injury, including increased oxidative tissue damage and cell death, particularly in the lungs and spleen. None of the sham-operated animals died or developed signs of organ damage. Zinc supplementation normalized the inflammatory response, greatly diminished tissue damage, and significantly reduced mortality. CONCLUSIONS: Subacute zinc deficiency significantly increases systemic inflammation, organ damage, and mortality in a murine polymicrobial sepsis model. Short-term zinc repletion provides significant, but incomplete protection despite normalization of inflammatory and organ damage indices.

Original languageEnglish (US)
Pages (from-to)1380-1388
Number of pages9
JournalCritical care medicine
Volume37
Issue number4
DOIs
StatePublished - Jan 1 2009

Fingerprint

Zinc
Sepsis
Mortality
Diet
Punctures
Ligation
Inbred C57BL Mouse
Vital Signs
Oxidants
Endotoxins
Biomedical Research
Cell Death
Spleen
Placebos
Cytokines
Inflammation
Lung
Control Groups
Survival
Wounds and Injuries

Keywords

  • Cecal ligation and puncture
  • Cell injury
  • Inflammation
  • Multiple organ dysfunction score
  • Oxidants

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Knoell, D. L., Julian, M. W., Bao, S., Besecker, B., MacRe, J. E., Leikauf, G. D., ... Crouser, E. D. (2009). Zinc deficiency increases organ damage and mortality in a murine model of polymicrobial sepsis. Critical care medicine, 37(4), 1380-1388. https://doi.org/10.1097/CCM.0b013e31819cefe4

Zinc deficiency increases organ damage and mortality in a murine model of polymicrobial sepsis. / Knoell, Daren L; Julian, Mark W.; Bao, Shengying; Besecker, Beth; MacRe, Jennifer E.; Leikauf, George D.; Disilvestro, Robert A.; Crouser, Elliott D.

In: Critical care medicine, Vol. 37, No. 4, 01.01.2009, p. 1380-1388.

Research output: Contribution to journalArticle

Knoell, DL, Julian, MW, Bao, S, Besecker, B, MacRe, JE, Leikauf, GD, Disilvestro, RA & Crouser, ED 2009, 'Zinc deficiency increases organ damage and mortality in a murine model of polymicrobial sepsis', Critical care medicine, vol. 37, no. 4, pp. 1380-1388. https://doi.org/10.1097/CCM.0b013e31819cefe4
Knoell, Daren L ; Julian, Mark W. ; Bao, Shengying ; Besecker, Beth ; MacRe, Jennifer E. ; Leikauf, George D. ; Disilvestro, Robert A. ; Crouser, Elliott D. / Zinc deficiency increases organ damage and mortality in a murine model of polymicrobial sepsis. In: Critical care medicine. 2009 ; Vol. 37, No. 4. pp. 1380-1388.
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abstract = "OBJECTIVE: Zinc deficiency is common among populations at high risk for sepsis mortality, including elderly, alcoholic, and hospitalized patients. Zinc deficiency causes exaggerated inflammatory responses to endotoxin but has not been evaluated during bacterial sepsis. We hypothesized that subacute zinc deficiency would amplify immune responses and oxidant stress during bacterial sepsis {lsqb;i.e., cecal ligation and puncture (CLP){rsqb; resulting in increased mortality and that acute nutritional repletion of zinc would be beneficial. DESIGN: Prospective, randomized, controlled animal study. SETTING: University medical center research laboratory. SUBJECTS: Adult male C57BL/6 mice. INTERVENTIONS: Ten-week-old, male, C57BL/6 mice were randomized into three dietary groups: 1) control diet, 2) zinc-deficient diet for 3 weeks, and 3) zinc-deficient diet for 3 weeks followed by oral zinc supplementation for 3 days (n = 35 per diet). Mice were then assigned to receive either CLP or sham operation (n = 15 each per diet). CLP and sham-operated treatment groups were further assigned to a 7-day survival study (n = 10 per treatment per diet) or were evaluated at 24 hours (n = 5 per treatment per diet) for signs of vital organ damage. MEASUREMENTS AND MAIN RESULTS: Sepsis mortality was significantly increased with zinc deficiency (90{\%} vs. 30{\%} on control diet). Zinc-deficient animals subject to CLP had higher plasma cytokines, more severe organ injury, including increased oxidative tissue damage and cell death, particularly in the lungs and spleen. None of the sham-operated animals died or developed signs of organ damage. Zinc supplementation normalized the inflammatory response, greatly diminished tissue damage, and significantly reduced mortality. CONCLUSIONS: Subacute zinc deficiency significantly increases systemic inflammation, organ damage, and mortality in a murine polymicrobial sepsis model. Short-term zinc repletion provides significant, but incomplete protection despite normalization of inflammatory and organ damage indices.",
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AU - MacRe, Jennifer E.

AU - Leikauf, George D.

AU - Disilvestro, Robert A.

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N2 - OBJECTIVE: Zinc deficiency is common among populations at high risk for sepsis mortality, including elderly, alcoholic, and hospitalized patients. Zinc deficiency causes exaggerated inflammatory responses to endotoxin but has not been evaluated during bacterial sepsis. We hypothesized that subacute zinc deficiency would amplify immune responses and oxidant stress during bacterial sepsis {lsqb;i.e., cecal ligation and puncture (CLP){rsqb; resulting in increased mortality and that acute nutritional repletion of zinc would be beneficial. DESIGN: Prospective, randomized, controlled animal study. SETTING: University medical center research laboratory. SUBJECTS: Adult male C57BL/6 mice. INTERVENTIONS: Ten-week-old, male, C57BL/6 mice were randomized into three dietary groups: 1) control diet, 2) zinc-deficient diet for 3 weeks, and 3) zinc-deficient diet for 3 weeks followed by oral zinc supplementation for 3 days (n = 35 per diet). Mice were then assigned to receive either CLP or sham operation (n = 15 each per diet). CLP and sham-operated treatment groups were further assigned to a 7-day survival study (n = 10 per treatment per diet) or were evaluated at 24 hours (n = 5 per treatment per diet) for signs of vital organ damage. MEASUREMENTS AND MAIN RESULTS: Sepsis mortality was significantly increased with zinc deficiency (90% vs. 30% on control diet). Zinc-deficient animals subject to CLP had higher plasma cytokines, more severe organ injury, including increased oxidative tissue damage and cell death, particularly in the lungs and spleen. None of the sham-operated animals died or developed signs of organ damage. Zinc supplementation normalized the inflammatory response, greatly diminished tissue damage, and significantly reduced mortality. CONCLUSIONS: Subacute zinc deficiency significantly increases systemic inflammation, organ damage, and mortality in a murine polymicrobial sepsis model. Short-term zinc repletion provides significant, but incomplete protection despite normalization of inflammatory and organ damage indices.

AB - OBJECTIVE: Zinc deficiency is common among populations at high risk for sepsis mortality, including elderly, alcoholic, and hospitalized patients. Zinc deficiency causes exaggerated inflammatory responses to endotoxin but has not been evaluated during bacterial sepsis. We hypothesized that subacute zinc deficiency would amplify immune responses and oxidant stress during bacterial sepsis {lsqb;i.e., cecal ligation and puncture (CLP){rsqb; resulting in increased mortality and that acute nutritional repletion of zinc would be beneficial. DESIGN: Prospective, randomized, controlled animal study. SETTING: University medical center research laboratory. SUBJECTS: Adult male C57BL/6 mice. INTERVENTIONS: Ten-week-old, male, C57BL/6 mice were randomized into three dietary groups: 1) control diet, 2) zinc-deficient diet for 3 weeks, and 3) zinc-deficient diet for 3 weeks followed by oral zinc supplementation for 3 days (n = 35 per diet). Mice were then assigned to receive either CLP or sham operation (n = 15 each per diet). CLP and sham-operated treatment groups were further assigned to a 7-day survival study (n = 10 per treatment per diet) or were evaluated at 24 hours (n = 5 per treatment per diet) for signs of vital organ damage. MEASUREMENTS AND MAIN RESULTS: Sepsis mortality was significantly increased with zinc deficiency (90% vs. 30% on control diet). Zinc-deficient animals subject to CLP had higher plasma cytokines, more severe organ injury, including increased oxidative tissue damage and cell death, particularly in the lungs and spleen. None of the sham-operated animals died or developed signs of organ damage. Zinc supplementation normalized the inflammatory response, greatly diminished tissue damage, and significantly reduced mortality. CONCLUSIONS: Subacute zinc deficiency significantly increases systemic inflammation, organ damage, and mortality in a murine polymicrobial sepsis model. Short-term zinc repletion provides significant, but incomplete protection despite normalization of inflammatory and organ damage indices.

KW - Cecal ligation and puncture

KW - Cell injury

KW - Inflammation

KW - Multiple organ dysfunction score

KW - Oxidants

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