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Interferon gamma increases sensitivity to endotoxin
G J Jurkovich1, W J Mileski, R V Maier
1Department of Surgery, University of Washington School of Medicine, Harborview Medical Center, Seattle 98104.
Abstract:
Interferon-gamma (IFN-gamma) has been proposed for use following severe trauma to reverse depressed macrophage (M phi) function and thereby reduce infection, sepsis, and subsequent multiple organ failure syndrome (MOFS). However, an excessive inflammatory response by M phi s and other components of the inflammatory cascade is thought to be central to the underlying pathophysiology of MOFS. Endotoxin (LPS) has been implicated as a principal mediator of sepsis-induced MOFS by stimulating M phi s and leukocytes (WBC). This study addresses the following question: Does IFN-gamma predispose normal rabbits to a pathophysiologic response to LPS infusion? Four groups of New Zealand White rabbits (n = 6, each group) were prepared for measurement of cardiac output, arterial pressure, arterial PO2, and WBC counts over a 6-hr period. Group I (control) was instrumented alone, Group II (LPS alone) was given a subclinical dose of 1.0 micrograms/kg of Escherichia coli LPS iv, Group III (IFN-gamma alone) was given recombinant rabbit IFN-gamma (5.0 micrograms/kg subcutaneous) for 3 days prior to preparation for measurements, and Group IV (IFN-gamma + LPS) received 3 days of IFN-gamma followed by LPS. One hour prior to sacrifice 5.0 microCi of 125I-albumin was given and bronchoalveolar lavage was performed at death to determine the lavage/plasma 125I ratio as an index of pulmonary permeability. The results indicate that IFN + LPS animals had significant decreases in cardiac output, PO2, and WBC counts, and increased lavage/plasma ratio of 125I-albumin when compared to all other groups (P less than 0.05 by ANOVA, t test). Neither LPS alone nor IFN-gamma alone had a significant effect on measured variables.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Interferon-gamma (IFN-gamma) combined with endotoxin (LPS) significantly worsened outcomes in rabbits, decreasing cardiac output and oxygen levels. This suggests IFN-gamma may increase susceptibility to LPS-induced shock and organ failure.
Area of Science:
- Immunology
- Critical Care Medicine
- Pathophysiology
Background:
- Interferon-gamma (IFN-gamma) is explored for trauma to enhance macrophage function and reduce sepsis-related multiple organ failure syndrome (MOFS).
- However, excessive inflammation, particularly from macrophages stimulated by endotoxin (LPS), is central to MOFS pathophysiology.
- LPS is a key mediator in sepsis-induced MOFS, stimulating macrophages and leukocytes (WBC).
Purpose of the Study:
- To investigate whether pre-treatment with IFN-gamma sensitizes rabbits to a pathophysiological response to LPS infusion.
- To evaluate the combined effects of IFN-gamma and LPS on physiological parameters in a rabbit model.
Main Methods:
- Four groups of rabbits (n=6) were studied: control, LPS alone, IFN-gamma alone, and IFN-gamma + LPS.
- Measurements included cardiac output, arterial pressure, arterial PO2, and WBC counts over 6 hours.
- Pulmonary permeability was assessed using a 125I-albumin lavage/plasma ratio.
Main Results:
- Rabbits receiving both IFN-gamma and LPS showed significant decreases in cardiac output, PO2, and WBC counts.
- The IFN-gamma + LPS group exhibited an increased lavage/plasma 125I-albumin ratio, indicating heightened pulmonary permeability.
- Neither LPS alone nor IFN-gamma alone significantly affected the measured variables.
Conclusions:
- Pre-treatment with IFN-gamma potentiates the adverse effects of LPS in rabbits, leading to shock-like conditions and increased lung permeability.
- IFN-gamma may predispose individuals to a severe inflammatory response and organ dysfunction when exposed to endotoxin, challenging its use in trauma patients.
- Further research is needed to understand the precise mechanisms and clinical implications of this interaction in sepsis and MOFS.