Interferon γ increases sensitivity to endotoxin

Interferon-γ (IFN-γ) has been proposed for use following severe trauma to reverse depressed macrophage (Mφ) function and thereby reduce infection, sepsis, and subsequent multiple organ failure syndrome (MOFS). However, an excessive inflammatory response by Mφs 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 Mφs and leukocytes (WBC). This study addresses the following question: Does IFN-γ 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 μg/kg of Escherichia coli LPS iv, Group III (IFN-γ alone) was given recombinant rabbit IFN-γ (5.0 μg/kg subcutaneous) for 3 days prior to preparation for measurements, and Group IV (IFN-γ + LPS) received 3 days of IFN-γ followed by LPS. One hour prior to sacrifice 5.0 μCi 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 < 0.05 by ANOVA, t test). Neither LPS alone nor IFN-γ alone had a significant effect on measured variables. In contrast to immunosuppressed animals, IFN-γ pretreatment of normal animals increases the host pathophysiologic response to endotoxin.