Am. J. Respir. Crit. Care Med., Volume 163, Number 1, January 2001, 234-243

Septic Shock and Acute Lung Injury in Rabbits with Peritonitis
Failure of the Neutrophil Response to Localized Infection

GUSTAVO MATUTE-BELLO, CHARLES W. FREVERT, OSAMU KAJIKAWA, SHAWN J. SKERRETT, RICHARD B. GOODMAN, DAVID R. PARK, and THOMAS R. MARTIN

Medical Research Service of the Veterans Affairs/Puget Sound Health Care System, and Department of Medicine, University of Washington School of Medicine, Seattle, Washington

The major goal of this study was to investigate the mechanisms that link the host response to a local infection in the peritoneal cavity with the development of sepsis and lung injury. Rabbits were infected by intraperitoneal inoculation of fibrin clots containing Escherichia coli at 10⁸, 10⁹, or 10¹⁰ cfu/clot. Physiologic, bacteriologic, and inflammatory responses were monitored, and the lungs were examined postmortem. At a dose of 10⁸ cfu/clot the animals had resolving infection, and a dose of 10⁹ cfu/clot resulted in persistent infection at 24 h, with minimal systemic manifestations. In contrast, inoculation of 10¹⁰ cfu/clot resulted in rapidly lethal local infection, with septic shock and lung injury. The onset of septic shock was associated with a paradoxical lack of identifiable polymorphonuclear leukocytes (PMN; neutrophils) in the peritoneal cavity. The absence of PMN in the peritoneum was due in part to lysis of intraperitoneal PMN, because the peritoneal fluids contained free myeloperoxidase and induced rapid death of normal rabbit PMN in vitro. Although most animals became bacteremic, only those with a severe systemic inflammation response developed lung injury. These data show that control of an infection in the first compartment in which bacteria enter the host is a critical determinant of the systemic response. Above a threshold dose of bacteria, failure of the local neutrophil response is a key mechanism associated with deleterious systemic responses. Bacteremia alone is not sufficient to cause lung injury. Lung injury occurs only in the setting of a severe systemic inflammatory response and an inadequate leukocyte response at the primary site of infection.

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