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Elucidation of the early events contributing to zymosan-induced multiple organ dysfunction syndrome using MIP-1alpha,
J Mahesh1, J Daly, W G Cheadle
1Department of Microbiology and Immunology, University of Louisville School of Medicine, Kentucky 40292, USA.
Abstract:
Using a zymosan-induced mouse model of multiple organ dysfunction syndrome (MODS), it has been shown that the absence of MIP-1alpha increased mortality fourfold, whereas the absence of C5 decreased mortality fourfold. The purpose of the present study was to determine the early events following zymosan injection in MIP-1alpha knockout and C5-deficient mice. B10.D2/nSnJ (C5-sufficient) and B10.D2/0SnJ (C5-deficient) and genetically matched MIP-1alpha +/+ and MIP-1alpha -/- mice were divided into 3 groups: Group1 received no injection, Group 2 received intraperitoneal saline injection (1.0 mL), and Group 3 were given intraperitoneal zymosan (1 mg/gm, 1.0 mL). Two hours, 24 h, and 48 h after injection, peritoneal exudate leukocyte counts, total WBC count, lung MPO levels, and organ histology were examined for signs of changes in cellular infiltration. An acute local and systemic inflammatory response characterized by an increase in the peritoneal leukocyte count, total WBC counts, and circulating neutrophil levels was observed within 2-48 h of zymosan injection. Lack of MIP-1alpha attenuated local recruitment of phagocytes into the peritoneal cavity, and absence of MIP-1alpha or C5 caused a decrease in circulating neutrophil levels. The presence or absence of either C5 or MIP-1alpha did not affect early pulmonary neutrophil sequestration. Organ histopathology suggested early neutrophil infiltration in the lung and spleen within 48 h. These studies indicate that MIP-1alpha and C5 play a critical role in modulating cellular changes associated with lethality in a zymosan model of MODS.
Insights
The absence of MIP-1alpha increased mortality in a multiple organ dysfunction syndrome (MODS) mouse model, while C5 deficiency decreased it. Early inflammatory events and cellular changes were investigated in knockout and deficient mice.
Area of Science:
- Immunology
- Pathophysiology
- Inflammation Research
Background:
- Multiple organ dysfunction syndrome (MODS) is a critical condition with high mortality.
- The roles of specific inflammatory mediators like MIP-1alpha and complement component C5 in MODS are not fully understood.
- Previous studies indicated opposing effects of MIP-1alpha and C5 on mortality in a zymosan-induced MODS model.
Purpose of the Study:
- To investigate the early cellular events and inflammatory responses in mice lacking MIP-1alpha or C5 following zymosan challenge.
- To elucidate the specific contributions of MIP-1alpha and C5 to the pathogenesis of zymosan-induced MODS.
Main Methods:
- Utilized a zymosan-induced mouse model of MODS.
- Employed MIP-1alpha knockout and C5-deficient mice, along with their respective controls.
- Analyzed peritoneal leukocyte counts, total white blood cell (WBC) counts, lung myeloperoxidase (MPO) levels, and organ histology at 2, 24, and 48 hours post-injection.
Main Results:
- Zymosan injection induced an acute local and systemic inflammatory response, marked by increased peritoneal leukocytes, total WBCs, and circulating neutrophils.
- Absence of MIP-1alpha attenuated phagocyte recruitment to the peritoneal cavity.
- Lack of either MIP-1alpha or C5 reduced circulating neutrophil levels, but did not affect early pulmonary neutrophil sequestration. Early neutrophil infiltration was observed in the lung and spleen.
Conclusions:
- MIP-1alpha and C5 play critical, distinct roles in modulating the cellular responses and inflammatory cascade in zymosan-induced MODS.
- These findings highlight the complex interplay of inflammatory mediators in the development of organ dysfunction.