Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase

Abstract

Mice deficient in inducible nitric oxide synthase (iNOS) were generated to test the idea that iNOS defends the host against infectious agents and tumor cells at the risk of contributing to tissue damage and shock. iNOS-/-mice failed to restrain the replication of Listeria monocytogenes in vivo or lymphoma cells in vitro. Bacterial endotoxic lipopolysaccharide (LPS) caused shock and death in anesthetized wild-type mice, but in iNOS-/-mice, the fall in central arterial blood pressure was markedly attenuated and early death averted. However, unanesthetized iNOS-/-mice suffered as much LPS-induced liver damage as wild type, and when primed with Propionobacterium acnes and challenged with LPS, they succumbed at the same rate as wild type. Thus, there exist both iNOS-dependent and iNOS-independent routes to LPS-induced hypotension and death.

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

“…Incidence of congenital malformations in fetuses of diabetic iNos +/+ and iNos −/− mice Next, we used mice lacking iNOS expression (iNos −/− ) to determine whether loss of iNOS function could prevent congenital anomalies induced by maternal diabetes. As iNos −/− mice have a normal life span and are fertile [26], the mutant strain was propagated by mating of iNos −/− homozygotes. In agreement with a previous report [26], iNos −/− fetuses were indistinguishable from wild-type fetuses in external appearance and also did not exhibit histological abnormalities.…”

“…The genetic background of iNos −/− mice is C57BL/6J. The iNos −/− line of mice has been previously established [24,25]; although they are deficient in iNOS expression, they are nevertheless fertile and no breeding problems have been reported [26]. The mice were bred under specific pathogen-free conditions at the Animal Facility of Nagoya University.…”

Genetic regulation of host responses to Salmonella infection in mice

“…Enhanced production of NO provides increased host defense against pathogens but also contributes to inflammation, tissue damage and even endotoxic shock. 124,126,127 Although Nos2 knockout mice are able to control the early replication of Salmonella in the RES organs, they are unable to suppress bacterial growth later during infection and eventually die. 124 This observation contrasts with the gp91 phox -deficient mice which are extremely susceptible to Salmonella Typhimurium early during the course of infection even with a very low inoculum.…”

Interleukin‐15 mediates protection against experimental tuberculosis: A role for NKG2D‐dependent effector mechanisms of CD8+ T cells

“…Both, CD4 + and CD8 + T cells, produce interferon-c (IFN-c) which in turn stimulates the anti-microbial activity of macrophages. Intracellular pathogens are then killed through reactive nitrogen intermediates produced by the inducible nitric oxide synthase [6] or through effector mechanisms mediated by the newly described member of the 47-kD guanosine triphosphatase family, LRG-47 [7].…”

“…Both, CD4 + and CD8 + T cells, produce interferon-c (IFN-c) which in turn stimulates the anti-microbial activity of macrophages. Intracellular pathogens are then killed through reactive nitrogen intermediates produced by the inducible nitric oxide synthase [6] or through effector mechanisms mediated by the newly described member of the 47-kD guanosine triphosphatase family, . CD8 + T cells can also cause death of both target cells and their intracellular bacterial cargo, either through perforin-dependent cytolysis by the release of granzymes and granulysin, or by ligation of Fas ligand (FasL) on their surface with Fas on infected macrophages [5,[8][9][10].…”