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Two chemotactic factors, C5a and MIP-1alpha, dramatically alter the mortality from zymosan-induced multiple organ
C G Miller1, D N Cook, G J Kotwal
1Department of Microbiology and Immunology, University of Louisville, School of Medicine, KY 40292, U.S.A.
Abstract:
Multiple organ dysfunction syndrome (MODS) is a major cause of morbidity and mortality in surgical intensive care units. It is characterized by progressive failure of two or more organs remote from the origin of injury. Since MODS results from a severe generalized inflammatory response, both chemokines and complement have had a proposed role in its pathophysiology. The availability of macrophage inflammatory protein 1 alpha (MIP-1alpha) knockout mice and congenic C5-deficient and C5-sufficient mice allowed us to investigate the individual contribution of these immune modulators in MODS. It has been demonstrated in this assay that MIP-1alpha has a protective role against MODS mortality, while C5a contributes to MODS mortality. Using a zymosan-induced MODS murine model, the absence of MIP-1alpha increased mortality four-fold, whereas the absence of C5 decreased mortality four-fold. Therefore, MIP-1alpha-dependent mediators are essential in the prevention of MODS related deaths, while C5-dependent mediators of inflammation can be considered to be contributing to the development of MODS related deaths.
Insights
Macrophage inflammatory protein 1 alpha (MIP-1alpha) protects against multiple organ dysfunction syndrome (MODS) mortality. Conversely, C5a exacerbates MODS mortality, highlighting distinct roles for these immune mediators in critical illness.
Area of Science:
- Immunology
- Critical Care Medicine
Background:
- Multiple organ dysfunction syndrome (MODS) is a leading cause of death in surgical intensive care units.
- MODS involves the failure of multiple organs due to a systemic inflammatory response.
- Chemokines and complement systems are implicated in MODS pathophysiology.
Purpose of the Study:
- To investigate the specific roles of macrophage inflammatory protein 1 alpha (MIP-1alpha) and complement component 5a (C5a) in MODS.
- To determine the contribution of these immune modulators to MODS-related mortality.
Main Methods:
- Utilized a zymosan-induced MODS murine model.
- Employed MIP-1alpha knockout mice and C5-deficient mice.
Main Results:
- Absence of MIP-1alpha resulted in a four-fold increase in MODS mortality.
- Absence of C5 (and thus C5a) led to a four-fold decrease in MODS mortality.
- MIP-1alpha demonstrated a protective effect, while C5a contributed to mortality.
Conclusions:
- MIP-1alpha-dependent pathways are crucial for preventing MODS-related deaths.
- C5-dependent inflammatory mediators contribute to the development of MODS-related mortality.
- Targeting these pathways could offer therapeutic strategies for MODS.