Angiotensin II Increases Host Resistance to Peritonitis

Abstract

Studies by other laboratories have shown that angiotensin II (AII) can affect the function of cells which comprise the immune system. In the present study, the effect of AII on the function of peritoneal macrophages and peripheral blood monocytes was assessed. In vitro exposure (4 h prior to assay) of peritoneal macrophages from mice and rats to AII increased the percentage of cells that phagocytosed opsonized yeast and the number of yeast per macrophage. Furthermore, AII increased the respiratory burst capacity of peritoneal macrophages from mice and rats and peripheral blood mononuclear cells from humans. Because of these observations, the effect of AII on host resistance to bacterial infection was assessed. Intraperitoneal administration of AII was shown to increase host resistance (reduced abscess formation) in an animal model of bacterial peritonitis. Studies were then conducted to assess whether parenteral administration of AII, a clinically relevant route, could affect peritoneal host resistance in a manner similar to that observed after peritoneal administration. These studies showed that subcutaneous administration of AII throughout the postinfection interval increased the level of host resistance to bacterial peritonitis. Furthermore, in a study which compared AII and Neupogen, an agent approved for use for the reduction of febrile neutropenia after myeloablative therapy, daily subcutaneous administration of AII reduced abscess size and incidence, whereas Neupogen did not have any therapeutic benefit in this model. These data suggest that AII may be of therapeutic benefit as an immunomodulatory agent.Angiotensin II (AII) is a product of the renin-angiotensin system which plays an important role in the regulation of blood pressure and fluid and electrolyte balance (49). However, this eight-amino-acid peptide does not exclusively control blood pressure; it has also been shown to modulate wound repair in several animal models. Rodgers et al. (35) found that administration of AII accelerated the repair of full-thickness excisional wounds in healthy and impaired rats, as well as diabetic mice. Furthermore, it has been shown that administration of AII accelerated the healing of partial-thickness burns (36). More recently, AII has been shown to act as a hematopoietic factor in the acceleration of the recovery of white blood cells and survival after myeloablative therapy (K. E. Rodgers et al., unpublished data). It is conceivable that part of the survival benefit was due to increased leukocyte function and subsequent host resistance to infection. The studies described here were conducted to test this hypothesis.Prabha et al. (32) first observed that AII, when tested at physiological concentrations, can increase free-radical generation by polymorphonuclear neutrophils (PMNs). This observation was confirmed by Kumar and Das (22). Hydrogen peroxide is an important component in the respiratory burst system that can be used to measure increased activation of neutrophils and macrophages. Based on these studies and ...

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